Resorbable, Phsophorylated Poly(ester urea) Surgical Adhesive to Enhance Fracture Healing

项目总结 这份提案提出了一项为期五年的研究职业发展计划，重点是优化身体素质 磷酸化聚(酯)脲(PPEU)稳定和愈合肋骨的生物学特性 骨折。候选人目前是外科和急危重症护理创伤的助理教授 杜克大学外科医生，具有生物材料和组织工程方面的研究经验 研究。他现在选择专注于材料科学和机械工程， 研究人员指导委员会，具有材料、聚合物、肌肉骨骼修复方面的专业知识 过程和干细胞研究。建议的实验和教学工作将为考生提供 一套独特的技能，将帮助他过渡到作为外科科学家的独立，并使他能够填补 在致力于肋骨骨折和伤口愈合的研究领域，存在着显著的“经验差距”。 肋骨骨折占每年所有骨折的近40%，超过25万 肋骨受伤。这些伤害可能会产生长期的影响，有时甚至是终身的。超过一半的肋骨骨折患者 感染肺炎，近三分之二的人在几年后仍将经历严重的胸壁疼痛 承受着伤势。而骨折的稳定促进了更快的愈合和降低了骨不连的发生率 (骨折无法愈合)，肋骨骨折是一个独特的挑战，因为固定只能是 通过侵入性外科干预完成。因此，与长骨骨折不同的是 稳定是标准的，这是保留在肋骨骨折，只有最严重的情况下。聚(酯)脲(PEU) 是以氨基酸为基础的生物降解聚合物，具有类似骨骼的机械性能。一种这样的磷酸化 PEU(PPEU)共聚物，以磷酸丝氨酸(PSer)为基础，乙醇可溶，可注射，具有很强的 骨粘附性和高弹性系数，使PPEU成为一种创新的、非侵入性的解决方案 肋骨骨折的稳定。然而，pSer化学计量比对PEU共聚物骨诱导的影响仍然存在。 未知，以及使用可吸收PU基胶粘剂的临时弹性骨痂是否可以加速 通过骨折的早期稳定进行骨愈合。这项提议将决定两国之间的关系 注射用pSer-PEU的物理和生物学特性及安全性和安全性检测 PSer-peu在大鼠肋骨骨折模型中的作用。这项提案的工作将1)描述 PU共聚物中的pSer化学计量比与生物力学(拉伸强度，弹性模量， 和硬度)，以及pSer-PEU的筋膜间黏附；2)定量骨髓基质细胞(BMSC)细胞骨架 重组和骨诱导以增加僵硬，以及3)评估骨折稳定性和骨痂形成 在表现最好的pSer-peu大鼠肋骨骨折模型中。这项工作的结果将作为以下工作的基础 未来的项目重点是使用功能化的生物材料来了解骨折的细胞机制。 治愈，以优化高危创伤患者的愈合。

PROJECT SUMMARY This proposal presents a five-year research career development program focused on optimizing the physical and biological characteristics of phosphorylated poly(ester ureas) (pPEU) for the stabilization and healing of rib fractures. The candidate is currently an Assistant Professor of Surgery and acute and critical care trauma surgeon at Duke University, with previous research experience in biologic materials and tissue engineering research. He has now chosen to focus on materials science and mechanical engineering with a diverse mentoring committee of investigators with expertise in materials, polymers, musculoskeletal reparative processes and stem cell research. The proposed experiments and didactic work will provide the candidate with a unique set of skills that will help him transition to independence as a surgeon-scientist and enable him to fill a significant “experience gap” in the field of research dedicated to rib fractures and wound healing. Rib fractures account for nearly 40% of all bone fractures sustained in the each year, with over a quarter million rib injuries. These injuries can have long-lasting effects, sometimes even for life. Over half of rib fracture patients contract pneumonia, and nearly two thirds will still experience significant pain in the chest wall years after sustaining the injury. While stabilization of a fracture promotes faster healing and decreased rates of non-union (failure of a broken bone to heal), rib fractures present a unique challenge in that immobilization can only be accomplished through invasive surgical intervention. Therefore, unlike long bone fractures where immediate stabilization is standard, this is reserved in rib fractures for only the most severe cases. Poly(ester ureas) (PEU) are amino acid based biodegradable polymers with bone like mechanical properties. One such phosphorylated PEU (pPEU) copolymer, based on phosphoserine (pSer) is ethanol soluble allowing for injection, with strong bone adhesion and high elastic moduli, making pPEU’s ideal as an innovative, non-invasive solution for the stabilization of rib fractures. However, the effect of pSer stoichiometry on PEU copolymer osteoinduction remains unknown, as well as if a provisional elastomeric callus using resorbable PEU based adhesive can accelerate bone healing through early fracture stabilization. This proposal will determine the relationships between the physical and biologic characteristics of injectable pSer-PEU for osteoinduction and test the safety and performance of pSer-PEU in a rat model of rib fracture. The work of this proposal will 1) characterize the relationship of pSer stoichiometry within the PEU copolymers on biomechanics (tensile strength, elastic modulus, and stiffness), and interfascial adhesion of pSer-PEU; 2) quantify bone marrow stromal cell (BMSC) cytoskeletal reorganization and osteoinduction to increased stiffness, and 3) evaluate fracture stability and callus formation in a rat rib fracture model with best performing pSer-PEU. The results of this work will serve as the basis for future projects focused on using functionalized biomaterials to understand the cellular mechanisms of fracture healing in order to optimize healing in the high risk trauma patient.