Chitosan Guided Bone Regeneration Membranes for Dual Local Delivery of Simvastatin and Raspberry Ketone

我们提出了新开发的电纺壳聚糖引导骨再生（GBR）膜， 局部递送辛伐他汀（SMV）（BMP-2的替代品）和乌藨子酮（RK）（抗- 炎性/促愈合剂，作为一种新的治疗移植牙/颅颌面的方法 缺陷GBR膜广泛用于牙科/颅颌面应用，以保护骨骼 移植的空间，从入侵的软组织和通过提供成骨环境，以提高 骨再生我们的壳聚糖GBR膜克服了当前GBR膜的局限性， 提供可预测的降解和具有互连孔隙的仿生生物结构 这是细胞闭塞的，但允许愈合的骨和上皮之间的液体和信号交换， 隔间所述纳米结构还提供了有利于药物释放的高表面积。 装载和运送。我们的目标是协同我们的壳聚糖GBR膜与局部递送 RK和SMV，以创造新的生物活性GBR膜，通过刺激GBR膜， 巨噬细胞表型从促炎症向促愈合和促进 骨生成显著增强了移植的牙齿/颅颌面缺损的愈合， 尤其是大的创伤性缺损。这项工作的创新源于我们独特的战略， 稳定电纺壳聚糖的微结构，并在SMV的局部递送中， 替代BMP-2用于刺激骨形成，以及新的RK化合物，以提供抗骨形成的抗骨形成活性。 炎症/促愈合特征。从我们的GBR膜输送这些试剂将导致 在为外科医生提供选择移植材料的灵活性的连续植入物中， GBR膜根据移植物的可用性、临床医生和患者因素，可以作为 在其他组织工程应用中克服炎症和刺激愈合的平台。 在这项工作中，我们将首先研究RK（目的1）和SMV（目的2）从膜的单独递送， 以及在体外和大鼠颅骨模型中对巨噬细胞表型和骨生成的影响。我们将 然后（目的3）研究双重释放对细胞和移植物愈合的协同/拮抗作用。 在大鼠模型中与市售GBR膜相比，最后（目的4）， 将在临床前猪模型中研究壳聚糖GBR膜， 商业设备。这项工作将对增加牙齿/颅颌面骨产生很大影响 再生，特别是在具有挑战性的创伤性骨损伤，并导致改善恢复面部 美学和随后的牙科/颅面种植体治疗。这些膜也可能发现 应用于挑战性大段骨科缺损的强化治疗

We propose newly developed electrospun chitosan guided bone regeneration (GBR) membranes for local delivery of simvastatin (SMV), an alternative to BMP-2, and raspberry ketone (RK), an anti- inflammatory/pro-healing agent, as a novel adjunctive therapy to heal grafted dental/craniomaxillofacial defects. GBR membranes are widely used in dental/craniomaxillofacial applications to protect bone grafted spaces from invasion by soft tissues and by providing an osteogenic environment for enhancing bone regeneration. Our chitosan GBR membranes overcome limitations of current GBR membranes by providing predictable degradation, and biomimetic nanofiber structure with an interconnected porosity that that is cell occlusive but allows exchange of fluids and signals between healing bone and epithelial compartments. The nanofiber structure also provides high surface area that is advantageous for drug loading and delivery. Our goal is to synergize our chitosan GBR membranes with local delivery of RK and SMV, to create novel bioactive GBR membranes that promote healing by stimulating the transition of the macrophage phenotype from pro-inflammation to pro-healing and promoting osteogenesis that significantly augments healing of grafted dental/craniomaxillofacial defects, especially large traumatic defects. Innovation of this work arises from our unique strategies that stabilize nanofiber structure of the electrospun chitosan and in the local delivery of SMV, an economical alternative to BMP-2 for stimulating bone formation, and the novel RK compound, to provide anti- inflammatory/pro-healing characteristics. Delivery of these agents from our GBR membranes will result in adjunctive implants that afford surgeons flexibility in choice of graft materials to be used with the GBR membrane in accordance with graft availability, clinician and patient factors, and may serve as a platform for overcoming inflammation and stimulating healing in other tissue engineering applications. In this work we will first, investigate individual delivery of RK (aim 1) and SMV (aim 2) from membranes, and effects on macrophage phenotype and osteogenesis in vitro and in rat calvarial models. We will then (aim 3) investigate dual release for synergistic/antagonistic effects on cells and healing of grafted site as compared to commercial GBR membrane in rat models. Finally (aim 4) the dual loaded bioactive chitosan GBR membranes will be investigated in a pre-clinical porcine model as compared to commercial devices. This work will have a large impact in augmenting dental/craniomaxillofacial bone regeneration especially in challenging traumatic bone injuries and lead to improved restoration of facial esthetics and subsequent dental/craniofacial implant therapies. These membranes may also find application in augmenting treatments in challenging large segmental orthopedic defects