TRB Distinguished Biomaterials Lecture

“Mice are not little people” – a refrain becoming louder as the strengths and weaknesses of animal models of human disease and drug responses become more apparent. At the same time, three emerging approaches are headed toward integration: powerful systems biology analysis of cell-cell and intracellular signaling networks in patient-derived samples; 3D tissue engineered models of human organ systems, often made from stem cells; and micro-fluidic and meso-fluidic devices that enable living systems to be sustained, perturbed and analyzed for weeks in culture. Endometriosis, adenomyosis, and other gynecological disorders are paradigms of chronic inflammatory diseases that can only partially be modeled in animal systems. In this talk, approaches to classify patients on the basis of analysis of cell-cell communication networks will be described as a motivation for building patient avatars that capture salient features of the disease processes. Then, approaches to use synthetic extracellular matrices to build tissue-engineered models of the endometrium and endometriosis lesions, including microvascular networks and immune cell recruitment, will be highlighted, along with the potential to integrate these approaches for developing new drugs to treat endometriosis and adenomyosis.

Linda G. Griffith is the School of Engineering Professor of Teaching Innovation in the Departments of Biological and Mechanical Engineering at MIT, where she directs the Center for Gynepathology Research. She has pioneered approaches in tissue engineering and organs-on-chips and now integrates these platform technologies with systems biology to humanize drug development. She has chaired numerous scientific meetings, including recently the Keystone Tissue Organoids Conference (2020), and has co-chaired the Open Endoscopy Forum at MIT annually since 2015. She is a member of the National Academy of Engineering (NAE), the National Academy of Medicine, the National Academy of Inventors, a Fellow of the American Academy of Arts and Sciences, and recipient of a MacArthur Foundation Fellowship, and several awards from professional societies. She is a co-recipient of the 2021 NAE Gordon Prize, for leadership in creating the new discipline of Biological Engineering. Dr. Griffith currently serves on the advisory board of the Society for Women’s Health Research and has served on the Advisory Committee to the Director of the National Institutes of Health. At MIT, she is a founding member of the Biological Engineering Department and led development of the undergraduate major in Biological Engineering, which was MIT’s first new undergraduate major in 39 years when it launched in 2005. She received her BS from Georgia Tech and PhD from UC Berkeley, both in chemical engineering.

With personal trainers and tailored suits, why don’t we have personalized medicine? Working at the interface of chemistry, biology, and engineering, we are designing strategies with the individual in mind. Before we get to the patient, we’re investigating models of disease to determine how we can better understand disease progression and how we can stop and reverse that disease instead of merely treating the symptoms. I will tell three stories that are promising in cancer, blindness and stroke. In each story, I will highlight both the underlying innovation and the opportunities that lay ahead. I will end with two short stories on how we are commercializing some of our fundamental discoveries.

Professor Molly Shoichet holds the Tier 1 Canada Research Chair in Tissue Engineering at the University of Toronto. She served as Ontario’s first Chief Scientist in 2018 where she worked to enhance the culture of science. Dr. Shoichet has published over 675 papers, patents and abstracts and has given over 400 lectures worldwide. She currently leads a laboratory of 25 and has graduated 190 researchers. Her research is focused on drug and cell delivery strategies in the central nervous system (brain, spinal cord, retina) and 3D hydrogel culture systems to model cancer. Dr. Shoichet co-founded four spin-off companies, is actively engaged in translational research and science outreach. Dr. Shoichet is the recipient of many prestigious distinctions and the only person to be inducted into all three of Canada’s National Academies of Science, Engineering and Health Sciences. Professor Shoichet is a Fellow of the Royal Society (UK) and Foreign Member of the US National Academy of Engineering. She is an Officer of the Order of Canada and holds the Order of Ontario. Dr. Shoichet is a University Professor – the highest distinction of the University of Toronto, which is held by less than 2% of the faculty. Dr. Shoichet was the L’Oreal-UNESCO For Women in Science Laureate for North America in 2015 and won the Killam Prize in Engineering in 2017. Dr. Shoichet received her SB from the Massachusetts Institute of Technology (1987) and her PhD from the University of Massachusetts, Amherst in Polymer Science and Engineering (1992).

We currently lack therapies that reduce the risk of thrombosis without an attendant risk of bleeding. Such strategies will be necessary to decrease the substantial morbidity and mortality currently attributable to venous thromboembolism, stroke, myocardial infarction, and peripheral arterial disease or otherwise improve our ability to develop clinically effective implantable artificial organs that interface with blood, including the artificial heart, lung, and kidney. This seminar will review our recent efforts to develop new drugs that inhibit platelet activation and the coagulation cascade, while breaking the link between the inhibition of thrombosis and preservation of hemostasis. We will discuss strategies that locally concentrate inhibitors of thrombosis at incipient sites of clot formation, blockade of leukocytes as an under-appreciated contributor to thrombosis, and approaches to regenerate anti-thrombogenic films on blood-contacting devices after device implantation.

