title: Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation.
abstract: Bone morphogenetic proteins (BMPs) show promise in therapies for improving bone formation after injury; however, the high supraphysiological concentrations required for desired osteoinductive effects, off-target concerns, costs, and patient variability have limited the use of BMP-based therapeutics. To better understand the role of biomaterial design in BMP delivery, a matrix metalloprotease (MMP)-sensitive hyaluronic acid (HA)-based hydrogel was used for BMP-2 delivery to evaluate the influence of hydrogel degradation rate on bone repair in vivo. Specifically, maleimide-modified HA (MaHA) macromers were crosslinked with difunctional MMP-sensitive peptides to permit protease-mediated hydrogel degradation and growth factor release. The compressive, rheological, and degradation properties of MaHA hydrogels were characterized as a function of crosslink density, which was varied through either MaHA concentration (1-5wt.%) or maleimide functionalization (10-40%f). Generally, the compressive moduli increased, the time to gelation decreased, and the degradation rate decreased with increasing crosslink density. Furthermore, BMP-2 release increased with either a decrease in the initial crosslink density or an increase in collagenase concentration (non-specific MMP degradation). Lastly, two hydrogel formulations with distinct BMP-2 release profiles were evaluated in a critical-sized calvarial defect model in rats. After six weeks, minimal evidence of bone repair was observed within defects left empty or filled with hydrogels alone. For hydrogels that contained BMP-2, similar volumes of new bone tissue were formed; however, the faster degrading hydrogel exhibited improved cellular invasion, bone volume to total volume ratio, and overall defect filling. These results illustrate the importance of coordinating hydrogel degradation with the rate of new tissue formation.
authors.affiliation: 210 S 33rd St, Skirkanich Hall Rm. 240, University of Pennsylvania, Philadelphia 19104, USA. Electronic address: jhollo@seas.upenn.edu.
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Holloway
authors.affiliation: 210 S 33rd St, Skirkanich Hall Rm. 240, University of Pennsylvania, Philadelphia 19104, USA. Electronic address: henry1@seas.upenn.edu.
authors.forename: Henry
authors.initials: H
authors.lastname: Ma
authors.affiliation: 210 S 33rd St, Skirkanich Hall Rm. 240, University of Pennsylvania, Philadelphia 19104, USA. Electronic address: rair@vet.upenn.edu.
authors.forename: Reena
authors.initials: R
authors.lastname: Rai
authors.affiliation: 210 S 33rd St, Skirkanich Hall Rm. 240, University of Pennsylvania, Philadelphia 19104, USA. Electronic address: burdick2@seas.upenn.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D017364:Collagenases / Q000378:metabolism; D019245:Compressive Strength; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006820:Hyaluronic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D020100:Hydrogels; D007700:Kinetics; D008297:Male; D008301:Maleimides / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011859:Radiography; D017207:Rats, Sprague-Dawley; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D055396:Bone Morphogenetic Protein 2; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D008301:Maleimides; D010455:Peptides; C043592:maleimide; D006820:Hyaluronic Acid; D017364:Collagenases
keywords: Bone morphogenetic protein; Bone repair; Calvarial defect; Hyaluronic acid; Hydrogel