Prevention of pelvic floor muscle dysfunction with extracellular matrix hydrogel

项目摘要 产妇分娩损伤是导致骨盆底肌肉功能障碍和由此产生的骨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。尽管患病率很高， 显著的发病率和与骨盆底疾病相关的经济负担， 几乎不存在，可用的治疗是延迟和补偿性的，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- 用于预防和治疗骨盆肌肉功能障碍的工程疗法。我们对骨盆的初步研究 经产妇女盆腔器官脱垂及大鼠模型的肌底形态计量学研究 产伤表现出实质性变性，特别是细胞死亡、肌纤维萎缩和纤维化。上述 改变使得肌肉对康复不敏感，并且与不良的临床结果相关。我们 开发了一种新的组织特异性可注射细胞外基质水凝胶，来自脱细胞猪 骨骼肌，促进肌肉再生。该提案围绕总体假设展开 骨骼肌基质水凝胶，其中包含组织特异性的线索，可以单独交付的时候， 出生损伤，以防止骨盆底肌肉功能障碍或以下适应不良出生后损伤恢复， 扭转骨盆底肌肉功能障碍。我们将在我们的妊娠相关模型中测试这一假设 通过比较未治疗和治疗的骨盆底肌肉表型、功能和转录特征， 出生损伤后的多个时间点，并确定细胞外基质水凝胶 增强再生能力。总的来说，这项创新研究将提供全面和功能相关的 评估这种低成本的无细胞微创再生疗法在骨盆底肌肉中的作用 产后恢复和产后恢复所涉及的生物过程的基本知识， 调节骨盆底肌肉再生。以上这些都具有很高的发展潜力 预防和治疗策略，以对抗骨盆肌肉功能障碍和相关的骨盆底 紊乱

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.