Abstract 345: Immunomodulatory Biomaterials (IMB) For The Disruption Of Chronic Inflammation In Diabetic Foot Ulcers

Background: Diabetic foot ulcerations (DFUs) become non-healing wounds once they stall in the chronic inflammatory phase (CIP), making it vulnerable to infection. Dysregulated secretion of pro-inflammatory cytokines and matrix metalloproteinase (MMPs) are responsible for DFUs that remain in the CIP. Limitations for the development of therapeutics and biologics are the focus upon a single target biomarker, or cellular process that ignores the multiple molecules responsible. Herein, we aim to evaluate a new class of immunomodulatory biomaterials (IMBs) based on phosphate crosslinked (Px) polyvinyl alcohol (PVA) biopolymers (PxPVA) to modulate multiple proinflammatory cytokines and shift the wound out of the CIP. Methods: We fabricated immunomodulatory biomaterials (IMB) by the chemical synthesis of PxPVA. Subsequently, we modified the physicochemical properties (hydrophilicity, surface pH, and surface charge; zeta potential) to selectively sequester pro-inflammatory cytokines IL-1β, IL-6, TNF-α. We measured the ability of IMBs to sequester these cytokines from in vitro cytokine solutions, in vivo mouse excisional skin wound model, and ex vivo human DFU samples by Luminex assays and quantitative polymerase chain reaction (q-PCR). Histology was performed on the mouse samples to analyze for re-epithelialization and collagen deposition. Results: Surface analysis on the IMBs demonstrated that the material is highly porous and hydrophilic with a negative surface charge. Our IMBs were implanted in mouse excisional skin wounds followed by q-PCR analysis on the 5 th day revealed that IMBs were able to capture significantly higher concentrations of IL-1β, IL-6, and TNF-α (* P ≤ 0.05, *** P ≤ 0.001) compared to polypropylene and PVA controls. Histological analysis of the IMB treated wounds demonstrated a thin and continuous epithelium formation with basket weave arrangement of collagen fibrils with a decreased type-1/type-3 collagen ratio. Conclusions: We demonstrated that the physicochemical properties of IMBs can be calibrated to reduce the inflammatory cytokine burden in the wound site and stimulate regenerative wound healing in the mouse model. This is mirrored by similar reductions in cytokine levels in ex vivo human DFU samples.