(17g) Folic Acid-Stabilized Copper Metal-Organic Frameworks Improve Wound Healing in Diabetes

Chronic non-healing wounds remain a major clinical challenge. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, multiple applications of copper salts or oxides to the wound bed are required, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. We hypothesized that copper based metal-organic framework nanoparticles (Cu-MOF NPs) referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu²⁺ resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity, and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity, enhanced cell migration, and increased wound closure rates by inducing angiogenesis, collagen deposition, and re-epithelialization during wound healing. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu²⁺ release, thus enabling the direct application of Cu-MOF NPs to wounds