Environmentally-responsive, dual-stage microparticle drug depots with healing-driven growth factor delivery for craniofacial bone regeneration

通常需要颅面手术和自体骨移植来解决先天性出生缺陷， 面部和下巴的外伤成骨蛋白生长因子的局部递送，特别是骨 形态发生蛋白-2（BMP 2）已显示促进这些损伤的愈合。骨缺损治疗 血管内皮生长因子（VEGF）等促血管生成疗法也可通过以下途径改善愈合： 改善组织血管化;令人信服的是，新出现的证据表明，序贯输送促血管生成素， 血管生成和促骨生成疗法比鞋底更能促进骨发育 任何一种药物的管理。尽管多年来努力开发生物材料系统作为局部生长因子 尽管骨再生的递送仓库，但这些技术中的许多仍然不能完全再生骨科 这主要是由于不良的药物药代动力学和过早的治疗释放。它是假设 将药物输送动力学与组织生长速率直接匹配将显著改善骨 颅面缺损的再生细胞产生的信号，特别是活性氧（ROS）， 可以被用来从可活化的生物材料系统中产生选择性的、“愈合响应”的药物释放。 这项拟议的工作旨在开发可注射的药物载体，将介导顺序，局部释放的 VEGF和BMP 2在骨再生过程中由细胞产生的氧化触发。这些反应灵敏的 将使用涂覆有ROS可降解层的ROS可降解微粒来制造递送载体， 层（LbL）薄膜，从而结合了两种控释技术的优势（注射抗氧化剂 颗粒、响应性表面涂层）进入单个药物递送平台。该项目的第一个目标将优化 这些包被的微粒用于双阶段蛋白质释放和氧化触发后的有效生物活性， 第二个目的是评价负载VEGF/BMP 2的LbL微粒的体内药物释放动力学和骨 关键大小的大鼠颅骨缺损的再生。我们预计，ROS响应，双负载颗粒 将促进比单一药物制剂或常规的非响应性微粒更稳健的骨修复 类似物简而言之，该提案汇集了一支高素质的研究团队，以实现整体项目 目标是开发和验证一种临床上可翻译的方法，用于控制、按需提供 再生生长因子，以促进强大的颅面骨再生。

Craniofacial surgeries and autologous bone grafts are often required to address congenital birth defects and traumatic injuries to the face and jaw. Local delivery of osteogenic protein growth factors, particularly bone morphogenetic protein-2 (BMP2), has been shown to promote healing in these injuries. Bone defect treatment with pro-angiogenic therapies such as vascular endothelial growth factor (VEGF) also improves healing through improved tissue vascularization; compellingly, emerging evidence indicates that sequential delivery of pro- angiogenic and pro-osteogenic therapies promotes even more pronounced bone development than sole administration of either drug. Despite years of effort developing biomaterial systems as localized growth factor delivery depots for bone regeneration, many of these technologies still fail to completely regenerate orthopedic tissue primarily due to poor drug pharmacokinetics and premature therapeutic release. It is hypothesized that directly matching drug delivery kinetics with the rate of tissue growth will significantly improve bone regeneration in craniofacial defects. Cell-produced signals, particularly reactive oxygen species (ROS), can be leveraged to produce selective, “healing-responsive” drug release from activatable biomaterial systems. This proposed work seeks to develop injectable drug carriers that will mediate sequential, localized release of VEGF and BMP2 upon triggering by cell-generated oxidation during bone regeneration. These responsive delivery vehicles will be created using ROS-degradable microparticles coated with ROS-degradable layer-by- layer (LbL) films, thereby combining the strengths of two controlled release technologies (injectable antioxidant particles, responsive surface coatings) into a single drug delivery platform. The project’s first aim will optimize these coated microparticles for dual-stage protein release and potent bioactivity upon oxidative triggering, while the second aim will evaluate VEGF/BMP2-loaded LbL microparticles for in vivo drug release kinetics and bone regeneration in critically-sized rat skull defects. We anticipate that the ROS-responsive, dually-loaded particles will promote more robust bone repair than single-drug formulations or conventional, non-responsive microparticle analogues. In short, the proposal brings together a highly-qualified research team to achieve the overall project goal of developing and validating a clinically-translatable approach for controlled, on-demand delivery of regenerative growth factors to foster robust craniofacial bone regeneration.