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和 面部和下巴有创伤性损伤。局部输送成骨蛋白生长因子，特别是骨 形态发生蛋白-2(BMP2)已被证明能促进这些损伤的愈合。骨缺损的治疗 使用促血管生成疗法，如血管内皮生长因子(VEGF)，也可以通过 改善组织血管形成；令人信服的是，新出现的证据表明，顺序递送前- 血管生成和促成骨疗法促进的骨发育甚至比单一的更明显 任一种药物的给药。尽管多年来努力开发生物材料系统作为本地化的生长因子 作为骨再生的传送库，这些技术中的许多仍然无法完全再生骨科 主要是由于药物药代动力学不佳和过早释放药物所致。据推测， 直接将药物释放动力学与组织生长速度相匹配将显著改善骨骼 颅面缺损的再生。细胞产生的信号，特别是活性氧簇(ROS)，可以 被用来从可激活的生物材料系统中产生选择性的、“愈合反应”的药物释放。 这项拟议的工作旨在开发可注射药物载体，以调节阿司匹林的连续、局部释放 在骨再生过程中由细胞产生的氧化触发的血管内皮生长因子和骨形态发生蛋白2。这些反应灵敏 运输车辆将使用ROS可降解的微粒包裹一层又一层的ROS-可降解的 层(LBL)膜，从而结合了两种控制释放技术(可注射抗氧化剂)的优点 颗粒、响应性表面涂层)集成到单一药物输送平台中。该项目的第一个目标是优化 这些包覆的微粒具有两个阶段的蛋白质释放和氧化触发时的强大生物活性，同时 第二个目的是评估携带血管内皮生长因子/骨形态发生蛋白2的LBL微粒在体内的药物释放动力学和骨 严重大鼠颅骨缺损的再生。我们预计ROS反应的双负载粒子 将比单一药物制剂或传统的、无反应的微粒更能促进骨修复 类似物。简而言之，该提案汇集了一支高素质的研究团队来实现整个项目 开发和验证临床可翻译的方法以实现受控、按需交付的目标 再生生长因子，以促进健壮的颅面骨再生。

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.