Implantation of Bioengineered Intrinsically Innervated Internal Anal Sphincter (BioSphincter) to Treat Fecal Incontinence

植入生物工程内在神经支配的肛门内括约肌（BioSphincter）治疗大便失禁

• 批准号: 9340657
• 负责人: KHALIL N BITAR
• 金额: $ 2.7万
• 依托单位: CELLF-BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340657
• 关键词: Adult; Animal Model; Animals; Applications Grants; Autologous; Behavior; Biocompatible Materials; Biofeedback; Biomedical Engineering; Biopsy; Businesses; Cell Differentiation process; Cells; Childhood; Circular layer of muscularis propria of anal canal; Clinical; Clinical Trials; Coculture Techniques; Colostomy Procedure; Constipation; Data; Diarrhea; Dimensions; Disease; Distress; Enteral; Enteric Nervous System; Evaluation Research; Excision; External anal sphincter structure; Fecal Incontinence; Feces; Functional disorder; Funding; Grant; Guidelines; Health; Human; Implant; Incontinence; Individual; Injection of therapeutic agent; Injury; Intestines; Life Experience; Long-Term Effects; Maintenance; Manometry; Marketing; Measures; Mediating; Methods; Modeling; Monitor; Motor; Muscle function; Neurons; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Pathology; Patients; Pharmaceutical Preparations; Physiological; Physiology; Procedures; Process; Productivity; Property; Protocols documentation; Psychological Stress; Qualifying; Quality Control; Quality of life; Randomized; Recurrence; Reflex action; Regenerative Medicine; Rest; Sacral nerve; Smooth Muscle; Smooth Muscle Myocytes; Sphincter; Symptoms; Techniques; Technology Transfer; Tissues; Translations; United States Food and Drug Administration; Work; base; cell type; design; experience; human tissue; implantation; improved; in vivo; injured; manufacturing process; meetings; nerve stem cell; neuromuscular; neuroregulation; novel; novel therapeutics; pre-clinical; pre-clinical trial; pressure; reconstitution; relating to nervous system; repaired; restoration; scale up; self esteem; sensory mechanism; social; social stigma; socioeconomics; sphincter ani muscle structure; success; tissue culture; treatment strategy

 DESCRIPTION (provided by applicant): We propose to bring to market, a novel regenerative medicine based therapy for fecal incontinence (FI). FI is the recurrent uncontrolled passage of fecal material. The Internal Anal Sphincter (IAS) is responsible for maintaining anorectal continence. Function of the IAS is dependent upon the neuromuscular integrity of both the smooth muscle and the intrinsic enteric nervous system (ENS). Currently, animal models of fecal incontinence do not mimic symptoms of passive FI observed in humans. We propose to further develop a novel surgical technique developed in lab to induce fecal incontinence in rabbits by damaging the IAS and utilize this model to validate the efficacy of implantation of bioengineered innervated IAS constructs for the treatment of FI. Our surgical procedure does not result in damage to the external anal sphincter (EAS), thereby limiting the injury to the smooth muscle layer of the IAS. Examination through anorectal manometry indicates the loss of IAS resting pressure as well as the neurally mediated rectoanal inhibitory reflex (RAIR) following partial IAS sphincterectomy. Our preliminary results indicate that rabbits undergoing partial IAS sphincterectomy are incontinent, with altered fecal behavior similar to symptoms of passive FI observed in humans (Aim 1). We have developed tissue culture based techniques to isolate circular smooth muscle cells from the IAS, and enteric neuronal progenitor cells from jejunal biopsies. We have optimized our bioengineering technique to generate innervated IAS constructs with neuromuscular integrity, including identifying factors important for neural progenitor cell differentiation. We propose to expand our bioengineering design to co-culture these two cell types to generate bioengineered autologous intrinsically innervated IAS constructs. These constructs are physiologically functional, and will be subject to intensive quality control to evaluate myogenic and neurogenic properties. We propose to conduct a pre-clinical randomized rabbit trial, whereby we will implant bioengineered IAS constructs in incontinent rabbits (Aim 2). The functionality of these constructs will be evaluated in vivo using anorectal manometry, and examine the reinstatement of the RAIR. Our preliminary studies indicate that reinstatement of this neurally mediated reflex occurs following implantation of bioengineered constructs. Lastly, in order to move this project towards an Investigative New Drug (IND) application to the FDA and qualify for First-in-Human studies, we propose to streamline our manufacturing and quality control protocols to fit Current Good Manufacturing Processes (CGMP) guidelines (Aim3). Our grant proposal is tailored to directly remedy the underlying pathology of FI, namely the loss of the neuromuscular integrity of the IAS. Our preliminary results provide proof of concept for the success of this regenerative medicine approach for treatment of FI.

 描述（由申请人提供）：我们建议将一种新型的基于再生的大便失禁（FI）疗法引入市场。FI 是肛门内括约肌（IAS）负责维持肛门直肠失禁。 IAS 的功能取决于平滑肌和内在肠神经系统 (ENS) 的神经肌肉完整性。目前，粪便动物模型。我们建议开发一种在实验室开发的新型手术技术，通过破坏 IAS 来诱导兔子大便失禁，并利用该模型来验证植入生物工程的进一步神经支配的 IAS 结构的有效性。我们的手术不会损伤肛门外括约肌 (EAS)，从而限制了通过肛门直肠检查对 IAS 平滑肌层的损伤。测压表明部分 IAS 括约肌切除术后 IAS 静息压力以及神经介导的直肠肛门抑制反射 (RAIR) 丧失。我们的初步指示结果表明，接受部分 IAS 括约肌切除术的兔子会出现失禁，粪便行为改变，类似于在 FI 中观察到的被动 FI 症状。我们开发了基于组织培养的技术，从 IAS 中分离圆形平滑肌细胞，并从 IAS 中分离肠神经元祖细胞。我们优化了我们的生物工程技术，以生成具有神经肌肉完整性的受神经支配的 IAS 结构，包括识别对神经祖细胞分化重要的因子。我们建议扩展我们的生物工程设计，以共培养这两种细胞类型，以生成生物工程的自体内在受神经支配的 IAS。这些构建体具有生理功能，并且将受到严格的质量控制以评估肌源性和神经源性特性，因此我们建议进行临床前随机兔试验。我们将在失禁兔子体内植入生物工程 IAS 结构（目标 2），并使用肛门直肠测压法在体内评估这些结构的功能，并检查 RAIR 的恢复情况。我们的初步研究表明，这种神经介导的反射会在植入后恢复。最后，为了推动该项目向 FDA 申请新药研究 (IND) 并获得首次人体研究的资格，我们简化提案。我们的生产和质量控制协议符合现行良好生产工艺 (CGMP) 指南（目标 3）。我们的拨款提案旨在直接补救 FI 的潜在病理，即 IAS 神经肌肉完整性的丧失。这种再生医学方法成功治疗 FI 的概念。