Inflammasome-modulating Polymeric Biomaterials to Augment Tissue Repair

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SUMMARY Wounds are a major national and global health burden with an annual incidence of more than 6 million cases of chronic skin wounds collectively costing more than $20 billion per year in the USA. Common comorbidities such as diabetes, burns and infection impair healing and increase morbidity and mortality. The biochemical hostility and sub-optimal vascularization in the injured tissue microenvironment combined with the multiphasic biological mechanisms of tissue repair, which are dysregulated in the diabetic host, limit the efficacy of therapeutic treatments. There is an urgent need for novel, engineered biomaterials to facilitate the temporal delivery of bioactives to augment and promote the effective resolution of intractable wounds. Silk fibroin (SF) and chitosan (CS) are biopolymers that can be specifically and systematically tuned to optimize key properties including loading capacity, release kinetics, biocompatibility, degradability and mechanical strength for effective drug delivery. This proposal will develop a biomaterial platform for temporally controlled sustained release of immunomodulating small molecules and growth factor nanoparticles to augment tissue repair. Aim 1 will focus on the development and characterization of a platform of unmodified and derivatized SF, CS and blend SF-CS scaffolds to deliver small molecule modulators of the inflammasome pathway and will test the platform in a relevant mouse model of impaired tissue injury. Aim 2 will focus on the combinatorial delivery of growth factor nanoparticles and small molecule drugs with distinct temporal release kinetics to further augment the efficacy and quality of tissue repair. The success of the research and career development plan in this K01 proposal is supported by a strong, diverse mentor team with complementary scientific expertise in drug delivery, growth factor nanoparticles, dermatopathology and immunobiology and substantial experience in advising early stage investigators. Dr. Yaron (PI) is an assistant research professor with a strong background in inflammation biology, immune modulation and tissue repair and the primary mentor, Dr. Rege, is an expert in biomaterials innovation for tissue repair. Dr. Yaron will receive training in the Design-Build-Test biomaterials development principles and bioengineering methods necessary to develop an independent research program on translational immunomodulation technologies for tissue repair. This proposal leverages the innovative, scientifically robust environment at Arizona State University to develop a novel biomaterial platform for the controlled delivery of small molecules and biological nanoparticles for therapeutically augmenting tissue repair, with a strong path to clinical translation.