Synthesis of hyaluronan haloacetates and biology of novel cross-linker-free synthetic extracellular matrix hydrogels.
Hyaluronan (HA) derivatives containing thiol-reactive electrophilic esters were prepared to react with thiol-modified macromolecules to give cross-linker-free hydrogels. Specifically, HA was converted to two haloacetate derivatives, HA bromoacetate (HABA) and HA iodoacetate (HAIA). In cytotoxicity assays, these reactive macromolecules predictably induced cell death in a dose-dependent manner. Cross-linker-free synthetic extracellular matrix (sECM) hydrogels were prepared by thiol alkylation using HAIA and HABA as polyvalent electrophiles and thiol-modified HA (CMHA-S) with or without thiol-modified gelatin (Gtn-DTPH) as polyvalent nucleophiles. When primary human fibroblasts were seeded on the surface of the sECMs containing only the electrophilic HA haloacetate and nucleophilic CMHA-S components, no significant cytoadherence was observed. Cell attachment and viability was 17% (HABA) to 30% (HAIA) lower on HA haloacetate cross-linked hydrogels than on CMHA-S that had been oxidatively cross-linked via disulfide-bonds. In contrast, sECMs that included Gtn-DTPH allowed fibroblasts to attach, spread, and proliferate. Taken together, the HA haloacetates are attractive candidates for producing cross-linker-free sECM biomaterials that can function either as anti-adhesive barriers or as cytoadhesive sECMs for cell culture in pseudo-3-D.
Serban
Monica A
MA
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
Prestwich
Glenn D
GD
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry*; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020100:Hydrogels / Q000737:chemistry* / Q000494:pharmacology; D007461:Iodoacetates / Q000138:chemical synthesis / Q000737:chemistry*; D013387:Succinic Anhydrides / Q000737:chemistry
D000085:Acetates; D020100:Hydrogels; D007461:Iodoacetates; D013387:Succinic Anhydrides; C016274:bromoacetate; C024249:S-acetylmercaptosuccinic anhydride; D006820:Hyaluronic Acid