Event
Bioengineering Seminar Series: Danielle S.W. Benoit
Friday, November 22, 2013
9:00 a.m.-10:00 a.m.
Pepco Room, Jeong H. Kim Engineering Building
Yu Chen
yuchen@umd.edu
Bone Allograft Repair Using Tissue Engineering Paradigms
Danielle S.W. Benoit
James P. Wilmot Distinguished Assistant Professor
Department of Biomedical Engineering
Department of Chemical Engineering
Center for Musculoskeletal Research
University of Rochester
There are limited options for reconstruction of critical sized bone defects that result from congenital anomalies, trauma, infection, and oncologic resection. Nearly one million bone graft procedures are performed annually, with decellularized allografts remaining the clinical gold standard of treatment. Of these allograft implantation procedures, nearly 60% fail within 10 years of implantation due to poor graft-host integration and microcrack propagation. Unlike allografts, autografts fully heal and integrate, mediated by the periosteum, a thin layer of osteogenic tissue surrounding bone, where healing is coordinated by a variety of contextual cues including periosteal cells (PCs), matrix, and paracrine factors. PCs, which persist during autograft healing for only ~21 days, are phenotypically similar to bone marrow-derived mesenchymal stem cells (MSCs). Therapeutically, however, MSCs are favored compared to PCs as they are isolated from bone marrow, reducing bone tissue morbidity resulting from PC isolation. Identification of the critical cues (paracrine factors, matrix interactions, etc.) that orchestrate autograft healing and are absent in allografts currently limits the translation of therapies to successfully revitalize allografts. Thus, we are developing periosteum mimetics composed of synthetic hydrogels (poly(ethylene glycol), PEG) designed to transplant and localize MSCs to the allograft surface to promote cell-mediated allograft healing/integration and, more fundamentally, isolate the critical factors of the periosteum for healing. PEG hydrogels mimic the periosteum and are formed around allografts to take advantage of allograft structural integrity and act as a temporary extracellular matrix for transplanted MSCs. Hydrogel microenvironments can also be tuned through alterations in degradation and biochemical functionalities to promote MSC-mediated allograft healing and integration. We have demonstrated that hydrolytically degradable PEG hydrogels designed to mediate MSC transplantation to and localization at the allograft surface can mimic PC mediated autograft healing. Using a murine segmental defect model, the tissue engineering approach resulted in increased graft vascularization (∼2.4-fold), endochondral bone formation (∼2.8-fold), and biomechanical strength (1.8-fold), as compared to untreated allografts, over 16 weeks of healing. Despite this enhancement in healing, the process of endochondral ossification was delayed compared to autografts, requiring further modifications to achieve clinically acceptable healing times. However, this bottom-up biomaterials approach, the engineered periosteum, is currently being modified through inclusion of osteogenic cell types but can also be altered to include matrix cues, growth factors, and/or other small molecule drugs to expedite the process of ossification. We are also exploring the role of MSCs in healing, including the role of paracrine factors such as VEGF, to potentiate a cell-free revitalization approach. Taken together, this work will advance our understanding of how MSCs coordinate allograft healing and integration and how to design synthetic polymer scaffolds to promote bone regeneration processes. In addition, this material platform can be readily tailored for applications towards regenerating tissues beyond bone, as well as providing specific advantages for future directions in the design of cell delivery vehicles.
About the Speaker
Danielle Benoit is the James P. Wilmot Distinguished Assistant Professor within the Department of Biomedical Engineering with appointments also in Chemical Engineering and the Center for Musculoskeletal Research. Her research specializes in the rational design of polymeric materials for regenerative medicine and drug delivery applications. Her work has provided insights into the translation of tissue engineering strategies for bone allograft repair, development of pH-responsive nanoparticles for nucleic acid and small molecule delivery, and novel targeting strategies for bone-specific delivery of therapeutics. Prof. Benoit received her undergraduate degree in Biological Engineering from the University of Maine and M.S. and Ph.D. in Chemical Engineering from the University of Colorado, where she was mentored by Dr. Kristi Anseth. She then trained at the University of Washington where she was a Damon Runyon Cancer Research Foundation Postdoctoral Fellow, working with Drs. Patrick Stayton and Allan Hoffman. Prof. Benoit joined the faculty at the University of Rochester in 2010.
