Inflammation Triggerable Peptide Hydrogel Materials for Targeting Damaged Heart Tissue following Myocardial Infarction
Self-Assembling Peptides (SAPs) are described, capable of catheter delivery and accumulation in damaged heart tissue after myocardial infarction (MI). We propose this as a platform technology for the delivery of biomaterials and therapeutics to the heart after MI, capable of aiding in the healing process.
In this paper, we describe a new class of biomaterial for delivery to the heart following heart attack. The materials fall into a broad category of self-assembling peptides (SAPs), that have been used in preclinical studies in myocardial infarction (MI) models, but suffer a key deficiency before they can be translated to the clinic. Simply, the SAPs so far developed are not amenable to miniminally invasive, catheter-based delivery because of their high viscosity. Here, we describe a new design, enabling injection of SAPs as engineered biomedical materials.
The key design feature is a cyclic, topologically restrained gelling peptide, that springs open in response to enzymes associated with the inflammatory response. We were inspired to design this type of material by the work of Nilsson and coworkers, who deployed a chemically responsive, triggered peptide gelator. We reasoned this design could be used to generate materials that are progelators for injection, wherein enzymatic signals associated with inflammation would cause gelation in vivo to accumulate materials at the site of MI (Bowerman, C. J. & Nilsson, B. L. A Reductive Trigger for Peptide Self-Assembly and Hydrogelation. Journal of the American Chemical Society132, 9526-9527, doi:10.1021/ja1025535 (2010)).
Injectable biopolymer hydrogels have gained increasing attention for clinical translation as engineered biomedical scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-MI. However, the majority of hydrogels tested are not candidates for minimally invasive catheter delivery because of excess material viscosity, rapid gelation times, and concerns regarding hemocompatibility and potential for embolism. As a result, clinical translation of most injectable biomaterials for the heart has been hindered. Solutions are needed for this broad class of promising biomaterial.
The versatility of our platform is shown through the functionalization of two different SAP sequences, which exhibit disparate self-assembly mechanisms, and yet form progelators with identical responsiveness. Hemocompatibility analyses and in vivo application in a rat ischemia repurfusion model provide evidence that our simple synthetic modifications do not induce toxicity nor alter the capacity to self-assemble within a biological environment. Finally, we demonstrate that labeling of our progelators with a small molecule dye (rhodamine) does not interfere with self-assembly. Thus we envision that a chemically complex hydrogel can be generated in vivo through a simple mixture of different progelators, each bearing a small molecule drug, tag, or reactive moiety.
The work presented in this article sets the stage for structurally dynamic biomaterials for therapeutic hydrogel delivery to the heart for the prevention of negative LV remodeling following MI.