(43f) Biomaterial Scaffolds for Local Immunomodulation

Biomaterial scaffolds are central to many strategies for regenerative medicine because they create and maintain a space for tissue growth, provide mechanical stability, and support cell migration. Porous poly(lactide-co-glycolide) (PLG) scaffolds have been developed that provide a platform for islet transplant and are able to reverse diabetes with a fraction of the islets that can be isolated from a mouse pancreas. However, transplant of allogeneic and xenogeneic tissue, which is of clinical relevance, requires that rejection be prevented by administration of immunosuppressive drugs, which increases patient susceptibility to infection and neoplasia. It has previously been demonstrated that co-transplant of CD4+CD25+Foxp3+ regulatory T cells (Tregs) with islets on scaffolds protects the islets from autoimmune rejection without the use of immunosuppressives in the NOD mouse model of type I diabetes. In the current studies the goal was to engineer an environment within the scaffold to attract circulating Tregs or induce Treg differentiation from precursor cells. Scaffolds were loaded with combinations of lentiviral particles encoding for immunomodulatory factors including CCL19, CCL22, IL10, TGFβ and IL2. Studies were carried out to characterize the level and duration of gene expression, frequency and activation state of leukocytes within the scaffold, and compatibility of lentiviral delivery with islet function in vivo. The data indicate that islets were able to reverse diabetes when delivered on virus-loaded scaffolds. Furthermore, factor delivery promoted localized gene expression capable of recruiting or inducing Tregs in situ. As biological components of allogeneic or xenogeneic origin, such as stem cells, are incorporated into tissue-engineering approaches, modulation of the immune response will be necessary to prevent tissue rejection. Controlling the local immune environment, such as directing the differentiation, activation, or trafficking of specific immune cells may be a promising alternative to systemic immunosuppression for the protection of transplanted tissue.