Abstract 2027: Enhancing Cell-based Therapies With Peptide-modified Thermoresponsive Citrate-based Biomaterials For Treatment Of Critical Limb Ischemia

Introduction: Critical limb ischemia (CLI) causes severe morbidity and mortality with limited treatment options. Cell-based therapy has potential to advance treatment outcomes but faces challenges in cell survival and engraftment during delivery. We hypothesize that an antioxidant niche that promotes cell adhesion and spreading will improve cell engraftment and survival rate, with the goal of limb salvage through improved perfusion. Methods: Thermoresponsive poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized and conjugated with laminin-derived (A5G81) or VEGF-mimic (QK) peptides. Human umbilical vein endothelial cells (HUVECs) expressing human sodium iodine symporter (hNIS) were mixed with materials and intramuscularly injected into nude mice hindlimbs and monitored with Single Photon Emission Computed Tomography with Computed Tomography (SPECT/CT) for cell survival. Next, a hindlimb ischemia model was used to assess the efficacy of cell delivery by evaluating limb perfusion, tissue loss, functional impairment and histological examination. Results: Cells delivered with PBS or PPCN demonstrated poor cell survival, with over 90% cell loss by day 7 (Figure 1a). In contrast, cells delivered with PPCN-A5G81 and PPCN-QK exhibited robust SPECT signal levels for up to four weeks (Figure 1a,b). In the hindlimb ischemia model, materials or cells alone did not demonstrate improvement in any of the parameters over the PBS control. However, cells delivered with PPCN-A5G81 and PPCN-QK showed significantly higher blood perfusion (Figure 1c-e), with improved tissue salvage and motor functions (Figure 1f-i) for both male and female mice. Conclusion: PPCN modified with A5G81 and QK promotes cell spreading, proliferation, survival, and tissue regeneration, with potential for more effective cell-based therapies for CLI.