The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. 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 Cu, 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 using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu release, thus enabling the direct application of Cu-MOF NPs to wounds.

Vertebral compression fractures due to osteoporosis are commonly treated with bone cements based on the non-degradable, mechanically stiff poly(methyl methacrylate) (PMMA), which relies on peroxide-initiated polymerization to quickly set the cement at the cost of high exothermic temperatures. Recently, there has been interest in developing degradable, bone mechanic-matching alternatives that pursue physiologically induced polymerization to both augment the handling of the material before application and to reduce high localized temperatures that may lead to tissue damage. Herein, we report the development and material characterization of a thermoresponsive, degradable bone cement that utilizes the azo-based radical initiator 2-2ʹ-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V70) and a liquid citrate-based biomaterial-ceramic composite of methacrylated poly(1,8 octamethylene citrate) (mPOC) and hydroxyapatite (HA) nanoparticles (mPOC-HA) that has improved handling and tissue compatibility characteristics. Our results show that: (a) these composites remain liquid until they are exposed to body temperature, which initiates polymerization to form a solid, tough material with desirable, modular compressive strengths comparable to trabecular bone; (b) the addition of HA decreases temperature generation below the threshold that leads to tissue necrosis; and (c) composites remain biocompatible in vitro and in vivo.