Engineering the open porous nanofibrous microsphere integrated fibrillar hydrogel for the co-delivery of antibacterial and angiogenic agents aimed at the rapid diabetic wound repair

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PROJECT SUMMARY This proposal aims to engineer a multifactorial wound dressing composed of open porous nanofibrous microspheres (NMs) integrated with a stimuli-responsive fibrillar hydrogel (FHG) to release therapeutics to accelerate diabetic wound healing. The open porous structure in the proposed wound dressing can enhance cell migration and granulation tissue formation for rapid wound closure. Initially, the porous NMs will be fabricated from electrospun short nanofiber segments using our newly invented core-shell electrospray technique with bubble technology. Afterward, the peptide-tethered matrix metalloproteinases (MMP) responsive FHG will be integrated with porous NMs to develop an injectable hybrid gel followed by photocrosslinking. Previously, we demonstrated that porous nanofiber scaffolds show tremendous improvements in cell migration and cell/tissue integration. Inspired by the results, we will develop a new wound dressing platform that improves the wound healing process in several aspects; (i) The extracellular matrix (ECM) mimetic porous structure of the NMs can accelerate the cell migration during the healing. (ii) Engineering an ECM mimetic FHG with methacrylate gelatin (GelMA) and MMP responsive peptide linker can offer to maintain the moist conditions and sustained delivery of therapeutic agents locally. (iii) The engineered peptide conjugated NMs integrated FHG can prevent diabetic wound infection and tune the angiogenesis by sustained release of antibacterial and angiogenic peptides. To achieve these goals, we will incorporate antibacterial LL-37 mimic W379 peptide, and vascular endothelial growth factor (VEGF) mimetic QK peptide to the NMs integrated FHG. Specifically, we have identified that porous NMs properties can modulate cell migration through the porous microarchitecture and improve wound healing compared with nonporous NMs composed gel. The fibrillar hydrogel network will provide moist conditions in the wound similar to ECM and the controlled release of peptides in the wound milieu. We will evaluate and optimize material properties using the following characterization workflow: the porosity of NMs, the injectability of hybrid gel, in vitro cytotoxicity quantification, in vitro gel degradation with different MMP cell responses (survival, proliferation, and migration), in vitro antibacterial efficacy of W379 peptide, in vitro angiogenic properties of QK peptide, in vivo immune response (analysis by Flow cytometry), in vivo material degradation (analysis by histology), and in vivo tissue healing/regeneration (analysis by immunohistology). Afterward, we will focus on an infected diabetic mouse (db/db) splinted wound healing model to evaluate the efficacy of the dressing with and without peptides . We expect to see accelerated wound healing through the open porous NMs composed of the injectable hydrogel compared with commercially available Geistlich Derma gideTM composed of the injectable hydrogel. This project has the potential to develop a new class of biomaterial and create an inexpensive and effective treatment for diabetic wounds by increasing our understanding of how to inhibit biofilm formation and porosity-induced cell migration in diabetic wound closure.