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

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 post-injury. 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.

Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction.

New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.

Design and characterization of an injectable pericardial matrix gel: a potentially autologous scaffold for cardiac tissue engineering.

Following ischemic injury in the heart, little to no repair occurs, causing a progressive degeneration of cardiac function that leads to congestive heart failure. Cardiac tissue engineering strategies have focused on designing a variety of injectable scaffolds that range in composition from single-component materials to complex extracellular matrix (ECM)-derived materials. In this study, the pericardial ECM, a commonly used biomaterial, was investigated for use as an injectable scaffold for cardiac repair. It was determined that a solubilized form of decellularized porcine pericardium could be injected and induced to gel in vivo, prompting investigation with human pericardium, which has the decided advantage of offering an autologous therapy. Characterization showed that the matrix gels retained components of the native pericardial ECM, with extant protein and glycosaminoglycan content identified. The results of an in vitro migration assay indicate that the porcine pericardial matrix is a stronger chemoattractant for relevant cell types, but in vivo results showed that the two materials caused statistically similar amounts of neovascularization, demonstrating feasibility as injectable treatments. Potential stem cell mobilization was supported by the presence of c-Kit+ cells within the matrix injection regions. With this work, the pericardium is identified as a novel source for an autologous scaffold for treating myocardial infarction.