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

可吸收的磷酸化聚（酯脲）手术粘合剂可促进骨折愈合

• 批准号: 10674973
• 负责人: Joseph S. Fernandez-Moure
• 金额: $ 16.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674973
• 关键词: Acceleration; Actins; Adhesions; Adhesives; Amino Acids; Award; Biocompatible Materials; Biologic Characteristic; Biomechanics; Biomedical Engineering; Bone Marrow; Bone Marrow Stem Cell; Bone callus; Breathing; Calcium; Cartilage; Cells; Chemicals; Chest wall structure; Chondrocytes; Clinical; Collagen; Contracts; Critical Care; Cues; Cytoskeletal Modeling; Data; Dedications; Deposition; Development; Elasticity; Elastomers; Engineering; Esters; Ethanol; Exhibits; External Fixation Devices; Failure; Flail Chest; Focal Adhesions; Formulation; Foundations; Fracture; Future; Generations; Glycols; Goals; Immobilization; In Vitro; Incidence; Injectable; Injections; Injury; Investigation; Laboratory Research; Life; Mechanics; Mentors; Metabolic; Modeling; Modification; Modulus; Musculoskeletal; Operative Surgical Procedures; Orthopedics; Osteoblasts; Pain; Patients; Performance; Phosphorylation; Phosphoserine; Play; Pneumonia; Polymers; Positioning Attribute; Program Development; Property; Public Health; Rattus; Research; Research Personnel; Rib Fractures; Scientist; Stem Cell Research; Stromal Cells; Surface; Surgeon; Tensile Strength; Testing; Tissue Engineering; Trauma; Trauma patient; Traumatic injury; United States; United States National Institutes of Health; Universities; Urea; Vertebral column; Work; acute care; base; biodegradable polymer; bone; bone fracture repair; bone healing; career; career development; clinical practice; copolymer; cortical bone; density; elastomeric; experience; experimental study; healing; high risk; improved; in vivo; innovation; inorganic phosphate; insight; interfacial; long bone; materials science; mechanical properties; mechanical signal; minimally invasive; monomer; novel; novel therapeutics; polymerization; professor; pulmonary function; reparative process; rib bone structure; safety testing; skills; stoichiometry; surgery material; trauma care; treatment strategy; wound healing

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.

项目概要 该提案提出了一个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）用于肋骨稳定和愈合的生物学特性 骨折。该候选人目前是外科和急性及重症护理创伤助理教授 杜克大学外科医生，拥有生物材料和组织工程研究经验 研究。他现在选择专注于材料科学和机械工程，具有多元化的专业知识 由具有材料、聚合物、肌肉骨骼修复专业知识的研究人员组成的指导委员会 过程和干细胞研究。拟议的实验和教学工作将为候选人提供 一套独特的技能将帮助他过渡到作为一名外科医生科学家的独立地位，并使他能够填补 在肋骨骨折和伤口愈合的研究领域存在显着的“经验差距”。 肋骨骨折占每年所有骨折的近 40%，超过 25 万例 肋骨受伤。这些伤害可能会产生长期影响，有时甚至是终生影响。超过一半的肋骨骨折患者 感染肺炎，数年后近三分之二的胸壁仍会感到剧烈疼痛 维持伤害。虽然骨折的稳定可以促进更快的愈合并降低不愈合率 （断骨无法愈合），肋骨骨折带来了独特的挑战，因为只能通过固定来固定 通过侵入性手术干预来完成。因此，与长骨骨折不同的是，长骨骨折会立即发生 稳定是标准的，只有在最严重的情况下才保留肋骨骨折。聚（酯脲）（PEU） 是基于氨基酸的可生物降解聚合物，具有类似骨骼的机械性能。一种这样的磷酸化 基于磷酸丝氨酸 (pSer) 的 PEU (pPEU) 共聚物可溶于乙醇，可注射，具有强效 骨粘附力和高弹性模量，使 pPEU 成为创新、非侵入性解决方案的理想选择 肋骨骨折的稳定。然而，pSer 化学计量对 PEU 共聚物骨诱导的影响仍然存在 未知，以及使用可吸收 PEU 粘合剂的临时弹性愈伤组织是否可以加速 通过早期骨折稳定来实现骨愈合。该提案将确定双方之间的关系 用于骨诱导的可注射 pSer-PEU 的物理和生物学特性并测试其安全性和 pSer-PEU 在肋骨骨折大鼠模型中的性能。本提案的工作将 1) 描述 PEU 共聚物内 pSer 化学计量与生物力学（拉伸强度、弹性模量、 和硬度），以及 pSer-PEU 的筋膜间粘附； 2) 量化骨髓基质细胞 (BMSC) 细胞骨架 重组和骨诱导以增加刚度，3) 评估骨折稳定性和愈伤组织形成 在具有最佳性能的 pSer-PEU 的大鼠肋骨骨折模型中。这项工作的结果将作为基础 未来的项目侧重于使用功能化生物材料来了解骨折的细胞机制 愈合以优化高风险创伤患者的愈合。