Elliot L. Chaikof is Chairman of the Roberta and Stephen R. Weiner Department of Surgery and Surgeon-in-Chief at the Beth Israel Deaconess Medical Center (BIDMC), as well as the Johnson and Johnson Professor of Surgery at Harvard Medical School. He is a member of the Wyss Institute of Biologically Inspired Engineering of Harvard University and the Harvard Stem Cell Institute. Dr. Chaikof received his B.A. and M.D. from Johns Hopkins University in Baltimore and his Ph.D. in Chemical Engineering from the Massachusetts Institute of Technology, where he focused on the design of artificial organs. He completed his training in General Surgery at the Massachusetts General Hospital and in Vascular Surgery at Emory University School of Medicine in Atlanta.

Our group focuses on the development of biomaterial matrices that can serve as advanced culture systems or in vivo delivery systems for primary cells. We exploit material chemistry as a tool to decipher how cells process signals from the extracellular matrix (ECM), and then use this information to design improved biomaterials that promote tissue regeneration. Specifically, we design synthetic ECM analogs that capture key features of the unique chemistry and physical properties of a cell’s niche—an environment that is not only tissue specific, but can be strikingly heterogeneous and dynamic. Unique to our approach is the ability to create cell-laden matrices in three-dimensional space in which the matrix properties can be changed on demand—so-called 4D biology. Here, our group has focused on the development of photochemical reactions to create tunable cell-laden matrices, for example, the thiol-ene photo-click reaction and complementary photo-clip reactions to introduce and remove biological signals from a complex milieu. These photochemical reactions not only proceed rapidly and with high specificity, but are bio-orthogonal, spatiotemporally controlled, and cytocompatible. This talk will illustrate how we leverage these and other reversible chemistries to create biologically responsive hydrogel matrices, and employ them to study the effects of matricellular signaling on diverse cellular functions and processes. For example, we exploit peptide-crosslinked PEG hydrogels to encapsulate stem cells and study how matrix density, degradability, elasticity, and adhesivity influence migration, proliferation, and differentiation. More recently, we have integrated photodegradable linkers into hydrogels and used these spatiotemporal controlled reactions to direct the growth and differentiation of stem cells into intestinal organoids.

Kristi S. Anseth is presently a Distinguished Professor of Chemical and Biological Engineering and Associate Faculty Director of the BioFrontiers Institute at the University of Colorado at Boulder. Her research interests lie at the interface between biology and engineering where she designs new biomaterials for applications in drug delivery and regenerative medicine. Dr. Anseth is an elected member of the National Academy of Engineering (2009), the National Academy of Medicine (2009), the National Academy of Sciences (2013), and the National Academy of Inventors (2016). She is also a dedicated teacher, who has received four University Awards related to her teaching, as well as the American Society for Engineering Education’s Curtis W. McGraw Award. Dr. Anseth is a Fellow of the American Association for the Advancement of Science, the American Institute for Medical and Biological Engineering, American Institute of Chemical Engineers, and the Materials Research Society. She also serves on the editorial boards or as associate editor of Biomacromolecules, Journal of Biomedical Materials Research — Part A, Acta Biomaterialia, Progress in Materials Science, and Biotechnology & Bioengineering.

Direct cell reprogramming or transdifferentiation, where adult cells are reprogrammed from one lineage to another without going through an intermediate stem cell-like stage, produces cells promising for regenerative medicine. It obviates the use of embryos and minimizes the risk of teratoma formation associated with the in vivo application of induced pluripotent stem cells. Direct reprogramming can also produce cells for disease modeling and drug screening. I will discuss our recent effort to convert human endothelial progenitors (hEPC) into induced smooth muscle cells (iSMC), hEPC into induced skeletal myocytes (iSkM), human fibroblasts into induced cardiomyocyte-like cells (iSML), and murine fibroblasts into induced neurons (iN). I will describe various approaches of achieving direct cell reprogramming using transcription factor overexpression, microRNA delivery, molecular pathway manipulation, and CRISPR/dCas9-based transactivation either separately or in combination. This will be presented from the perspective of how biomaterials and biomedical engineering researchers can help advance this exciting field.

Kam W. Leong is the Samuel Y. Sheng Professor of Biomedical Engineering at Columbia University. He received his PhD in Chemical Engineering from the University of Pennsylvania. After serving as a faculty in the Department of Biomedical Engineering at The Johns Hopkins School of Medicine for almost 20 years, he moved to Duke University in 2006 to study the interactions of cells with nanostructures for therapeutic applications. After moving to Columbia University in September 2014, he continues to work on nanoparticle-mediated nonviral gene delivery and immunotherapy. The lab also works on the application of nanostructured biomaterials for regenerative medicine, particularly on understanding cell-topography interactions and on the application of nonviral vectors for direct cellular reprogramming and genome editing. He has published ~330 peer-reviewed research manuscripts with ~33,000 citations, and holds more than 50 issued patents. His work has been recognized by a Young Investigator Research Achievement Award of the Controlled Release Society, Distinguished Scientist Award of the International Journal of Nanomedicine, Clemson Award for Applied Research of the Society for Biomaterials, and Life Time Achievement Award of the Chinese American Society of Nanomedicine and Nanotechnology. He is the Editor-in-Chief of Biomaterials, a member of the National Academy of Inventors, and a member of the National Academy of Engineering.

