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

基本信息

  • 批准号:
    10565241
  • 负责人:
  • 金额:
    $ 45.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Dong Wang其他文献

Dong Wang的其他文献

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{{ truncateString('Dong Wang', 18)}}的其他基金

Recognition of Synthetic Unnatural Base Pairs by RNA Polymerase
RNA 聚合酶对合成非天然碱基对的识别
  • 批准号:
    10561543
  • 财政年份:
    2023
  • 资助金额:
    $ 45.3万
  • 项目类别:
Towards Precision Nutrition for Alzheimer's Dementia Prevention: A Prospective Study of Dietary Patterns, the Gut Microbiome and Cognitive Function
预防阿尔茨海默病的精准营养:饮食模式、肠道微生物组和认知功能的前瞻性研究
  • 批准号:
    10447872
  • 财政年份:
    2022
  • 资助金额:
    $ 45.3万
  • 项目类别:
Towards Precision Nutrition for Alzheimer's Dementia Prevention: A Prospective Study of Dietary Patterns, the Gut Microbiome and Cognitive Function
预防阿尔茨海默病的精准营养:饮食模式、肠道微生物组和认知功能的前瞻性研究
  • 批准号:
    10629237
  • 财政年份:
    2022
  • 资助金额:
    $ 45.3万
  • 项目类别:
Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain
用于治疗肌肉骨骼疼痛的非成瘾性阿片类药物前体纳米药物
  • 批准号:
    10700168
  • 财政年份:
    2022
  • 资助金额:
    $ 45.3万
  • 项目类别:
Molecular Mechanisms for DNA Damage Processing by Transcription Machinery
转录机器处理 DNA 损伤的分子机制
  • 批准号:
    10435882
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
The Gut Microbiome and Personalized Mediterranean Diet Interventions for Cardiometabolic Disease Prevention
用于预防心血管代谢疾病的肠道微生物组和个性化地中海饮食干预措施
  • 批准号:
    10275622
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
The Gut Microbiome and Personalized Mediterranean Diet Interventions for Cardiometabolic Disease Prevention
用于预防心血管代谢疾病的肠道微生物组和个性化地中海饮食干预措施
  • 批准号:
    10493258
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
The Gut Microbiome and Personalized Mediterranean Diet Interventions for Cardiometabolic Disease Prevention
用于预防心血管代谢疾病的肠道微生物组和个性化地中海饮食干预措施
  • 批准号:
    10653220
  • 财政年份:
    2021
  • 资助金额:
    $ 45.3万
  • 项目类别:
Mediterranean Diet, Polyphenol-Rich Foods, Gut Microbiota and Type 2 Diabetes
地中海饮食、富含多酚的食物、肠道微生物群和 2 型糖尿病
  • 批准号:
    10457834
  • 财政年份:
    2020
  • 资助金额:
    $ 45.3万
  • 项目类别:
Mediterranean Diet, Polyphenol-Rich Foods, Gut Microbiota and Type 2 Diabetes
地中海饮食、富含多酚的食物、肠道微生物群和 2 型糖尿病
  • 批准号:
    10178327
  • 财政年份:
    2020
  • 资助金额:
    $ 45.3万
  • 项目类别:

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