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.

摘要