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 美国四分之一的女性人口受到骨盆底疾病（PFD）的影响。它们包括骨盆 器官脱垂，尿液和粪便尿失禁。最普遍的PFD包括压力尿失禁 估计率为15-17％，其次是粪便失禁，患病率为9.4％。 PFD代表主要 公共卫生问题鉴于其高流行，对生活质量和相关经济的负面影响 负担。外部尿道括约肌（EUS）和外部肛门括约肌（EAS）的产妇出生损伤是 PFD发病机理中的关键事件。而阴道分娩则增加了开发PFD的风险 与选修剖宫产相比，这种最后的交付方式与发病率的高风险有关 费用。虽然，两种情况的治疗方面都有持续的进展，但目前可用的标准 方法继续延迟和补偿性，因为它们并不直接针对负责的途径 对于肌肉功能障碍，并且因此无法解决疾病发展的病因。 基于细胞的疗法导致细胞存活不良，增加结缔组织层厚度， 防止肌纤维再生。基督教实验室以前已经证明 再生骨骼肌细胞外基质（MECM）水凝胶，通过增加而促进肌肉再生 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，拟议的研究假设MECM水凝胶促进EUS和EAS再生以及 防止出生后的长期括约肌肌肉功能障碍。为了检验这一假设，我们的目标是： 目标1：评估MECM对肌源性再生途径的功效和功能 出生后的EUS恢复。 目标2：评估MECM对肌源性再生途径的影响以及对功能的影响 出生后的EAS恢复。 该项目将使用各种多尺度工具，包括生物材料制造技术，体内小型 动物模型，体内压力测量和离体肌肉力的产生，免疫组织化学， 和生物信息学。这些技术对于实现拟议的目标并开发PI至关重要 科学研究的职业。随着妇女每天分娩，PFD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 通过对微创，可注射，低成本的机械理解，易于制造的结局 脱细胞材料。