Developing hyaluronic acid based hydrogels as potential immunomodulatory myocardial supports in heart failure

Cardiomyopathy and a myocardial infarction are the leading drivers of heart failure caused by damaging and weakening myocardial tissue. Patients with heart failure have a reduced quality of life and shortened life expectancy. Current treatments and medical devices fail to directly prevent mechanical weakening, therefore stabilisation of the ventricle wall is a promising strategy to treat heart failure. Hydrogels as soft tissue supports are currently being investigated in clinical trials to prevent myocardial wall weakening. As hyaluronic acid hydrogels are known for exhibiting remarkable compressive and mechanical tuning abilities across a range of diseases and condition, they could become a hydrogel treatment solution by preventing myocardial wall thinning, and therefore the development of heart failure. This thesis aims to characterise hyaluronic acid-tyramine hydrogels as candidates for future myocardial stabilisation by studying different hydrogel formulations under compression and torsional tests, reflecting the forces exerted within a myocardial wall. Candidate hydrogels were selected based on their mechanical properties in the range similar to healthy and scarred myocardial tissue. The immunomodulatory peptide therapeutic Sm16, was used as a strategy to reduce the likelihood of a negative immune response to the implantation of the hyaluronic acid-tyramine hydrogels. Candidate hydrogels were able to encapsulate and release bioactive Sm16. The release profile varied from the hydrogels due to the difference in mechanical properties and crosslinking networks, which affected the entrapment and release kinetics of Sm16. Following release, Sm16 importantly remained bioactive by preventing the production of IL-6 and TNF-α in macrophages following the application of lipopolysaccharide which was used as a trigger to induce inflammation. Hyaluronic acid-tyramine hydrogels loaded with Sm16 were implanted into the subcutaneous space of Balb/c mice to assess the biocompatibility of these hydrogel candidates. After fourteen days of implantation, no adverse inflammatory response was observed with a systemic release of Sm16 achieved from candidate hydrogels. Hyaluronic acid-tyramine hydrogels are therefore suitable carriers for Sm16, capable of altering the release profile without negatively impacting its bioactivity. Finally, these hydrogels were deliverable through a catheter-like set up which was used to mimic delivery for future clinical translation. Sm16 was also tested on a cardiac cell line and significantly reduced production of pro-inflammatory cytokines IL-6 and TNF-α, indicating its potential for immunomodulation in cardiac tissue. Hydrogels developed in this thesis have the potential to act as supportive interventions in early heart failure. By tuning the mechanical, hydration, and degradation properties of hydrogels, they can play a crucial role supporting the weakened myocardium, with Sm16 immunomodulation attenuating any issued related to tissue inflammatory responses.

Funder

Science Foundation Ireland

Publisher

University of Galway

Rights

Attribution-NonCommercial-NoDerivatives 4.0 International

cbn

Collections

University of Galway Theses (PhD Theses)