Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

Abstract

BACKGROUND There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. OBJECTIVES We sought to elucidate the tissue level mechanisms underlying the therapeutic benefits of myocardial matrix injection. METHODS Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks post-injection. Whole transcriptome microarrays were performed on ribonucleic acid (RNA) isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histological quantification confirmed expression of key genes and their activation in altered pathways. RESULTS Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected controls. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing post-MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. CONCLUSIONS These results indicate that the myocardial matrix alters several key pathways post-MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.

Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen–nanodiamond hydrogel

“…Our photo-crosslinked chitosan hydrogel was degradable by lysozyme as confirmed in previous studies (41,42). Furthermore, prior studies have shown that PEG-based hydrogels have tunable degradation rates and are well tolerated (66,67), and the use of DMSO in our E2/ND/G platform was shown to have no biological effects or adverse toxicities. We used methacrylated glycol chitosan G, which enabled local delivery of E2/ND in a minimally invasive manner using blue-light assisted gelification.…”

“…In addition, ND safety and biocompatibility have been recently demonstrated in a nonhuman primate study involving systemic administration of NDs to both genders, where no apparent toxicity or impaired organ function was observed (64). Similarly, the safety and biocompatibility of hydrogels allow for their versatile applications in tissue engineering (36)(37)(38)66). Our photo-crosslinked chitosan hydrogel was degradable by lysozyme as confirmed in previous studies (41,42).…”

Extracellular matrix hydrogels from decellularized tissues: Structure and function

“…While injectability may be related to the viscoelastic properties (ECM pre-gel viscosity and gelation time), injectability has been independently confirmed in vitro and/or in vivo for heart [55, 60, 74–81], spinal cord [82], small intestine [26, 51], umbilical cord [63], skeletal muscle [63, 64, 83], tendon [59, 84], dermal [23], lung [49], liver [57], cartilage [70], urinary bladder [21, 22, 24, 82] and adipose [50, 67] ECM hydrogels with reported 18–27 gauge syringes or catheters. For example, porcine myocardial gel (6 mg/mL) was confirmed to be injectable through a 27 gauge catheter [75] , and then confirmed to be injectable via NOGA guided MyoSTAR catheter (27 gauge), which is the current gold standard delivery device used in cellular cardiomyoplasty procedures [75].…”

Three-Dimensional and Biomimetic Technology in Cardiac Injury After Myocardial Infarction: Effect of Acellular Devices on Ventricular Function and Cardiac Remodelling

“…Cardiac scafold is a therapeutic intervention with low cost and eicacy and has signiicantly improved patients' quality of life and prolonged their longevity [71][72][73][74]. The scafold must reduce local micro-environment hostility persist for a suicient time period over injured area to facilitate native cell migration and integration with native tissue to be feasible for cardiac repair/remodelling.…”

“…This model of study therefore provides an opportunity to interrogate the molecular and cellular mechanism governing regeneration of immature human heart tissue [73,77].…”