A liposome/gelatin methacrylate nanocomposite hydrogel system for delivery of stromal cell-derived factor-1α and stimulation of cell migration

Chronic, non-healing skin and soft tissue wounds are susceptible to infection, difficult to treat clinically, and can severely reduce a patient's quality of life. A key aspect of this issue is the impaired recruitment of mesenchymal stem cells (MSCs), which secrete regenerative cytokines and modulate the phenotypes of other effector cells that promote healing. We have engineered a therapeutic delivery system that can controllably release the pro-healing chemokine stromal cell derived factor-1α (SDF-1α) to induce the migration of MSCs. In order to protect the protein cargo from hydrolytic degradation and control its release, we have loaded SDF-1α in anionic liposomes (lipoSDF) and embedded them in gelatin methacrylate (GelMA) to form a nanocomposite hydrogel. In this study, we quantify the release of SDF-1α from our hydrogel system and measure the induced migration of MSCs in vitro via a transwell assay. Lastly, we evaluate the ability of this system to activate intracellular signaling in MSCs by using Western blots to probe for the phosphorylation of key proteins in the mTOR pathway. To our knowledge, this is the first study to report the delivery of liposomal SDF-1α using a nanocomposite approach. The results of this study expand on our current understanding of factors that can be modified to affect MSC behavior and phenotype. Furthermore, our findings contribute to the development of new hydrogel-based therapeutic delivery strategies for clinical wound healing applications. STATEMENT OF SIGNIFICANCE: Chronic, non-healing wounds promote an inflammatory environment that inhibits the migration of mesenchymal stem cells (MSCs), which secrete pro-healing and regenerative cytokines. The goal of this project is to apply principles of tissue engineering to achieve controllable release of the pro-healing chemokine SDF-1α to modulate the intracellular signaling and migratory behavior of MSCs. In this work, we introduce a nanocomposite strategy to tailor the release of SDF-1α using a liposome/gelatin methacrylate hydrogel approach. We are the first group to report the delivery of liposomal SDF-1α using this strategy. Our findings aim to further elucidate the role of MSCs in directing wound healing and guide the development of immunomodulatory and therapeutic delivery strategies for clinical wound healing applications.