Happening @ Michigan https://events.umich.edu/list/rss RSS Feed for Happening @ Michigan Events at the University of Michigan. RNA Innovation Seminar (October 4, 2021 4:00pm) https://events.umich.edu/event/86162 86162-21631753@events.umich.edu Event Begins: Monday, October 4, 2021 4:00pm
Location: 1027 E. Huron Building
Organized By: Center for RNA Biomedicine

"Fluorescent nucleoside analogues with new properties"

HYBRID EVENT
in-person: Forum Hall, Palmer Commons
Zoom: https://umich.zoom.us/webinar/register/WN__vvE2dtHQi-R3h05JUHBzQ

ABSTRACT
Fluorescent nucleoside analogues (FNAs) are powerful probes for studying the structure and dynamics of nucleic acids, which are vital to understanding RNA function, DNA damage repair, nucleic acid–protein interactions, regulatory mechanisms for gene expression, and other aspects of nucleic acid function. Existing FNAs are prone to quenching by base pairing and stacking, are clustered at the blue–green end of the visible spectrum, and have limited brightness as compared with conventional fluorophores. Studies of nucleic acid function would benefit greatly from overcoming these limitations. We have designed, synthesized, and studied a series of fluorescent pyrimidine analogues, aiming to address these limitations and develop a detailed understanding of the relationships between chemical structure and fluorescent responses to local environment in nucleic acids. Included in this series is a tricyclic cytidine analogue DEAtC that is nearly non-fluorescent as a nucleoside, but responds to matched base pairing and stacking with a fluorescence turn-on. A chlorinated tricyclic cytidine 8-Cl-tCO reports on local environment by changes in the vibrational fine structure of its emission spectra. To address the problem of limited brightness, we have design and synthesized a new NFA that we call ABN, which has a conjugated push–pull system similar to those found in bright fluorophores such as rhodamines. ABN is the brightest known FNA when present in duplex nucleic acids, and it is readily detected in single-molecule fluorescence measurements using both 1-photon and 2-photon excitation. Collectively, these FNAs offer new capabilities for biophysical studies on nucleic acids. Comparisons of their structure and properties help to reveal mechanisms for fluorescence changes in response to local environment in nucleic acids.

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Lecture / Discussion Fri, 10 Sep 2021 11:29:04 -0400 2021-10-04T16:00:00-04:00 2021-10-04T17:00:00-04:00 1027 E. Huron Building Center for RNA Biomedicine Lecture / Discussion Byron Purse, San Diego State University
BME 500 Seminar: Imaging neural, hemodynamic, and cerebrospinal fluid dynamics in the sleeping brain (October 7, 2021 4:00pm) https://events.umich.edu/event/87782 87782-21645945@events.umich.edu Event Begins: Thursday, October 7, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Sleep is essential for cognition and maintenance of healthy brain function. Sleep changes diverse aspects of brain physiology, and exhibits unique behavioral states, electrophysiological oscillations, vascular dynamics, and waste clearance properties. Our research integrates multiple neuroimaging technologies to understand the neural circuits controlling sleep and the consequences of sleep for brain physiology. To investigate how these multiple aspects might be coupled during sleep, we used simultaneous fast fMRI and EEG to measure fluid and neural dynamics in the human brain. We found a coherent pattern of coupled electrophysiological, hemodynamic, and cerebrospinal fluid (CSF) dynamics that appears during non-rapid eye movement sleep. Our results demonstrate that the sleeping brain exhibits waves of CSF flow on a macroscopic scale, and suggests a neural mechanism that can regulate CSF flow. Next, using fast fMRI at ultra-high field (7 Tesla), we tracked subsecond dynamics throughout thalamocortical networks across transitions between sleep and wakefulness. We identified a temporal sequence of activity across individual thalamic nuclei that appears at the moment of awakening from sleep and predicts subsequent behaviour. Together, these studies develop multimodal imaging approaches for tracking human brain physiology at fast timescales, and identify neural and fluid dynamics unique to the sleeping brain.

Zoom Link: https://umich.zoom.us/j/97723483179

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Lecture / Discussion Mon, 04 Oct 2021 09:29:19 -0400 2021-10-07T16:00:00-04:00 2021-10-07T17:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Seminar Event
RNA Innovation Seminar: Tim Stasevich, Ph.D., Colorado State University (October 18, 2021 4:00pm) https://events.umich.edu/event/86166 86166-21631758@events.umich.edu Event Begins: Monday, October 18, 2021 4:00pm
Location: Off Campus Location
Organized By: Center for RNA Biomedicine

KEYWORDS: translational regulation, gene expression, fluorescence microscopy, intrabodies, single-molecule imaging

ABSTRACT: My lab is creating technology to image mRNA translation in real time and with single-molecule precision in living cells. In this talk, I will introduce our technology and describe how it can be used to amplify fluorescence from newly synthesized proteins as they are being translated from single mRNAs. I will show how we quantify these signals to determine the size, shape, subcellular localization, and mobilities of mRNA translation sites, as well as their protein synthesis dynamics. I will then highlight a few recent applications of our technology, focusing mainly on a new biosensor we have developed to quantify how individual regulatory factors impact single mRNA translation dynamics. Using this biosensor, we provide evidence that human Argonaute2 (Ago2) shuts down translation by down regulating translation initiation on the minutes timescale and helping usher translationally silent mRNAs into P-bodies on the hours timescale. I will conclude by discussing new fluorescent intrabodies my lab is engineering to light up nascent and mature proteins in multiple colors. As these intrabodies can be encoded on plasmids, they can easily be adapted by other labs to image gene activity in diverse living systems.
Timothy J. Stasevich is an Associate Professor in the Department of Biochemistry and Molecular Biology at Colorado State University (CSU). His lab uses a combination of advanced fluorescence microscopy, genetic engineering, and computational modeling to study the dynamics of gene regulation in living mammalian cells. His lab helped pioneer the imaging of real-time single-mRNA translation dynamics in living cells1. Dr. Stasevich received his B.S. in Physics and Mathematics from the University of Michigan, Dearborn, and his Ph. D. in Physics from the University of Maryland, College Park. He transitioned into experimental biophysics as a post-doctoral research fellow in the laboratory of Dr. James G. McNally at the National Cancer Institute. During this time, he developed technology based on fluorescence microscopy to help establish gold-standard measurements of live-cell protein dynamics. Dr. Stasevich next moved to Osaka University, where he worked with Dr. Hiroshi Kimura as a Japan Society for the Promotion of Science Foreign Postdoctoral Research Fellow. While there, he helped create technology to image endogenous proteins and their post-translation modifications in vivo. This allowed him to image the live-cell dynamics of epigenetic histone modifications during gene activation for the first time2. Before joining the faculty at CSU, Dr. Stasevich spent a year as a Visiting Fellow at the HHMI Janelia Research Campus, where he applied superresolution fluorescence microscopy to improve the spatiotemporal resolution of endogenous protein imaging in live cells.
1. Morisaki, T. et al. Real-time quantification of single RNA translation dynamics in living cells. Science 352, 1425–1429 (2016).
2. Stasevich, T. J. et al. Regulation of RNA polymerase II activation by histone acetylation in single living cells. Nature 516, 272–275 (2014).

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Lecture / Discussion Thu, 30 Sep 2021 10:17:54 -0400 2021-10-18T16:00:00-04:00 2021-10-18T17:00:00-04:00 Off Campus Location Center for RNA Biomedicine Lecture / Discussion Tim Stasevich, Colorado State University
BME 500 Seminar: “Elucidating and engineering microbial communities: systems and synthetic biology approaches” (October 21, 2021 4:00pm) https://events.umich.edu/event/88452 88452-21654121@events.umich.edu Event Begins: Thursday, October 21, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Microbes are everywhere in nature and they live in diverse communities that show remarkable metabolic capabilities and robustness. On the other hand, disruption of microbiome homeostasis and associated changes in the community’s structure/function underlies numerous health or environmental issues. My lab has been developing methods and tools rooted in engineering to study microbial communities in order to discover the underlying cellular and molecular mechanisms. In particular, we have pioneered a technological pipeline, based on nanoliter-scale microfluidic droplets, to co-cultivate sub-communities and characterize interactions between community members. A number of technological modules have been created and the pipeline is being applied to the investigation of a range of health or environment related microbiomes. A second distinct yet complementary research thrust in my lab, inspired by naturally occurring synergistic microbial communities, has been the design and construction of synthetic microbial consortia for microbial engineering and biochemical production. One application focus has been synthesis of fuels and chemicals from lignocellulosic biomass. For instance, we designed and optimized a consortium consisting of a cellulolytic fungus capable of hydrolyzing hemicellulose and cellulose (main components of lignocellulosic biomass) into mono and oligosaccharides and a genetically engineered bacterium for converting mono and oligosaccharides into isobutanol, an advanced biofuel. The general framework of engineering defined co-cultures of coordinated specialists also offers exciting new opportunities for the efficient and flexible production of many valuable chemicals from other non-conventional bio-feedstocks.

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Workshop / Seminar Wed, 20 Oct 2021 10:08:36 -0400 2021-10-21T16:00:00-04:00 2021-10-21T17:00:00-04:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME LOGO
CANCELLED: SAVE THE DATE 11th INTERNATIONAL SYMPOSIUM (October 25, 2021 10:00am) https://events.umich.edu/event/84621 84621-21631581@events.umich.edu Event Begins: Monday, October 25, 2021 10:00am
Location:
Organized By: Center for Cell Plasticity and Organ Design

With the current state of things we have decide to cancel the Save the Date for the CPOD International Symposium.

We will update you with the new details as soon as we have a new date.

Thank you for your understanding as we work to make adjustments with the safety of all participants in mind.

Questions/Comments please contact us at: organogenesis@umich.edu

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Conference / Symposium Wed, 01 Sep 2021 10:40:09 -0400 2021-10-25T10:00:00-04:00 2021-10-25T11:00:00-04:00 Center for Cell Plasticity and Organ Design Conference / Symposium CPOD Center for Cell Plasticity and Organ Design
“The role of muscle activity in structure-function relationships of embryonic tendon development” (October 28, 2021 4:00pm) https://events.umich.edu/event/88592 88592-21656086@events.umich.edu Event Begins: Thursday, October 28, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

BME 500 Seminar Series
Thursday, October 28, 2021
4:00 – 5:00 pm

Zoom Link: https://umich.zoom.us/j/97723483179

Spencer Szczesny, Ph.D.
Biomedical Engineering,
Pennsylvania State University

“The role of muscle activity in structure-function relationships of embryonic tendon development”

Abstract:

While there is significant interest in using tissue engineering techniques to create tendon and ligament replacements, no engineered biomaterial has been successful in replicating their physiological function. This is because there is a fundamental lack of understanding of how to produce a robust tensile load-bearing biological tissue. Previous work suggests that tendon maturation is driven by rapid increases in collagen fibril length and molecular crosslinking mediated by mechanical stimulation due to muscle activity. However, the effect of mechanical stimulation on the tensile mechanics of developing tendons and the functional significance of the structural changes that occur during development are still unclear. To address this knowledge gap, we investigated the multiscale structure-function relationships of embryonic tendons during normal development and following the loss of mechanical stimulation via immobilization. Using multiscale mechanical testing, we found that the strain transmitted to the collagen fibrils in tendons at embryonic days 16, 18, and 20 is less than the strain applied to the tissue, suggesting the collagen fibrils remain discontinuous throughout embryonic development. However, the ratio of the fibril strains to the tissue strains increased with developmental age; this indicates that more strain is being transmitted to the fibrils and that there is less interfibrillar sliding, which is consistent with an increase in the average fibril length and an increase in the macroscale mechanics during this period of development. Additionally, there was a decrease in the macroscale tensile modulus and the fibril:tissue strain ratio with flaccid (but not rigid) immobilization, suggesting that complete loss of mechanical stimulation inhibits fibril elongation and strain transmission to the collagen fibrils, resulting in impaired functional maturation. Consistent with these mechanical assessments, we found that collagen fibril bundling was impaired with immobilization. Interestingly, while the enthalpy required to denature the tendons increased with increasing age, there was no effect with immobilization. This suggests that although intermolecular crosslinks in embryonic tendons increase with development, the loss of tensile mechanical properties with immobilization is potentially not due to a reduction in functional crosslinking. Together, these data suggest that the key structural change induced by mechanical stimulation during tendon development is an increase in the strain transmitted to the collagen fibrils, which is consistent with fibril elongation. These data provide fundamental insight into the mechanisms driving tendon development and will guide the design of improved techniques for engineering tendon/ligament replacements.

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Lecture / Discussion Mon, 25 Oct 2021 09:25:42 -0400 2021-10-28T16:00:00-04:00 2021-10-28T17:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion U-M BME Event
"Cell cycle regulation in microbes" (November 4, 2021 4:00pm) https://events.umich.edu/event/88883 88883-21658814@events.umich.edu Event Begins: Thursday, November 4, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

BME 500 Seminar Series
Ariel Amir, Ph.D.
Applied Mathematics and Physics
Harvard University

"Cell cycle regulation in microbes"

Abstract:
Microbial cells are remarkable in their abilities to adapt to different environments while maintaining cellular homeostasis. How cells coordinate the various events within the cell cycle, notably cell division and DNA replication, remains an outstanding problem for cells of all domains of life. I will discuss our current understanding of cell cycle regulation in microbes, including recent results demonstrating a tight coupling between DNA replication and cell division in E. coli.

DATE: Thursday, November 4, 2021
TIME: 4:00-5:00 pm
ZOOM LINK: https://umich.zoom.us/j/97723483179

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Presentation Tue, 02 Nov 2021 09:04:43 -0400 2021-11-04T16:00:00-04:00 2021-11-04T17:00:00-04:00 Off Campus Location Biomedical Engineering Presentation BME Logo
RNA Innovation Seminar (November 8, 2021 4:00pm) https://events.umich.edu/event/86167 86167-21631759@events.umich.edu Event Begins: Monday, November 8, 2021 4:00pm
Location: Off Campus Location
Organized By: Center for RNA Biomedicine

"Harnessing diverse compact CRISPR-Cas3 for long-range genome engineering"
Zhonggang Hou, Ph.D.
Research Investigator
Biological Chemistry

and

"Microscopic Examination of Spatial Transcriptome through Seq-Scope"
Jun Hee Lee, PhD
Associate Professor
Molecular & Integrative Physiology

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Lecture / Discussion Mon, 25 Oct 2021 13:33:17 -0400 2021-11-08T16:00:00-05:00 2021-11-08T20:00:00-05:00 Off Campus Location Center for RNA Biomedicine Lecture / Discussion Zhonggang Hou, Biological Chemistry & Jun Hee Lee, Molecular & Integrative Physiology
"Diet and metabolic therapeutics in cancer metabolism" (November 11, 2021 4:00pm) https://events.umich.edu/event/89035 89035-21660280@events.umich.edu Event Begins: Thursday, November 11, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

BME 500 Seminar Series
Jason Locasale, Ph.D.
Pharmacology and Cancer Biology
Duke University

"Diet and metabolic therapeutics in cancer metabolism"
Abstract:
This presentation will focus on methionine metabolism in health and cancer. I will first
discuss methionine content in human food and dietary patterns . I will next focus on
how changes to dietary methionine can produce defined consequences on cellular
metabolism. I will then discuss work on dietary influences on the activity of the
pathway and its relation to the regulation of one carbon metabolism in cancer. How
methionine restricted diets may allow for interventions in cancer treatment and relevant
mechanisms will be discussed including how changes to dietary methionine can
influence interventions that target one carbon metabolism involving radiation and
antimetabolite chemotherapies such as 5-fluorouracil. The link between nutritional
methionine status and chromatin biology and epigenetics will also be introduced in this
talk.
Details:
DATE: Thursday, November 11, 2021
TIME: 4:00-5:00 pm
ZOOM LINK: https://umich.zoom.us/j/97723483179

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Presentation Mon, 08 Nov 2021 10:30:52 -0500 2021-11-11T16:00:00-05:00 2021-11-11T17:00:00-05:00 Off Campus Location Biomedical Engineering Presentation BME Event
BME 500 Seminar: "Engineering next-generation T cells for cancer immunotherapy" (November 18, 2021 4:00pm) https://events.umich.edu/event/89279 89279-21661695@events.umich.edu Event Begins: Thursday, November 18, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated clinical efficacy in the treatment of advanced cancers, with anti-CD19 CAR-T cells achieving up to 90% complete remission among patients with relapsed B-cell malignancies. However, challenges such as antigen escape and immunosuppression limit the long-term efficacy of adoptive T-cell therapy. Here, I will discuss the development of and clinical data on next-generation T cells that can target multiple cancer antigens and resist antigen escape. I will also present recent work on tuning CAR signaling activities via rational protein design to achieve greater in vivo anti-tumor efficacy. This presentation will highlight the potential of synthetic biology in generating novel mammalian cell systems with multifunctional outputs for therapeutic applications.
Details:
DATE: Thursday, November 18, 2021
TIME: 4:00-5:00 pm
ZOOM LINK: https://umich.zoom.us/j/97723483179

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Lecture / Discussion Mon, 15 Nov 2021 15:53:04 -0500 2021-11-18T16:00:00-05:00 2021-11-18T17:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion Yvonne Chen, Ph.D.
Alan J. Hunt Memorial Lecture: "Moving takes energy: the intersection of cell motility with cellular metabolism" (November 19, 2021 2:00pm) https://events.umich.edu/event/89276 89276-21661669@events.umich.edu Event Begins: Friday, November 19, 2021 2:00pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

2021 Alan J. Hunt Memorial Lecture

"Moving takes energy: the intersection of cell motility with cellular metabolism"

Cynthia Reinhart-King, Ph.D.
Cornelius Vanderbilt Professor of Engineering
Professor of Biomedical Engineering
Vanderbilt University

November 19, 2021, 2:00 PM - 3:30 PM

Please save the date and RSVP below for the 2021 Alan J. Hunt Memorial Lecture on Friday, November 19, 2021, from 2:00 PM - 3:30 PM. The lecture will take place in 1130 Lurie Biomedical Engineering Building (classroom) featuring Cynthia Reinhart-King, Ph.D. the Cornelius Vanderbilt Professor of Engineering and Professor of Biomedical Engineering at Vanderbilt University. Following the lecture, a reception will be held in the BME Commons.

Details:
DATE: Friday, November 19, 2021
TIME: 2:00 PM - 3:30 PM (Reception; 3:30 PM - 4:30 PM)
LOCATION: 1130 Lurie Biomedical Engineering; A reception will follow in the BME Commons

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Lecture / Discussion Mon, 15 Nov 2021 15:16:23 -0500 2021-11-19T14:00:00-05:00 2021-11-19T16:30:00-05:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Lecture / Discussion Alan J Hunt
Genetic Study Design in CVFS (December 1, 2021 2:00pm) https://events.umich.edu/event/85338 85338-21626251@events.umich.edu Event Begins: Wednesday, December 1, 2021 2:00pm
Location: Off Campus Location
Organized By: Institute for Social Research

This webinar series on the Chitwan Valley Family Study (CVFS) is about global and comparative population research. Sessions include measuring mental health, Covid-19, linking data, genetics, & migrant data.

Webinar 6: Genetic Study Design in CVFS
Wednesday, December 1, 2021
2-3pm EDT
Presenter: Colter Mitchell

This webinar will provide an overview of the design of the genetic data in CVFS, planned research activities, and potential uses. There will be a Q&A session after the presentation.

The webinar will be hosted using Zoom. Registration is required to attend the webinar. Support provided by NICHD (R25 HD101358).

