Prevention of Urethral and Anal Sphincters Dysfunction with an Acellular Biomaterial

用无细胞生物材料预防尿道和肛门括约肌功能障碍

• 批准号: 10020187
• 负责人: Pamela Duran
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020187
• 关键词: Affect; Animal Model; Animals; Anus; Biocompatible Materials; Bioinformatics; Biological; Birth; Birth trauma; Cell Death; Cell Nucleus; Cell Survival; Cell Therapy; Cesarean section; Cessation of life; Childbirth; Collagen; Connective Tissue; Development; Disease; Economic Burden; Embryo; Etiology; Event; External anal sphincter structure; Extracellular Matrix; Family suidae; Fecal Incontinence; Female; Fiber; Functional disorder; Gene Expression; Generations; Goals; Harvest; Head; Health Care Costs; High Prevalence; Hydrogels; Hypoxia; Immunohistochemistry; Incidence; Injectable; Injections; Injury; Intervention; Laceration; Liquid substance; Lung; Measurement; Mechanics; Medicine; Mesenchymal Stem Cell Transplantation; Modeling; Morbidity - disease rate; Morphology; Muscle; Muscle function; Myosin Heavy Chains; Natural regeneration; Nerve; Outcome; Pathogenesis; Pathway interactions; Patients; Pelvic Floor Disorders; Pelvic floor structure; Pelvis; Phenotype; Population; Prevalence; Prevention; Public Health; Quality of life; Rattus; Recovery of Function; Research; Risk; Saline; Skeletal Muscle; Sphincter; Stress Urinary Incontinence; Techniques; Testing; Therapeutic; Thick; Time; Tissues; United States; Urethra; Urethral sphincter; Urinary Incontinence; Vagina; Vascularization; Woman; base; career; cost; fetal; high risk; in vivo; limb injury; minimally invasive; muscle degeneration; muscle regeneration; novel; pelvic organ prolapse; preservation; pressure; prevent; progenitor; protein expression; recruit; regenerative; scaffold; sphincter ani muscle structure; stem cells; tool; transcriptome

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.

项目摘要 四分之一的美国女性人口受到骨盆底疾病（PFDs）的影响。包括骨盆 器官脱垂和大小便失禁。最常见的PFDs包括压力性尿失禁 估计患病率为15- 17%，其次是大便失禁，患病率为9.4%。PFDs代表了一个主要的 鉴于其高流行率、对生活质量和相关经济的负面影响， 负担产妇分娩时尿道外括约肌（EUS）和肛门外括约肌（EAS）的损伤是一种常见的并发症。 在PFDs发病机制中的关键事件。虽然阴道分娩使患PFDs的风险增加一倍， 与选择性剖宫产相比，最后一种分娩方式与高发病率风险相关， 成本虽然这两种疾病的治疗都在不断取得进展，但目前可用的标准 这些方法仍然是延迟和补偿性的，因为它们不直接针对负责的途径， 对于肌肉功能障碍，因此不能解决疾病发展的病因。 基于细胞的疗法导致细胞存活率差，结缔组织层厚度增加， 阻止肌纤维再生。Christman实验室先前已经证明，一种非细胞的，亲- 再生骨骼肌细胞外基质（mECM）水凝胶，通过增加 这有助于促进血管化，增强肌肉祖细胞的募集和分化，并减少细胞死亡。 因此，提出的研究假设mECM水凝胶促进EUS和EAS再生， 预防产伤后长期括约肌功能障碍。为了验证这一假设，我们的目标是： 目的1：评价mECM对肌源性再生途径和功能性再生的有效性。 产伤后EUS恢复。 目的2：评价mECM对肌源性再生途径和功能性再生的影响。 产伤后EAS的恢复。 该项目将使用多样化的多尺度工具，包括生物材料制造技术，在体内小 动物模型，体内压力测量和离体肌肉力量产生，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发展PI是必不可少的， 从事科学研究随着妇女每天分娩，PFDs的发病率增加， 预计到2050年将增加4300万人。总之，这项研究有可能减少这种极端 通过对微创、可注射、低成本、易于制造的机械理解获得结果 脱细胞材料。