(A-32) A pro-angiogenic dermoconductive regenerative dressing

Introduction:: Diabetes is one of the leading causes of death in the United States affecting more than 37.3 million Americans, it was estimated to be at a yearly cost of $327 billion dollars¹. The costs associated with wound treatments, such as chronic diabetic foot ulcers (DFUs), are often overlooked. DFUs are responsible for 4 per 1,000 nontraumatic lower-limb amputations, costing these patients between $30,000 and $60,000². Currently, there is no efficient treatment for chronic DFUs. We have previously developed poly (polyethylene glycol citrate-co-N-isopropylacylamide) (PPCN) with a covalently conjugated laminin-derived peptide A5G81 for wound regeneration. PPCN is a dressing that consists of a thermoresponsive macromolecule that is dermo-conductive, dermo-inductive, and antioxidative; and has been demonstrated to accelerate dermal wound closure in diabetic mice by stimulating keratinocyte and fibroblast proliferation and migration and reducing oxidative stress³. We have also shown that copper (Cu²⁺) ions, slowly eluted from metal-organic framework nanoparticles (CMOF) within PPCN, can accelerate wound closure via enhanced angiogenesis in a diabetic rodent model⁴. In this study, we seek to engineer a viable, low-cost, biocompatible, PPCN-A5G81 with the sustained release of Cu²⁺ via a copper metal-organic framework that accelerates diabetic wound closure.

Materials and Methods:: We modified A5G81-PPCN by incorporating a copper metal-organic framework (CMOF) as a source of Cu²⁺ to enhance angiogenesis and its antimicrobial ability to promote wound healing. The antioxidant macromolecule PPCN was synthesized via a polycondensation and free radical reaction to obtain PPCN and functionalized with N-β-maleimidopropionic acid hydrazide (BMPH) as a linker^3,4. Briefly, the laminin-derived dodecapeptide A5G81 contains a terminal cysteine and can be covalently conjugated to BMPH-PPCN via click chemistry. A5G81-PPCN-CMOF was prepared by loading PPCN-A5G81 with a non-cytotoxic concentration of CMOF. CMOF nanoparticles (NPs) were obtained following the reaction between copper nitrate and terephthalic acid at room 65°C for 24 hrs⁵.


Results, Conclusions, and Discussions:: Due to the incorporation of copper, PPCN-CMOF demonstrates a distinct blue color. The successful synthesis of CMOF was validated (Fig. 1b-c). PPCN-CMOF was validated to have its thermoresponsive characteristic intact (fig. 1d). We evaluated cytocompatibility using L929 fibroblasts for which we observed that the sustained release of copper ions of 1 mM was nontoxic. We additionally assessed the tubulogenic properties of PPCN-A5G81 and found enhanced tubulous when compared to PPCN (data not shown).

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References (Optional): : (1) American Diabetes Association. Economic Costs of Diabetes in the U.S. In 2017. Diabetes Care 2018, 41 (5), 917–928. https://doi.org/10.2337/dci18-0007. (2) Geiss, L. S.; Li, Y.; Hora, I.; Albright, A.; Rolka, D.; Gregg, E. W. Resurgence of Diabetes-Related Nontraumatic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. Diabetes Care 2019, 42 (1), 50–54. https://doi.org/10.2337/dc18-1380. (3) Zhu, Y.; Cankova, Z.; Iwanaszko, M.; Lichtor, S.; Mrksich, M.; Ameer, G. A. Potent Laminin-Inspired Antioxidant Regenerative Dressing Accelerates Wound Healing in Diabetes. Proceedings of the National Academy of Sciences 2018, 115 (26), 6816–6821. https://doi.org/10.1073/pnas.1804262115.(4) Xiao, J.; Chen, S.; Yi, J.; Zhang, H. F.; Ameer, G. A. A Cooperative Copper Metal-Organic Framework-Hydrogel System Improves Wound Healing in Diabetes. Advanced Functional Materials 2016, 27 (1), 1604872. https://doi.org/10.1002/adfm.201604872. (5) Carson, C. G.; Hardcastle, K.; Schwartz, J.; Liu, X.; Hoffmann, C.; Gerhardt, R. A.; Tannenbaum, R. Synthesis and Structure Characterization of Copper Terephthalate Metal–Organic Frameworks. European Journal of Inorganic Chemistry 2009, 2009 (16), 2338–2343. https://doi.org/10.1002/ejic.200801224.