Registration is required for this event: https://umich.zoom.us/meeting/register/tJctdOChrj4rGN3gN0TKhn3r6F1bAMYUyA3A

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Presentation Tue, 17 Aug 2021 14:33:56 -0400 2021-12-01T14:00:00-05:00 2021-12-01T15:00:00-05:00 Off Campus Location Institute for Social Research Presentation Nepal mountains
"Hybrid Models to Accelerate Discovery and Optimize Design in Neural Engineering" (December 2, 2021 4:00pm) https://events.umich.edu/event/89543 89543-21664063@events.umich.edu Event Begins: Thursday, December 2, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
Neural engineers try to fight disease by interfacing directly with the nervous system to correct or circumvent the pathology, but the complexities of neurophysiology make designing these therapies very difficult. The sophisticated interactions of neural control systems with the body and mind has limited our ability to predict the effects of neural interfaces in advance, which forces the field to rely on painstaking animal experiments to test and design the devices. This work presents an alternate way forward using new functionally predictive hybrid models that let us prototype and test neural interfaces in cheap, low-risk settings to get the most out of the cumbersome and expensive animal and human studies that require implanted electrodes. The key innovation is to combine parts of traditionally separate model systems (animal, human, mathematical, or statistical) into hybrid frameworks that use the strengths of each type to make accurate, use-case predictions about the effects of new neural interfaces.
Details:
DATE: Thursday, December 2, 2021
TIME: 4:00-5:00 pm
LOCATION: Cooley G906
ZOOM LINK: https://umich.zoom.us/j/97723483179

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Lecture / Discussion Mon, 29 Nov 2021 09:57:50 -0500 2021-12-02T16:00:00-05:00 2021-12-02T17:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
BME PhD Defense: Melissa Lemke (December 8, 2021 1:00pm) https://events.umich.edu/event/89542 89542-21664062@events.umich.edu Event Begins: Wednesday, December 8, 2021 1:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Department of Biomedical Engineering Final Oral Examination

Melissa Lemke

A Systems Approach to Elucidate Personalized Mechanistic Complexities of Antibody-Fc Receptor Activation Post-Vaccination

One of the most significant challenges to current human healthcare is the emergence of antigenically variable viruses that evade traditional vaccination approaches. Human immunodeficiency virus (HIV) is one such virus that emerged over 30 years ago and still has no effective vaccine. Like many other antigenically variable viruses, after infection, HIV quickly mutates to evade broadly neutralizing antibodies that bind tightly to key sites to prevent infection. Over 250 clinical trials have been performed to date to develop an effective HIV vaccine, with only one providing moderate protection; the RV144 Thai trial, estimated to be 31% effective but has not been replicated in other populations. Rather than broadly neutralizing antibodies, the trial identified IgG antibodies with the capacity to induce Fc effector functions as a correlate of protection. These functions are triggered by less specific antibodies that bind HIV antigen and Fc receptors on the surface of innate immune cells to form immune complexes to activate protective cellular functions. Understanding how to increase the formation of IgG-FcR complexes may improve vaccine efficacy, but variation in IgG and FcR features across individuals suggests that protective mechanisms need to be understood on a personalized basis. There are multiple subclasses of protective IgGs, each having different concentrations and affinities to FcRs in different individuals. Genetics can also play a role, with FcR polymorphisms changing FcR binding affinity and IgG1 allotypes changing IgG subclass concentrations. Mechanistic ordinary differential equation (ODE) modeling of this system offers the opportunity to account for these factors on a personalized basis and deconvolve which are most influential and determine how to improve protection universally.


We developed an ODE model of IgG-FcγRIIIa immune complex formation to elucidate how personalized variability in IgG subclass concentration and genetic factors may contribute to complex formation after vaccination. We validated the model with RV144 plasma samples and used it to discover new mechanisms that underpin complex formation. This enabled the identification of genetic and post-translational features that influenced complex formation and suggested the best interventions on a personalized basis. For example, although IgG3 was associated with protection in RV144 and has the highest affinity to FcγRIIIas, the model suggested that IgG1 may play a more essential role, though it also may be highly variable; due to high IgG1 concentration variability across individuals. The model identified RV144 vaccinees who were predicted to be sensitive, insensitive, or negatively affected by increases in HIV-specific IgG1, which was validated experimentally with the addition of HIV-specific IgG1 monoclonal antibodies to vaccine samples. The model also gave important insights into how to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. We found that individuals with certain IgG1 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody affinity (e.g., glycosylation modifications) compared to other allotypes, which were predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody concentration. Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may depend upon the frequency of a specific IgG1 allotype (G1m-1,3) in the population. Overall we believe that this approach represents a valuable tool that will help understand the role of personalized immune mechanisms in response to vaccination and address challenges related to under-represented genetic populations in vaccine trials.

Date: Wednesday, December 8, 2021
Time: 1:00 PM
Zoom: https://umich.zoom.us/j/96971889814
Meeting ID: 969 7188 9814 Passcode: 663036
Chair: Dr. Kelly Arnold

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Lecture / Discussion Mon, 29 Nov 2021 09:50:43 -0500 2021-12-08T13:00:00-05:00 2021-12-08T14:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
"EPICode, a multiplexed epitope barcoding strategy that enables dynamic cellular phenotypic screens" (December 9, 2021 4:00pm) https://events.umich.edu/event/89887 89887-21666282@events.umich.edu Event Begins: Thursday, December 9, 2021 4:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Pooled genetic libraries have improved screening throughput for mapping genotypes to phenotypes. However, selectable phenotypes are limiting, restricting screening to outcomes with a low spatiotemporal resolution. Here, we integrated live-cell imaging with pooled library-based screening. To enable intracellular multiplexing, we developed a method, called EPICode (Epitope-Phenotype Immunofluorescence barCode), that uses a combination of short epitopes to facilitate optical screening. By using the subcellular localization of the barcode as an additional channel, our method exponentially increases multiplexing capacity. Thus, after using live-cell microscopy to characterize a phenotype of interest, subjected to sequential stimulatory/inhibitory manipulations, the genotype of each cell in the population can be identified. To demonstrate applicability, we developed a live-cell PKA kinase translocation reporter with improved sensitivity and specificity. The use of epitopes as fluorescent barcodes introduces a scalable strategy for high-throughput screening broadly applicable to protein engineering and drug discovery settings where image-based phenotyping is desired.
Details:
DATE: Thursday, December 9, 2021
TIME: 4:00-5:00 pm
ZOOM LINK: https://umich.zoom.us/j/97723483179

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Workshop / Seminar Wed, 08 Dec 2021 11:33:18 -0500 2021-12-09T16:00:00-05:00 2021-12-09T17:00:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Event
BME Ph.D. Defense: Thomas A. Davidson (December 10, 2021 8:00am) https://events.umich.edu/event/89701 89701-21665017@events.umich.edu Event Begins: Friday, December 10, 2021 8:00am
Location: Off Campus Location
Organized By: Biomedical Engineering

Nearly 90% of adults in the US will develop dental caries needing treatment with dental restorations within their lifetimes. An increasing number of restorations are done using composite rather than amalgams. Dental composites have some benefits, but the longevity of these restorations is shorter (5 to 7 years) than amalgams (10+ years). The leading cause of dental restoration failure is development of secondary caries. Secondary caries is decay at or near the margins of dental restorations that occurs when bacteria or acid infiltrate the interface and cause demineralization. A reduction in infiltration would prevent the development of secondary caries. The focus of this dissertation is the development of a method for improving the integrity of the interface using peptide engineering. It was hypothesized that a mineral binding peptide identified via phage display for affinity to apatite could be modified to A) chemically incorporate with dental composites during polymerization and increase bond strength and B) act as an anchor for a mineralization promoting peptide to increase remineralization at the interface.


First, this thesis describes the characterization of VTKHLNQISQSY (VTK) peptide and phosphorylated variants (pVTK) for their affinity to dentin and enamel and the increase in adhesion strength at the nano-scale. pVTK showed strong affinity to dentin and enamel, and both VTK and pVTK exhibited strong adhesion to dentin and enamel at the nanoscale under dry and wet conditions. Binding at the nanomolecular level translated to modest shear bond strength (SBS) increases at the interface when pVTK (7.4%) was modified with a cysteine that incorporated with the methacrylate-based bonding agent and composite during polymerization. Using a competitive risk model incorporating failure mode and SBS, a small increase in bond strength (VTK: 3%; pVTK: 10%) was observed.


The second modification to VTK was the addition of a remineralization domain using 8DSS, a known remineralization peptide consisting of 8 repeats of Asp-Ser-Ser (DSS). The dual-functioning peptide (VTK-8DSS) was applied to in vitro cross sections of dentin and enamel and an in situ model of class V dental restorations. Mineral deposition and quality were assessed over 7 days in remineralization solution. VTK-8DSS increased the mineral quality (recovering 75% of young’s modulus and hardness compared to 50% of 8DSS control) determined using nanoindentation over the 7 day time course of the study.


These modifications were also analyzed under challenging conditions for their protective effect to the interface. VTK and pVTK doped composites were exposed to thermal cycling and had a 43% and 49% reduction in microleakage as measured by silver nitrate penetration using micro CT. Cross sections and dental restorations were used to assess the function of VTK-8DSS in artificial saliva containing proteins that competitively bind to dentin and enamel and an acidic cycling model where samples were exposed to acid every day in addition to remineralization solution. VTK-8DSS in both artificial saliva and acidic cycling models showed a slight increase in mineral deposition (95% and 95% recovery) compared to 8DSS (80% and 50% respectively) and a large increase mineral quality (70% vs 10% and 60% vs 30%).


Taken together, the data in this dissertation demonstrates the ability to engineer interfacial surfaces using peptides derived for their affinity to specific tissues. This system could be applied more broadly to improve the interactions or integration of any number of biomaterials that directly interface with native tissue.


Date: Friday, December 10, 2021
Time: 8:00 AM EST
Zoom: https://umich.zoom.us/j/97816028147 (Zoom link requires prior registration)
Chair: Dr. David Kohn

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Lecture / Discussion Thu, 02 Dec 2021 09:36:52 -0500 2021-12-10T08:00:00-05:00 2021-12-10T09:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
BME PH.D. Defense: Christopher D. Davidson (December 10, 2021 1:00pm) https://events.umich.edu/event/89668 89668-21664759@events.umich.edu Event Begins: Friday, December 10, 2021 1:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

The ability of cells to communicate and coordinate their activity is crucial to the development and homeostatic function of all tissues. In addition to the well-established means of biochemically mediated signaling, a more recent body of evidence has indicated that cells can also communicate via cell-generated forces transmitted to neighboring cells through the extracellular matrix (ECM). One setting in which a deeper understanding of mechanical intercellular communication (MIC) would be extremely valuable is in vasculogenesis, or the de novo formation of a microvascular network. This dynamic process involves the assembly and organization of individual endothelial progenitor cells into an interconnected network of capillaries, thus requiring cellular communication and coordination over large spatial scales. If fully understood and harnessed, vasculogenic assembly presents a promising approach to vascularizing engineered tissue constructs for regenerative medicine applications. We hypothesize physical properties of the ECM are critical to MIC as the matrix context defines not only the generation of cell forces but also force transmission through the matrix to nearby cells. Thus, the focus of this dissertation is to study cell force propagation and MIC between endothelial cells (ECs) in controllable synthetic ECMs towards the informed design of biomaterials that drive rapid self-assembly of functional microvascular networks.



First, this thesis explores how physical attributes of the ECM regulate the assembly of ECs into interconnected multicellular networks. To mimic the fibrous microenvironments where neovascularization typically occurs in the body, we developed a novel model of the EC network formation assay utilizing 2.5D matrices of electrospun synthetic dextran methacrylate (DexMA) polymeric fibers. Our results revealed that active cell-mediated matrix deformations and fiber recruitment through actomyosin force generation occurs concurrently with the formation and stabilization of multicellular EC networks.



Next, this thesis describes the development and characterization of a new material system composed of electrospun dextran vinyl sulfone (DexVS) polymeric fibers that possess longer-term mechanical stability in culture as compared to DexMA matrices. These matrices were utilized for two major objectives: 1) investigating the role of matrix mechanics on the activation of fibroblasts into myofibroblasts, a key component of wound healing and the fibrotic progression, and 2) exploring the impact of nonlinear matrix mechanical properties on vasculogenic assembly by imbuing fibers with crimped microstructure.



Lastly, this thesis describes the mechanism of MIC between individual ECs during vasculogenic assembly. By combining electrospun DexMA fiber matrices with a microfabrication-based cell-patterning method, we investigated EC force-mediated matrix displacements and MIC as a function of matrix stiffness and identified the critical cellular machinery required for ECs to sense and respond to mechanical signals emanating from neighboring cells. We then sought to harness these observations in more translatable 3D hydrogel constructs by using a composite approach where fibrin hydrogels were reinforced with electrospun DexVS fiber segments. While traditional approaches to prevascularize 3D hydrogels require long-term co-cultures of ECs and support stromal cells, our work demonstrated that mechanical cues from synthetic fibers enable ECs alone to rapidly self-assemble into networks of lumenized capillary-like structures.



Overall, the work presented in this dissertation integrates biomaterials, tissue engineering, and microfabrication approaches to investigate the mechanobiology of how cell forces regulate intercellular communication during vasculogenic assembly. The results presented here are critical to the design of biomaterials that promote robust capillary network assembly for applications in tissue engineering and regenerative medicine.



Date: Friday, December 10, 2021

Time: 1:00 PM EST

Zoom: https://umich.zoom.us/meeting/register/tJAoceuhqD0rHdwL8duV6QwOcYjLXl14kysD (Zoom link requires prior registration)

Chair: Dr. Brendon Baker

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Lecture / Discussion Wed, 01 Dec 2021 11:44:48 -0500 2021-12-10T13:00:00-05:00 2021-12-10T14:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
RNA Faculty Candidate Seminar (December 13, 2021 4:00pm) https://events.umich.edu/event/89524 89524-21663803@events.umich.edu Event Begins: Monday, December 13, 2021 4:00pm
Location: Taubman Biomedical Science Research Building
Organized By: Center for RNA Biomedicine

In-person/Hybrid seminar co-hosted by the Center for RNA Biomedicine and the Department of Molecular, Cellular, and Developmental Biology

Talk title: “Resolving the localisation and dynamics of mRNA and protein synthesis within neurons”

Keywords: mRNA dynamics, local protein synthesis, neurons, neuronal cell biology, synaptic plasticity, in vivo imaging

If you are having trouble registering, please contact Martina Jerant at mjerant@umich.edu

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Lecture / Discussion Tue, 30 Nov 2021 13:12:23 -0500 2021-12-13T16:00:00-05:00 2021-12-13T17:00:00-05:00 Taubman Biomedical Science Research Building Center for RNA Biomedicine Lecture / Discussion Paul Donlin-Asp, Ph.D.,
BME PhD Defense: Olga M. Wroblewski (January 12, 2022 10:00am) https://events.umich.edu/event/90462 90462-21671089@events.umich.edu Event Begins: Wednesday, January 12, 2022 10:00am
Location: Off Campus Location
Organized By: Biomedical Engineering

Volumetric muscle loss (VML) is a common pathological condition caused by traumatic loss of skeletal muscle that exceeds the muscle’s regenerative capabilities and results in functional impairment. Current surgical standards-of-care frequently fail to fully recover contractile function. To address these limitations, our laboratory has developed scaffold-free tissue engineered skeletal muscle units (SMUs) for the treatment of VML. Isolated skeletal muscle stem cells (satellite cells) and fibroblasts are cultured into a confluent cell monolayer before being rolled into a cylindrical 3D construct. Ideally, these SMUs could be engineered from small autogenic muscle biopsies, alleviating the limitations of donor site morbidity and immune rejection seen in current VML treatments. These SMUs are biocompatible, incorporate into surrounding muscle tissue upon implantation, and have shown efficacy to partially repair a 30% VML in rat and sheep models. There are two key challenges that must be resolved to successfully translate our technology to a human cell-sourced model. To date, it has been difficult to grow human cell-sourced SMUs with any noteworthy contractile function. Secondly, many satellite cells are required for SMU fabrication. Any methodology that can optimize the number of cells obtained in a human skeletal muscle biopsy and enhance the functional properties of the resultant muscle tissue will advance SMUs towards clinical use.

Human epidermal growth factor (hEGF), a mitogen, has shown promise enhancing myobundle formation and contractile function in vitro. Prior to this thesis work, the impact of hEGF treatment during the proliferation and differentiation phases of SMU fabrication had yet to be evaluated. We investigated the effects of hEGF on SMU fabrication, structure, and biomechanical function. Our results indicated that hEGF was critical for the development of contractile function in human cell-sourced SMUs.

Due to the small amount of satellite cells present in skeletal muscle, we also sought to optimize our methodologies so that fewer satellite cells are needed to be isolated to fabricate SMUs. Currently, we have been successful at fabricating functional SMUs using lower cell-seeding densities compared to rat and sheep models. By altering the timing of our fabrication protocol and allowing cell cultures to reach >90% confluency in media that promotes proliferation, we found that we could lower starting cell-seeding density by 90% compared to ovine models with no detrimental impact to monolayer development or SMU function.

To further expand the capabilities of satellite cells from a single autogenic skeletal muscle biopsy, we evaluated the impact of in vitro cell proliferation (increasing cell number by cell passaging) on human primary skeletal muscle cells within an engineered skeletal muscle tissue environment. While cell passaging decreased the percentage of myogenic cells in the total cell population, results indicated that human primary skeletal muscle cells can be passaged without negatively impacting the contractile function of a skeletal muscle construct compared to one created with unpassaged cells. A single passage can increase the total cell yield from a human skeletal muscle biopsy fiftyfold compared to cells harvested without a passage.

Overall, this work significantly contributed to the field of skeletal muscle tissue engineering by advancing fabrication methodologies to develop SMUs of appropriate structure and function for human application. We addressed two key limitations in human cell-sourced skeletal muscle tissue engineering by optimizing cell culture conditions to increase the cell yield from a single skeletal muscle biopsy while promoting SMU biomechanical function.

Date: Wednesday, January 12, 2022
Time: 10:00 AM EST
Zoom: https://umich.zoom.us/meeting/register/tJUocu2gqjMpGdelbor8Vj43NvRde859Q-EE
(Zoom link requires prior registration)
Chair: Dr. Lisa Larkin

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Lecture / Discussion Wed, 05 Jan 2022 08:59:08 -0500 2022-01-12T10:00:00-05:00 2022-01-12T11:00:00-05:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
A Truly Subject-Specific, Shared Model of the Human Tricuspid Valve (January 13, 2022 3:30pm) https://events.umich.edu/event/90763 90763-21673517@events.umich.edu Event Begins: Thursday, January 13, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract: Computer simulations have become critical elements of the medical device design and regulatory approval process. Naturally, the predictability and therefore value of such simulations depends highly on their accuracy. Especially for the design of heart valve replacements and repair technologies computer simulations have become a critical tool. While much progress has been made in modeling the aortic valve and the mitral valve, much less effort has been spent on modeling the tricuspid valve. The reasons are multi-fold, but include the general neglect of the valve as well as the high complexity of the valve in comparison to the three other valves. In our most recent work, we are beginning to fulfill this gap. Specifically, our objective is to develop, validate, and then publicly provide a truly subject-specific, shared model of the human tricuspid valve. To this end, we combine multi imaging-modality based measurements in beating human hearts that have been prepared in an organ preservation system, with in-vitro measurements of heart valve geometric, structural, and mechanical properties. Once built, we conduct finite element simulations with this valve and validate dynamic simulations throughout the cardiac cycle against in-situ measurements. Finally, we show case our model by first mimicking a diseased valve, which we then repair using a surgical and an interventional approach.

Bio: Dr. Rausch is an assistant professor at the University of Texas at Austin where he directs the soft tissue biomechanics laboratory. His laboratory's objective is to use complimentary imaging modalities, mechanical testing, and numerical methods to understand and predict soft tissue disease. The specific problems he studies include pressure ulcers, right heart heart failure, tricuspid valve regurgitation, and thrombotic disease. Check out his work on www.manuelrausch.com and follow him on Twitter under @ManuelKRausch1.

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Workshop / Seminar Mon, 10 Jan 2022 16:14:23 -0500 2022-01-13T15:30:00-05:00 2022-01-13T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
Structure and Mechanics of the Myocardium: Modeling and Simulation (January 20, 2022 3:30pm) https://events.umich.edu/event/90947 90947-21674997@events.umich.edu Event Begins: Thursday, January 20, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Bio:
Gerhard A. Holzapfel is Professor of Biomechanics and Head of the Institute of Biomechanics at Graz University of Technology (TUG), Austria, since 2007. He is also Adjunct Professor at the Norwegian University of Science and Technology (NTNU), Trondheim, Norway, and Visiting Professor at the University of Glasgow, Scotland. Until 2013 he was Professor of Biomechanics at the Royal Institute of Technology (KTH) in Stockholm, Sweden, for 9 years (7 years as an Adjunct Professor). After his PhD in Mechanical Engineering in Graz he received an Erwin-Schrödinger Scholarship for foreign countries to be a Visiting Scholar at Stanford University (1993-95). He achieved his Habilitation at TU Vienna in 1996 and received a START-Award in 1997, which is the most prestigious research award in Austria for young scientists. In the following years (1998-2004) he was the Head of a research group on "Computational Biomechanics" at TUG. Among several awards and honors in the past years he is listed in "The World's Most Influential Scientific Minds: 2014" (Thomas Reuters), he received the Erwin Schrödinger Prize 2011 from the Austrian Academy of Sciences for his lifetime achievements, and he was awarded the 2021 William Prager Medal and the 2021 Warner T. Koiter Medal.

Professor Holzapfel has authored a graduate textbook entitled "Nonlinear Solid Mechanics. A Continuum Approach for Engineering" (John Wiley & Sons), and co-edited seven books. He contributed chapters to 25 other books, and published 240+ peer-reviewed journal articles. He is the co-founder and co-editor of the International Journal "Biomechanics and Modeling in Mechanobiology" (Springer-Verlag, Berlin, Heidelberg).

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Workshop / Seminar Thu, 13 Jan 2022 11:51:20 -0500 2022-01-20T15:30:00-05:00 2022-01-20T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
Programmable Biomaterials/Regenerative Medicine Grand Challenge (January 24, 2022 1:00pm) https://events.umich.edu/event/88715 88715-21677237@events.umich.edu Event Begins: Monday, January 24, 2022 1:00pm
Location: Off Campus Location
Organized By: Regenerative Medicine Biosciences Initiative

Programmable Biomaterials/Regenerative Medicine Grand Challenge #1

Theme: How to regenerate tissues/organs to optimally integrate with the host

Goal: Bring together clinicians, scientists, and engineers to explore new ideas and catalyze new collaborations to address key barriers to the translation of regenerative medicine technologies

Format: Short talks identifying clinical problems and emerging technologies, followed by breakout sessions to identify opportunities

Breakouts: Based on problems identified, what are transformative things UM can do to solve? We’re looking for big ideas that involve new, heterogeneous groups. Themes/challenges that emerge from breakouts will define an RFA

Outcome: Funding for collaborative proposals that emerge from the grand challenge session w/ criteria that proposals are novel and integrative, satisfying one or more of the following elements:
•High risk, cross-cutting, transformative
•Leverage strengths at UM in new ways
•Pull together new combinations of people
•Tackle new problems or existing problems in new ways
•Topics that will have greatest impact and potential for extramural funding
•We anticipate awarding 3 grants at ~100K each
Please join us for our 2-day VIRTUAL event January 24 and January 25.

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Workshop / Seminar Tue, 18 Jan 2022 19:32:41 -0500 2022-01-24T13:00:00-05:00 2022-01-24T18:30:00-05:00 Off Campus Location Regenerative Medicine Biosciences Initiative Workshop / Seminar Purple Pipette
Programmable Materials/Regenerative Medicine Grand Challenge-Breakout Sessions (January 25, 2022 9:00am) https://events.umich.edu/event/88716 88716-21656961@events.umich.edu Event Begins: Tuesday, January 25, 2022 9:00am
Location: Off Campus Location
Organized By: Regenerative Medicine Biosciences Initiative

Programmable Biomaterials/Regenerative Medicine Grand Challenge Breakout Rooms

Theme: How to regenerate tissues/organs to optimally integrate with the host

Goal: Bring together clinicians, scientists, and engineers to explore new ideas and catalyze new collaborations to address key barriers to the translation of regenerative medicine technologies

Format: Short talks identifying clinical problems and emerging technologies, followed by breakout sessions to identify opportunities

Breakouts: Based on problems identified, what are transformative things UM can do to solve? We’re looking for big ideas that involve new, heterogeneous groups. Themes/challenges that emerge from breakouts will define an RFA

Outcome: Funding for collaborative proposals that emerge from the grand challenge session w/ criteria that proposals are novel and integrative, satisfying one or more of the following elements:
•High risk, cross-cutting, transformative
•Leverage strengths at UM in new ways
•Pull together new combinations of people
•Tackle new problems or existing problems in new ways
•Topics that will have greatest impact and potential for extramural funding
•We anticipate awarding 3 grants at ~100K each
Please join us for our 2-day VIRTUAL event January 24 and January 25.

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Workshop / Seminar Tue, 18 Jan 2022 19:31:38 -0500 2022-01-25T09:00:00-05:00 2022-01-25T12:00:00-05:00 Off Campus Location Regenerative Medicine Biosciences Initiative Workshop / Seminar Regenerative Medicine Grand Challenge
Elasticity Imaging: From Fibrosis and Tumor Pressure to Mechanotransduction and Visualizing Primary Neuronal Activity (January 27, 2022 3:30pm) https://events.umich.edu/event/91489 91489-21680069@events.umich.edu Event Begins: Thursday, January 27, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
Only recently have we understood the importance of mechanical forces between cells to generate tissue homeostasis. This translates equally to the organ level with tissue biomechanics an excellent proxy for pathological alterations.

In this lecture we will review the current method of quantifying tissue biomechanics via MRI using mechanical shear waves elicitated at the surface of the patient, new ways to quantify non-invasively tumour pressure via non-linear mechanics, and look into mechanical changes induced by neuronal activities. Finally, we will change our position from being a passive bystander quantifying tissue mechanics to an active player altering cellular fate via shear waves.
Bio:
Professor Ralph Sinkus is a physicist with a background in high energy physics, nuclear physics and MRI. He has dual labs at King’s College London’s School of Biomedical Engineering and Imaging Sciences as well as at INSERM (University Paris Diderot, Sorbonne Paris Cité, Hôpital Bichat/Beaujon, Paris, France). After a PhD in high energy physics (DESY, Deutsches Elektronen Synchrotron, Hamburg, Germany), Professor Sinkus took a position at Philips Medical Systems Research Laboratories (Hamburg, Germany) focusing on magnetic resonance imaging (MRI) and elastography. Moving back to academia, Professor Sinkus worked for the Laboratoire Ondes et Acoustique (ESPCI) in Paris, France as a research director until accepting a chair position at King’s College London. Professor Sinkus is an expert in MRI and MR-elastography, and works with a diverse range of clinicians, biomedical engineers, physists and mathematicians for the translation of these technologies to address clinical diagnostics through imaging.
Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

Zoom Link: https://umich.zoom.us/j/96508834308

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Workshop / Seminar Tue, 25 Jan 2022 13:56:46 -0500 2022-01-27T15:30:00-05:00 2022-01-27T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
Targeting and monitoring focused ultrasound in the brain with MRI (February 3, 2022 3:30pm) https://events.umich.edu/event/91561 91561-21680566@events.umich.edu Event Begins: Thursday, February 3, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Focused ultrasound is a noninvasive therapeutic modality in which ultrasound waves are focused to a point in the body to manipulate a target without affecting intervening tissue. Some of the most promising applications for focused ultrasound are in the brain, where it is FDA-approved for thermal ablation in movement disorders, and is also being explored for blood brain barrier opening and neuromodulation. MRI plays a critical role in targeting and monitoring the effects of transcranial focused ultrasound through its ability to image not only fine brain structures but also temperature and tissue displacement. In this talk I will present our efforts to overcome the myriad technical challenges associated with MRI guidance of transcranial focused ultrasound, including achieving volumetric coverage in brain thermometry, alleviating signal voids and artifacts caused by the presence of the transducer and its coupling media, and rapidly imaging tissue displacement to localize the focus and compensate acoustic aberrations caused by the skull. 

Bio:
Will Grissom is an Associate Professor of Biomedical Engineering at Vanderbilt University. He received his PhD from the University of Michigan in 2008, completed a postdoctoral fellowship at Stanford University in 2009, and worked as a Research Engineer at GE Global Research in Munich Germany until 2011. He then joined the Department of Biomedical Engineering and the Institute of Imaging Science at Vanderbilt University where he works on RF pulse design, image reconstruction, and RF coils for MRI from 47 mT to 7 T, and develops interventional MRI methods for guiding focused ultrasound and laser ablation and neuromodulation.

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

Zoom Link: https://umich.zoom.us/j/96508834308
Location: 1131 LBME, 1101 Beal Ave., Ann Arbor, MI 48109-2110

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Workshop / Seminar Wed, 26 Jan 2022 15:42:01 -0500 2022-02-03T15:30:00-05:00 2022-02-03T16:30:00-05:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME Seminar
Physiologic mechanics drive contractile development in stem cell derived cardiac muscle to model genetic heart disease (February 10, 2022 3:30pm) https://events.umich.edu/event/92035 92035-21686280@events.umich.edu Event Begins: Thursday, February 10, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Physiologic mechanics drive contractile development in stem cell derived cardiac muscle to model genetic heart disease

Abstract:
Disorganized mechanics and immaturity of stem cell derived cardiomyocytes have been hurdles to reproducible applications for regenerative medicine or disease modeling. We developed a platform of micron-scale cardiac muscle bundles to control biomechanics in arrays of thousands of purified, independently contracting cardiac muscle strips on two-dimensional elastomer substrates. By defining geometry and workload in this reductionist platform, we show that myofibrillar alignment and auxotonic contractions at physiologic workload drive maturation of contractile function, calcium handling, and electrophysiology. Using transcriptomics, reporter hPSC-CMs, and quantitative immunofluorescence, these cardiac muscle bundles can be used to parse orthogonal cues in early development, including contractile force, calcium load, and metabolic signals. Additionally, the resultant organized biomechanics facilitates automated extraction of contractile kinetics from brightfield microscopy imaging, increasing the accessibility, reproducibility, and throughput of pharmacologic testing. Our lab is working toward applications of this system to understand human cardiomyopathies caused by variants that affect cardiomyocyte structure and function.

Bio:
Dr. Helms is a physician-scientist in the Division of Cardiovascular Medicine at the University of Michigan. He co-directs the Inherited Cardiomyopathy and Arrhythmia Clinic. His lab studies genetic cardiomyopathy using stem cell derived cardiomyocyte and mouse models. 

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Wed, 09 Feb 2022 10:16:37 -0500 2022-02-10T15:30:00-05:00 2022-02-10T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
Restoring Fine Finger Control to Paralyzed Hands Using a Low-Power Brain-Controlled Functional Electrical Stimulation Neuroprosthesis (February 14, 2022 9:30am) https://events.umich.edu/event/91820 91820-21683195@events.umich.edu Event Begins: Monday, February 14, 2022 9:30am
Location: Off Campus Location
Organized By: Biomedical Engineering

Paralysis of the upper extremity is a devastating outcome of many neurological diseases and disorders. Brain-machine interfaces (BMIs) attempt to bypass the disability by recording information directly from the subject’s brain and predicting the user’s intentions to control a prosthetic device. Modern brain-machine interfaces have made limited translation to clinical use, where studies have not expanded far beyond controlled laboratory environments. Two of the primary hindrances to their widespread clinical translation is their dependence on stacks of power-hungry computers and performance compared to the able-bodied hand. The aim of this work is to establish low-power brain-machine interface technologies that restore fine control to paralyzed hands.

The first study presents the 300-1,000Hz spiking band power (SBP), which is a low power neural spiking feature that requires 90% less data than the standard threshold crossing rate (TCR) neural feature. In simulation, we found that SBP can extract accurate neural spiking patterns at lower signal-to-noise ratios and with greater unit specificity than TCR. Because of this, closed-loop decoders which used SBP performed as well or better than decoders using TCR in two rhesus macaques.

In the second study, we investigated whether BMIs could be implemented on embedded devices fit for implantation. We used three off-the-shelf low-power amplifiers controlled by a 32-bit microcontroller to perform SBP recording, feature extraction, and decoding. The device could achieve equivalent performance to our high-powered BMI when closed-loop predicting one-finger movements and comparable performance when predicting two-finger movements in a nonhuman primate. To do so, the device required 58.4mW (equivalent to 11.3hr usage time with a standard 200mAh implantable battery), which we could compress to 12.5mW (52.8hr usage time) with an optimized processing pipeline implemented on an integrated circuit.

The third study showed, for the first time, that BMIs can control the simultaneous and independent movements of two finger groups in real-time with nonhuman primates. With the BMI, the primate could acquire targets at a rate of nearly 2 per second. Additionally, we found that cortical activity for independent finger movements and combined finger movements were similar. This allowed linear models to predict behaviors that were not used for training with a correlation coefficient at least 90% as high as a linear decoder trained on all behaviors.

In the fourth study, we investigated how well continuous finger movements could be restored with a brain-controlled functional electrical stimulation (BCFES) system. Following temporary paralysis delivered via nerve block, a nonhuman primate improved success rates to 89% with a 1.4s median target acquisition time in a one-finger task by using the BCFES system, up from 2.6% and a 9.5s median target acquisition time (near chance) when using his paralyzed native hand. Additionally, we allowed the monkey to use the BMI (no stimulation) to complete the two-finger version of the task following paralysis, and performance could be recovered by performing recalibrated feedback-intention training one time following paralysis, despite the absence of sensory feedback.

The results of this work demonstrate that low-power BMIs can restore substantial function in cases of upper extremity paralysis. All of the work presented here uses low-power technology that can simply be implemented on implantable devices. Next steps for this work will require validation of the hand control results in humans and development of completely implantable neuroprostheses to restore native hand functions to people with paralysis.

Date: Monday, February 14, 2022
Time: 9:30 AM EST
Location: NCRC Building 10 Research Auditorium
Zoom: https://umich.zoom.us/j/99401963138?pwd=N1JoMnQzNmNFa3FYa0EwSnVFZk9kZz09 Passcode 842683
Chair: Dr. Cindy Chestek

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Workshop / Seminar Tue, 01 Feb 2022 12:36:47 -0500 2022-02-14T09:30:00-05:00 2022-02-14T10:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Event
Engineering Folliculogenesis in a Biomimetic Matrix (February 16, 2022 3:00pm) https://events.umich.edu/event/92270 92270-21688760@events.umich.edu Event Begins: Wednesday, February 16, 2022 3:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Cancer survivorship has increased in recent decades due to advancements in anticancer treatments, yet cancer survivors continue to suffer from irreversible premature ovarian insufficiency and loss of fertility caused by radiation and chemotherapy. Restoration of reproductive function is uniquely challenging because women are born with a non-renewable reserve of ovarian follicles, the functional units of the ovary each carrying an oocyte (egg) and hormone producing somatic cells. Removal of ovarian tissue prior to gonadotoxic treatments and culture of isolated ovarian follicles is a safe fertility preservation option for pediatric and adult patients and does not require delays in treatment or hormonal stimulation. However, a high-yield, translational, and reproducible in vitro culture system that produces fertilizable eggs does not exist. Survival, growth, and maturation of early-stage primordial follicles, which constitute the majority of the follicular reserve, depend on bidirectional paracrine signaling through soluble cytokines and interactions with the extracellular matrix (ECM). To meet the needs of growing ovarian follicles we designed a biomimetic hydrogel for in vitro follicle culture that restores critical cell-cell and cell-matrix interactions for improved follicle outcomes. We hypothesized that a degradable poly(ethylene glycol) (PEG)-based matrix with tunable biophysical properties would (1) enable co-encapsulation of follicles and cells for paracrine signaling and (2) mimic the ECM functions of ovarian tissue.

First, we established that our degradable hydrogel could support co-culture of multiple cell types by co-encapsulating isolated murine primary follicles with adipose-derived stem cells (ADSCs) that secrete survival- and growth-promoting cytokines, compensating for the loss of native stromal cells. Bidirectional crosstalk between follicles and ADSCs promoted folliculogenesis and follicles doubled in size compared to follicles cultured without the ADSCs. Second, we incorporated ECM-sequestering peptides that retain cell-secreted ECM molecules, such as laminin, fibronectin, collagen type 1, and perlecan, thereby restoring cell-matrix interactions and improving growth factor binding. Secondary follicles cultured in PEG functionalized with peptides that bind basement membrane proteins exhibited greater than 93% survival, reached 340 µm in diameter, and achieved oocyte maturation rates of 84%. Lastly, we combined these approaches for restoring paracrine signaling and ECM function for culture of primordial follicles, the most immature and difficult to grow, but most abundant type of follicle in the ovary. We embedded hydrogels with ECM-sequestering dextran fibers to act as a scaffold for ECM deposition, better mimicking the fibrous structure of native ECM. ECM deposition and subsequent cell binding to fibers facilitated follicle and cell aggregation within the hydrogel matrix. Oocyte survival and growth was significantly improved in conditions which formed follicle-like aggregates surrounded by stroma, likely due to restoration of key cell-cell and cell-matrix interactions that promote follicle development.

In conclusion, we have engineered a fully synthetic hydrogel culture system that recapitulates the cellular and extracellular components of native ovarian tissue for improved follicle outcomes. This translational biomaterial is significant for guiding the development of a standardized in vitro culture system for maturation of human follicles and a safe fertility preservation option for cancer survivors unable to produce mature eggs. This biomimetic hydrogel also has broader impacts in the field of tissue engineering as it facilitates cell-driven reconstruction of their native microenvironments, providing a more comprehensive model for deciphering key mechanisms that drive regeneration in vitro.

Date: Wednesday, February 16, 2022
Time: 3:00 PM EST
Zoom: https://umich.zoom.us/j/99438979027 Passcode: GoFollicle
Chair: Dr. Ariella Shikanov

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Presentation Fri, 11 Feb 2022 16:43:57 -0500 2022-02-16T15:00:00-05:00 2022-02-16T16:00:00-05:00 Off Campus Location Biomedical Engineering Presentation BME Defense Announcement
Machine Learning in Drug Development (February 17, 2022 3:30pm) https://events.umich.edu/event/92334 92334-21690196@events.umich.edu Event Begins: Thursday, February 17, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
An undesirable side effect of drugs are cardiac arrhythmias, in particular a condition called torsades de pointes. Current paradigms for drug safety evaluation are costly, lengthy, and conservative, and impede efficient drug development. Here we combine multiscale experiment and simulation, high-performance computing, and machine learning to create an easy-to-use risk assessment diagram to quickly and reliable stratify the pro-arrhythmic potential of new and existing drugs. We capitalize on recent developments in machine learning and integrate information across ten orders of magnitude in space and time to provide a holistic picture of the effects of drugs, either individually or in combination with other drugs. We show, both experimentally and computationally, that drug-induced arrhythmias are dominated by the interplay of two currents with opposing effects: the rapid delayed rectifier potassium current and the L-type calcium current. Using Gaussian process classification, we create a classifier that stratifies safe and arrhythmic domains for any combinations of these two currents. We demonstrate that our classifier correctly identifies the risk categories of 23 common drugs, exclusively on the basis of their concentrations at 50% current block. Our study shapes the way towards establishing science-based criteria to accelerate drug development, design safer drugs, and reduce heart rhythm disorders.
Bio:
Ellen Kuhl is the Walter B. Reinhold Professor in the School of Engineering and Robert Bosch Chair of Mechanical Engineering at Stanford University. She received her PhD from the University of Stuttgart in 2000 and her Habilitation from the University of Kaiserslautern in 2004. Her area of expertise is Living Matter Physics, the design of theoretical and computational models to simulate and predict the behavior of living systems. Ellen has published more than 200 peer-reviewed journal articles, edited two books, and published a textbook on COVID-19. She is a founding member of the Living Heart Project, a translational research initiative to revolutionize cardiovascular science through realistic simulation with 400 participants from research, industry, and medicine from 24 countries. Ellen is the current Chair of the US National Committee on Biomechanics and a Member-Elect of the World Council of Biomechanics. She is a Fellow of the American Society of Mechanical Engineers and of the American Institute for Mechanical and Biological Engineering. She received the National Science Foundation Career Award in 2010, was selected as Midwest Mechanics Seminar Speaker in 2014, and received the Humboldt Research Award in 2016 and the ASME Ted Belytschko Applied Mechanics Award in 2021. Ellen is an All American triathlete, a multiple Boston, Chicago, and New York marathon runner, and a Kona Ironman World Championship finisher.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Mon, 14 Feb 2022 10:57:37 -0500 2022-02-17T15:30:00-05:00 2022-02-17T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
Small Aperture Ultrasound Transducers for Advanced Imaging and Therapy (February 24, 2022 3:30pm) https://events.umich.edu/event/92542 92542-21692154@events.umich.edu Event Begins: Thursday, February 24, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Ultrasound imaging and therapy have been increasingly important in disease diagnosis, treatment guidance, treatment and post treatment assessment. In this talk, novel small aperture ultrasound transducers are presented for advanced intravascular ultrasound imaging (IVUS), intravenous sonothrombolysis, localized tissue ablation and drug delivery. In specific, high frequency (40-60 MHz) micromachined piezoelectric composite transducers and arrays with broad bandwidth (-6 dB fraction bandwidth of ~ 80%) were developed and integrated into 3-Fr catheters for intravascular ultrasound (IVUS) imaging. Dual frequency transducers and arrays (6.5 MHz/30 MHz, 3 MHz/30 MHz) were also successfully demonstrated for contrast enhanced intravascular superharmonic imaging (or acoustic angiography) toward detection of plaque vulnerability. For the case of intravenous thrombolysis, small aperture (diameter <2 mm) sub-MHz forward-looking transducers were successfully demonstrated, in-vitro, for microbubbles/nanodroplets-mediated sonothrombolysis. Other transducer techniques such as small aperture high intensity focused ultrasound (HIFU) transducers, laser ultrasound transducers and dual-mode transducers were also investigated for localized tissue ablation, drug delivery and intravascular sonothrombolysis. Finally, challenges and future perspectives of ultrasound transducers are discussed for advanced ultrasound imaging, therapy, and drug delivery.

Biography:
Dr. Xiaoning Jiang is a Dean F. Duncan Distinguished Professor of Mechanical and Aerospace Engineering and a University Faculty Scholar at North Carolina State University. He is also an Adjunct Professor of Biomedical Engineering at North Carolina State University and University of North Carolina, Chapel Hill, and an Adjunct Professor of Neurology at Duke University. Dr. Jiang received his Ph.D. degree from Tsinghua University (1997) and his postdoctoral training from the Pennsylvania State University (1997-2001). He was the Chief Scientist and Vice President for TRS Technologies, Inc. prior to joining NC State in 2009. Dr. Jiang is the author and co-author of two books, six book chapters, nine issued US Patents, 150 peer reviewed journal papers and over 120 conference papers on piezoelectric ultrasound transducers, ultrasound for medical imaging and therapy, drug delivery, ultrasound NDT/NDE, smart materials and structures and M/NEMS. Dr. Jiang serves as the Vice President for Technical Activities of IEEE Nanotechnology Council (2022 and 2023), an editorial board member for the journal Sensors, and a Senior Associate Editor for the ASME Journal of Engineering and Science in Medical Diagnostics and Therapy. Dr. Jiang was an IEEE NTC Distinguished Lecturer in 2018 and 2019, Co-EIC of IEEE Nanotechnology Magazine (2020 and 2021), and he is an ASME Fellow and a SPIE Fellow.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Thu, 17 Feb 2022 16:14:40 -0500 2022-02-24T15:30:00-05:00 2022-02-24T16:30:00-05:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME 500 Seminar
Designing polymeric nanoparticles for systemic delivery in vivo to enhance therapeutic effects in key tissues (March 3, 2022 3:30pm) https://events.umich.edu/event/92893 92893-21697941@events.umich.edu Event Begins: Thursday, March 3, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
The primary barrier for clinical translation of nanomedicines remains delivery to target tissues in vivo. In this seminar, I will describe our work on developing polymeric nanoparticles (NPs) to deliver therapeutic nucleic acids to a variety of tissues following systemic intravenous administration, with a focus on peptide nucleic acid (PNA)-based gene editing therapeutics in cystic fibrosis and b-thalassemia disease contexts. These monogenic disorders are attractive targets for gene editing and can be corrected using non-nuclease-based PNA gene editing agents. PNAs designed to bind specific sites in genomic DNA can initiate an endogenous DNA repair response and site-specific modification of the genome when “donor DNA” templates containing a desired sequence modification are co-delivered using polymeric vehicles. In recent work, we have found that gene editing efficiency can be significantly enhanced using a new class of polymeric vehicles consisting of poly(amine-co-ester) (PACE) polymers designed for safe and effective nucleic acid delivery. To close the talk, I will describe a robust high-throughput quantitative microscopy-based platform to standardize and accelerate the analysis of circulation half-life of nanomedicines to facilitate pre-clinical screening in vivo. This tool, alongside the development of novel polymeric carriers, can be used to study the structure-function relationships that guide the physiological fate of NPs in order to rationally design more effective delivery vehicles for future applications.
Bio:
Dr. Alexandra S. Piotrowski-Daspit, Ph.D. is a Postdoctoral Fellow in the Biomedical Engineering Department at Yale University. Alexandra received her bachelor's degree in Chemical-Biological Engineering and Biology from the Massachusetts Institute of Technology (MIT) in 2011 and her Ph.D. in Chemical & Biological Engineering from Princeton University in 2016, where she worked in the laboratory of Professor Celeste Nelson on developing three-dimensional cell culture models to study cell behavior during development and disease processes. At Yale, she works on a highly interdisciplinary team under the mentorship of Professors W. Mark Saltzman, Peter Glazer, and Marie Egan, focusing on developing polymeric vehicles for the delivery of a variety of therapeutic nucleic acids.

Dr. Piotrowski-Daspit’s main project involves synthesizing novel biodegradable polymers and formulating them into vehicles to deliver peptide nucleic acid (PNA)-based gene editing therapeutics for the treatment of hereditary diseases such as Cystic Fibrosis. She has received funding from the NIH (NHLBI K99/R00 Pathway to Independence Award) and the Cystic Fibrosis Foundation (Postdoc-to-Faculty Transition Award) to support her interdisciplinary research in chemical/biomedical engineering, biomaterials, genetics, and drug delivery to develop therapeutic strategies to treat hereditary disorders with a focus on lung diseases.

Zoom Link: https://umich.zoom.us/j/96508834308

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Workshop / Seminar Wed, 02 Mar 2022 09:03:37 -0500 2022-03-03T15:30:00-05:00 2022-03-03T16:30:00-05:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME Seminar
Finding Funding: Identifying Opportunities & Scoping the Grants Landscape (March 8, 2022 12:00pm) https://events.umich.edu/event/91560 91560-21680564@events.umich.edu Event Begins: Tuesday, March 8, 2022 12:00pm
Location: Off Campus Location
Organized By: OVPR Office of Research Development

Hosted by U-M Research Development & Proposal Services, library experts Judy Smith and Paul Barrow will present a workshop to help investigators at all levels use online tools to be proactive in identifying federal, state, and foundation research funding. Topics will include efficient searching of funding databases and setting up funding alerts through examining the special features of Foundation Directory Online and Pivot. The workshop also will direct researchers to units at U-M that will support their grantseeking endeavors.

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Livestream / Virtual Wed, 26 Jan 2022 15:26:33 -0500 2022-03-08T12:00:00-05:00 2022-03-08T13:00:00-05:00 Off Campus Location OVPR Office of Research Development Livestream / Virtual Finding funding
Potential and Pitfalls of Polygenic Scores For Social Demographic Research (March 9, 2022 2:00pm) https://events.umich.edu/event/85344 85344-21626257@events.umich.edu Event Begins: Wednesday, March 9, 2022 2:00pm
Location: Off Campus Location
Organized By: Institute for Social Research

This webinar series on the Chitwan Valley Family Study (CVFS) is about global and comparative population research. Sessions include measuring mental health, Covid-19, linking data, genetics, & migrant data.

Webinar 12: Potential and Pitfalls of Polygenic Scores For Social Demographic Research
Wednesday, March 9, 2022
2-3pm EDT
Presenter: Colter Mitchell

This webinar will provide an overview of the methodology around the construction of polygenic scores and their applications in demographic research. There will be a Q&A session after the presentation.

The webinar will be hosted using Zoom. Registration is required to attend the webinar. Support provided by NICHD (R25 HD101358).

Registration is required for this event: https://umich.zoom.us/meeting/register/tJwqde2tpzovGt21ffMiK7ndNIVGOovGaCqi

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Presentation Tue, 17 Aug 2021 15:01:18 -0400 2022-03-09T14:00:00-05:00 2022-03-09T15:00:00-05:00 Off Campus Location Institute for Social Research Presentation Nepal mountains
Biomechanics of the Female Reproductive System: Role of Smooth Muscle Contractility (March 10, 2022 3:30pm) https://events.umich.edu/event/92876 92876-21697628@events.umich.edu Event Begins: Thursday, March 10, 2022 3:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
The tissues of the female reproductive system drastically remodel their shape and function in response to altered biomechanical and biochemical signals during processes such as pregnancy and aging. Tissue dynamics may include both passive remodeling of the extracellular matrix composition and organization, as well as the active response via changes in the amount, organization, and contractile response of smooth muscle cells.  Lack of adaptations in response to variable pressures may lead to structural instability in the female reproductive system, contributing to significant health problems, such as obstetric injury, preterm birth, and pelvic organ prolapse. The vagina is central to pelvic floor support; however, the relationship between vaginal extracellular matrix, smooth muscle contractility, and mechanical properties are not fully elucidated. In this talk, I will present our efforts to delineate the mechanical role of smooth muscle cells and potential interactions with elastic fibers in the murine vagina, and how these relationships evolve in a mouse model of pelvic organ prolapse and with reproductive age.

Bio:
Dr. Kristin S. Miller is an Associate Professor of Biomedical Engineering at Tulane University. Dr. Miller’s research interests are focused on the mechanobiology of soft tissues, including evaluating the role of elastic fibers and contractility in the female reproductive system. Before joining Tulane, Dr. Miller conducted postdoctoral research at Yale University and received her PhD in Bioengineering at the University of Pennsylvania. In 2018, Kristin was awarded the NSF CAREER award to develop a biomechanical model that can predict how elastic fibers in the soft tissues of the female reproductive system changes in response to mechanical pressure. In 2021, Kristin was awarded the YC Fung Early Career Award from the American Society of Mechanical Engineers.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Tue, 01 Mar 2022 13:59:46 -0500 2022-03-10T15:30:00-05:00 2022-03-10T16:30:00-05:00 Off Campus Location Biomedical Engineering Workshop / Seminar BME Seminar
“Mechanobiology of vertebrate gut morphogenesis" (March 15, 2022 4:00pm) https://events.umich.edu/event/92788 92788-21695466@events.umich.edu Event Begins: Tuesday, March 15, 2022 4:00pm
Location: Off Campus Location
Organized By: Center for Cell Plasticity and Organ Design

The Center for Cell Plasticity and Organ Design is proud to present the following seminar with guest speaker Nandan L. Nerurkar, PhD, Assistant Professor of Biomedical Engineering at Columbia University.

The talk is entitled, "Mechanobiology of vertebrate gut morphogenesis."

Faculty Host: Brendon Baker, PhD, Biomedical Engineering

For more information, please email Organogenesis@umich.edu

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Lecture / Discussion Thu, 24 Feb 2022 21:22:04 -0500 2022-03-15T16:00:00-04:00 2022-03-15T17:00:00-04:00 Off Campus Location Center for Cell Plasticity and Organ Design Lecture / Discussion Nerurkar Flyer
A Systems Approach to Overcome Tumor-cell Heterogeneity in Drug Response: Metrics and Mechanisms (March 16, 2022 1:00pm) https://events.umich.edu/event/92868 92868-21697508@events.umich.edu Event Begins: Wednesday, March 16, 2022 1:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Resistance due to tumor cell heterogeneity poses a major challenge to the use of targeted therapies for cancer treatment. Targeted therapies that are designed to block oncogenic signaling in tumor cells often yield substantial responses initially, but fail to fully eradicate tumors. Among the major barriers to full cures is the cell-to-cell heterogeneity in drug response that arises even among genetically identical cells. Recent single-cell studies have revealed that such non-genetic heterogeneity can prime a rare, transient subpopulation of tumor cells to be intrinsically drug-tolerant or render them cellular plasticity to adapt to drug-induced stresses dynamically. These therapy escapees constitute a reservoir of reversibly drug-tolerant cells, which can then acquire more stably resistant phenotypes with continuous drug exposure, ultimately driving tumor relapse. Although the emergence and consequences of such heterogeneity are widely recognized, the molecular basis for such intrinsic and adaptive heterogeneities and their connections to variable states of drug sensitivity remain elusive. Furthermore, the dynamic responses of these rare residual subpopulations are often obscured by fixed-time population-based measurements in most pre-clinical drug-response assays, posing another challenge to the design of effective therapeutic strategies to block such drug resistance.

The focus of this dissertation is to address these gaps in our knowledge by quantifying and dissecting the origins of cell-to-cell heterogeneities in cancer drug response using systems biology approaches. First, I developed new experimental and mathematical frameworks to evaluate time-dependent drug responses using probabilistic metrics that quantify drug-induced phenotypic events (i.e., cell death and division) at the single-cell level. These probabilistic metrics can reveal the time-varying drug responses and drug combination interactions in heterogeneous tumor cell populations. Therefore, these metrics have important implications for designing efficacious combination therapies, especially those designed to block drug-tolerant subpopulations of tumor cells.

Second, this thesis investigates the molecular basis of cellular plasticity, focusing on the activator protein 1 (AP-1) transcription factor family, for their roles as key effectors of the mitogen-activated protein kinase (MAPK) pathway. Using melanoma as a model system with dysregulated MAPK signaling, I employed systems biology approaches that integrated data-driven modeling with multiplexed measurements to capture single-cell heterogeneity before and after MAPK inhibitor treatments in BRAF-mutated melanoma cells. I showed that the state of the AP-1 network plays a unifying role in explaining the intrinsic diversity of phenotypic states and adaptive responses to MAPK inhibitors. Perturbing the state of the AP-1 network through genetic depletion of specific AP-1 proteins, or by MAPK inhibitors, shifts cellular heterogeneity in a predictable fashion. Thus, AP-1 may serve as a critical node for manipulating cellular plasticity with potential therapeutic implications. Together, this thesis may facilitate future efforts for the rational design of therapeutic strategies that aim at overcoming the challenge of drug resistance arising due to tumor cell heterogeneity and plasticity.

Date: Wednesday, March 16, 2022
Time: 1:00 PM EST
Zoom: https://virginia.zoom.us/j/95703185539?pwd=WUhEUVRrZnkwK3ZlekhOTmFibVNXZz09 Passcode: brafmel316
Chair: Dr. Mohammad Fallahi-Sichani

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Presentation Tue, 01 Mar 2022 10:28:11 -0500 2022-03-16T13:00:00-04:00 2022-03-16T14:00:00-04:00 Off Campus Location Biomedical Engineering Presentation BME PhD defense
Cardiac mechanobiology: Modeling altered cardiac biomechanics across scales to understand mechanisms of disease (March 17, 2022 3:30pm) https://events.umich.edu/event/93213 93213-21701540@events.umich.edu Event Begins: Thursday, March 17, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Many forms of cardiac disease, including myocardial infarction (MI) and hypertrophic cardiomyopathy (HCM), are characterized by changes in contractile function and tissue stiffness. Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, and one of the most common sites of disease causing mutations is beta cardiac myosin, the motor protein responsible for contraction. While HCM is characterized clinically by muscle cell (cardiomyocyte) growth and hypercontractility, HCM mutations cause a diverse range of effects on the molecular function of myosin that has important implications for disease severity and treatment options. Using gene-edited human induced pluripotent stem cells in engineered environments, I measured the effects of these mutations at the cellular scale; namely: increased traction force generation, increased cell size, increased signaling of hypertrophic pathways, and altered cytoskeletal and cell junction organization. I have used computational models to link measured changes in molecular and cellular biomechanics, probed sources of cellular variability, and identified mechanisms of hypercontractility. In addition to cardiomyocyte hypertrophy, myofibroblast activation contributes to fibrotic tissue remodeling in many cardiac conditions and is affected by changes in tissue mechanics and interactions with other cardiac cells. In my doctoral research, I found that therapeutic targeting of a cadherin expressed in myofibroblasts and inflammatory cells after MI can limit harmful remodeling. My research leverages engineering tools to clarify the mechanical and biological mechanisms of cardiac disease and can help inform the development and application of new therapies for HCM and other cardiac diseases. 

Bio:
Alison Schroer Vander Roest received her undergraduate degree in biomedical engineering at the University of Virginia. She then received a PhD in biomedical engineering at Vanderbilt University with Dr. Dave Merryman, studying fibroblast mechanobiology and the role of cadherin-11 in fibrotic and inflammatory remodeling after myocardial infarction. After completing her doctoral work, Dr. Vander Roest pursued postdoctoral training at Stanford University as part of a collaborative team between the mechanical and bioengineering, biochemistry, and pediatric cardiology departments. Her project at Stanford has been co-mentored by Dr. Beth Pruitt, Dr. Jim Spudich, and Dr. Dan Bernstein and aims to understand mechanisms linking mutations in beta-cardiac myosin to phenotypes of hypertrophic cardiomyopathy using stem cell models and engineered environments. Dr. Vander Roest has also developed collaborations to incorporate transcriptome analysis, FRET tension sensors, and computational modeling of myosin kinetics to better understand cardiomyocyte mechanobiology. This project has been awarded a K99/R00 Pathway to Independence Award that will fund future research into multiscale mechanisms of cardiac disease.  

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Wed, 09 Mar 2022 16:20:47 -0500 2022-03-17T15:30:00-04:00 2022-03-17T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME Seminar
Pre-Clinical Investigation of Histotripsy for Non-Invasive Ablation of Liver Cancer (March 18, 2022 1:30pm) https://events.umich.edu/event/92996 92996-21698984@events.umich.edu Event Begins: Friday, March 18, 2022 1:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Liver cancer, including hepatocellular carcinoma (HCC) is one of the top ten causes of cancer related deaths worldwide and in the United States. The liver is also a frequent site for metastases originating from colorectal cancer, pancreatic cancer, melanoma, lung cancer and breast cancer. Depending on the location, severity and staging of liver cancer, multiple treatment options are currently available including surgical resection, liver transplantation, chemotherapy, radiation therapy, targeted drug therapy, immunotherapies, and ablation techniques including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, high intensity focused ultrasound (HIFU), yet the prognosis of HCC remains poor with five-year survival rates reported at only 18% in the US. Even after treatment, the high prevalence of tumor recurrence and metastasis highlights the clinical need for improving outcomes of liver cancer.

Histotripsy is a novel non-invasive, non-ionizing, and non-thermal ablation technique that mechanically destroys target tissue by controlled acoustic cavitation. High pressure (p->30MPa), microsecond-length ultrasound pulses cause endogenous nanometer-scale gas nuclei in the target tissue to rapidly expand and collapse, generating high mechanical stress and strain to disrupt the cellular structure into an acellular homogenate. This dissertation investigates histotripsy as a therapeutic ultrasound treatment option of liver cancer and other solid tumors.

The first study evaluated the safety and feasibility and survival benefits of histotripsy in an in vivo murine liver tumor model. Results showed that non-invasive histotripsy ablation reduced local tumor progression of subcutaneous human-derived HCC tumor and improved survival outcomes in immunocompromised mice. This study also characterized the radiological features correlating to the histotripsy tumor response.

The second study investigated the anti-tumor immune response generated by histotripsy ablation of subcutaneous murine melanoma and HCC tumors. Histotripsy stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations, promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity and was able to amplify the efficacy of checkpoint inhibition immunotherapy.

The third study evaluated the safety, feasibility, and tumor volume reduction effects of histotripsy for liver cancer ablation in an orthotopic, immune-competent in vivo rat HCC model. For the first time, it was demonstrated that complete as well as partial histotripsy ablation of tumors can result in complete tumor regression with no recurrence.

The fourth study evaluated the effects of partial histotripsy tumor ablation on tumor response, risk of metastases and immune infiltration in an orthotopic, immunocompetent, metastatic rodent hepatocellular carcinoma (HCC) model. Results showed that histotripsy significantly improved survival outcomes with no increased risk of metastasis compared to controls and demonstrated that augmented tumor immune infiltration may have contributed to the eventual regression even with partial treatment of tumors.

The fifth study compared the safety, tumor response and survival outcomes between single and repeat histotripsy treatments of human-derived HCC tumors in immunocompromised murine hosts and mouse-derived HCC tumors in immunocompetent murine hosts. One week after the initial histotripsy treatment, animals received a repeat histotripsy treatment. Results showed that while both histotripsy groups significantly improved survival outcomes over control, the repeat histotripsy group demonstrated slower tumor growth and increased survival compared to single histotripsy.

Overall, this dissertation demonstrated the potential and in vivo feasibility of histotripsy for successful non-invasive tumor ablation, reduction of local tumor burden and prevention of metastasis. Future studies will continue to investigate the safety, efficacy, and biological effects of histotripsy liver cancer treatment for potential translation to clinic.

Date: Friday, March 18, 2022
Time: 1:30 PM EST
Zoom: https://umich.zoom.us/j/95042725076 Passcode: EarthPass
Chair: Professor Zhen Xu

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Presentation Fri, 04 Mar 2022 09:28:05 -0500 2022-03-18T13:30:00-04:00 2022-03-18T14:30:00-04:00 Off Campus Location Biomedical Engineering Presentation BME PhD Defense
Approaches to Prevascularize Pancreatic Islets: A Preliminary Study for Diabetic Cell Therapy (March 21, 2022 3:00pm) https://events.umich.edu/event/93457 93457-21704627@events.umich.edu Event Begins: Monday, March 21, 2022 3:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

This research is seeking to examine two approaches to vascularize a scaffold material, toward the goal of engineering a prevascularized islet implant. Type 1 diabetes mellitus (T1DM) is a chronic condition that affects millions of people worldwide. It is indicated by the autoimmune destruction of beta cells within pancreatic islets which results in significantly decreased or no production of insulin. Without enough insulin, the body cannot maintain healthy blood glucose levels, and this deficiency can lead to a range of other issues. A previous cell therapy method has been established to attempt to permanently cure T1DM, but the need for harsh immunosuppressive drugs, as well as poor vascularization, keep this protocol from being widely used. The scaffold vascularization strategies utilized in this research aim to mitigate the negative aspects of this preceding protocol.

The first part of this study characterized the effects of cell-specific media formulations on in vitro endothelial network development. In these experiments, hybrid media formulations containing varying ratios of vascular growth medium and beta cell medium were used to culture cellular fibrin hydrogels for 5 and 7 days. 3D vessel density analysis was performed for each gel, and the results showed that increasing the amount of beta cell medium in the gel culture media significantly decreased overall vessel density, and decreased vessel growth between day 5 and 7.

The second part of this study evaluated how the extent of in vitro endothelial network development in 3D fibrin hydrogels was affected by applying a modular tissue engineering strategy. Cellular fibrin microbeads were fabricated for this experiment. One group was immediately embedded into fibrin hydrogels, and a second group was kept in preculture for 5 days before being embedded. These embedded hydrogels were allowed to culture for 7 days before being analyzed for extent of vascularization. Average vessel sprout lengths were determined for each experimental group and compared, and the results of this study showed that the precultured microbeads were able to sprout statistically significantly longer vessels than non-precultured microbeads by the end of the 7-day culture period.

These studies help to demonstrate directions that could be pursued to develop a successful method for pre-vascularizing islet implants. The islet beta cell medium is not well suited for vascularization strategies because it lacks growth factors and supplements needed for endothelial network development. Because the islet’s media environment is incompatible with direct endothelial network growth, utilizing a precultured microtissue within an islet-containing hydrogel could aid in network growth even with beta cell medium. The microtissue itself serves as a temporary environment for an endothelial network to form before being exposed to beta medium, and the preformed endothelial network is beneficial in promoting vessel sprouting mechanisms and secreting proangiogenic factors lacking in the beta cell medium. Overall, incorporating precultured microtissues to vascularize islets could be a promising step towards treating T1DM.

