Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation.
Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation.
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DOI：
10.1016/j.jconrel.2014.05.053
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发表时间：
2014-10-10
期刊：
影响因子：
--
通讯作者：
Burdick JA
中科院分区：
文献类型：
--
作者：
Holloway JL;Ma H;Rai R;Burdick JA
骨形态发生蛋白（BMPs）在促进损伤后骨形成的治疗中显示出希望；然而，为达到理想的骨诱导效果所需的高生理浓度、脱靶问题、成本和患者的可变性限制了基于bmp的治疗方法的使用。为了更好地了解生物材料设计在BMP递送中的作用，我们采用基质金属蛋白酶（MMP）敏感透明质酸（HA）为基础的水凝胶用于BMP-2递送，以评估水凝胶降解率对骨修复的体内影响。具体来说，马来酰亚胺修饰的HA （MaHA）大分子与双功能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、流变和降解性能是交联密度的函数，交联密度随MaHA浓度（1-5 wt%）或马来酰亚胺功能化（10 - 40% f）而变化。总的来说，随着交联密度的增加，压缩模量增加，凝胶化时间缩短，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（非特异性MMP降解）的增加而增加。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释放谱的水凝胶配方。六周后，在空白或仅用水凝胶填充的缺陷中观察到骨修复的最小证据。对于含有BMP-2的水凝胶，形成了相似体积的新骨组织；然而，更快降解的水凝胶表现出更好的细胞侵袭，骨体积与总体积比和整体缺陷填充。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。
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 (1–5 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 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.
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DOI：
10.1002/jbm.10011
发表时间：
2002-03-05
期刊：
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH
影响因子：
--
作者：
Kim, HD;Valentini, RF
通讯作者：
Valentini, RF
影响因子：
2.9
作者：
BITTER, T;MUIR, HM
通讯作者：
MUIR, HM
影响因子：
41.2
作者：
Khetan S;Guvendiren M;Legant WR;Cohen DM;Chen CS;Burdick JA
通讯作者：
Burdick JA
DOI：
10.1073/pnas.0737381100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Lutolf, MP;Lauer-Fields, JL;Hubbell, JA
通讯作者：
Hubbell, JA
影响因子：
3
作者：
Boden, SD;Kang, J;Heller, JG
通讯作者：
Heller, JG