TY - JOUR
T1 - Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation
AU - Holloway, Julianne L.
AU - Ma, Henry
AU - Rai, Reena
AU - Burdick, Jason A.
N1 - Funding Information:
The authors would like to acknowledge the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health (NIH), for funding under Award Number 5F32 AR063598 . Additional funding was provided by the Department of Defense under Grant Number OR090203 . The authors would also like to acknowledge the research division within Philadelphia's Veterans Affairs Medical Center and Dr. Kurt Hankenson at the University of Pennsylvania for use of their μCT and X-Ray facilities, respectively.
PY - 2014/10/10
Y1 - 2014/10/10
N2 - 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 ofMaHA hydrogelswere characterized as a function of crosslink density, which was varied through either MaHA concentration (1-5 wt.%) 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 formulationswith distinct BMP-2 release profileswere evaluated in a critical-sized calvarial defect model in rats. After six weeks, minimal evidence of bone repair was observedwithin 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.
AB - 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 ofMaHA hydrogelswere characterized as a function of crosslink density, which was varied through either MaHA concentration (1-5 wt.%) 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 formulationswith distinct BMP-2 release profileswere evaluated in a critical-sized calvarial defect model in rats. After six weeks, minimal evidence of bone repair was observedwithin 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.
KW - Bone morphogenetic protein
KW - Bone repair
KW - Calvarial defect
KW - Hyaluronic acid
KW - Hydrogel
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U2 - 10.1016/j.jconrel.2014.05.053
DO - 10.1016/j.jconrel.2014.05.053
M3 - Article
C2 - 24905414
AN - SCOPUS:84906946132
SN - 0168-3659
VL - 191
SP - 63
EP - 70
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -