Ratner, BuddyZhen, Le2020-04-302020-04-302020Zhen_washington_0250E_21259.pdfhttp://hdl.handle.net/1773/45456Thesis (Ph.D.)--University of Washington, 2020Tissue Engineering has long promised to regenerate tissues for restoring health in patients. However, the requirements of cell harvesting, in vitro expansion, cell seeding, maturation in bioreactors, and decellularization involved in traditional tissue engineering often make the time and costs for engineering tissues unaffordable to patients. As a result, there’s currently no tissue engineered product that withstands the test of the market, hindering the delivery of the promise of regeneration to patients. In situ tissue engineering, by recruiting cells from the body directly to the site to be regenerated and using the body as the bioreactor, bypasses all the in vitro works, eliminating the time and costs associated with them. Thus such an approach is more likely to be translational. The research from the Ratner Lab has demonstrated that precision-engineered porous material with pore sizes in the range of 30-40 μm maximizes the recruitment of macrophages which in turn orchestrate blood vessels and other tissues to integrate into the material. Here, we focus on in situ tissue engineered vascular grafts using such angiogenic and regenerative materials for the replacement of blood vessels. First, we developed a biostable elastic polymer (elastomer) with tunable mechanical property able to match that of the native blood vessels. Second, we demonstrated, in a mouse subcutaneous implant model, the precision-engineered elastomer eliminates the foreign body capsule (FBC) and maximizes the ingrowth of capillary blood vessels. Such effects are accompanied and potentially explained by the increase of macrophage recruitment and the decrease of inflammatory macrophages. Third, we manufactured the vascular graft by integrating the porous elastomer, a reinforcement fabric, and a sealant with tunable degradation rate. Fourth, we are conducted short-term implantation studies in both pig and sheep models. We hypothesize that, combining the pro-angiogenic effect, matching mechanical property, and reduction of FBC, our vascular graft will improve healing and reduce intimal hyperplasia (IH). Our first target for clinical application is to improve the performance of vascular grafts for hemodialysis access, which currently have a failure rate of 50% within the first year. If proven successful, such vascular graft can be easily applied to address to broad clinical problems of cardiovascular diseases (CVDs) that are responsible for one in every three deaths. The strategy of co-optimizing porous structure, mechanical property, and bio-degradability is also being applied to developing skin grafts and grafts for regeneration after spinal cord injury (SCI).application/pdfen-USCC BY-NC-SAforeign body reactionhealingimmunomudulationsheeptissue engineeringvascular graftChemical engineeringChemical engineeringThesis