Prevention of pelvic floor muscle dysfunction with extracellular matrix hydrogel

项目总结 产妇分娩损伤是盆底肌肉功能障碍和由此导致的盆底的主要危险因素 疾病，包括盆腔器官脱垂和大小便失禁。尽管流行率很高， 与盆底疾病相关的重大发病率和经济负担，预防策略是 几乎不存在，可用的治疗是延迟和补偿的，因为它们不直接针对 潜在的病理生理学。因此，我们的长期目标是开发新的微创组织- 预防和治疗盆腔肌功能障碍的工程疗法。我们对骨盆的初步研究 盆腔器官脱垂产妇及模拟大鼠模型的底肌形态计量学特征 出生损伤表现为大量变性，特别是细胞死亡、肌纤维萎缩和纤维化。以上内容 肌肉的改变使肌肉对康复不敏感，并与不良的临床结果有关。我们 开发了一种新型的组织特异性可注射细胞外基质水凝胶，来源于脱细胞猪 骨骼肌，促进肌肉再生。这一建议是围绕着总体假设提出的 骨骼肌基质水凝胶，包含组织特异性提示，可以在当时单独提供 产伤预防盆底肌肉功能障碍或产后适应不良损伤恢复 扭转盆底肌肉功能障碍。我们将在我们的翻译相关怀孕模型中测试这一假设 通过比较未经治疗和治疗的盆底肌肉的表型、功能和转录特征 产伤后的多个时间点及细胞外基质水凝胶的测定机制 增强再生能力。总体而言，这项创新的研究将提供全面的和功能相关的 这种低成本无细胞微创再生疗法在盆底肌肉中的作用 产伤后的康复以及与产伤相关的生物过程的基本知识 盆底肌肉再生的调节。以上这些都是小说发展的巨大潜力 预防和治疗策略以对抗骨盆肌肉功能障碍和相关的盆底 精神错乱。

PROJECT SUMMARY Maternal childbirth injury is the leading risk factor for pelvic floor muscle dysfunction and the resultant pelvic floor disorders, which include pelvic organ prolapse and urinary and fecal incontinence. Despite high prevalence, significant morbidities, and economic burden associated with pelvic floor disorders, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. Thus, our long-term goal is the development of new, minimally invasive tissue- engineered therapies for the prevention and treatment of pelvic muscle dysfunction. Our pilot studies of pelvic floor muscle morphometric properties in parous women with pelvic organ prolapse and the rat model of simulated birth injury demonstrate substantial degeneration, specifically cell death, myofiber atrophy and fibrosis. The above alterations render muscles insensitive to rehabilitation and are associated with poor clinical outcomes. We developed a novel tissue-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, which promotes muscle regeneration. This proposal is centered around the overall hypothesis that the skeletal muscle matrix hydrogel, which contains tissue-specific cues, can be delivered alone at the time of birth injury to prevent pelvic floor muscle dysfunction or following a maladaptive post birth injury recovery to reverse pelvic floor muscle dysfunction. We will test this hypothesis in our translationally-relevant pregnant model by comparing untreated and treated pelvic floor muscle phenotypic, functional, and transcriptional signatures at multiple time points following birth injury and determining mechanisms by which the extracellular matrix hydrogel enhances regeneration. Collectively, this innovative study will provide comprehensive and functionally relevant assessments of the role of this low-cost acellular minimally invasive regenerative therapy in pelvic floor muscle recovery following birth injury and the fundamental knowledge of the biological processes involved in the regulation of pelvic floor muscle regeneration. The above has a high potential for the development of novel preventative and therapeutic strategies to counteract pelvic muscle dysfunction and the related pelvic floor disorders.