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

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 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 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 Aim 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 PUBLIC HEALTH RELEVANCE Passive fecal incontinence FI the involuntary passage of stool is mainly due to internal anal sphincter IAS dysfunction Current treatments do not successfully treat the underlying pathology of the disease and demonstrate disappointing long term effects Utilizing a regenerative medicine based approach we aim to repair and reinstate the function of the injured IAS through implantation of bioengineered autologous innervated IAS constructs and the impact of restoration of bowel control will offer tremendous hope for the psychological stress social for stigma decreased self esteem and productivity associated with such devastating disorders