title: In vivo response to dynamic hyaluronic acid hydrogels.
abstract: Tissue-specific elasticity arises in part from developmental changes in extracellular matrix over time, e.g. ~10-fold myocardial stiffening in the chicken embryo. When this time-dependent stiffening has been mimicked in vitro with thiolated hyaluronic acid (HA-SH) hydrogels, improved cardiomyocyte maturation has been observed. However, host interactions, matrix polymerization, and the stiffening kinetics remain uncertain in vivo, and each plays a critical role in therapeutic applications using HA-SH. Hematological and histological analysis of subcutaneously injected HA-SH hydrogels showed minimal systemic immune response and host cell infiltration. Most importantly, subcutaneously injected HA-SH hydrogels exhibited time-dependent porosity and stiffness changes at a rate similar to hydrogels polymerized in vitro. When injected intramyocardially host cells begin to actively degrade HA-SH hydrogels within 1week post-injection, continuing this process while producing matrix to nearly replace the hydrogel within 1month post-injection. While non-thiolated HA did not degrade after injection into the myocardium, it also did not elicit an immune response, unlike HA-SH, where visible granulomas and macrophage infiltration were present 1month post-injection, likely due to reactive thiol groups. Altogether these data suggest that the HA-SH hydrogel responds appropriately in a less vascularized niche and stiffens as had been demonstrated in vitro, but in more vascularized tissues, in vivo applicability appears limited.
authors.affiliation: Department of Bioengineering, University of California, San Diego, CA 92093, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Young
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tuler
authors.forename: Rebecca
authors.initials: R
authors.lastname: Braden
authors.forename: Pamela
authors.initials: P
authors.lastname: Schüp-Magoffin
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Schaefer
authors.forename: Kyle
authors.initials: K
authors.lastname: Kretchmer
authors.forename: Karen L
authors.initials: KL
authors.lastname: Christman
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage* / Q000737:chemistry; D002478:Cells, Cultured; D055119:Elastic Modulus / Q000187:drug effects; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry; D007273:Injections, Intramuscular; D008422:Materials Testing; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000008:administration & dosage*
chemical_list: D001672:Biocompatible Materials; D020100:Hydrogels; D013438:Sulfhydryl Compounds; D006820:Hyaluronic Acid