DATE: Monday, March 21, 2002
TIME: 3:00 PM
Zoom: https://umich.zoom.us/j/8624071458 (Passcode: 932317)
Chair: Prof. Jan Stegemann

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Lecture / Discussion Tue, 15 Mar 2022 15:21:55 -0400 2022-03-21T15:00:00-04:00 2022-03-21T16:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Master's Defense
Biomechanical Strain Sensors and FRESH 3D Bioprinted Microfluidics for Tissue Engineering and Disease Modeling (March 24, 2022 3:30pm) https://events.umich.edu/event/93522 93522-21705224@events.umich.edu Event Begins: Thursday, March 24, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
The pursuit of an ideal model system to study the pathophysiology of vascular disease has included the use of tissue engineered blood vessels (TEBV), vascularizing engineered volumetric tissue, silicone-based “organ-on-a-chip” platforms, and tissue decellularization; yet we are still far from generating engineered vascular tissue that recapitulates native physiology. 3D bioprinting has led to additive manufacturing approaches for creating fluidic channels; however, it remains challenging to produce continuous networks with vessels ranging from large (>6 mm) to small (<1 mm) diameter using soft native-like extracellular matrix (ECM) that mimics the mechanical properties, geometric organization, and compositional complexity of the cellular and extracellular microenvironment. An ideal engineering strategy would combine the advantages of additive manufacturing with the controlled fluid flow achieved by organ-on-a-chip platforms, and the ECM structure, composition, and biomechanics of decellularized tissue. In this presentation I will highlight recent work on developing i) a fluorescence-based mechanical strain sensor for mapping 3D surface strain of contractile cells, developing tissue, and engineered blood vessels, ii) 3D bioprinted ECM microfluidics using Freeform Reversible Embedding of Suspended Hydrogels (FRESH), and iii) an in-process imaging platform for error detection and 3D gauging using optical coherence tomography (OCT). Together, this work highlights the exciting potential for FRESH printed ECM-based microfluidic scaffolds and vascular tissue engineering that will set the foundation for future work studying how ECM composition, mechanical properties, and fluid flow contribute to vascular disease. In addition to vascular biology, the collagen-based microfluidics and fluorescence strain sensor are platform technologies amenable to other organ systems, and can be utilized to study cell proliferation, metastasis, ECM remodeling, and biomechanics in a 3D environment.
Bio:
Dr. Shiwarski received a B.S. in Cell Biology and Biochemistry from Bucknell University and a Ph.D. in Biology and Neuroscience from Carnegie Mellon University. During his doctoral research, he investigated how opioid receptor membrane trafficking events influence pain inhibition and opioid addiction using advanced live cell fluorescence imaging and analysis techniques to track exocytic and endocytic events. In 2017 he began a postdoctoral fellowship in Dr. Adam Feinberg’s Lab in the Department of Biomedical Engineering at Carnegie Mellon University where he has: 1) studied how biomechanical forces are essential for cellular and tissue physiology by developing a fluorescence-based nanomechanical biosensor to map real-time changes in cell and tissue strain, 2) was a key contributor on the development of the 3D bioprinting technology FRESH 2.0,  which provided the ability to print unmodified collagen into functional components of the human heart, and 3) designed and published a series of open-source hardware and software platforms for 3D bioprinting, bi-axial mechanical testing, and in-process monitoring for additive manufacturing. Dr. Shiwarski has a broad background in cell biology, quantitative imaging, and tissue engineering with specific expertise in live cell fluorescence imaging, cellular biosensors, computational image analysis, 3D bioprinting, and cellular biomechanics. His future work focuses on engineering FRESH printed ECM-based microfluidic scaffolds as a platform technology for vascular tissue engineering that will set the foundation for studying how vascular smooth muscle cell differentiation, ECM composition, mechanical properties, and fluid flow contribute to hypertensive vascular disease. 

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Wed, 16 Mar 2022 14:21:05 -0400 2022-03-24T15:30:00-04:00 2022-03-24T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME Seminar
6th Annual RNA Symposium (March 25, 2022 8:00am) https://events.umich.edu/event/93125 93125-21700908@events.umich.edu Event Begins: Friday, March 25, 2022 8:00am
Location: Taubman Biomedical Science Research Building
Organized By: Center for RNA Biomedicine

Symposium Agenda

8:30 / Morning Welcome: President Mary Sue Coleman
8:40 / Jack Szostak "The emergence of RNA from heterogeneous prebiotic chemistry"
9:35 / Gigi Storz "RNA-mediated regulation within protein-coding sequences"
10:30 / coffee break
10:55 / Chris Burge "Impact of RNA-Binding Proteins on Human Genomic Variation"
12:00 / Lunch - please register for free box lunch
1:00 / Afternoon Welcome: Rebecca Cunningham, Vice President for Research
1:10 / Wendy Gilbert “Decoding the untranslated”
2:05 / Michelle Hastings "Splice-Modulating Antisense Oligonucleotides for the Treatment of Disease"
2:55 / Panel discussion with keynote speakers
Topic: Future of RNA Therapeutics, moderated by John Androsavich, Pfizer Global Lead, RNA Medicine

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Lecture / Discussion Wed, 16 Mar 2022 15:43:32 -0400 2022-03-25T08:00:00-04:00 2022-03-25T16:00:00-04:00 Taubman Biomedical Science Research Building Center for RNA Biomedicine Lecture / Discussion 6th Annual RNA Symposium
Mechanisms of Action and Sources of Variability in Neurostimulation for Chronic Pain (March 25, 2022 12:00pm) https://events.umich.edu/event/93458 93458-21704629@events.umich.edu Event Begins: Friday, March 25, 2022 12:00pm
Location: North Campus Research Complex Building 10
Organized By: Biomedical Engineering

Chronic pain is a debilitating neurological disorder which affects hundreds of millions of people worldwide. Neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are non-addictive alternatives for managing chronic neuropathic pain that is refractory to conventional medical management. SCS and DRGS apply sequences of brief electrical impulses to neural tissue. However, not all patients receiving these therapies obtain adequate pain relief, and patient outcomes are not improving despite decades of clinical experience and advancements in stimulation technology. This dissertation addresses two crucial knowledge gaps limiting the success of neurostimulation therapies: 1) we do not understand the physiological mechanisms of electrical stimulation-induced pain relief, and 2) we do not understand the sources of variability affecting the neural response to stimulation.

The first portion of this thesis examined the mechanisms of action of DRGS. We developed statistical models of neural element (i.e., cell bodies, axons) locations in histological samples of human dorsal root ganglia (DRG) tissue. Next, we employed a histologically informed field-cable modeling approach to study the neural response to DRGS. We coupled a finite element method model of the potential distribution generated by DRGS to multi-compartment cable models of DRG neurons to simulate which types of sensory neurons are activated by therapeutic DRGS. Our data suggest that clinical DRGS directly activates the subset of sensory neurons that code non-painful touch sensations, which may trigger pain-inhibition neural networks in the spinal cord dorsal horn.

The second portion of this thesis investigated how biological variability at different scales (e.g., single cells, patient anatomy) affected the neural response to stimulation. We implemented a Markov Chain Monte Carlo (MCMC) method to parametrize populations of neurons with heterogeneous ion channel expression profiles. We incorporated this approach in our field-cable model of DRGS and showed that variability in ion channel expression can affect the stimulation amplitude required to generate activity in target neurons. We further applied this population-modeling approach to investigate how pathology induced changes in ion channel expression can affect the behavior of neural circuits governing sensory transmission. Finally, we developed a framework for constructing patient-specific field-cable models of patients receiving SCS. This framework captured the effect of key anatomical details (e.g., the amount of cerebrospinal fluid between a patient’s SCS electrode array and the spinal cord) on neural activation during stimulation. Furthermore, this patient-specific modeling framework allows the comparison of model predictions of neural activation during SCS with clinical data, such as patient-reported outcomes (e.g., pain relief).

The results of this dissertation suggest that DRGS may share mechanisms of action with other neurostimulation therapies for pain management, such as SCS. This dissertation also developed frameworks for studying the effect of biological variability on the nervous system’s response to electrical stimulation. To develop safe and effective therapies for neurological disorders, it is crucial to understand both the physiological mechanisms of symptom relief, and how the neural response to therapy may vary across cells, circuits, and patients. This dissertation provides novel insights on both aspects as they relate to neurostimulation for chronic pain.

Date: Friday, March 25, 2022
Time: 12:00 PM EST
Zoom link: https://umich.zoom.us/j/93382361344 (password: neuron)
Chair: Dr. Scott F. Lempka

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Class / Instruction Tue, 15 Mar 2022 15:42:02 -0400 2022-03-25T12:00:00-04:00 2022-03-25T13:00:00-04:00 North Campus Research Complex Building 10 Biomedical Engineering Class / Instruction BME PhD Defense
Strategies for finding genes in time-dependent human phenotypes: The genetics of delta-t (March 31, 2022 3:30pm) https://events.umich.edu/event/93968 93968-21712968@events.umich.edu Event Begins: Thursday, March 31, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Each person's physiology (phenotype) changes over their lives. While there are common patterns in these changes as we age, there are also significant differences between individuals. Differences in phenotype are dependent on the interaction of the individual's environment and their unique genetic makeup (genotype). What are the genes -- and variants in these genes -- in the human population that impact the variation we see in time-dependent phenotypes? The talk will address the challenges of studying the complexity of human age- and time-dependent (longitudinal) phenotypes. TIme-dependent experimental strategies will require new types of reproducible, non-invasive, quantitative phenotype measurement tools. And, to have a general impact, human measurement technologies should be broadly accessible, particularly to under-served populations. A low-cost, quantitative system for measuring neurological status will be presented as an initial prototype for non-invasive longitudinal phenotype assessment.
Bio:
Dr. Burke is a Professor in the Department of Human Genetics, University of Michigan Medical School. His research centers on developing experimental strategies and technologies for exploring complex, multi-gene genetics in humans. Dr. Burke is interested in understanding the interaction of genetic variation and the environment with chronic, late-life diseases. Before joining the University of Michigan in 1991, he was a post-doctoral fellow in molecular genetics at Princeton University where he studied the laboratory mouse as a model genetic system. Dr. Burke obtained his PhD in the Department of Genetics at Washington University in St. Louis, where he was working on the initial stages of the Human Genome Project. During his time at Michigan, he has worked collaboratively with research groups in the UM College of Engineering, primarily in the area of microfluidics.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Fri, 25 Mar 2022 08:58:52 -0400 2022-03-31T15:30:00-04:00 2022-03-31T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME Seminar
Immunotherapeutic and Diagnostic Potential of Engineered Materials (April 6, 2022 2:00pm) https://events.umich.edu/event/94118 94118-21722028@events.umich.edu Event Begins: Wednesday, April 6, 2022 2:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Globally, breast cancer has the highest rates of incidence and mortality among women. For breast cancer diagnoses, while there is a 99% five-year relative survival rate for localized disease, survival drops to 29% for progression to metastatic disease. And, although robust advances have been made in the treatment of localized breast cancer, few therapies exist to effectively treat metastases. As such, distant spread marks the disease stage where treatment no longer has curative intent, and disease progression leads to mortality. The increased mortality with metastasis motivates the development of diagnostic and therapeutic strategies for managing metastatic disease, and I hypothesize that the microenvironment at the metastatic niche can serve as a target for these strategies.

First, I present a study investigating the utility of cargo-free PLGA nanoparticles (NPs) that, upon intravenous delivery, can be internalized by myeloid cells and subsequently alter their impact on the metastatic niche. We demonstrated that NPs reduce metastatic colonization of the lungs in a murine model of metastatic triple negative breast cancer (mTNBC). The NPs were found to modulate the immune microenvironment of the lungs, skewing myeloid cells toward inflammatory, anti-tumor phenotypes through single cell RNA sequencing. We then found that the reduction of metastatic spread was dependent on mature T-cells. Finally, NPs were administered in a primary tumor (PT) resection model and shown to lead to clearance of established metastatic lesions when delivered as an adjuvant therapy, following surgical resection.

The treatment of TNBC with immune checkpoint blockade (ICB) therapy, a T-cell targeted immunotherapy, has shown robust improvements in patient outcomes. However, while ICB-sensitive patients have durable responses to therapy, no effective biomarkers are available for predicting ICB-response and stratifying ICB-sensitivity from ICB-resistance. Our lab has previously shown that the immune milieu of a microporous PCL implant, which recapitulates key features of the native metastatic niche, can be longitudinally probed for monitoring 1) progression of cancer and 2) response to a PT resection. I investigate the hypothesis that the microporous implant can be longitudinally probed for ICB-response. Divergent responses in TNBC progression, as a result of anti-PD-1 administration, were identified and gene expression at the implant allowed for the ability to monitor ICB-response. Differential lymphocyte and myeloid cell responses were also identified that are correlative of the divergent responses to therapy. Finally, implant-derived gene expressions were probed prior to treatment to investigate predictive analytes for ICB-response before initiating therapy.

Overall, this dissertation demonstrates the potential for applying engineered materials to 1) modulate cancer-associated myeloid cells to enhance anti-tumor T-cell surveillance with the goal of clearing metastatic disease and 2) probe biomarkers to stratify ICB-response and investigate mechanisms underlying therapy resistance.

Date: Wednesday, April 6, 2022
Time: 2:00 PM EST
Zoom: https://umich.zoom.us/j/94478502873
Chair: Professor Lonnie D. Shea

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Presentation Tue, 29 Mar 2022 13:19:30 -0400 2022-04-06T14:00:00-04:00 2022-04-06T15:00:00-04:00 Off Campus Location Biomedical Engineering Presentation BME Ph.D. Defense
Dynamical network models of the epileptic brain to improve surgical outcomes (April 7, 2022 3:30pm) https://events.umich.edu/event/94203 94203-21724114@events.umich.edu Event Begins: Thursday, April 7, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:

Medically-refractory epilepsy (MRE) is a devastating neurological disease that is defined by recurrent and unprovoked seizures that are insufficiently controlled by anti-epileptic medication. If the seizures are originating from a specific region of the brain, surgical removal or stimulation of the epileptogenic region can be an effective therapy for these patients. The accurate localization of the seizure onset zone (SOZ) is critical for surgical success, but localizing the SOZ often requires implantation of intracranial EEG electrodes and continuous monitoring in the hospital for days to weeks so that seizures are recorded. Despite the longevity and invasiveness of this procedure, surgical success rates can be as low as 34%. In this talk, I will describe a study that aims to improve seizure onset localization and expedite the intracranial monitoring process by employing dynamical network models that investigate the patient’s epileptogenic network with recordings obtained during single-pulse electrical stimulation (SPES). We hypothesize that a dynamical quantification of the connectivity networks derived from the evoked responses induced by SPES could also be used to accurately localize the SOZ and guide clinicians in eliciting native seizures with electrical stimulation. I will give an overview of these dynamical network techniques and describe their potential impact in the clinical treatment of medically-refractory epilepsy.

Bio:

Rachel June Smith is a postdoctoral fellow in the Biomedical Engineering Department and Institute for Computational Medicine at Johns Hopkins University. She received her B.S. in Biomedical Engineering from the University of Tennessee, Knoxville, in 2014 and her M.S. and Ph.D. from UC Irvine in Biomedical Engineering in 2019. Her doctoral work focused on the development of computational metrics in scalp EEG data that reflected disease burden and predicted response to treatment in patients with infantile spasms. Currently, Rachel uses dynamical systems and control theory techniques to localize the onset of seizures in the epileptic brain. Rachel has been recently recognized for her work by the American Epilepsy Society where she won a 2020 Young Investigator Award and was named an AES Fellow.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:

Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Wed, 30 Mar 2022 15:27:55 -0400 2022-04-07T15:30:00-04:00 2022-04-07T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME 500 Seminar
Isolation of NK Cell-Derived Extracellular Vesicles Using the Single Cell Droplet Microfluidics CellMag-CARWash System (April 14, 2022 3:00pm) https://events.umich.edu/event/94381 94381-21736328@events.umich.edu Event Begins: Thursday, April 14, 2022 3:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

The Extracellular vesicles (EVs) secreted by cells play a crucial role in intercellular communication by transporting chemical signaling molecules like proteins, lipids, DNA, and RNA through the extracellular environment. The importance of EVs in signaling pathways has only recently been widely recognized, and while many studies investigate EV secretion in bulk cell samples, few studies are published on this occurrence at a single cell level. By examining single cell-derived EVs, variations in the cell populations could be better characterized, demonstrating cellular heterogeneity in populations of cells. Cellular heterogeneity affects the behavior of individual cells in complex cellular networks, which is why novel techniques for single cell isolation are being developed to better characterize individual cell phenotypes. One specific method of sample purification is droplet microfluidics, in which the sample is contained by aqueous droplets suspended in an oil layer that can be manipulated using microfluidics. Benefits of this method include low reagent volume requirements and high throughput.

In my thesis, an experimental workflow for the isolation of single NK cell-derived EVs is presented and optimized. NK cells are cultured, dyed, attached to magnetic beads, encapsulated in an oil droplet at a single cell level, and inputted into the “Coalesce-Attract-Resegment Wash” (CAR-Wash) system developed by the Bailey lab. Using microfluidic junctions and magnetic forces, the CAR-Wash separates NK cell-bead complexes from any other cells or waste in the solution. The droplets are then observed over time to monitor EV secretion. Aspects such as encapsulated cell viability, generation of fluorescent exosomes, and blocking of non-specific binding between EVs and paramagnetic beads are investigated through extensive testing. This is done using techniques such as nanoparticle tracking analysis and fluorescence microscopy. To apply the EV isolation approach described above, NK cells are exposed to IL-18 and their EV secretion is monitored to determine how IL-18 influences EV biogenesis on a single cell level.

DATE: Thursday, April 14, 2022
TIME: 3:00 PM
Zoom: https://umich.zoom.us/j/93165855971 (passcode: bmedefense)
Chair: Prof. Sunitha Nagrath

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Lecture / Discussion Tue, 05 Apr 2022 15:43:11 -0400 2022-04-14T15:00:00-04:00 2022-04-14T16:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Master's Defense
Breaking barriers to drug and cellular delivery for cancer and other diseases (April 14, 2022 3:30pm) https://events.umich.edu/event/94382 94382-21736329@events.umich.edu Event Begins: Thursday, April 14, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
A myriad of challenges plague current efforts toward safe and effective disease treatment. In the realm of small molecule drugs and biologicals, systemic administration leads to diffuse biodistribution and systemic side effects that limit doses and efficacy. Local depot can overcome some of these challenges, but these suffer from depot exhaustion and dose-limiting local impact. With cellular therapeutics, a costly and labor-intensive manufacturing process inflates the price and limits patient access. This seminar will describe our lab’s efforts to tackle the challenges of therapeutic delivery and access through the development of two technologies. First, we have developed injectable drug-eluting depots that can be repeatedly and noninvasively refilled by systemic administration of inert protodrug refills. Refillable depots enable repeat local drug presentation, temporal regulation, and the prospect of changing drug or dose with disease progression. Second, we have developed biomaterial scaffolds that recapitulate the key functions of ex vivo CAR-T cell production (activation, transduction, expansion) inside the body, reducing CAR-T cell manufacturing from the conventional 4-8 weeks of effort to a single day. The application and utility of these technology in both cancer as well as other diseases will be highlighted.
Bio:
Yevgeny is a Joint Assistant Professor in the Department of Biomedical Engineering at UNC – Chapel Hill and NC State – Raleigh. He earned dual B.A. degrees in Chemistry and Biophysics with minors in Math and Philosophy. He obtained his PhD in Organic Chemistry at Harvard University, developing directed evolution technologies with Prof. David R. Liu. Dr. From there, he went on to do a postdoctoral fellowship at the Wyss Institute at Harvard with Prof. David Mooney, developing controlled release drug delivery technologies for cancer and regenerative medicine. He joined UNC/NC State in 2017, with research interests that span organic synthetic chemistry, materials science and pharmacology. Dr. Brudno’s research rooted in the belief that advances in Chemistry and the basic molecular sciences can generate meaningful change in how therapies are designed, produced, and administered. More information about his group’s work can be found at https://pharmaco.bme.unc.edu/.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery

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Workshop / Seminar Tue, 05 Apr 2022 16:09:14 -0400 2022-04-14T15:30:00-04:00 2022-04-14T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Workshop / Seminar BME 500 Seminar
The Promise of Inclusivity in Biosocial Research - Lessons from Population-based Studies (April 18, 2022 12:00pm) https://events.umich.edu/event/92210 92210-21688190@events.umich.edu Event Begins: Monday, April 18, 2022 12:00pm
Location: Off Campus Location
Organized By: Institute for Social Research

Inclusive Research Matters Series
The Promise of Inclusivity in Biosocial Research - Lessons from Population-based Studies
April 18, 2022, noon ET via Zoom

Speakers:
- Jessica Faul, Research Associate Professor, SRC, Institute for Social Research
- Colter Mitchell, Research Associate Professor, SRC, Institute for Social Research

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Lecture / Discussion Thu, 10 Feb 2022 14:42:54 -0500 2022-04-18T12:00:00-04:00 2022-04-18T13:10:00-04:00 Off Campus Location Institute for Social Research Lecture / Discussion flyer
Integration of Extracellular Matrix of Chondrogenic Pellet Cultures with Chondrocyte-Binding Peptide (April 21, 2022 12:00pm) https://events.umich.edu/event/94519 94519-21747487@events.umich.edu Event Begins: Thursday, April 21, 2022 12:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Articular cartilage injuries (ACIs), which predominantly affect about 37% of young high-level athletes and around 40% of adults over the age of 65, consist of acute and intense joint loading causing sharp pain, joint dysfunction, effusion, and a potential progression to joint degeneration. ACIs are characterized by several severities of lesions, namely low-grade or chondral lesions (grades 1-3) that do not fully reach the bone and are characterized by cartilage swelling or partial-thickness loss, and full-thickness or subchondral lesions (grade 4) that do fully reach the bone. Although intrinsic healing is possible in both cases, these injuries collectively disrupt the integration of the cartilage extracellular matrix and consequently interrupt mechanical load distribution throughout the cartilage and joint as a whole. The mechanical mismatch can eventually lead to osteoarthritis, which leads to the progressive loss of cartilage, destruction of the subchondral bone, and deterioration of ligaments, among other damaging effects, as well as a detrimental loss of aggrecan, an important component of cartilage. Current interventions to aid in the repair of cartilage include microfracture,osteochondral autograft transplantation, and autologous chondrocyte implantation. These surgeries can aid in providing improved temporary comfort to the patient and artificial repairs to the site of injury but fail in significantly reintegrating the cartilage extracellular matrix and maintaining the mechanical load distribution present prior to the injury.

