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: 9041772
• 负责人: KHALIL N BITAR
• 金额: $ 22.5万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041772
• 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; 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; pre-clinical; preclinical study; pressure; public health relevance; 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（应用程序提供）：我们建议将基于再生医学的新型粪便尿失禁（FI）带入市场。 FI是粪便材料的反复不受控制的通过。内部肛门括约肌（IAS）负责维持厌食直肠连续性。 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。当前，粪便失禁的动物模型不会模仿人类观察到的被动FI症状。我们建议进一步开发一种在实验室中开发的新型外科手术技术，以通过损害IAS并利用该模型来验证生物工程神经支配的IAS构建体的植入效率，以诱发兔子的粪便失禁。我们的外科手术不会导致外部肛门括约肌（EAS）损坏，从而限制了IAS平滑肌层的损伤。通过肛门直肠测量法检查表明，部分IAS括约肌切除术后IAS静止压力的损失以及中性介导的直肠抑制反射（RAIR）。我们的初步结果表明，接受部分IAS括约肌切除术的兔子是遗漏的，粪便行为的改变类似于人类观察到的被动FI症状（AIM 1）。我们已经开发了基于组织培养的技术，可以将圆形平滑肌细胞与IAS分离，并从空肠活检中输入神经元祖细胞。我们已经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神经IAS构建体，包括确定对神经祖细胞分化重要的因素。我们建议将生物工程设计扩展到这两种细胞类型的共同培养，以生成生物工程的自体固有神经支配的IAS构建体。这些构建体具有物理功能，并且将受到密集的质量控制，以评估肌源性和神经源特性。我们建议进行一项临床前随机兔试验，从而将生物工程的IAS构建体植入失败的兔子中（AIM 2）。这些构建体的功能将在体内使用肛门直肠测压法进行评估，并检查RAIR的恢复原状。我们的初步研究表明，恢复这种自然介导的反射是在植入生物工程结构后发生的。最后，为了将该项目朝着调查性新药（IND）申请到FDA并有资格进行第一名人类研究，我们建议简化我们的制造和质量控制方案，以适合当前的良好制造过程（CGMP）指南（AIM3）。我们的赠款提案是为直接记住FI的基本病理而定制的，即IAS神经肌肉完整性的丧失。我们的初步结果为这种再生医学方法的成功提供了概念证明。