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.