Therefore, this project seeks to utilize chondrocyte-binding peptide RLD-RLD to improve extracellular matrix integration at the interface between cartilage. The first part of the study consists of verifying the adsorption of RLD-RLD to ATDC5 chondrogenic cells. These cells were grown in both 2D as a monolayer and 3D as cell pellets, and the adsorption of RLD-RLD and VTK, a peptide previously identified to have a high affinity for apatite, was measured. After ensuring the adsorption of RLD-RLD to ATDC5 cells, 3D ATDC5 pellets were combined after a 7-day culture period and the peptide was added to chondrogenic media for 3- and 7-day periods. Pellets were then sectioned and stained to visualize the integration of ECM at the interface, and a quantitative scoring system was used to characterize the pellets with and without the use of the peptide. Finally, pellets were again grown for a 7-day period and then combined along with RLD-RLD for a 3-day period, and atomic force microscopy was performed on the pellets to determine the mechanical integration strength between the pellets.

Overall, the data demonstrated an increase in integration at the interface between pellets with the chondrocyte-binding peptide compared to the control group with no peptide. These findings can be utilized for future investigation of the use ofRLD-RLD in many cartilage applications, specifically in using a form of this peptide for integration at the cartilage-bone interface, which would be useful for the healing of subchondral lesions. It would also be beneficial to continue these studies in vivo with a mice model to investigate its advantage when applied directly to injured cartilage.

DATE: Thursday, April 21, 2022
TIME: 12:00 PM (Noon)
Zoom: https://umich.zoom.us/j/99821287326 (Passcode: 926901)
Chair: Prof. David Kohn

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Lecture / Discussion Mon, 11 Apr 2022 08:56:53 -0400 2022-04-21T12:00:00-04:00 2022-04-21T13:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Master's Defense
Studying Immunosuppressive Tumor Microenvironments for the application of CAR-T cell therapy in treatment of Metastatic Triple Negative Breast Cancer (April 21, 2022 12:30pm) https://events.umich.edu/event/94645 94645-21753255@events.umich.edu Event Begins: Thursday, April 21, 2022 12:30pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Triple Negative Breast Cancer (TNBC) is a highly aggressive form of breast cancer that makes up approximately 10 - 15 percent of cases. This specific subtype is characterized by the absence of Estrogen Receptors, Progesterone Receptors and Human Epidermal Growth Factor Receptor 2 (HER-2) on its cells. These three receptors are often targeted in commonly used breast cancer treatments and their absence limits treatment options for patients suffering with TNBC. A common treatment regimen for TNBC typically comprises a combination of chemotherapy followed by surgical intervention and radiation. However, this has many systemic side effects and limited efficacy in clearing advanced disease. The five-year survival rate for patients who suffer from a metastatic form of TNBC is 11% - making the prognosis for these patients quite devastating.

Chimeric Antigen Receptor (CAR) T cell therapy is an exciting new development in the field of cancer immunotherapy. T cells are engineered to have a receptor that targets a specific antigen that is commonly expressed on the surface of cancer cells. This therapy has been granted FDA approval largely for the treatment of blood related cancer such as leukemias and lymphomas through targeting the highly expressed CD19 antigen. Currently, work is being done to extend this promising therapy for the treatment of solid tumors (such as TNBC) in order to give people who suffer from this disease an effective alternative treatment. However, this has proven to be quite difficult for several reasons - one of them being the presence of an immunosuppressive tumor microenvironment.

Throughout this body of work, a CD19-expressing 4T1 murine triple negative breast cancer cell line was used as a model system to explore the immunosuppressive microenvironment in metastasizing TNBC and elucidate specific cellular mechanisms that cause suppression of CART therapy. First, T cell proliferation was measured in normal and conditioned media that were made from the primary 4T1 and metastatic 4T1 lung tumors grown in balb/c mice at the Day 7, 14 and 21 timepoints. The cytotoxicity of CD19 positive CAR-T cells was then measured when co-cultured with CD19-expressing 4T1 cells in the conditioned media from the metastatic 4T1 lung tumors. Next, single-cell RNA sequencing was performed on lungs from tumor-bearing mice in order to characterize the metastatic microenvironment and find potential transcription factors and specific cellular pathways that were upregulated. Finally, T cells were transfected with fluorescent transcription factor reporters in order to confirm the activation of specific transcription factors when cultured in the conditioned medias from metastatic 4T1 lung tumors.

As a result of these experiments, the presence of an immunosuppressive microenvironment that is specific to the conditioned media produced from metastatic 4T1 lung tumors at the Day 21 time point was shown. Results obtained also suggested the role of neutrophils in activating the transcription factor STAT3 which in turn upregulates the activity of the pd1/pdl1 pathway and leads to the suppression of T cell function in the metastatic microenvironment of Triple Negative Breast Cancer. Identifying these mechanisms are crucial as they will help improve CAR-T cell therapy and extend their application to the treatment of solid tumors.

DATE: Thursday, April 21, 2022
TIME: 12:30 PM
Zoom: https://umich.zoom.us/j/92806777883
Chair: Prof. Lonnie Shea

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Lecture / Discussion Thu, 14 Apr 2022 14:50:58 -0400 2022-04-21T12:30:00-04:00 2022-04-21T13:30:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Event
Applications of Diffusion Tensor Imaging in Deep Brain Stimulation (April 21, 2022 2:00pm) https://events.umich.edu/event/94518 94518-21747486@events.umich.edu Event Begins: Thursday, April 21, 2022 2:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Deep brain stimulation (DBS) is a neurosurgical procedure that has been commonly used to treat a variety of conditions such as Parkinson’s Disease, Essential Tremor (ET), and epilepsy, among others. Briefly, DBS is a procedure where a surgeon implants electrodes into targeted areas of the brain. Despite being a well-established therapy, DBS has a high revision rate. The most common reason is improper electrode placement, which can be caused by placing the electrodes in a different location than intended or using a suboptimal stimulation site. The research areas associated with finding solutions to these problems are generally referred to as intraoperative localization and pre-operative targeting. In this thesis, Diffusion Tensor Imaging (DTI) data is used to investigate patient-specific approaches to ultimately reduce the revision rate of DBS.

The first study of this thesis explores a novel method of lead localization through both single electrode and dual electrode impedance measurements. First, it provides a theoretical basis for each impedance-based method using real patient data on theoretical trajectories. Second, the study investigates the relationship between DTI data and simulated impedance measurements on hypothetical DBS trajectories. Third, the study shows the potential value of monopolar simulated impedance measurements by evaluating its viability for localization. Lastly, this study shows that real monopolar impedance measured intraoperatively can match simulated impedance profiles. In full, we present the basis for a computationally efficient and patient specific method for intra operative lead localization through DTI-based impedance measurements.

The second study in this thesis retrospectively evaluates the potential of the motor hyperdirect pathway (HDP) as a target for DBS. The motor HDP connects the subthalamic nucleus (STN), a traditional DBS target, directly to the motor regions of the brain. This study uses DTI to create patient-specific models of the motor HDP to determine if it is a viable alternative target for DBS. However, we find that while the study explored several potentially useful applications of DTI for targeting, higher activation of motor HDP fibers was not associated with better patient outcomes.

This thesis presents two methods for improved electrode placement during DBS. The first study provides a foundation for an impedance-based localization scheme that has the potential to be applied not only during STN-targeted DBS (STN-DBS) but across a broad range of other stereotactic neurosurgeries. The second study found that increased motor HDP stimulation did not lead to a statistically significant increase in patient outcomes. However, this study presented a DTI-driven approach to targeting that can be used in future work. It can be used to understand the specific DT properties of targets that have found a statistically significant correlation to patient outcomes but were only conducted using MRI data. This is important as while MRI-based studies can find usable targets, they less explicitly elucidate the mechanism behind why the target was suitable.

DATE: Thursday, April 21, 2022
TIME: 2:00 PM
Zoom: https://umich.zoom.us/j/97612255859 (passcode: 840422)
Chair: Assoc. Prof. Parag Patil

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Lecture / Discussion Mon, 11 Apr 2022 08:52:08 -0400 2022-04-21T14:00:00-04:00 2022-04-21T15:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Master's Defense
Defined Culture Environments Create an Improved Human Intestinal Organoid Model System to Study Intestinal Development (April 28, 2022 3:00pm) https://events.umich.edu/event/94646 94646-21753258@events.umich.edu Event Begins: Thursday, April 28, 2022 3:00pm
Location: Taubman Biomedical Science Research Building
Organized By: Biomedical Engineering

Organoids are small stem cell-derived tissues that mimic some aspects of the structure and function of the organs they are modelled after. Thus, organoids provide a 3D model for studying human development and disease in a complex human-derived in vitro system, and offer advantages over traditionally utilized 2D in vitro cell culture platforms or in vivo animal models. Intestinal organoids have been well characterized and used for over a decade to model intestinal pathologies and advance our understanding of intestinal biology. However, intestinal organoid models have been limited by a reliance on commercial basement membrane extracellular matrix (ECM) products such as Matrigel which introduce experimental variability, limit experimental control, and are unsuitable for downstream clinical applications due to their xenogeneic origin. Additionally, current intestinal organoids are relatively immature and do not contain all of the key cell types found in the human intestine. In particular, a serosal mesothelium, the outermost layer of the intestine that provides a protective boundary for the gut, has not been observed within previous in vitro intestinal models.

In this dissertation, I describe improved culture methods for pluripotent stem cell-derived human intestinal organoids (HIOs) that eliminate reliance on Matrigel and more faithfully recapitulate the organization of the human small intestine. I show that HIOs do not require biochemical support from a 3D ECM matrix as they contain both epithelial and mesenchymal compartments, which enables the formation of a supportive niche within the organoid. Thus, HIOs can be cultured in bioinert environments including unmodified alginate hydrogels and even suspension culture. Alginate and suspension culture provide simple, cost effective culture systems for HIOs that offer increased experimental control and decreased variability compared to Matrigel. I demonstrate that alginate and suspension culture are effective replacements for Matrigel that support the HIO epithelium, as HIOs cultured in alginate and suspension give rise to expected intestinal epithelial cell types.

Additionally, HIOs cultured in bioinert conditions (alginate or suspension) form an organized outer mesenchymal layer that closely resembles the human intestine. Strikingly, HIOs cultured in alginate and suspension form an outer serosal mesothelium that has not been previously observed in Matrigel HIOs. This serosa formation is enhanced in suspension culture compared to alginate. I characterized HIO-serosa to demonstrate that it is molecularly and functionally similar to human intestinal serosal mesothelium. I then utilized suspension HIOs as a model to investigate serosal development and identified roles for HH and WNT signaling in human intestinal serosa formation and patterning. Overall, this work provides improved, defined culture methods for human intestinal organoids that better recapitulate the native intestine for enhanced studies of intestinal development and disease modelling.

Date: Thursday, April 28, 2022
Time: 3:00 PM EST
Location: BSRB Kahn Auditorium
Chair: Professor Jason R. Spence

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Lecture / Discussion Thu, 14 Apr 2022 14:55:51 -0400 2022-04-28T15:00:00-04:00 2022-04-28T16:00:00-04:00 Taubman Biomedical Science Research Building Biomedical Engineering Lecture / Discussion BME PhD Defense
A Multicellular, Biomaterial-based Platform for the Engineering of Vascularized Bone (May 9, 2022 11:00am) https://events.umich.edu/event/94843 94843-21776805@events.umich.edu Event Begins: Monday, May 9, 2022 11:00am
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Cell-based tissue engineering offers the potential to greatly improve the treatment of large and complex bone defects by addressing the main shortcomings associated with current bone grafting procedures. A main challenge is the ischemic environment that can result from traumatic bone injury, resulting in the death of transplanted cells and tissue constructs. Achieving an adequate vascular supply is a critical barrier preventing the translational success of cell-based regeneration approaches. Therefore, a variety of strategies have been developed to prevascularize engineered tissue constructs prior to transplantation. Adult mesenchymal stromal cells (MSC) and endothelial cells (EC) are key players in native orthopaedic tissue regeneration and vascularization, and represent promising cell types for tissue engineering strategies to create vascularized bone. However, to effectively harness the regenerative potential of MSC, the appropriate phenotype must be achieved before implantation. A main challenge in engineering vascularized bone tissue is creating an appropriate culture environment to support multiple cell phenotypes. Therefore, this work focuses on designing a cell-based, biomaterial-enabled strategy that provides spatiotemporal control of key microenvironmental cues to support the co-development of osseous and vascular tissues, with the end goal of generating vascularized, bone-forming constructs.

First, this thesis explores how temporal control of the culture environment can be used to maintain preformed vessels and subsequent osteogenic development in engineered tissue constructs. To mimic the sequential process of native bone development, in which vascularization precedes tissue ossification, we generated cell-laden hydrogel constructs cultured in vasculogenic growth medium to induce vessel development, and subsequently supplemented the medium with osteoinductive components to promote osteogenic differentiation. Our results revealed conflicting effects of the two culture environments, in which osteoinductive factors compromised cellular viability and MSC pericyte-like function, leading to ~93% regression of preformed vessels. Further, vasculogenic culture conditions inhibited MSC-mediated matrix mineralization as evidenced by impaired calcium deposition.

Next, this thesis describes the development and characterization of a modular biomaterial approach that provides control of discrete environmental properties designed to promote vasculogenic and osteogenic tissue development. Separate populations of cell-laden microtissues were fabricated and independently cultured under specific differentiation conditions to support either osteogenic or pericyte-like lineage commitment of MSC. This approach enabled the formation of primitive osteogenic microtissues exhibiting mineralization of the extracellular matrix, and vascular microtissues with demonstrated EC sprouting potential. The combination of microtissues led to the generation of a multiphase construct that supported extensive vessel development. While osteogenic activity was maintained without exogenous osteoinductive factors, the vasculogenic culture environment was not conducive for sustained mineralization.

Lastly, this thesis describes a novel approach incorporating the modular biomaterial platform with a biomimetic induction process emulating the native endochondral ossification (EO) pathway to better couple vascular and osteogenic tissue development. Chondrogenically-primed MSC were matured to hypertrophy to form hypertrophic pellets resembling EO, as evidenced by MMP-mediated remodeling and mineralization of the formed cartilaginous matrix. Hypertrophic induction of MSC was associated with secretion of distinct angiogenic factors which stimulated EC vasculogenesis. When combined with vasculogenic microtissues, hypertrophic pellets supported robust vessel development and cell-mediated mineralization without exogenous vasculogenic medium or osteoinductive components.

Overall, this dissertation presents an attractive strategy for generating vascularized bone-like tissue. By integrating the modular biomaterial platform with an EO-based induction process, we successfully leveraged physiologic cues of hypertrophic MSC to achieve concomitant vasculogenic and osteogenic development.

Date: Monday, May 9, 2022
Time: 11:00 AM
Location: 1130 LBME and Zoom (https://umich.zoom.us/j/96133803682 Passcode: bones)
Chair: Dr. Jan Stegemann

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Presentation Wed, 27 Apr 2022 14:28:01 -0400 2022-05-09T11:00:00-04:00 2022-05-09T12:00:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Presentation BME PhD Defense
Scalable online modeling and perturbations for adaptive neuroscience experiments (May 12, 2022 3:30pm) https://events.umich.edu/event/95066 95066-21788408@events.umich.edu Event Begins: Thursday, May 12, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Systems neuroscience is increasingly able to leverage new recording tools and statistical analyses to describe the coordinated activity of large neuronal populations, even entire brains. Combined with precise stimulation technologies, we could begin to dissect large-scale circuits in vivo, constructing models that causally relate neural activity to behavior. Perturbative testing of hypothesized brain-behavior links, however, requires statistically efficient methods for both estimating and intervening on population-level neural dynamics in real time. To build neural models online, we describe a new machine learning method that combines fast, stable dimensionality reduction with a soft tiling of the resulting neural manifold, allowing dynamics to be approximated as a probability flow between tiles. This method can be fit efficiently, scales to large populations, and outperforms existing methods when dynamics are noise-dominated or feature multi-modal transition probabilities. Using online modeling, we can also ‘close the loop’ by selecting optimal circuit interventions to create maps of causal influence within large networks. Our algorithm uses online convex optimization and adaptive stimulation selection to quickly infer the binary network connectivity, rendering the inference of networks of tens of thousands of neurons in vivo feasible in a single experiment. We additionally present a neural response optimization method with multi-output Gaussian processes that uses active stimulus selection to acquire data at locations where models are likeliest to be wrong given the data seen so far. These methods, which combine online neural modeling with adaptive intervention, open the door to automated, theory-driven circuit dissection at scale, providing a powerful new means of interrogating neural function.

Bio:
Dr. Anne Draelos is a Postdoctoral Associate in the Pearson Lab at Duke University focused on machine learning and statistical techniques to facilitate real-time analysis of high-dimensional neural and behavioral data. She is currently a Swartz Foundation Fellow for Theory in Neuroscience and received a 2021 Career Awards at the Scientific Interface from the Burroughs Wellcome Fund.

Zoom Link: https://umich.zoom.us/j/91252848761?pwd=MkpCaDRHcjlRRWxuUzFEakQyM1RYUT09

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Lecture / Discussion Tue, 10 May 2022 10:07:27 -0400 2022-05-12T15:30:00-04:00 2022-05-12T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Lecture / Discussion BME Seminar Event
Glenn V. Edmonson Lecture & 2022 Biomedical Engineering Symposium (May 18, 2022 10:00am) https://events.umich.edu/event/94970 94970-21788170@events.umich.edu Event Begins: Wednesday, May 18, 2022 10:00am
Location: Palmer Commons
Organized By: Biomedical Engineering

The Inaugural Glenn V. Edmonson Lecture and 2022 Biomedical Engineering Symposium are intended to build the BME community across campus and honor the legacy of the first graduate chair of the Biomedical Engineering program. These events will provide a forum for BME faculty and students campus-wide along with our collaborators to present current research progress and discuss future research opportunities at the interface of engineering and medicine.

The events will take place on Wednesday, May 18th, from 10:00 AM - 5:00 PM at Palmer Commons (4th Floor). Please RSVP by Friday, May 6th, 2022.

RSVP Link: https://forms.gle/QB7kS8UnQftWrZaX9

Schedule:
10:00 AM - 10:15 AM Welcome and Introduction from BME Interim Chair, Mary-Ann Mycek Ph.D., and Symposium Chairs, Rhima Coleman, Ph.D., and Tim Bruns, Ph.D.

10:15 AM - 11:05 AM Cell and In vitro
Sue Brooks Herzog, Ph.D.
Sherman Fan, Ph.D.
Geeta Mehta, Ph.D.

11:05 AM - 11:15 AM Break

11:15 AM - 12:05 PM In Vivo
Jiande Chen, Ph.D.
Megan Killian, Ph.D.
Cindy Chestek, Ph.D.

12:05 PM - 1:00 PM LUNCH BREAK - with Poster Viewing

1:00 PM - 1:50 PM Computational
Indika Rajapakse, Ph.D.
David Nordsletten, Ph.D.
Ellen Arruda, Ph.D.

1:50 PM - 2:00 PM Break

2:00 PM - 2:50 PM Clinical / Human Subjects
Susan Shore, Ph.D.
Jon-Fredrik Nielsen, Ph.D.
David Zopf, M.D., M.S.

2:50 PM - 3:00 PM Break

3:00 PM – 4:15 PM Glenn V. Edmonson Lecture
Paul Cederna, M.D. FACS

4:15 PM - 5:00 PM POSTER SESSION and Reception

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Conference / Symposium Wed, 04 May 2022 14:01:07 -0400 2022-05-18T10:00:00-04:00 2022-05-18T17:00:00-04:00 Palmer Commons Biomedical Engineering Conference / Symposium BME Symposium
Tissue Engineering and Regenerative Medicine Approaches to Study Fat-Cartilage Crosstalk (May 19, 2022 3:00pm) https://events.umich.edu/event/95137 95137-21788505@events.umich.edu Event Begins: Thursday, May 19, 2022 3:00pm
Location: Taubman Library
Organized By: Regenerative Medicine Biosciences Initiative

Dr. Collins received her PhD in Biomedical Engineering in 2017 in Dr. Walter Herzog’s lab at the University of Calgary on diet-induced obesity in a rat model of osteoarthritis. As a Postdoctoral Research Scholar in the Guilak Laboratory at Washington University in St. Louis, Kelsey has created a niche in adipose-cartilage signaling, stem-cell biology, synthetic biology, and drug delivery to evaluate systemic contributors and novel therapeutic strategies in osteoarthritis and rheumatoid arthritis.

