Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Abstract

A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (∼8 versus ∼43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.L eft ventricular (LV) remodeling caused by a myocardial infarction (MI) is responsible for almost 70% of the 5 million cases of heart failure that have occurred in the United States in recent years (1). Early infarct expansion or stretching has been associated with poor long-term prognosis (2-4) and has been identified as the mechanical phenomenon that initiates and sustains the process of adverse post-MI LV remodeling that leads to heart failure (5-10). Infarct expansion causes abnormal stress distribution in myocardial regions outside the infarction, especially in the adjacent borderzone region, putting this region at a mechanical disadvantage. With time, increased regional stress is the impetus for several maladaptive biologic processes, such as myocyte apoptosis and matrix metalloproteinase activation, that inherently alter the contractile properties of normally perfused myocardium (11,12). Once initiated, these maladaptive processes lead to a heart failure phenotype that is difficult to reverse by medical or surgical means.We have demonstrated that ventricular restraint early after MI reduces infarct expansion and limits long-term global LV remodeling in large-animal infarction models (10, 13-16). To circumvent the surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials to limit infarct expansion and normalize the regional stress distribution (17-26). Such an approach offers th...

Injectable Acellular Hydrogels for Cardiac Repair

“…This study demonstrated that although both materials similarly thickened, or bulked, the infarcted myocardial wall, high MeHA was able to also decrease infarct size and dilation as well as improve function under stress compared to the infarct control. This provides evidence that the mechanical properties of the injectable [61] material are important to consider for attenuating LV remodeling. Studies with tunable injectable materials will broaden the understanding of factors, such as mechanics and degradation that should be regarded to target LV remodeling via bulking agents.…”

“…Improvements with hydrogel injection were attributed to the biological role of HA, which like fibrin has proven to play a large role in wound healing processes. Additional work with engineered HA hydrogels [61] will be discussed in a section below on modulating hydrogel properties.…”

“…3) [61]. A highly modified HA polymer (methacrylated HA (MeHA)) with a high compressive modulus (43 kPa) was directly compared to lower modified MeHA with a low compressive modulus (7.7 kPa).…”

A Fast pH‐Switchable and Self‐Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

“…Natural hydrogels for myocardial injection therapies that have been investigated include fi brin, [ 9 ] collagen, [ 10 ] alginate, [ 11 ] Matrigel, [ 12 ] hyaluronic acid, [ 13 ] and chitosan. [ 14 ] These hydrogels can potentially be delivered in combination with cells or drugs, however, they are derived from a natural source and therefore show batch-to-batch differences.…”

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

“…Moreover, cell loss in the process of aggregate formation and mechanical injury to the cells during injection are still inevitable. Alternatively, biomaterial-assisted cell delivery approaches have been developed in which responsive biomaterials (e.g., thermal or pH-sensitive hydrogel) can be coinjected with the cells in aqueous form at ambient condition and cross-linked in situ in the body to realize gelation and cell encapsulation (16). However, in situ cross-linked biomaterials such as hydrogel do not allow priming of cells, which could facilitate ECM accumulation and cell-cell interactions for construction of the cellular niche in vitro before transplantation, resulting in immediate exposure of the delivered cells to ischemic and inflammatory microenvironment at the lesion sites.…”