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

我们提出了新的电纺壳聚糖引导骨再生(GBR)膜用于 局部给药的辛伐他汀(SMV)，骨形态发生蛋白-2的替代品，以及覆盆子酮(RK)，抗骨形态发生蛋白-2 炎症/促愈剂作为修复移植牙/颅颌面部的一种新的辅助疗法 缺陷。GBR膜广泛应用于牙科/颅颌面部保护骨骼 通过提供成骨环境防止软组织入侵并为增强 骨骼再生。我们的壳聚糖GBR膜克服了目前GBR膜的局限性，通过 提供可预测的降解和具有相互连接的孔隙率的仿生纳米纤维结构 这是细胞闭塞的，但允许愈合的骨骼和上皮之间交换液体和信号 车厢。纳米纤维结构还提供有利于药物的高表面积 装船和送货。我们的目标是将我们的壳聚糖GBR膜与本地释放的 RK和SMV，以创造新的生物活性GBR膜，通过刺激 巨噬细胞表型由促炎向促愈合和促促进的转变 成骨显著促进移植的牙科/颅颌面缺损的愈合， 尤其是巨大的创伤性缺陷。这项工作的创新源于我们独特的战略 稳定电纺壳聚糖纳米纤维结构并在局部输送SMV，一种经济 BMP-2的替代物，用于刺激骨形成，以及新型RK化合物，以提供抗 炎症/促进愈合的特征。将这些试剂从我们的GBR膜中释放出来 在辅助植入物中，使外科医生能够灵活地选择移植材料与 GBR膜根据移植物的可获得性、临床医生和患者的因素，可作为一种 在其他组织工程应用中用于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(目标1)和SMV(目标2)从膜中的个体递送， 以及在体外和大鼠颅骨模型中对巨噬细胞表型和成骨的影响。我们会 然后(目的3)研究双释放对细胞的协同/拮抗作用和移植的愈合 在大鼠模型中，与商品GBR膜进行比较。最后(目标4)双负载生物活性 壳聚糖GBR膜将在临床前猪模型中进行研究，并与 商用设备。这项工作将对增强牙齿/颅颌面骨产生很大的影响 尤其是在挑战创伤性骨损伤和改善面部修复方面的再生 美学和随后的牙科/颅面种植疗法。这些膜可能还会发现 强化治疗在解决大型节段性骨科缺损中的应用

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