MULTIFUNCTIONAL BIOMATERIAL SYSTEM FOR DRUG DELIVERY AND SCAFFOLDING TO PROMOTE NEOVASCULARIZATION IN TISSUE ENGINEERING

The successful development of engineered tissues requires extensive vascular network formation. The overall goal of this work is to develop a multifunctional biomaterial system for scaffolding and drug delivery to promote neovascularization in engineered tissue. Firstly, a drug delivery system was developed for molecules of different properties. Poly(lactic-co-glycolic acid) (PLGA) was prepared into microspheres using a double emulsion process for delivery of hydrophobic chlorhexidine (CHX) and hydrophilic platelet-derived growth factor-BB (PDGF-BB). Both drugs exhibited bioactivity after release and the efficacy of dual drug delivery was evaluated with an infected wound animal model. The simultaneous delivery of CHX and PDGF-BB improved wound healing and neovascularization while reducing bacteria levels. Therefore, the PLGA microspheres can be used for long-term active delivery of both hydrophobic and hydrophilic molecules in tissue engineering applications. Secondly, a 3D scaffold was developed for tissue engineering applications. Poly(ethylene glycol) (PEG) hydrogels with interconnected pores were generated with a salt leaching technique. Fibrin was filled in the pores by adding fibrinogen solution to hydrogel scaffolds pre-loaded with thrombin. The hydrogels were evaluated in a rodent subcutaneous implant model, showing that tissue invasion with a higher vascular density occurred when the hydrogels were loaded with fibrin. This composite hydrogel supports vascularized tissue ingrowth, and thus holds potential for tissue engineering applications. Thirdly, approaches from the previous studies were combined to develop a multifunctional biomaterial system for tissue engineering scaffolding and sequential xi growth factor delivery. PLGA microspheres were incorporated into a fibrin loaded porous hydrogel, in which the PEG based scaffold was modified to allow controlled degradation via hydrolysis. Different growth factors were encapsulated in fibrin and PLGA microspheres to provide temporal control of delivery. Growth factors released with the appropriate sequence promoted stable and functional blood vessel formation. In conclusion, a multifunctional biomaterials system was developed to provide structural and mechanical support for tissue regeneration, as well as delivery of signals that stimulate neovascularization. The system holds great potential for tissue engineering applications. Future work will require the extensive collaboration from interdisciplinary fields towards the successful development of engineered tissue substitutes.PH.D in Biomedical Engineering, May 201