Therapeutic cancer vaccines typically depend on extensive manipulation of cells in the laboratory, but subsequent cell infusion typically leads to large-scale cell death and limited efficacy. We are instead developing biomaterials that provide controlled delivery of immunomodulatory factors, in certain ways mimicking aspects of microbial infection, to target immune cells in the body and bypass the need to manipulate cells in the laboratory. These material strategies allow control over immune cell trafficking and activation, cause tumor regression in preclinical models, and are currently in a Phase I clinical trial.

David Mooney is the Pinkas Family Professor of Bioengineering in the Harvard School of Engineering and Applied Sciences, and a Core Faculty Member of the Wyss Institute. His laboratory designs biomaterials to make cell and protein therapies effective and practical approaches to treat disease. His team created the first biomaterial-based, therapeutic cancer vaccine, currently in a clinical trial for melanoma. He is a member of the National Academy of Engineering, and the National Academy of Medicine. He has won numerous awards, including the Clemson Award from the SFB, MERIT award from the NIH, Distinguished Scientist Award from the IADR, Phi Beta Kappa Prize for Excellence in Undergraduate Teaching, and the Everett Mendelsohn Excellence in Mentoring Award from Harvard College. His inventions have been licensed by twelve companies, leading to commercialized products, and he is active on industrial scientific advisory boards.

Recently there has been a paradigm shift in what is considered to be the therapeutic promise of mesenchymal stem cells (MSCs) in diseases of vital organs. Originally, research focused on MSCs as a source of regenerative cells through the differentiation of transplanted cells into lost cell types. It is now clear that trophic modulation of inflammation, cell death, fibrosis, and tissue repair are primary mechanisms of MSC therapy. This has been clarified in studies where delivery of growth factors, cytokines, and other signaling molecules secreted by MSCs is often sufficient to obtain the therapeutic effects. In this presentation, we provide a several examples of MSC therapy in disease models of vital organs using models of acute liver failure, acute kidney failure, and spinal cord injury. Some critical gaps in our knowledge hampering experimental progress and clinical implementation are discussed.

Martin L. Yarmush is an internationally recognized bioengineer and translational scientist whose laboratory has been a pioneer and leader in multiple fields including: tissue engineering and regenerative medicine, applied immunology and biotechnology, and BioMEMS and medical devices. Dr. Yarmush currently serves as the Director of the Center for Engineering in Medicine at the Massachusetts General Hospital/Harvard Medical School, and the Paul and Mary Monroe Professor of Science and Engineering and Distinguished Professor of Biomedical Engineering at Rutgers University. Over the last 30 years, Dr. Yarmush has: 1) published more than 400 journal articles, 2) has co-authored more than 40 patents and patent applications, 3) has mentored over 120 postdoctoral fellows and graduate students, and 4) has taught a spectrum of courses from Molecular Genetics and Immunology, to Thermodynamics and Transport Phenomena, to Innovation and Entrepreneurship for Science and Technology and Bioengineering in the Biotechnology and Pharmaceutical Industries. More than 70 of his former fellows have gone on to successful careers in academia both here and abroad, while many others have gone on to become leaders in the pharmaceutical, biotechnology and medical device industries. In addition to his teaching and research achievements, Dr. Yarmush has contributed to the advancement of science and engineering through service as: (1) a member of NIH, NSF, FDA, and Office of Technology Assessment review panels; (2) an advisory board member for foundations (e.g. the Whitaker Foundation, Juvenile Diabetes Foundation, and Doris Duke Foundation), academic-based centers, and industrial firms; and 3) an editor of several science and engineering journals. A frequent invited speaker at major conferences and institutions, and winner of over 25 local and national awards, Dr. Yarmush’s research “pushes the envelope” on several healthcare technology frontiers through the use of state-of-the-art techniques that include microfabrication and nanotechnology, genomics, proteomics and genetic engineering, advanced microscopic imaging, physiologic instrumentation, and numerical simulation. He has been credited with many pioneering scientific and technological advances including: innovative cell culture systems, stem cell therapies, dynamic cell and tissue microsystems, point-of-care devices, bioartificial organs development, targeted therapies for tumors and infections, recombinant protein purification techniques, and recombinant retrovirus production and purification techniques. Some of these developments have resulted in licensed patents and the formation and development of 10 companies based on these advances. Dr. Yarmush received his Bachelor’s Degree from Yeshiva University, his MD degree from Yale University, and completed PhD work at The Rockefeller University in biophysical chemistry and at MIT in chemical engineering.