This is a hybrid event, in-person at Taubman Library 2901, and also available via Zoom.

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Workshop / Seminar Fri, 13 May 2022 11:56:20 -0400 2022-05-19T15:00:00-04:00 2022-05-19T16:30:00-04:00 Taubman Library Regenerative Medicine Biosciences Initiative Workshop / Seminar Dr. Kelsey Collins
Tissue Engineering and Regenerative Medicine Approaches to Study Fat-Cartilage Crosstalk (May 19, 2022 3:00pm) https://events.umich.edu/event/95137 95137-21788506@events.umich.edu Event Begins: Thursday, May 19, 2022 3:00pm
Location: Off Campus Location
Organized By: Regenerative Medicine Biosciences Initiative

Dr. Collins received her PhD in Biomedical Engineering in 2017 in Dr. Walter Herzog’s lab at the University of Calgary on diet-induced obesity in a rat model of osteoarthritis. As a Postdoctoral Research Scholar in the Guilak Laboratory at Washington University in St. Louis, Kelsey has created a niche in adipose-cartilage signaling, stem-cell biology, synthetic biology, and drug delivery to evaluate systemic contributors and novel therapeutic strategies in osteoarthritis and rheumatoid arthritis.

This is a hybrid event, in-person at Taubman Library 2901, and also available via Zoom.

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Workshop / Seminar Fri, 13 May 2022 11:56:20 -0400 2022-05-19T15:00:00-04:00 2022-05-19T16:30:00-04:00 Off Campus Location Regenerative Medicine Biosciences Initiative Workshop / Seminar Dr. Kelsey Collins
Bone Marrow Stromal Cells Regulate Functional States of ER+ Breast Cancer Cells (May 25, 2022 1:00pm) https://events.umich.edu/event/94936 94936-21786532@events.umich.edu Event Begins: Wednesday, May 25, 2022 1:00pm
Location: Off Campus Location
Organized By: Biomedical Engineering

Even with targeted therapies, patients with the most common subtype of breast cancer, estrogen-receptor-positive (ER+) disease, face an ongoing, progressively increasing risk of metastases. ER+ breast cancer predominantly metastasizes to bone marrow (~70% of patients with advanced disease). Current hormone therapies frequently suppress, but fail to eliminate, both proliferating and quiescent breast cancer cells in bone marrow. While drug resistance may arise from cancer-cell intrinsic mechanisms, studies implicate interactions between ER+ breast cancer cells and bone marrow mesenchymal stromal cells (MSCs) as a pivotal cause of resistance to hormone therapies and transitions to CSC states. This dissertation focuses on elucidating targetable mechanisms for MSC-induced increases in cancer cell plasticity and resistance to antiestrogenic therapy.

This work began showing that direct co-culture with MSCs induces resistance to antiestrogenic therapy in ER+ breast cancer cells, in part through increases in intracellular iron. Combining iron chelators or novel lysosomal iron-targeting compounds with clinical antiestrogenic therapy reduced resistance of cancer cells to therapy. Next, we showed that co-culture with MSCs increased oxidative metabolism, intracellular ATP, glucose, and metabolic plasticity in ER+ breast cancer cells treated with antiestrogenic therapy, including under conditions of nutrient stress. We successfully limited metabolic plasticity, heterogeneous treatment responses, and drug resistance by inhibiting monocarboxylate transporters. Finally, we utilized a physiologically-relevant 3D co-culture model with MSCs that successfully recapitulated slow proliferation, signaling, and metabolic profiles of disseminated ER+ breast cancer cells. Simultaneous treatment with inhibitors of Akt and thioredoxin reductase effectively reduced cancer burden versus antiestrogenic therapy in both in vitro and in vivo models. By exploiting adaptations of ER+ breast cancer cells to the stromal microenvironment, we identified multiple clinically-actionable approaches to overcome stromal-mediated drug resistance, paving the way toward more effective treatments against bone marrow metastases.

Date: Wednesday May 25, 2022
Time: 1:00 PM
Zoom: https://umich.zoom.us/j/96774775771
Chair: Dr. Gary Luker

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Presentation Tue, 03 May 2022 08:39:58 -0400 2022-05-25T13:00:00-04:00 2022-05-25T14:00:00-04:00 Off Campus Location Biomedical Engineering Presentation BME PhD Defense
“Genetic regulation of epithelial homeostasis and injury” (June 7, 2022 4:00pm) https://events.umich.edu/event/95318 95318-21789154@events.umich.edu Event Begins: Tuesday, June 7, 2022 4:00pm
Location:
Organized By: Center for Cell Plasticity and Organ Design

The NIH T32 Training Program in Organogenesis trainees are please to present a Special Series, "Building and Rebuilding: Regulation of Cell Signaling in Development and Regeneration," featuring guest speaker, Adam D. Gracz, PhD.

Dr. Gracz is an Assistant Professor of Medicine-Division of Digestive Disease at Emory University.

The talk is entitled, “Genetic regulation of epithelial homeostasis
and injury.”

Trainee Host
Megan Radyk, PhD-Lyssiotis & Shah Labs

For more information email: Organogenesis@umich.edu

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Lecture / Discussion Thu, 26 May 2022 10:58:57 -0400 2022-06-07T16:00:00-04:00 2022-06-07T17:00:00-04:00 Center for Cell Plasticity and Organ Design Lecture / Discussion Gracz flyer
BME PhD Defense: Feiran Li (June 13, 2022 12:00pm) https://events.umich.edu/event/95461 95461-21789961@events.umich.edu Event Begins: Monday, June 13, 2022 12:00pm
Location: North Campus Research Complex Building 520
Organized By: Biomedical Engineering

Cell-based therapies are emerging for Type I diabetes mellitus (T1D), an autoimmune disease characterized by the destruction of insulin producing pancreatic β-cells, as a means to provide long term restoration of glycemic control. The limited supply of donor islets has motivated research into methods for differentiating pancreatic β-cells from renewable pluripotent stem cells such as human pluripotent stem cells (hPSCs). Biomaterial scaffolds maintain the integrity of cell-to-cell and cell-to-matrix connections by avoiding the disruption of the cell niche during handling. This dissertation addresses three key questions with respect to cell therapy and immunomodulation for T1D, including culture system on porous PLG scaffold, functionalized scaffold for improved cell viability and maturation, and immunomodulation with the membrane coated nanoparticles (MCNPs).

Culture on porous biomaterial scaffolds of hPSCs was investigated at multiple stages of differentiation between Stage 0 and 6 for improved differentiation. Scaffolds are biomaterial devices that could provide chemical and physical cues to control the microenvironment and subsequently alter cellular behavior by facilitating cell-cell interactions. The culture of cells on the scaffolds was found to support maturation of SC derived beta cells depending on the stage of seeding. Suspension cultured-pancreatic progenitors seeded onto scaffolds for stage 5 culture (pancreatic endocrine development), demonstrated enhanced expression for many maturation genes compared to cells that remained in suspension culture through the end of stage 6. This study showcased the scaffold culture as a promising platform for maturation that allows cells to develop a niche and may allow for direct transplantation without manipulating cells.

Early engraftment and development of β-cells post transplantation are a major limitation for stem cell derived beta cells due in part to their being immature. The survival and development of hPSC-derived β-cells seeded onto PLG microporous scaffolds were investigated within the initial 2 weeks post transplantation. Early inflammatory events induced by the biomaterial and transplanted cells heavily affected hPSC-derived β-cell engraftment due to the innate immune response. The inflammation includes the production of soluble mediators, inflammatory cytokines and the recruitment of innate cells at the graft site, hindering early graft engraftment and in-vivo hPSC-derived β-cell maturation. The PLG-based biodegradable scaffold chemically linked with a novel form of FasL chimeric with streptavidin, SA-FasL, was applied to create an immunoprivileged transplant site by modulating the local inflammatory microenvironment. The β-cell viability and differentiation were found improved at the SA-FasL induced immunoprivileged site together with a suppressed inflammatory reaction.

Life-long systemic immune suppression due to allogenic graft/cell transplant also limits the translation of cell therapies for T1D. We investigated the design of membrane-coated nanoparticles (MCNPs), with membranes derived from bone marrow-derived dendritic cells and coated onto poly(lactic-co-glycolic acid) (PLGA) nanoparticle cores, to directly interact with both naïve and activated T cells. Mechanistic studies revealed that the developed MCNPs have the capability to communicate with allogenic T cells by modulating the cytokine secretion levels similar to professional antigen presenting cells. Furthermore, the MCNPs can be engineered pre- and post-fabrication for upregulated surface molecules or varied antigen binding and can be functionalized by biotinylation for a wider range of protein loading.

Overall, this dissertation discussed optimization and early immunomodulation of the biomaterial culturing system for hPSC-derived β cells, and development of tunable MCNPs for direct T cell communication.

Date: Monday, June 13, 2022
Time: 12:00 PM
Location: NCRC Building 520 Room 1122 and Zoom (https://umich.zoom.us/j/93840656651)
Chair: Dr. Lonnie Shea

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Lecture / Discussion Tue, 07 Jun 2022 09:22:42 -0400 2022-06-13T12:00:00-04:00 2022-06-13T13:00:00-04:00 North Campus Research Complex Building 520 Biomedical Engineering Lecture / Discussion BME Defense
Understanding and engineering microbes for solving complex problems in biology and medicine (June 16, 2022 3:30pm) https://events.umich.edu/event/95526 95526-21790074@events.umich.edu Event Begins: Thursday, June 16, 2022 3:30pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:

The microbiome represents an exciting frontier in medicine, and early successes in the field have demonstrated the dynamic interactions among individual microbial species and highlighted the crosstalk between microbiota and their hosts at the mucosal interface.  The Li research group in the Department of Bioengineering at Northeastern University focuses on the development of molecular and live cell-based therapeutics, with a major emphasis on harnessing innovative synthetic biology and drug delivery approaches for improving human health in a sustainable manner. In this talk, I will present our work from the past three years in interrogating and manipulating commensal bacteria and probiotics as therapeutic platforms to promote human health.

Bio:

Jiahe Li obtained his PhD in Biomedical Engineering at Cornell University in 2015, where he leveraged synthetic biology approaches and cell biology to engineer bacteria and platelets as platforms for treating metastatic cancer. Later, he pursued his postdoctoral training at the Koch Institute for Integrative Cancer Research at MIT from 2015-2018, where he gained complementary expertise in polymer science and gene delivery. He started a tenure-track faculty position in the Department of Bioengineering at Northeastern University in 2019, and his current research is supported by NIH, DoD, and various biotech companies.

Zoom Link: https://umich.zoom.us/j/97247012805

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Lecture / Discussion Thu, 09 Jun 2022 15:34:33 -0400 2022-06-16T15:30:00-04:00 2022-06-16T16:30:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Lecture / Discussion BME Seminar
Discovery and Development of Agonist Antibodies for T Cell Receptors (July 29, 2022 10:00am) https://events.umich.edu/event/96254 96254-21792188@events.umich.edu Event Begins: Friday, July 29, 2022 10:00am
Location: Off Campus Location
Organized By: Biomedical Engineering

Agonist antibodies that activate co-stimulatory immune receptors, such as the tumor necrosis factor (TNF) receptors OX40 and CD137, are an important class of emerging therapeutics due to their ability to regulate immune cell activity. Despite their promise, there are no approved agonist antibodies for treating cancer as demonstrated by previous unsuccessful clinical trials. Although multiple factors are responsible for poor clinical efficacy, one major bottleneck is the reliance on FcγR-mediated crosslinking for sufficient receptor activation. This is inherently problematic because FcγR expression varies greatly on different immune cells, leading to a wide range of receptor agonism. Emerging research suggests that antibodies engaging two different epitopes on the same immune receptor mediate receptor superclustering and enable robust antibody agonism without extrinsic Fc crosslinking. However, there are no systematic methods for identifying such biepitopic (also known as biparatopic) agonist antibodies. Therefore, the objective of this research work is to develop facile methods for reliably identifying biepitopic antibodies to activate immune receptors for immunotherapeutic applications.

Biepitopic antibodies have been shown to mediate potent receptor activation for a variety of immune receptors. Traditionally, the generation of these antibodies requires key steps including animal immunization, epitope binning to identify unique antibody pairs, and combining antibody pairs to engineer biepitopic antibodies. While this approach has been used to successfully discover biepitopic antibodies, it suffers from key limitations. Notably, animal immunization and subsequent antibody isolation is an arduous and unpredictable process. Even when successful clones are discovered from these processes, further epitope binning experiments are needed to select antibody pairs to discover potent immune therapeutics. To overcome these limitations, we developed an antibody screening strategy that greatly simplifies the discovery of biepitopic antibodies. Our approach eliminates the need for animal immunization by using existing, off-the-shelf IgG antibodies specific to the target receptor. Next, we perform in vitro selections by blocking the receptor epitope of the existing antibody and conducting subsequent sorts to identify single-chain antibodies with orthogonal binding domains. Thus far, our work has shown that the antibody screening strategy can be used to discover antibodies for a variety of TNF receptors including OX40 and CD137.

Given that receptor clustering of three or more receptors is critical for activating TNF receptors, we first generated biepitopic tetravalent OX40 antibodies by attaching novel single-chain antibodies to the C-termini of the light chain of existing clinical-stage antibodies. These tetravalent biepitopic antibodies showed remarkable T cell proliferation and cytokine secretion for biepitopic antibodies compared to their monoepitopic counterparts. Next, we sought to improve the additional clinical-stage OX40 IgGs engineered as biepitopic antibodies to show the generality of our findings that biepitopic antibodies can mediate superior and FcγR-independent activities. Beyond OX40 IgGs, we also show that biepitopic antibodies can be used to mediate superior T cell proliferation for other TNF receptors including CD137. Looking forward, we anticipate that these research advancements will accelerate the discovery and development of the next generation of immune therapeutics.

Date: Friday, July 29, 2022
Time: 10:00 AM
Zoom: https://umich.zoom.us/j/5163583658
Co-Chairs: Professors Peter Tessier and Lonnie Shea

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Lecture / Discussion Tue, 26 Jul 2022 13:09:39 -0400 2022-07-29T10:00:00-04:00 2022-07-29T11:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Ph.D. Defense
Hierarchical motion modeling of abdominal motions for radiation therapy (August 9, 2022 10:00am) https://events.umich.edu/event/96536 96536-21792631@events.umich.edu Event Begins: Tuesday, August 9, 2022 10:00am
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:

Human abdominal organs are subject to a variety of physiological forces that superimpose their effects to influence local motion and configuration. Motions include breathing, gastric contraction, and other types of less periodic slow configuration changes. Breathing motion has been extensively studied and well characterized; however, gastric contraction and slow configuration motion have been rarely investigated. By using a golden angle stack-of-star radial sampling magnetic resonance image (MRI) sequence, we constructed a hierarchical motion model that characterizes each of these three motions, as well as their combined effects. Breathing motion is extracted and corrected as the first step, following by reconstruction of gastric motion and slow configuration changes. The model shows non-neglectable geometric displacements raised by all three motion modes. These motions, if not managed properly during radiation therapy, may potentially result in overdose to normal tissue or underdosage to the tumor target. Magnetic resonance guided radiotherapy (MRgRT) systems have been developed which have the technical capability to address these complex motions, but to date their primary applications have been relegated to management of breathing motion. In this dissertation, we proposed a gastric motion prediction framework to allow real-time management of contractile motion during MRgRT taking advantage of the intra-scan stability of gastric contraction motion observed in patients under standard pre-session eating restrictions. The framework was able to achieve submillimeter prediction error with a sufficient future prediction time to overcome the latency introduced by the image sampling reconstruction, motion assessment and treatment interruption or modification on MR-guided linear accelerators. Motions and deformations during radiation treatment present a challenge to precisely and accurately measure the radiation dose delivered to abdominal organs. A dose accumulation tool, developed based on the hierarchical motion model, was built to estimate dose distributions with abdominal motions. The tool demonstrates potential deviations of dose due to motion and shows exceeding of dose constraints in certain cases. It could support offline adaptation or help record delivered dose more accurately than stationary images used for daily patient positioning and/or online adaptation of treatment plans. The motion model is also currently supporting other clinical applications, including providing improved image quality reconstructions from free-breathing scans for improvement of accuracy of perfusion as well as liver functional maps. In the future, the model can be further utilized in other fields including radiology or gastroenterology.  

Room: LBME 2185 / Zoom Link: https://umich.zoom.us/j/93620134849 Meeting ID: 936 2013 4849 Passcode: 268890

Committee Chair(s): Dr. James Balter and Dr. Rojano Kashani

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Lecture / Discussion Fri, 05 Aug 2022 10:05:16 -0400 2022-08-09T10:00:00-04:00 2022-08-09T11:00:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Lecture / Discussion BME Defense
Effects of Electric Stimulation on Physiology and Anatomy of the Visual Pathway (August 10, 2022 12:00pm) https://events.umich.edu/event/96539 96539-21792637@events.umich.edu Event Begins: Wednesday, August 10, 2022 12:00pm
Location:
Organized By: Biomedical Engineering

Abstract:
Retinal degenerative diseases that progressively lead to severe blindness impact the affected individual’s quality-of-life. Visual prosthesis technology aims to provide an individual a potential means of obtaining visual information lost to them by blindness. Since the proof-of-concept success in 1968 of a device implanted in a human, visual prostheses have had sustained academic research and commercial interest. However, commercial failure of two retinal prosthesis device has raised concerns for the visual prosthesis field. To learn from this experience, research in this dissertation is aimed at understanding the impact of electric stimulation on the target neural tissue and investigating technology for a visual cortex prosthesis, which can reach a larger patient population (compared to a retinal prosthesis).

My first set of experiments assessed, in an animal model of retinal degeneration, the condition of the brain and its ability to receive artificial vision information. Retinitis Pigmentosa has been proven to impact the human brain. My study investigated the extent to which this was replicated in a rat animal model of a single genetic mutation of Retinitis Pigmentosa. The P23H-1 rat was investigated with electrophysiology and immunohistochemistry to understand the brain’s function and structural condition. The rat brain’s response to light and electric stimulation was investigated, and the change of visually evoked responses and maintenance of electrically evoked responses was observed. Histology images show a relatively stable macrostructure of the blind rat brain.

I also performed retinal and cortical implant procedures to test newly developed visual prosthesis technology to enable investigations into researching neural change occurring from blindness and electric stimulation. A retinal device with Parylene-C as its main component was tested and its feasibility in the small eye of a rat animal model was investigated. The device can survive 4-weeks of implantation and is stable within the eye. In support of the development of a novel cortical visual prosthesis device that fits the need of blind individuals, I used a small animal model first to prove the efficacy and safety of a novel neurostimulation electrode. The device, named StiMote, is in preclinical development. I worked to characterize the full ability of the neural interface, High-Density Carbon Fibers with electrodeposited Platinum-Iridium. The ability of PtIr-HDCF as a recording and stimulation neural interface device was verified using electrochemical measurements before, during, and after a long-duration 7-hour electric stimulation session that simulates a full day of device use.

PtIr-HDCF as a neural interface device was verified by my previous work and its improvement in reducing neuroinflammatory response compared to other microelectrode array archetypes has been previously researched. As a result, PtIr-HDCF can be used as a device to monitor the brain and can better extract the effect of electric stimulation on the brain alone. I recorded neural electrophysiology to verify the rat brain’s sensitivity to stimuli before and after 7-hour stimulation. To supplement the already existing neural implant and electric stimulation inflammation data, Spatial Transcriptomics as a novel method to define electric stimulation safety was performed. Spatial Transcriptomics showed that PtIr-HDCF, when compared to a conventional microwire array, performs better in sustaining neural health by reducing neuroinflammation and eliciting mRNA upregulation of neurotrophic factors.

Findings of this project can be used to better inform future investigations into brain electrophysiology and transcriptomics projects aimed to understand the neural change from blindness and electric stimulation.

Committee Chair(s): Dr. James Weiland

Location: 1501 Auditorium, NCRC Bldg 32 & https://umich.zoom.us/j/91500987159?pwd=RWIvQkZVT2FHZjQ2S1BBS2k0ck1SUT09

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Lecture / Discussion Fri, 05 Aug 2022 10:32:21 -0400 2022-08-10T12:00:00-04:00 2022-08-10T13:00:00-04:00 Biomedical Engineering Lecture / Discussion BME Defense
Data-driven Methods for Automated Assessment of Coronary Artery Disease (August 30, 2022 9:00am) https://events.umich.edu/event/97256 97256-21794237@events.umich.edu Event Begins: Tuesday, August 30, 2022 9:00am
Location: Lurie Robert H. Engin. Ctr
Organized By: Biomedical Engineering

Abstract:

The current gold standard for Coronary Artery Disease (CAD) diagnosis is X-ray angiography. Visual estimation can be subjective, therefore semi-automated software tools such as Quantitative Coronary Angiography (QCA) have been developed to quantify disease severity. Alternatively, functional metrics such as Fractional Flow Reserve (FFR) have demonstrated better diagnostic outcomes than anatomical assessment, but they are not widely used due to cost and risk. Ideally, quantitative and functional information could be derived directly from X-ray angiography images without the additional risks, time, and cost associated with performing FFR or QCA.

