Tuesday, April 30, 2024
4/30/2024
Project summary/Abstract Skeletal muscle has a remarkable regenerative capability when the extent of the injury is relatively minor. However, following traumatic muscle injuries such as volumetric muscle loss (VML), the endogenous repair potential of skeletal muscle becomes inadequate, which causes physical disability and adversely influences the quality of life. Biomaterial scaffolds hold great promise for improving the functional recovery of skeletal muscle by providing both physical and biochemical cues to facilitate cell adhesion, migration, proliferation, and differentiation. Particularly, acellular scaffolds are promising and clinically transformative as they obviate limitations associated with using exogenous cells, including limited sources and immunogenicity. However, existing acellular bioscaffolds have failed to induce the formation of a sufficient amount of de novo myofibers and achieve appreciable muscle functional improvement, limitations that have been largely attributed to the poor ability of acellular scaffolds to recruit endogenous cells, especially muscle stem cells (MuSCs). Therefore, developing an acellular scaffold capable of active cell recruitment represents a major technological advance in the treatment of VML. Inspired by the native tissues such as skin that generate electrical signals to guide cell migration during injury repair, we propose to develop a biodegradable piezoelectric scaffold comprised of a fibrin- based hydrogel containing boron nitride nanotubes (fibrin/BNNTs). Our scaffold is designed to convert mechanical stimuli (e.g., via ultrasound and exercise-induced muscle contraction) to electrical signals with the goal of promoting cell recruitment. In this proposal, we will test our central hypothesis that, upon ultrasound stimulation, fibrin/BNNTs piezoelectric scaffolds enhance endogenous cell recruitment and MuSC differentiation, thus accelerating the functional recovery of skeletal muscle after VML. Two specific aims are proposed to test our central hypothesis. Specific Aim 1 studies will optimize the fibrin/BNNTs scaffold composition and ultrasound stimulation to promote MuSC recruitment and myogenic differentiation in vitro using a novel 3D VML muscle construct model. In Specific Aim 2, using our validated VML male and female mouse models, we will evaluate the ability of ultrasound-stimulated piezoelectric scaffolds to promote in vivo skeletal muscle regeneration, and we will evaluate whether these effects are sex-dependent. We anticipate that the successful completion of these studies will not only offer a promising new strategy for enhancing skeletal muscle regeneration but also provide novel insights into scaffold design for other applications, such as skin and cardiac regeneration.
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