Short bowel syndrome (SBS) is a devastating surgical disease with a high morbidity and mortality. SBS results in a series of adaptive processes, including proliferation, apoptosis, and increased absorptive capacity. Despite these changes, lack of a sufficient length of intestine may prohibit a patient from ever being able to take in a sufficient amount of nutrition from the intestine. One critical factor for tissue growth that has been recently studied is mechanotransduction. By this, mechanical forces cause a cascade of actions which alter cell-cell contact, cell adhesion and activation of proliferative mechanisms. Although not well described in the intestine, these forces have been used in a multitude of organ systems to induce growth of bone, lung and neural tissue. Such mechanical forces may well have a useful application for the lengthening of the small intestine - and provide substantially more bowel to enhance adaptation. Preliminary data demonstrate that mechanical force, with an intraluminally implanted device, can significantly (~3-fold) lengthen pig small intestine over a 15 day period (enterogenesis). This suggests that the intestine may well respond in a similar fashion. Additional data show a substantial increase in surface area, with preservation of intestinal function - as assessed with Ussing chamber experiments. Based on this, the specific aims of the proposal are to: 1) Investigate if a linearly applied mechanical force on the small intestine will enhance small intestinal length, as well as absorptive and motility function. This will be done in two parts. First, segments of mid-small bowel will be progressively lengthened. This will be followed by a secondary re-implantation of the lengthened bowel into the normal enteric flow of the gastrointestinal tract. 2) The second aim will consist of an assessment of what qualities of mechanotransduction (intervals of force application and amount of force) result in optimization of enterogenesis. For these latter experiments, it will be necessary to refine the development of the bowel lengthening device. It is anticipated that this proposal will give important insight into the potential use of mechanotransduction for the lengthening of small bowel. It is further anticipated that findings derived from these studies will lead to the development of a clinically applicable device which may be used in the treatment of SBS. This research proposal will test the hypothesis that the application of distractive forces can successfully lead to a lengthening of the small intestine, and that this lengthening will result in a net gain in intestinal absorptive and motility function. Knowledge gained from this project could greatly improve the care of patients who suffer from short bowel syndrome. ? ? ?
