In situ tissue engineering eliminates cell harvesting surgeries and reduces manufacturing costs substantially. Bypassing cell seeding and cell culture steps improve clinical translatability. This approach was proven by our previous study demonstrating that a bilayer cell-free vascular graft composed of an elastomeric poly(glycerol sebacate) (PGS) tubular core and a tough polycaprolactone (PCL) sheath undergoes constructive host remodeling into neo-arteries in rat abdominal aorta. In the clinical setting, elderly human patients will have lower regenerative capability than young healthy animals used in this and most other biomedical research. Accumulating evidences support that aging is a major risk factor of chronic vascular diseases, and is associated with impaired neovascularization and reduced functionality and mobility of progenitor cells. Thus, we anticipate that arterial regeneration via in situ approach will be more challenging in human patients. To narrow the gap of technology translation to the clinics, this project will: 1, use 18-month-old rats to better predict host remodeling in human patients, and 2, evaluate the effectiveness of using stromal cell-derived factor (SDF)-1? released from the vascular grafts to recruit progenitor cells to compensate for the reduced motility of progenitor cells in older individuals. The objective of this supplement research is to engineer cell-free vascular grafts that can enhance host progenitor cell recruitment in situ and evaluate their transformation into artery-like tissues in aged animals. SDF-1? is a potent chemoattractant for inducing progenitor cell engraftment. It will be released from a coacervate (a form of emulsion) delivery system in a sustained manner. Our preliminary results show that coacervate maintains bioactivity of SDF-1?, supports its long-term sustained release, and enhances migration and recruitment of human progenitor cells in vitro. We hypothesize that active cell recruitment will promote constructive host remodeling in situ, leading to rapid transformation to a neo-artery. The cost of large animals is not justified at this early phase of research, however aged rats will be used to best mirror human patient population. To test our hypothesis, we will accelerate host cell recruitment and endothelialization by controlled release of SDF-1?. We will use both male and female 18 month-old rats to reflect 50-to-65 year old human patients and implant both bare (control) and SDF-1? coacervate-loaded vascular grafts to common carotid arteries up to 6 months. We will examine early host responses including inflammation and cell infiltration, and correlation between the phenotypes and organization of the recruited cells. We will also investigate the impact of SDF-1? on the rate of endothelialization and ECM production. Successful completion of the proposed research will enhance the aims of the parent R01 and provide an appropriate animal model to address the effect of aging on in situ tissue engineering for arterial regeneration.
Many treatments of cardiovascular disease require bypassing or replacing diseased blood vessels. Despite considerable success with current procedures, polymer-based engineered conduits can enable off-the-shelf availability with sizes and properties better suited for both the pediatric and adult populations. The goal of this project is to design a vascular graft with active cell homing signals that can be transformed into a native artery- like tissue in situ and test the graft in an aged animal model.
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