Effective local delivery of bone anabolic agent to accelerate the healing of delayed fracture union

有效局部输送骨合成代谢剂加速骨折延迟愈合

• 批准号: 10565241
• 负责人: Dong Wang
• 金额: $ 45.3万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565241
• 关键词: Acceleration; Address; Affect; Aftercare; Aging; Alcohol consumption; American; Anabolic Agents; Animal Model; Anticoagulants; Antiinflammatory Effect; Autoimmune Diseases; Autologous; Biodistribution; Biology; Biomechanics; Blood Vessels; Blood flow; Bone Injury; Bone Transplantation; Bone callus; COVID-19 patient; Cells; Characteristics; Chronic; Clinical; Clinical Management; Contrast Media; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Estrogen deficiency; Euthanasia; Event; Exhibits; Exposure to; FDA approved; Femoral Fractures; Femur; Flow Cytometry; Formulation; Fracture; Glucocorticoids; Goals; Hospitalization; Hydrogels; Immunofluorescence Immunologic; Impaired healing; Impairment; In Vitro; Inflammatory; Investments; Label; Lasers; Microfils; Molecular; Molecular Weight; Monitor; Mus; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Osteogenesis; Osteoporosis; Pathologic; Perfusion; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase Transition; Polymers; Population; Postmenopause; Prednisone; Preparation; Procedures; Process; Prodrugs; Property; Quality of life; Regimen; Research; Resolution; Risk Factors; Safety; Salvia miltiorrhiza; Sampling; Site; Skeleton; Temperature; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Tobacco; Tobacco use; Transition Temperature; Treatment Efficacy; Viscosity; Water; Weight; X-Ray Medical Imaging; angiogenesis; aqueous; bone; bone fracture repair; bone quality; candidate selection; chronic pain; clinical efficacy; clinical translation; coronavirus disease; current pandemic; density; design; drug release kinetics; effective therapy; fracture risk; functional disability; healing; improved; in vivo; in vivo optical imaging; infection rate; infection risk; insight; lipophilicity; liquid chromatography mass spectrometry; methacrylamide; microCT; mouse model; musculoskeletal injury; novel; osteogenic; post-pandemic; preclinical study; side effect; standard care; water solubility

ABSTRACT Fracture is the leading musculoskeletal injury affecting over 9.4 million Americans annually. Approximately ~10% of fractures are complicated by delayed healing or non-union, resulting chronic pain, impaired mobility and poor quality of life. Pathophysiological and habitual risk factors, including fracture site instability, concurrent diseases (e.g., diabetes), chronic exposure to certain medications (e.g., glucocorticoids or GCs) and tobacco/alcohol use are also major contributing causes, which may interfere with the fracture healing biology and lead to delayed healing or non-union. GCs are widely used in treating hospitalized COVID patients. Given the scale of the current pandemic and the significant COVID infection rate among the US population, a post pandemic surge of fracture risk and delayed fracture healing cases may be anticipated. Currently, orthopaedic surgery and autologous bone grafts are still the gold standard in clinical management of delayed fracture healing. There are few FDA approved non-invasive therapeutic interventions for the treatment of GC-induced delayed fracture healing. To address this significant unmet clinical need, we have developed a N-(2- hydroxypropyl)methacrylamide (HPMA)-based water-soluble thermoresponsive polymeric prodrug (P-TAN) of Tanshinone IIA (TAN, a potent bone anabolic agent). The aqueous solution of P-TAN is free-flowing at room temperature and transitions into a hydrogel (ProGel-TAN) at ≥ 27°C, which provide a unique mechanism for sustained local delivery of TAN. When tested in a prednisone-induced delayed fracture healing mouse model, two consecutive monthly ProGel-TAN treatments were found to accelerate the fracture healing by 5 weeks without any side effects observed. The biomechanical properties of the bone were also fully restored. While two monthly ProGel-TAN treatment seems to be very promising, the current orthopaedic practice favors a single dose treatment at the time of the fracture stabilization procedure for pragmatic reasons as well as less infection risk. Therefore, we hypothesize that with further structural and formulation optimization, we will be able to identify an optimized single dose ProGel-TAN formulation that is highly effective and safe in treating the GC-induced delayed fracture union. To test this hypothesis, we propose three Specific Aims in this project: 1. To characterize the impact of different structural and formulation parameters of ProGel-TAN; 2. To identify single dose ProGel- TAN formulations that provide optimal fracture healing efficacy; 3. To understand ProGel-TAN’s unique pharmacology and putative mechanisms of action. At the successful completion of the proposed research, we anticipate the identification of at least one optimal ProGel-TAN formulation that would satisfy the demand for a single dose treatment to accelerate the healing of the GC-induced delayed fracture union by ~ 5 weeks and normalize biomechanical properties of the injured bone in mice. It will then be subjected to further pre-clinical studies on large animal models in preparation for clinical translation.

抽象的 骨折是每年影响超过940万美国人的主要肌肉骨骼损伤。大约 〜10％的骨折因延迟愈合或非工会而复杂，导致慢性疼痛，活动性受损和 生活质量差。病理生理和惯性危险因素，包括骨折部位不稳定性，并发 疾病（例如糖尿病），长期暴露于某些药物（例如糖皮质激素或GC）和 烟草/饮酒也是主要的原因，这可能会干扰骨折愈合生物学 并导致延迟治愈或非工会。 GC被广泛用于治疗住院的共同患者。给出 当前大流行的规模和美国人口中的显着互联感染率，这是一个职位 可能会预计骨折风险和延迟骨折愈合病例的大流行激增。目前，骨科 手术和自体骨移植仍然是延迟骨折愈合的临床管理的金标准。 FDA很少有批准的非侵入性治疗干预措施用于治疗GC引起的延迟 断裂愈合。为了满足这种巨大的未满足临床需求，我们开发了n-（2- 羟丙基）甲基丙烯酰胺（HPMA）基于水溶性的热呼应聚合物前药（P-tan） Tanshinone IIA（TAN，潜在的骨合成代谢剂）。 p-tan的水溶液在房间里自由流动 温度和过渡到≥27°C的水凝胶（Progel-tan），这为独特的机制提供了 棕褐色的持续当地分娩。当在泼尼松诱导的延迟断裂愈合小鼠模型中测试时， 发现连续两次每月progel-tan治疗可加速骨折愈合5周 没有观察到任何副作用。骨骼的生物力学特性也已完全恢复。尽管 两次每月的前卫棕褐色治疗似乎非常有前途，目前的骨科实践有利于一个 骨折稳定程序时的剂量治疗出于务实的原因，感染较少 风险。因此，我们假设通过进一步的结构和公式优化，我们将能够识别 优化的单剂量progel-tan公式，在治疗GC诱导的方面非常有效且安全 延迟断裂联盟。为了检验这一假设，我们提出了该项目的三个特定目标：1。 Progel-tan的不同结构和配方参数的影响； 2。确定单剂 提供最佳骨折愈合效率的棕褐色公式； 3。了解Progel-Tan的独特 药理学和推定的作用机制。在成功完成拟议的研究时，我们 预期至少可以识别一个最佳的棕褐色公式，以满足对一个的需求 单剂量治疗以加速GC诱导的延迟骨折联合的愈合约5周，并且 使小鼠受伤骨的生物力学特性正常化。然后将进行进一步的临床前 关于大型动物模型的研究，以准备临床翻译。