Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

Abstract

Peripheral artery disease (PAD) currently affects approximately 27 million patients in Europe and North America, and if untreated, may progress to the stage of critical limb ischemia (CLI), which has implications for amputation and potential mortality. Unfortunately, few therapies exist for treating the ischemic skeletal muscle in these conditions. Biomaterials have been used to increase cell transplant survival as well as deliver growth factors to treat limb ischemia; however, existing materials do not mimic the native skeletal muscle microenvironment they are intended to treat. Furthermore, no therapies involving biomaterials alone have been examined. The goal of this study was to develop a clinically relevant injectable hydrogel derived from decellularized skeletal muscle extracellular matrix and examine its potential for treating PAD as a stand-alone therapy by studying the material in a rat hindlimb ischemia model. We tested the mitogenic activity of the scaffold's degradation products using an in vitro assay and measured increased proliferation rates of smooth muscle cells and skeletal myoblasts compared to collagen. In a rat hindlimb ischemia model, the femoral artery was ligated and resected, followed by injection of 150 µL of skeletal muscle matrix or collagen 1 week postinjury. We demonstrate that the skeletal muscle matrix increased arteriole and capillary density, as well as recruited more desmin-positive and MyoD-positive cells compared to collagen. Our results indicate that this tissue-specific injectable hydrogel may be a potential therapy for treating ischemia related to PAD, as well as have potential beneficial effects on restoring muscle mass that is typically lost in CLI.

Biologic Scaffolds

“…ECM hydrogels from different source tissues have been shown to support in vitro cell growth of different cell types, including ECs, smooth muscle, myoblasts, cardiomyocytes (Freytes et al 2008a), cardiovascular progenitor cells (Williams et al 2015), and primary calvarial cells (Sawkins et al 2013). ECM hydrogels have also been shown to support myogenesis (DeQuach et al 2012;Wolf et al 2012) and to recruit cardiomyocytes in vivo (Singelyn et al 2012).…”

Biomaterials based strategies for skeletal muscle tissue engineering: Existing technologies and future trends

“…A solution to this problem could be the conversion of ECM into a hydrogel which is better at space filling, and adopts the shape of the defect. De Quach and colleagues demonstrated this by using decellularized skeletal muscle to produce injectable hydrogels by a two-stage freezing and lyophilization method, and studied its influence on skeletal muscle cell proliferation and angiogenesis [119]. This method could destroy the existing vascular framework and overall architecture of the native tissue, but likely preserves the protein signals and cytokines which could promote angiogenesis.…”

Efficacy, safety and influencing factors of intra‑calf muscular injection of bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus‑induced lower extremity vascular disease

“…The stem cell recruiting ability is decreased in patients with DM, as late glycation end-products may inhibit the proliferation and migration of the stem cells (3). Furthermore, reduced neovascularization, collagen matrix formation disorders or infection may cause ischemia or delay the repair of damaged tissues, and thus impede wound healing (4). Currently, medical treatments are ineffective and surgical intervention or vascular bypass surgery is only suitable for certain patients, which causes DM treatment to be challenging and affects patient prognosis.…”