BioSphincter to Treat Fecal Incontinence. Phase 1/2 Clinical Trial. SBIR Phase IIB

项目概要/摘要： 粪便失禁（FI），即不同量的液体和固体粪便的不自主污染，通常是 从社会、心理和卫生的角度来看都是毁灭性的。男性和女性同样患有FI， 在20 - 30岁的人群中，范围为2 - 6%。在70岁以上的人群中，患病率增加到15%以上 几年1. FI可能是由于平滑肌功能（IAS）、骨骼肌功能（AS）、肌纤维化和肌纤维化的单独或联合丧失所致。 功能（EAS），肛门直肠感觉机制或神经控制。 FI的治疗最初是保守的，试图散装粪便，调整或停止药物， 腹泻或便秘，以及生物反馈2，3。虽然这些保守的措施可能会改善 FI的严重程度，需要额外的治疗来进行全面的症状管理。注射各种生物材料 增加肛门内括约肌也被证实4，但结果是可变的和有限的 有效期。在过去，已经尝试了前/后手术修复的手术尝试 例如股薄肌成形术和骶神经刺激5，6，但长期结果不佳6。 迫切需要新的治疗方法来解决FI，特别是对于患有严重FI的患者。 被动性尿失禁和低IAS压力。再生医学方法，其中一个新的国际会计准则 BioSphincter™是从患者自身细胞生物工程和植入，以恢复结构和 功能的IAS和治疗FI，代表了一个合理的和新的方法，这种衰弱的疾病。 IAS“BioSphincter™”的再生和植入可以恢复IAS的生理功能， 改善或解决FI，提高生活质量。在啮齿动物体内植入后， 变得血管化并保持其表型和功能7，8。在我们的大型动物研究中， 开发的IAS BioSphincter™经验证可治疗FI并成功恢复肛门直肠 功能在兔子9，10和非人类灵长类动物11。IAS BioSphincter™在GLP条件下开发 根据GMP指导原则进一步扩大生产规模，并将其组合在一起以供FDA申请。根据 对于NIDDK，NIH，三分之一的人由于大便失禁而向卫生保健提供者报告，因此， IAS“Biospincter ™”的再生和植入将使大量社会困扰的人受益， 通过恢复IAS的生理功能，解决FI，提高生活质量。 I期临床试验研究的主要目的是：1）确定植入物的安全性 生物工程IAS治疗重度FI患者，2）分析数据以评估初始疗效 植入的IAS在减少重度尿失禁患者的尿失禁发作次数方面的潜力 菲这种新的创新方法将为患者提供更好的生活质量，并恢复其功能， 通过提供从他们自己的细胞生物工程化的附加功能性内在神经支配的IAS。

Project Summary/Abstract: Fecal incontinence (FI), the involuntary soiling of various amounts of liquid and solid stool, is often devastating from a social, psychological, and hygiene perspective. Men and women suffer from FI equally with a range of 2 - 6% in people aged 20 - 30 years. The prevalence increases to over 15% in people older than 70 years1. FI may result from an isolated or combined loss of smooth muscle function (IAS), skeletal muscle function (EAS), anorectal sensory mechanisms or neural control. Treatment of FI is initially conservative with attempts to bulk the stool, adjust or stop drugs that cause either diarrhea or constipation, and biofeedback2,3. While these conservative measures may improve the severity of FI, additional therapies are needed for total symptom management. Injection of various biomaterials to augment the internal anal sphincter has also been attempted4, but results have been variable and of limited duration when effective. In the past, surgical attempts with anterior/posterior surgical repair have been tried such as graciloplasty and sacral nerve stimulation5,6, but long-term results have been disappointing6. There is a critical need for new therapies to address FI, particularly for patients who have severe passive incontinence and low IAS pressure. Regenerative medicine methods, wherein a new IAS BioSphincter™ is bioengineered from the patient's own cells and implanted to restore the structure and function of the IAS and treat FI, represents a rational and novel approach to this debilitating disease. Regeneration and implantation of the IAS “BioSphincter™” can restore physiological function of the IAS, improve or resolve FI, and improve quality of life. Following implantation in rodents, the engineered sphincters became vascularized and maintained their phenotype and functionality7,8. Further in our large animal studies, the developed IAS BioSphincter™ were validated to treat the FI and successfully restored anorectal functionality in rabbit9,10 and non-human primates11. The IAS BioSphincter™ was developed in GLP condition further scaled up for manufacturing following GMP guidelines and put together for FDA application. According to NIDDK, NIH, one out of three people report to health care providers owing to fecal incontinence, therefore, regeneration and implantation of the IAS “Biosphincter™” will benefit a large socially distressed segment of population via restoration of physiological function of the IAS, resolve FI, and improving quality of life. The primary objectives of the phase I clinical trial study are to: 1) determine the safety of the implanted bioengineered IAS in patients with severe FI and 2) to analyse the data in order to assess the initial efficacy potentials of the implanted IAS in decreasing the number of episodes of incontinence in patients with severe FI. This new innovative approach will provide the patients with a better quality of life, and reinstate continence, by providing an additive functional intrinsically innervated IAS bioengineered from their own cells.