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

壳聚糖引导骨再生膜用于辛伐他汀和覆盆子酮的双重局部递送

• 批准号: 9289263
• 负责人: JOEL D BUMGARDNER
• 金额: $ 33.09万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289263
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autologous; Autologous Transplantation; Biomimetics; Bone Injury; Bone Regeneration; Bone Transplantation; Calvaria; Cells; Characteristics; Chitosan; Chronic; Clinical; Collagen; Complication; Defect; Dental; Dental Implants; Devices; Dose; Environment; Epithelial; Esthetics; Excision; Extracellular Matrix; Face; Family suidae; Goals; Gold; Health; Human; Implant; Implantation procedure; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Injury; Ketones; Kinetics; Liquid substance; Mandible; Membrane; Modeling; Mus; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteogenesis; Patients; Periodontal Diseases; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological; Polytetrafluoroethylene; Porosity; Property; Raspberries; Rattus; Recombinant Growth Factor; Regenerative Medicine; Rodent; Signal Transduction; Simvastatin; Site; Societies; Speech; Stromal Cells; Structure; Surface; Surgeon; Testing; Therapeutic; Tissue Engineering; Transplanted tissue; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; base; biomaterial compatibility; bone; bone healing; bone lead; bone loss; bone morphogenetic protein 2; controlled release; craniofacial; craniomaxillofacial; design; dosage; experience; flexibility; graft healing; healing; improved; in vivo; innovation; macrophage; mechanical properties; member; nanofiber; novel; osteogenic; pre-clinical; prevent; reconstruction; regenerative; regenerative therapy; response; restoration; scaffold; soft tissue; success

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

我们提出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）和覆盆子酮 (RK)（一种抗 炎症/促愈合剂，作为愈合移植牙/颅颌面的新型辅助疗法 缺陷。 GBR 膜广泛用于牙科/颅颌面应用以保护骨骼 移植空间免受软组织侵袭并提供成骨环境以增强 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率的仿生纳米纤维结构 这是细胞闭塞的，但允许愈合骨和上皮细胞之间进行液体和信号交换 隔间。纳米纤维结构还提供了有利于药物的高表面积 装载和交付。我们的目标是协同我们的壳聚糖 GBR 膜与局部递送 RK 和 SMV，创造新型生物活性 GBR 膜，通过刺激 巨噬细胞表型从促炎症转变为促愈合和促进 成骨显着促进移植牙/颅颌面缺损的愈合， 特别是大的创伤性缺陷。这项工作的创新源于我们独特的策略， 稳定电纺壳聚糖的纳米纤维结构和 SMV 的局部递送，这是一种经济的 替代 BMP-2 刺激骨形成，以及新型 RK 化合物，提供抗- 炎症/促愈合特征。从我们的 GBR 膜中输送这些试剂将导致 在辅助植入物中，外科医生可以灵活选择与植入物一起使用的移植材料 GBR 膜根据移植物可用性、临床医生和患者因素，可作为 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，我们将首先研究从膜中单独递送 RK（目标 1）和 SMV（目标 2）， 以及对体外和大鼠颅骨模型中巨噬细胞表型和成骨的影响。我们将 然后（目标 3）研究双重释放对细胞和移植物愈合的协同/拮抗作用 与大鼠模型中的商用 GBR 膜相比。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 商业设备。这项工作将对增强牙齿/颅颌面骨产生巨大影响 再生，尤其是在具有挑战性的创伤性骨损伤中，并改善面部的恢复 美学和随后的牙科/颅面植入治疗。这些膜还可能发现 在挑战大节段骨科缺损的增强治疗中的应用