title: Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium.
abstract: Injection of a bulking material into the ventricular wall has been proposed as a therapy to prevent progressive adverse remodeling due to high wall stresses that develop after myocardial infarction. Our objective was to design, synthesize and characterize a biodegradable, thermoresponsive hydrogel for this application based on copolymerization of N-isopropylacrylamide (NIPAAm), acrylic acid (AAc) and hydroxyethyl methacrylate-poly(trimethylene carbonate) (HEMAPTMC). By evaluating a range of monomer ratios, poly(NIPAAm-co-AAc-co-HEMAPTMC) at a feed ratio of 86/4/10 was shown to be ideal since it formed a hydrogel at 37 degrees C, and gradually became soluble over a 5 month period in vitro through hydrolytic cleavage of the PTMC residues. HEMAPTMC, copolymer and degradation product chemical structures were verified by NMR. No degradation product cytotoxicity was observed in vitro. In a rat chronic infarction model, the infarcted left ventricular (LV) wall was injected with the hydrogel or phosphate buffered saline (PBS). In the PBS group, LV cavity area increased and contractility decreased at 8 wk (p<0.05 versus pre-injection), while in the hydrogel group both parameters were preserved during this period. Tissue ingrowth was observed in the hydrogel injected area and a thicker LV wall and higher capillary density were found for the hydrogel versus PBS group. Smooth muscle cells with contractile phenotype were also identified in the hydrogel injected LV wall. The designed poly(NIPAAm-co-AAc-co-HEMAPTMC) hydrogel of this report may thus offer an attractive biomaterial-centered treatment option for ischemic cardiomyopathy.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Kazuro L
authors.initials: KL
authors.lastname: Fujimoto
authors.forename: Zuwei
authors.initials: Z
authors.lastname: Ma
authors.forename: Devin M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Jianjun
authors.initials: J
authors.lastname: Guan
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Tobita
authors.forename: William R
authors.initials: WR
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006334:Heart Function Tests; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007150:Immunohistochemistry; D007267:Injections; D009682:Magnetic Resonance Spectroscopy; D008422:Materials Testing; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D051381:Rats; D012996:Solutions; D013696:Temperature; D014463:Ultrasonography
chemical_list: D001672:Biocompatible Materials; D002148:Calmodulin-Binding Proteins; D012996:Solutions; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate