Abstract
Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). However, most hydrogels tested in preclinical studies are not candidates for minimally invasive catheter delivery due to excess material viscosity, rapid gelation times, and/or concerns regarding hemocompatibility and potential for embolism. We describe a platform technology for progelator materials formulated as sterically constrained cyclic peptides which flow freely for low resistance injection, and rapidly assemble into hydrogels when linearized by disease-associated enzymes. Their utility in vivo is demonstrated by their ability to flow through a syringe and gel at the site of MI in rat models. Additionally, synthetic functionalization enables these materials to flow through a cardiac injection catheter without clogging, without compromising hemocompatibility or cytotoxicity. These studies set the stage for the development of structurally dynamic biomaterials for therapeutic hydrogel delivery to the MI.
Highlights
Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI)
We began with a gellable core based on a model self-assembling peptides (SAPs) consisting of the repeat sequence (KLDL)[3], which has been studied as a non-immunogenic, non-hemolytic, and antimicrobial scaffold for tissue engineering applications[39,40,41]
We first evaluated whether the addition of non-gelling amino acids from the matrix metalloproteinases (MMPs)-2/9 recognition sequence (PLG|LAG) and cysteine residues used for macrocyclization into the SAP sequences would interfere with their ability to self-assemble (Fig. 2a)
Summary
Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). Despite many successful preclinical studies, wide spread translation and initiation of clinical trials has been slow, with current studies limited to a myocardial ECM hydrogel (clinicaltrials.gov identifier NCT02305602) and alginate (NCT3082508 and NCT01311791) One reason for this lack of translation is that the majority of these hydrogels are not candidates for minimally invasive catheter delivery because of excess material viscosity, their quick gelling nature that can lead to catheter clogging, and concerns regarding hemocompatibility since materials can leak into the bloodstream upon injection into a beating heart[15,16,17]. We demonstrated that soluble peptide–polymerbased nanoparticles can aggregate into macromolecular scaffolds in diseased tissue through the action of endogenously expressed inflammatory-related enzymes, MMPs, providing a viable method for targeted accumulation[24], prolonged tissue retention[25], and therapeutic delivery[26] These materials employed a nonbiodegradable functionalized polynorbornene backbone and did not possess viscoelastic properties. MMP-2/92,31 and elastase[32,33], which are endogenously expressed at the site of MI during the acute inflammatory (days) and fibrotic (weeks) phases, provide a useful handle, playing key roles in the healing process through degradation of ECM and fibrinogen[2]
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