UC San Diego
Structurally Dynamic Biosynthetic Polymers for Myocardial Tissue Engineering
- Author(s): Carlini, Andrea Sylvia
- Advisor(s): Gianneschi, Nathan C.
- et al.
In recent history, application of macromolecular biomaterials for therapeutic tissue engineering after severe injury has presented a promising strategy to for positive remodeling. Herein, the design of structurally dynamic vehicles for noninvasive delivery and stimuli-responsive self-assembly is investigated. These proof-of-concept platforms were explored for the purpose of expanding the utility of insert biomaterial platforms for practical clinical applications. Ultimately, we envision formulation with biotherapeutics will provide a smart mechanism for treating inflammatory diseases.
First, nanomaterials were designed to respond to matrix metalloproteinases (MMPs) and acutely upregulated at the site of myocardial infarction (MI). Ring opening metathesis polymerization (ROMP) of a brush peptide-polymer amphiphile was explored to generate intravenous (IV) injectable 20 nm nanoparticles that respond to MMP-2/9 through self-assembly into micron-scale aggregate scaffolds. The in vivo targeting efficiency, biodistribution, and toxicity of such constructs was investigated. These materials demonstrate targeted accumulation, nonimmunogenicity, and prolonged retention up to 30 days at the site of MI.
Cyclic peptide progelators were designed as structurally dynamic and biodegradable materials for targeted hydrogelation at the site of myocardial infarction. Self-assembling peptides (SAPs), which stack as β-sheets via intermolecular electrostatic, hydrophobic, and in some cases, π-π interactions were sterically constrained through macrocyclization. This modified construct was sufficient to prevent gelation and lower sample viscosity, enabling delivery via minimally invasive catheter delivery. These peptides respond to MMP-2/9 and elastase upregulated at the MI, as well as to the robust nonspecific protease, thermolysin, through self-assembly into viscoelastic hydrogels. Hemocompatibility and in vivo response of one such construct demonstrated the utility of this platform design.
Next, the strategy for generation of catheter-injectable SAPs was expanded into pH-sensitive low viscosity progelators. The pH-responsiveness of the KLD-12 SAP was tuned via temporary modification with substituted maleamic acids to afford polyanionic peptide solutions. The deprotection of these “caps” recapitulates the zwitterionic KLD-12 SAP under physiologically relevant levels of tissue acidosis (pH 6.8). Progelators were catheter injectable and hemocompatible, whereas acid-treated samples produce solid gels that resist material spreading and are reheable. Finally, this platform exhibited acid-induced drug encapsulation, a useful property for targeted therapeutics without complex synthetic manipulation.
Finally, we turned back to nondegradable ROMP co-polymers for studying architectural influence on biomimetic hydrogel assembly. Three amino acid-functionalized monomers were designed to mimic the alternating KLD-12 SAP cationic, neutral hydrophobic, and anionic charges, respectively, that imbue self-assembling behavior. Modification to the degree of polymerization (DP), number of blocks, block lengths, and hydrophobicicity, were explored to investigate their propensity for hydrogel self-assembly and stability. This investigation provides general insight into physical hydrogel polymer design as well as proteolytic-resistant biomaterials for potential applications as long-term implantable hydrogels.