The goal of this project is to develop automated data-driven approaches for anatomical and functional quantification of disease severity using X-ray angiography images. To this end, we have developed algorithms for 1) automated coronary vessel segmentation, 2) stenosis detection and characterization, 3) 3D reconstruction of coronary anatomy, and 4) image-based flow extraction. These algorithms can be used in conjunction with computational fluid dynamics (CFD) modeling to assess the functional significance of disease.

We first present AngioNet, a neural network for coronary segmentation from X-ray angiography images. Conventional algorithms relying on thresholding or filtering cannot distinguish between the coronary vessels and the catheter used to inject the dye. AngioNet’s key innovation is an Angiographic Processing Network, or APN, which learns the best possible combination of pre-processing filters to improve segmentation performance. AngioNet demonstrates state-of-the-art segmentation accuracy (Dice score = 0.864) and does not segment the catheter in challenging cases where other neural networks fail.

Building upon AngioNet, we developed combination of neural networks and image processing algorithms to automatically localize, segment, and measure stenoses. This pipeline was able to measure stenosis diameter within 0.206±0.155mm or approximately 1 pixel of ground truth measurements from QCA. It is also the first automated pipeline to quantify rather than categorize disease severity.

Although measuring stenosis diameter in 2D images is useful, a more robust approach would be to measure diameters in the 3D coronary anatomy. Another advantage of the 3D coronary anatomy is that it can be used to perform CFD simulations of blood flow and compute functional metrics such as FFR. To this end, we developed a machine learning approach for automated 3D vessel reconstruction from a series of uncalibrated 2D X-ray angiography images. This approach is superior to projective geometry methods for 3D reconstruction due to their semi-automatic nature and reliance on accurate knowledge of input image acquisition angles. Our machine learning approach has demonstrated sub-pixel error in radius reconstruction (0.16±0.07mm) and 1% error in FFR computed in a reconstructed coronary tree.

In addition to the 3D coronary geometry, information about patient-specific flow or pressure is required to perform a hemodynamics simulation and compute FFR. We developed an algorithm that tracks vessel area in sequential frames of a segmented angiography series to estimate relative flow in each branch. We validated the algorithm in the simplest possible case, using a simulation of dye transport under steady flow conditions as the ground truth. On average, the difference in relative flow per branch was 5.15% for a healthy coronary tree and 3.68% in a coronary tree with stenosis.

We finally demonstrated the successes and limitations of the methods developed in this thesis by comparing computational FFR derived using the above algorithms against clinically measured FFR. The error between the calculated and clinically measured FFR was 0.1, corresponding to an 11% error.

Committee Chair(s):
Dr. C. Alberto Figueroa and Dr. Brahmajee K. Nallamothu

Zoom Link: https://umich.zoom.us/j/94364657250, Passcode: 390041 *Registration is required

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Workshop / Seminar Mon, 22 Aug 2022 16:54:04 -0400 2022-08-30T09:00:00-04:00 2022-08-30T10:00:00-04:00 Lurie Robert H. Engin. Ctr Biomedical Engineering Workshop / Seminar BME Defense Announcement
A Novel Bioelastomer Platform with Tailorable Design Parameters for Cartilage Regeneration (August 30, 2022 11:00am) https://events.umich.edu/event/97426 97426-21794553@events.umich.edu Event Begins: Tuesday, August 30, 2022 11:00am
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:

Articular cartilage has limited ability to self-repair, which often causes focal defects to progress into post traumatic osteoarthritis. Autologous chondrocyte implantation, a process in which chondrocytes are harvested from the patient, expanded in monolayer culture, and injected into the defect site, is one of the most common approaches to treat cartilage defect. However, chondrocyte dedifferentiation during this process reduces their ability to durably restore cartilage function. Chondrocyte-based cartilage tissue engineering offers alternative approaches for cartilage repair to overcome the limitations of current clinical options by developing environments that combines cues from synthetic scaffold and biological factors to enhance chondrocyte function. However, the translation to the clinic has been limited by our incomplete understanding of how scaffold design parameters interact together to control cell function. Therefore, this dissertation focuses on designing a chondrocyte-based biomaterial platform made with a novel elastomeric synthetic scaffold, poly(glycerol dodecanedioate) (PGD), to investigate the combinatory effects of design parameters on chondrocytes behavior in vitro.

First, this thesis evaluates the effects of surface modification of PGD on the shape and extracellular matrix (ECM) production of chondrocyte, both of which are crucial for robust cartilage formation. I investigated two different strategies to generate a biomaterial surface with high cell affinity: 1) coating with various concentration of collagen type I or hyaluronic acid individually or in combination, or 2) altering the surface charge and roughness using various level of alkaline hydrolysis. Our results revealed the combinatorial effects of ligand composition and density or surface charge and roughness on human articular chondrocyte function.

Lastly, I used finite element analysis to determine if the local strain fields that developed inside the pores under load could be tuned to be within the range shown to have an anabolic effect on chondrocyte function. The tensile strains that develop along 31% – 71% pore surfaces inside of porous PGD scaffolds, according to varying pore size and porosity, were at levels shown to stimulate chondrocyte ECM production, indicating that the pore structural parameters could be tuned to optimize cellular-level strain profiles. These results suggest that porous PGD scaffolds have the potential to guide cartilage regeneration.

Overall, this dissertation produces a platform for cartilage tissue engineering using a novel bioelastomer PGD, in which the scaffold design parameters, such as surface modification and cellular strain, can be modified to enhance chondrocyte function.

Committee Chair(s):
Dr. Rhima Coleman

Zoom Link: https://umich.zoom.us/j/91391389305, Passcode: PGD

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Presentation Thu, 25 Aug 2022 11:41:37 -0400 2022-08-30T11:00:00-04:00 2022-08-30T12:00:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Presentation BME Ph.D. Defence
Biomaterials and Synthetic Biology for Monitoring Immune Function (September 1, 2022 4:30pm) https://events.umich.edu/event/97432 97432-21794558@events.umich.edu Event Begins: Thursday, September 1, 2022 4:30pm
Location: Electrical Engineering and Computer Science Building
Organized By: Biomedical Engineering

Abstract:
Although the prevalence of autoimmune diseases continues to grow, monitoring these conditions remains a challenge resulting in delayed diagnosis, ineffective treatment, and ultimately increased patient morbidity. The PRecision Immune MicroEnvironments (PRIME) Lab, seeks to address this challenge by combining biomaterials and synthetic biology to create a minimally invasive toolset for monitoring immune responses within tissues. Our work on biomaterial-based immunological niches demonstrates that implantable materials enable the formation of an engineered tissue that can be biopsied to monitor multiple sclerosis (MS). These niches provide insights into the phenotype of immune cells that control disease activity, and can be used to monitor disease dynamics or to gauge the effectiveness of treatment. To move beyond biopsy, we are developing synthetic biology tools that enable detection of specific biomarkers of immune function. I will conclude my talk with a brief discussion of my planned research program that aims to leverage materials, immune engineering, and synthetic biology to build translatable tools for real-time monitoring of tissue immunity.

Bio:
Dr. Aaron Morris is an Assistant Professor in the Department of Biomedical Engineering at the University of Michigan, and runs the PRecision Immune MicroEnvironments Laboratory (PRIME Lab). Dr. Morris completed a B.S. in BME at Georgia Tech, followed by a Ph.D. in BME from Yale University. As a postdoc, Dr. Morris worked with Dr. Lonnie Shea at the University of Michigan to use biomaterials to interrogate the immune system during autoimmunity and with Dr. Joshua Leonard at Northwestern University to build synthetic, modular receptor systems for synthetic biology platforms. Dr. Morris’s work has been supported through a number of mechanisms including the NIH K99/R00, NSF GRFP, NIH T32, Michigan Life Sciences Institute Fellows program, and a Michigan Precision Health grant, and a TED Fellowship (check out his TED talk here if interested).

Zoom:
https://umich.zoom.us/j/91375430500

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Workshop / Seminar Thu, 01 Sep 2022 10:47:54 -0400 2022-09-01T16:30:00-04:00 2022-09-01T17:30:00-04:00 Electrical Engineering and Computer Science Building Biomedical Engineering Workshop / Seminar BME 500 Seminar
From molecules to development: biological timing and patterning (September 8, 2022 4:30pm) https://events.umich.edu/event/97913 97913-21795312@events.umich.edu Event Begins: Thursday, September 8, 2022 4:30pm
Location: Electrical Engineering and Computer Science Building
Organized By: Biomedical Engineering

Abstract:
Organisms from bacteria to humans employ complex biochemical or genetic oscillatory networks, termed biological clocks, to drive a wide variety of cellular and developmental processes for robust timing and patterning. Despite their complexity and diversity, many of these clocks share the same core architectures that are highly conserved from species to species, suggesting an essential role of network structures underlying clock functioning. The Yang lab, bridging biophysics and systems & synthetic biology, has integrated modeling with experiments in minimal cells and live embryos to elucidate universal physical mechanisms underlying the complex processes during development. In this talk, I will focus on our recent efforts in understanding the design and interaction of cellular clocks in cell cycles and embryonic developmental patterns. Computationally, we have identified network motifs, notably incoherent inputs, that universally enhance systems' robust performance. Experimentally, we developed a unique synthetic-cell system in microfluidic droplets to analyze circuits and functions of robustness and tunability. We also established single-cell assays of zebrafish embryos combined with biomechanics to analyze the role of energy and mechanical and biochemical signaling in spatiotemporal patterns.

Bio:
Qiong Yang received a Ph.D. in Physics from MIT in 2009 before joining the Department of Chemical and Systems Biology at Stanford University for postdoctoral research, supported by the Stanford Dean’s Postdoctoral Fellowship and a Damon Runyon Cancer Research Fellowship. She was appointed as an Assistant Professor in Biophysics at the University of Michigan in 2014 and was promoted to Associate Professor in 2022. Her research group is affiliated with the departments of Physics, Applied Physics, BME, Complex Systems, and Computational Medicine & Bioinformatics at UM. She has received awards including NSF CAREER, NIH MIRA, Sloan Fellowship, Elizabeth C. Crosby Award, and Class of 1923 Memorial Teaching Award.​​​​​​​

Zoom:
https://umich.zoom.us/j/91375430500

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Workshop / Seminar Thu, 01 Sep 2022 10:44:42 -0400 2022-09-08T16:30:00-04:00 2022-09-08T17:30:00-04:00 Electrical Engineering and Computer Science Building Biomedical Engineering Workshop / Seminar BME 500 Seminar
Engineering Operational Transplant Tolerance via Biomaterials (September 15, 2022 4:30pm) https://events.umich.edu/event/97969 97969-21795406@events.umich.edu Event Begins: Thursday, September 15, 2022 4:30pm
Location: Electrical Engineering and Computer Science Building
Organized By: Biomedical Engineering

Abstract:
Organ and cell replacement therapies hold great promise for the treatment of multiple conditions, including autoimmune diseases such as type 1 diabetes. Restoration of endogenous insulin production, via cell delivery, has shown to be clinically successful in lowering complications and improving glucose sensing in patients. Yet, a widespread application has been hampered by the need for chronic immunosuppressive drugs to prevent strong inflammatory and immunological responses to the graft. Engineered materials offer a powerful approach for local, selective targeting of immune functionalities without compromising systemic immune function. In this talk, we will highlight engineered synthetic polymeric materials that can promote tissue integration and induce operational tolerance to cell therapies by generating a multifaced regulatory network.

Bio:
Prof Coronel is a Biological scholar and Assistant Professor of Biomedical Engineering at the University of Michigan. Her lab is centered on engineering biomaterials for perturbing and investigating immunological responses. Dr. Coronel received her BS degree in Biomedical Engineering from the University of Miami, and her Ph.D. in Biomedical Engineering from the University of Florida. She also obtained a certificate in Clinical Translational Research from Emory University Public Health School. She finished her postdoctoral fellowship at the Georgia Institute of Technology. Her work has been funded by JDRF, NIH, and the programmable materials initiative at the University of Michigan.

Zoom:
https://umich.zoom.us/j/91375430500

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Workshop / Seminar Thu, 01 Sep 2022 15:04:37 -0400 2022-09-15T16:30:00-04:00 2022-09-15T17:30:00-04:00 Electrical Engineering and Computer Science Building Biomedical Engineering Workshop / Seminar BME 500 Seminar
CPOD Seminar Talk: Brian Capell, MD, PhD, (UPenn) Chromatin at the nexus of epithelial development, differentiation, and cancer (September 20, 2022 4:00pm) https://events.umich.edu/event/98510 98510-21796732@events.umich.edu Event Begins: Tuesday, September 20, 2022 4:00pm
Location: Off Campus Location
Organized By: Center for Cell Plasticity and Organ Design

Center for Cell Plasticity and Organ Design with UM-Skin Biology and Disease Resource based Center presents:

Brian Capell, MD, PhD
University of Pennsylvania
Chromatin at the nexus of epithelial development, differentiation, and cancer
In-Person: BSRB ABC Seminar Rooms
Zoom Meeting Option ID: 932 944 30678

Faculty Host: Rajesh Rao, MD
Leonard G. Miller Professor of Ophthalmology and Visual Sciences

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Lecture / Discussion Mon, 12 Sep 2022 11:52:11 -0400 2022-09-20T16:00:00-04:00 2022-09-20T17:00:00-04:00 Off Campus Location Center for Cell Plasticity and Organ Design Lecture / Discussion Capell
Metabolic Reprogramming of Donor Hearts to Improve Function (September 22, 2022 4:30pm) https://events.umich.edu/event/98895 98895-21797323@events.umich.edu Event Begins: Thursday, September 22, 2022 4:30pm
Location: Electrical Engineering and Computer Science Building
Organized By: Biomedical Engineering

Abstract:
Harmful metabolic processes are well underway during cold preservation of donor hearts. We discovered a method to increase the expression of beneficial enzymes which augment the production of anti-inflammatory metabolites. This leads to lowered oxidative stress, reduced myocardial injury and translates into better cardiac function following transplantation. Future strategies to reduce primary graft dysfunction could involve precise modulation of these cardiac metabolic pathways.

Bio:
Paul Tang is an Assistant Professor of Cardiac Surgery at the University of Michigan-Ann Arbor. His cardiothoracic surgery training was completed at Duke University Medical Center where he also received advanced training in heart transplantation, ventricular assist devices and aortic surgery. He has given talks and published widely on the natural history and surgical outcomes of these diseases. At Yale University, Dr. Tang completed a PhD focused on cardiovascular immunology. Dr. Tang's clinical practice includes surgical treatment of heart failure (i.e. heart transplantation, ventricular assist devices), valvular repair or replacement, and aortic aneurysm surgery. He is an investigator in various national clinical trials for heart failure management, and is a member of professional societies such as The International Society for Heart and Lung Transplantation, Southern Thoracic Surgical Association, American Heart Association, and the Society of Thoracic Surgeons.​​​​​​​

Zoom:
https://umich.zoom.us/j/91375430500

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Workshop / Seminar Fri, 16 Sep 2022 16:19:36 -0400 2022-09-22T16:30:00-04:00 2022-09-22T17:30:00-04:00 Electrical Engineering and Computer Science Building Biomedical Engineering Workshop / Seminar BME 500 Seminar
Predictive analysis and deep learning of functional MRI in Alzheimer's disease (September 26, 2022 10:00am) https://events.umich.edu/event/97916 97916-21795315@events.umich.edu Event Begins: Monday, September 26, 2022 10:00am
Location: Off Campus Location
Organized By: Biomedical Engineering

Abstract:
Alzheimer's disease (AD) and dementia pose a significant burden to individuals and public health. AD is expected to grow in prevalence in the coming decades due to the aging population. Brain atrophy is a major component of AD pathology and can occur before symptoms of cognitive impairment. However, pathological brain atrophy and symptoms of cognitive impairment may be a result of many years of disease impacts. Evidence supports the need for early detection of impacted neurocircuitry to foresee future progression to advanced stages of AD and develop treatments. This dissertation examines predictive modeling and deep learning methods to identify brain-behavior relationships and learn low-dimensional representations of brain activity from MR imaging data. The dissertation and methods are separated into four parts.  

Part one of this work examines multivariate analysis approaches applied to functional connectivity from subjects with an early clinical phenotype of AD, mild cognitive impairment (MCI). A regression framework using partial least squares and feature selection demonstrated significant brain-behavior relationships with measures of cognition and memory. The results also confirm other findings that ecologically relevant task-based connectivity serves as a ``stress-test" for memory-related deficits such as those observed in MCI. This approach elucidated brain regions that may be implicated in MCI and warrant future study (superior temporal gyrus, inferior parietal lobule, and superior frontal gyrus). Part two extends the multivariate analyses studied in part one to an additional brain imaging modality, arterial spin labeling (ASL). Cerebral blood flow (CBF) as measured by ASL demonstrated brain-behavior relationships with composite measures of memory and learning in a cohort along the spectrum of AD, demonstrating that CBF data warrant further investigation as a predictor in this application.

Parts three and four utilize a variational autoencoder (VAE) model, a deep learning approach to encode latent representations that aim to disentangle sources of fMRI signal. A surface-based VAE trained on only healthy controls is shown to be generalizable to patients with known AD pathology. The results maintained individual separation and high input/decoder output spatial reconstruction correlation of r=0.8 across all three groups. Part four extended the surface-based model used in part three to a volumetric fMRI approach. Similarly to the surface-based model, high reconstruction accuracy (NRMSE=0.68) and temporal correlation (r=0.8) between input and decoder output are demonstrated. This approach is more readily applicable to 3D fMRI data as compared to the surface-based model. 

In summary, this work has proposed and developed multivariate and deep learning analysis techniques for brain imaging data in the context of AD with the ultimate goal of improving detection and intervention for early pathological changes in the brain.

Zoom Link: https://umich.zoom.us/meeting/register/tJIpcOigrjIsHtJq_xJ1aboK1T0PdWpTkBP5
*Registration Required

Committee Chair(s):
Dr. Scott J. Peltier and Dr. Douglas C. Noll

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Lecture / Discussion Thu, 01 Sep 2022 11:07:14 -0400 2022-09-26T10:00:00-04:00 2022-09-26T11:00:00-04:00 Off Campus Location Biomedical Engineering Lecture / Discussion BME Ph.D. Defense
Evaluation of Phosphate Treatment and Long-Term RUNX2 Suppression On Adult Human MSC Chondrogenesis and Neo-Cartilage Formation (September 26, 2022 3:15pm) https://events.umich.edu/event/99026 99026-21797474@events.umich.edu Event Begins: Monday, September 26, 2022 3:15pm
Location: Lurie Biomedical Engineering (formerly ATL)
Organized By: Biomedical Engineering

Abstract:
Clinical repair strategies for articular cartilage defects are limited by the inability of the tissue to self-repair, often resulting in post-traumatic osteoarthritis (PTOA). PTOA arises from the degradation of structural cartilage extracellular matrix (ECM) proteins responsible for maintaining articular cartilage mechanics, such as aggrecan and collagen. Current cartilage tissue engineering strategies aim to utilize human-derived cells to regenerate cartilage prior to the onset of PTOA. Limited availability of chondrocytes – the primary cell type in articular cartilage – imposes a need for alternatives. Human mesenchymal stem cells (hMSCs) are a promising solution as they can be found in a variety of tissues and can differentiate into MSC-derived chondrocytes (MdChs). However, MSCs are limited by their inability to produce a stable chondrogenic phenotype and deposit and maintain ECM in long-term culture due to maturation, (hypertrophy) where metalloproteinases cleave collagen II and aggrecan. As a result, MSC-derived cartilage regeneration techniques are not yet suitable for clinical use. The central objective of this thesis is to increase cartilage matrix accumulation for more clinically functional cartilage tissue by increasing matrix deposition and stabilizing the chondrogenic phenotype of MSCs.

We investigated two approaches to increase cartilage ECM accumulation and improve MdCh-based cartilage tissue engineering functional outcomes: inorganic phosphate (Pi) treatment and RUNX2 suppression. First, we found that Pi increased cartilage ECM production, but also increased MdCh hypertrophy, while RUNX2 suppression increased stiffness of neo-cartilage tissues long-term. Finally, we showed that combined treatment of Pi and RUNX2 suppression exhibited reduced MdCh hypertrophy but did not significantly increase matrix accumulation. Overall, this dissertation explores methodologies that promote both cartilage matrix accumulation and reduces cartilage matrix loss during long-term culture to better support the use of MdChs in cartilage defect repair strategies.

Zoom Link: https://umich.zoom.us/j/98189564171 Password: cartilage

Committee Chair: Dr. Rhima Coleman

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Lecture / Discussion Mon, 19 Sep 2022 15:31:39 -0400 2022-09-26T15:15:00-04:00 2022-09-26T16:15:00-04:00 Lurie Biomedical Engineering (formerly ATL) Biomedical Engineering Lecture / Discussion BME PhD Defense