Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
Biomater Sci. 2021 Mar 10;9(5):1668-1682. doi: 10.1039/d0bm01728k.
Bone nonunions arising from large bone defects and composite injuries remain compelling challenges for orthopedic surgeons. Biological changes associated with nonunions, such as systemic immune dysregulation, can contribute to an adverse healing environment. Bone morphogenetic protein 2 (BMP-2), an osteoinductive and potentially immunomodulatory growth factor, is a promising strategy; however, burst release from the clinical standard collagen sponge delivery vehicle can result in adverse side effects such as heterotopic ossification (HO) and irregular bone structure, especially when using supraphysiological BMP-2 doses for complex injuries at high risk for nonunion. To address this challenge, biomaterials that strongly bind BMP-2, such as heparin methacrylamide microparticles (HMPs), may be used to limit exposure and spatially constrain proteins within the injury site. Here, we investigate moderately high dose BMP-2 delivered in HMPs within an injectable hydrogel system in two challenging nonunion models exhibiting characteristics of systemic immune dysregulation. The HMP delivery system increased total bone volume and decreased peak HO compared to collagen sponge delivery of the same BMP-2 dose. Multivariate analyses of systemic immune markers showed the collagen sponge group correlated with markers that are hallmarks of systemic immune dysregulation, including immunosuppressive myeloid-derived suppressor cells, whereas the HMP groups were associated with immune effector cells, including T cells, and cytokines linked to robust bone regeneration. Overall, our results demonstrate that HMP delivery of moderately high doses of BMP-2 promotes repair of complex bone nonunion injuries and that local delivery strategies for potent growth factors like BMP-2 may positively affect the systemic immune response to traumatic injury.
大骨缺损和复合伤引起的骨不连仍然是骨科医生面临的巨大挑战。与骨不连相关的生物学变化，如全身免疫失调，可能导致不良的愈合环境。骨形态发生蛋白 2（BMP-2）是一种具有成骨作用和潜在免疫调节作用的生长因子，是一种很有前途的策略；然而，从临床标准的胶原海绵给药载体中突然释放可能会导致不良反应，如异位骨化（HO）和不规则的骨结构，特别是在使用超生理剂量的 BMP-2 治疗高风险的复杂骨不连时。为了解决这一挑战，可以使用能够强烈结合 BMP-2 的生物材料，如肝素甲基丙烯酰胺微球（HMPs），来限制暴露并在损伤部位空间限制蛋白质。在这里，我们在两个表现出全身免疫失调特征的具有挑战性的骨不连模型中研究了在可注射水凝胶系统中以中等剂量 BMP-2 输送 HMPs 的情况。与相同 BMP-2 剂量的胶原海绵给药相比，HMP 给药系统增加了总骨体积，减少了峰值 HO。对系统免疫标志物的多变量分析表明，胶原海绵组与全身免疫失调的标志物相关，包括免疫抑制性髓系来源的抑制细胞，而 HMP 组与免疫效应细胞相关，包括 T 细胞和与强有力的骨再生相关的细胞因子。总的来说，我们的结果表明，HMP 输送中等剂量的 BMP-2 可促进复杂骨不连损伤的修复，并且像 BMP-2 这样的有效生长因子的局部给药策略可能会对创伤性损伤的全身免疫反应产生积极影响。
