Holloway Julianne L, Ma Henry, Rai Reena, Burdick Jason A
210 S 33rd St, Skirkanich Hall Rm. 240, University of Pennsylvania, Philadelphia 19104, USA.
J Control Release. 2014 Oct 10;191:63-70. doi: 10.1016/j.jconrel.2014.05.053. Epub 2014 Jun 4.
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.
骨形态发生蛋白（BMPs）在改善损伤后骨形成的治疗中显示出前景；然而，实现所需骨诱导作用所需的高超生理浓度、脱靶问题、成本以及患者个体差异限制了基于BMP的治疗方法的应用。为了更好地理解生物材料设计在BMP递送中的作用，一种基于基质金属蛋白酶（MMP）敏感的透明质酸（HA）的水凝胶被用于递送BMP-2，以评估水凝胶降解速率对体内骨修复的影响。具体而言，马来酰亚胺修饰的HA（MaHA）大分子单体与双功能MMP敏感肽交联，以允许蛋白酶介导的水凝胶降解和生长因子释放。MaHA水凝胶的压缩、流变学和降解特性被表征为交联密度的函数，交联密度通过MaHA浓度（1-5wt.%）或马来酰亚胺功能化（10-40%f）而变化。一般来说，随着交联密度的增加，压缩模量增加，凝胶化时间减少，降解速率降低。此外，BMP-2的释放随着初始交联密度的降低或胶原酶浓度的增加（非特异性MMP降解）而增加。最后，在大鼠临界尺寸颅骨缺损模型中评估了两种具有不同BMP-2释放曲线的水凝胶制剂。六周后，在空的或仅填充有水凝胶的缺损内观察到骨修复的证据极少。对于含有BMP-2的水凝胶，形成了相似体积的新骨组织；然而，降解较快的水凝胶表现出改善的细胞侵袭、骨体积与总体积比以及整体缺损填充情况。这些结果说明了协调水凝胶降解与新组织形成速率的重要性。
