Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA.
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA.
Biomaterials. 2014 Jul;35(21):5453-61. doi: 10.1016/j.biomaterials.2014.03.055. Epub 2014 Apr 13.
Non-healing bone defects present tremendous socioeconomic costs. Although successful in some clinical settings, bone morphogenetic protein (BMP) therapies require supraphysiological dose delivery for bone repair, raising treatment costs and risks of complications. We engineered a protease-degradable poly(ethylene glycol) (PEG) synthetic hydrogel functionalized with a triple helical, α2β1 integrin-specific peptide (GFOGER) as a BMP-2 delivery vehicle. GFOGER-functionalized hydrogels lacking BMP-2 directed human stem cell differentiation and produced significant enhancements in bone repair within a critical-sized bone defect compared to RGD hydrogels or empty defects. GFOGER functionalization was crucial to the BMP-2-dependent healing response. Importantly, these engineered hydrogels outperformed the current clinical carrier in repairing non-healing bone defects at low BMP-2 doses. GFOGER hydrogels provided sustained in vivo release of encapsulated BMP-2, increased osteoprogenitor localization in the defect site, enhanced bone formation and induced defect bridging and mechanically robust healing at low BMP-2 doses which stimulated almost no bone regeneration when delivered from collagen sponges. These findings demonstrate that GFOGER hydrogels promote bone regeneration in challenging defects with low delivered BMP-2 doses and represent an effective delivery vehicle for protein therapeutics with translational potential.
非愈合性骨缺损带来了巨大的社会经济成本。尽管在某些临床环境中取得了成功，但骨形态发生蛋白 (BMP) 治疗需要超生理剂量的递送才能进行骨修复，从而增加了治疗成本和并发症风险。我们设计了一种由蛋白酶可降解的聚乙二醇 (PEG) 合成水凝胶组成，该水凝胶经过功能化处理，具有三螺旋、α2β1 整合素特异性肽 (GFOGER)，可用作 BMP-2 的递送载体。与 RGD 水凝胶或空缺陷相比，缺乏 BMP-2 的 GFOGER 功能化水凝胶指导人干细胞分化，并在临界尺寸骨缺损内产生显著增强的骨修复。GFOGER 功能化对于 BMP-2 依赖性愈合反应至关重要。重要的是，这些工程水凝胶在低 BMP-2 剂量下修复非愈合性骨缺损的效果优于当前的临床载体。GFOGER 水凝胶提供了包封的 BMP-2 的持续体内释放，增加了缺陷部位成骨前体细胞的定位，增强了骨形成，并诱导了缺陷桥接和机械坚固的愈合，而当从胶原海绵递送时，BMP-2 几乎没有刺激骨再生。这些发现表明，GFOGER 水凝胶可在低剂量 BMP-2 下促进挑战性缺陷中的骨再生，是具有转化潜力的蛋白质治疗的有效递送载体。
