Prevention of Urethral and Anal Sphincters Dysfunction with an Acellular Biomaterial

项目摘要 四分之一的美国女性人口受到盆底疾病(PFD)的影响。包括骨盆 器官脱垂，大小便失禁。最常见的压力性尿失禁包括压力性尿失禁 其次是大便失禁，患病率为9.4%。PFD代表着一个主要的 公共卫生问题，因为其高流行率、对生活质量的负面影响以及相关的经济 负担。产妇分娩对外道括约肌(EUS)和肛门外括约肌(EAS)的损伤是 PFDs发病机制中的关键事件。而阴道分娩使患产后功能障碍的风险增加一倍 与择期剖宫产相比，这种最后一种分娩方式与发病率和 成本。虽然，在治疗这两种疾病方面不断取得进展，但目前可用的标准 方法仍然是延迟和补偿的，因为它们不直接针对负责的路径 对于肌肉功能障碍，因此没有解决疾病发展的病因。 基于细胞的治疗导致细胞存活率低，结缔组织层厚度增加， 阻止肌纤维再生。克里斯曼实验室此前已经证明，一种脱细胞、亲- 再生骨骼肌细胞外基质(MECM)水凝胶，通过增加 血管形成，增强肌肉祖细胞的招募和分化，减少细胞死亡。 因此，建议的研究假设mECM水凝胶促进EUS和EAS的再生和 预防产伤后长期的括约肌功能障碍。为了验证这一假设，我们的目标是： 目的1：评价mECM对肌源性再生通路和功能的影响。 产伤后EUS的恢复情况。 目的2：评价mECM对肌源性再生通路和功能的影响。 产伤后EAS的恢复。 该项目将使用多种多尺度工具，包括生物材料制造技术，在活体小 动物模型，体内压力测量和体外肌力产生，免疫组织化学， 和生物信息学。这些技术对于实现所提出的目标和开发PI是必不可少的 从事科学研究。随着妇女每天分娩，产后功能障碍的发生率增加， 预计到2050年将增加4300万。总而言之，这项研究有可能减少这种极端情况 通过对微创、可注射、低成本、易于制造的机械理解的结果 脱细胞材料。

Project Summary A quarter of the United States female population is affected by pelvic floor disorders (PFDs). They include pelvic organ prolapse, and urinary and fecal incontinence. The most prevalent PFDs include stress urinary incontinence with an estimated rate of 15-17%, followed by fecal incontinence with 9.4% prevalence. PFDs represent a major public health issue given their high prevalence, negative impact on quality of life and associated economic burden. Maternal birth injuries to the external urethral sphincter (EUS) and external anal sphincter (EAS) are a critical event in the pathogenesis of PFDs. While vaginal childbirth doubles the risk for developing PFDs compared to elective cesarean section, this last mode of delivery is associated with high risks of morbidity and costs. Although, there is a continuous progress in the treatment of both conditions, currently available standards approaches continue to be delayed and compensatory, as they do not directly target the pathways responsible for muscle dysfunction, and in consequence do not address the etiology of the disease development. Cell based therapies have resulted in poor cell survival, increase connective tissue layer thickness, preventing myofiber regeneration. The Christman lab has previously demonstrated that an acellular, pro- regenerative skeletal muscle extracellular matrix (mECM) hydrogel, promotes muscle regeneration by increasing vascularization, enhancing the recruitment and differentiation of muscle progenitors and reducing cell death. Therefore, the proposed research hypothesize that mECM hydrogel promotes EUS and EAS regeneration and prevents long-term sphincteric muscle dysfunction following birth injury. To test this hypothesis, we aim to: Aim 1: Evaluate the efficacy of mECM on the myogenic regenerative pathways and on the functional recovery of EUS following birth injury. Aim 2: Evaluate the impact of mECM on the myogenic regenerative pathways and on the functional recovery of EAS following birth injury. This project will use a diverse multi-scale tools, including biomaterial fabrication techniques, in vivo small animal models, in vivo pressure measurements and ex vivo muscle force generation, immunohistochemistry, and bioinformatics. These techniques are essential for accomplishing the proposed aims and develop the PI for a career in scientific research. With women giving birth every day, the incidence of PFDs increases, being expected to increase by 43 million by 2050. In conclusion, this research has the potential to reduce this extreme outcome through mechanistic understanding of minimally invasive, injectable, low cost, easily fabricated decellularized material.