Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
Department of Comparative Medicine, Medical University of South Carolina, Division of Lab Animal Resources 30 Courtenay Drive, Charleston, South Carolina.
Wound Repair Regen. 2019 Jul;27(4):335-344. doi: 10.1111/wrr.12710. Epub 2019 Mar 9.
Large bone injuries, defects, and chronic wounds present a major problem for medicine. Several therapeutic strategies are used clinically to precipitate bone including a combination therapy delivering osteoinductive bone morphogenetic protein 2 (rhBMP-2) via an osteoconductive scaffold (absorbable collagen sponge [ACS], i.e., INFUSE). Adverse side effects reportedly associated with rhBMP2 administration include rampant inflammation and clinical failures. Although acute inflammation is necessary for proper healing in bone, inflammatory cascade dysregulation can result in sustained tissue damage and poor healing. We hypothesized that a subclinical dose of rhBMP2 modeled in the murine calvarial defect would not precipitate alterations to inflammatory markers during acute phases of bone wound healing. We utilized the 5 mm critical size calvarial defect in C57BL6 wild-type mice which were subsequently treated with ACS and a subclinical dose of rhBMP2 shown to be optimal for healing. Three and 7-day postoperative time points were used to assess the role that rhBMP-2 plays in modulating inflammation vs. ACS alone by cytokine array and histological interrogation. Data revealed that rhBMP-2 delivery resulted in substantial modulation of several markers associated with inflammation, most of which decreased to levels similar to control by the 7-day time point. Additionally, while rhBMP-2 administration increased macrophage response, this peptide had a little noticeable effect on traditional markers of macrophage polarization (M1-iNOS, M2-Arg1). These results suggest that rhBMP-2 delivered at a lower dose does not precipitate rampant inflammation. Thus, an assessment of dosing for rhBMP-2 therapies may lead to better healing outcomes and less surgical failure.
大骨损伤、缺陷和慢性伤口是医学面临的主要问题。临床上有几种治疗策略可用于促进骨形成，包括通过骨传导支架（可吸收胶原海绵[ACS]，即 INFUSE）联合传递成骨诱导性骨形态发生蛋白 2（rhBMP-2）的联合治疗。据报道，rhBMP2 给药的不良反应包括炎症失控和临床失败。尽管急性炎症是骨愈合所必需的，但炎症级联失调可导致持续的组织损伤和愈合不良。我们假设在鼠颅骨缺损中模拟亚临床剂量的 rhBMP2 不会在骨创伤愈合的急性阶段引发炎症标志物的改变。我们利用 C57BL6 野生型小鼠的 5mm 临界尺寸颅骨缺损，随后用 ACS 和已证明对愈合最有效的亚临床剂量 rhBMP2 进行治疗。在术后 3 天和 7 天的时间点，通过细胞因子阵列和组织学检测来评估 rhBMP-2 在调节炎症与 ACS 单独作用中的作用。数据显示，rhBMP-2 的递送导致与炎症相关的几个标志物发生了显著变化，其中大多数标志物在 7 天时间点下降到与对照相似的水平。此外，虽然 rhBMP-2 给药增加了巨噬细胞反应，但该肽对传统的巨噬细胞极化标志物（M1-iNOS、M2-Arg1）几乎没有明显影响。这些结果表明，低剂量的 rhBMP-2 不会引发炎症失控。因此，rhBMP-2 治疗剂量的评估可能会带来更好的愈合效果和更少的手术失败。
