Altering fibrotic and rejection responses using biomaterial systems

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From the established (e.g. stitches) to the futuristic (e.g. tissue-engineered constructs), polymers have found diverse applications as implanted biomaterials. Yet, their utility is limited by the accumulation of fibrous tissue that inevitably occurs and accompanying immune responses. The long-term objective of the proposed research program is to design biomaterial systems that minimise fibrosis and allogeneic rejection. In order to accomplish these goals, we have two major aims within the five year duration of the grant. 1) Using a model biomaterial, we will deliver candidate anti-fibrotic drugs to decrease local scarring responses. 2) By delivering key compounds from the biomaterial, we will induce tolerogenic cells that reduce allogeneic rejection. Creation of biologically active "combination" devices is relatively recent and has been driven primarily by tissue engineering. However (and despite more complex regulatory issues), the field of implanted devices will also benefit greatly from biomaterials that actively direct responses away from fibrosis and rejection. The macrophage has been identified as the key cell activated by biomaterials. Recent research has shown that macrophages can differentiate into a spectrum of phenotypes that control subsequent wound-healing, scarring and immune responses. We hypothesize that controlled release of drugs from a biomaterial construct will direct these macrophages to regenerative, tolerogenic phenotypes. Thus, subsequent responses to a biomaterial scaffold would abrogate scarring and induce tolerance to allogeneic cells introduced as part of the tissue engineered construct. This engineering challenge is both scientifically and clinically significant. By moving beyond chemistry, we have the opportunity to rationally design biomaterial systems that actively interact with the recipient's inflammatory, fibrotic and immune responses. Moving to biologically active "combination products" will improve outcomes for traditional medical devices and for newer regenerative medicine applications.