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

通常需要进行颅面手术和自体骨移植来解决先天性出生缺陷和 面部和下巴外伤。局部递送成骨蛋白生长因子，特别是骨 形态发生蛋白 2 (BMP2) 已被证明可以促进这些损伤的愈合。骨缺损治疗 使用血管内皮生长因子 (VEGF) 等促血管生成疗法也可通过以下方式改善愈合 改善组织血管化；令人信服的是，新出现的证据表明，顺序交付亲 血管生成和促成骨治疗比单独治疗更能促进骨骼发育 服用任何一种药物。尽管多年来努力开发生物材料系统作为局部生长因子 骨再生的输送库，其中许多技术仍然无法完全再生骨科 组织的不良反应主要是由于药物药代动力学较差和治疗药物过早释放所致。假设 将药物输送动力学与组织生长速率直接匹配将显着改善骨骼 颅面缺损的再生。细胞产生的信号，特别是活性氧 (ROS)，可以 可用于从可激活的生物材料系统中产生选择性的“治疗响应”药物释放。 这项拟议的工作旨在开发可注射药物载体，以介导顺序、局部释放 骨再生过程中细胞产生的氧化触发 VEGF 和 BMP2。这些反应灵敏的 运载工具将使用逐层涂有可降解活性氧的微粒来制造 层（LbL）薄膜，从而结合了两种控释技术（注射抗氧化剂 颗粒、响应性表面涂层）整合到单一药物输送平台中。该项目的首要目标是优化 这些涂层微粒可在氧化触发时实现双阶段蛋白质释放和有效的生物活性，同时 第二个目标是评估负载 VEGF/BMP2 的 LbL 微粒的体内药物释放动力学和骨 严重大小的大鼠颅骨缺损的再生。我们预计 ROS 响应的双负载颗粒 与单一药物制剂或传统的无反应微粒相比，将促进更强大的骨修复 类似物。简而言之，该提案汇集了高素质的研究团队来实现整个项目 开发和验证临床可转化方法的目标是受控、按需交付 再生生长因子可促进颅面骨的强劲再生。

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.