Development of a novel approach to safely couple the intestine to a distraction-induced device for intestinal growth: use of reconstructive tissue matrix.

BACKGROUND: Distraction-induced intestinal growth may be a novel treatment for short bowel syndrome. Longitudinal, distractive tension created by the application of force creates a significant challenge: to produce adequate force, yet not cause perforation at the fixation points. This paper describes our development of a coupling strategy to allow for successful bowel lengthening. METHODS: A curvilinear hydraulic device was implanted in an isolated Roux limb of small bowel in young Yorkshire pigs. Bowel was lengthened over a 2-week period. Study groups included: Group 1: Twelve silk transmural anchoring sutures into an engineered-coupling ring at the ends of each device. Group 2: Addition of felt pledgets to the coupling rings on the serosal surface of the small bowel. Group 3: Extraluminal use of either thin AlloDerm(®), thick AlloDerm(®), or Strattice™ mesh to anchor the device. RESULTS: Group 1 (suture-only) resulted in a gradual pulling through the suture with increasing tension and no lengthening. Felt pledgets eroded in a similar fashion, causing abdominal sepsis. Thin AlloDerm(®) failed to prevent erosion; however, it protected against gross contamination. Animals in which either thick AlloDerm(®) or Strattice™ mesh was used survived complication free to the study endpoint. Both thick AlloDerm(®) and Strattice™ prevented erosion and perforation allowing for an average of 10.85 cm expansion. CONCLUSION: This study demonstrates the use of either thick AlloDerm(®) or Strattice™ reconstructive tissue matrix which allows for safe and effective coupling. Further, we suggest this approach could be an adjunct to esophageal lengthening procedures.

Mesenteric neovascularization with distraction-induced intestinal growth: enterogenesis.

BACKGROUND: Distraction-induced enterogenesis, whereby the intestine lengthens with application of linear forces, is an emerging area which may provide a unique treatment for short bowel syndrome. With an increase in overall tissue mass, there is an increase in oxygen and nutrient demand. We hypothesized that a neovascularization within the mesentery is necessary to support the growing small bowel. METHODS: A curvilinear hydraulic device was used to induce growth within the small bowel of Yorkshire pigs, and the intestine was harvested after 14 days. High-resolution gross pictures were recorded of the mesentery at implantation and at harvest, and CT imaging of the bowel and mesentery was performed at harvest after dye injection. RESULTS: After 2 weeks of distraction, an average of 72.5 % (8.7 cm) bowel lengthening was achieved. Gross images of the mesentery between major vessels showed a blossoming of the microvasculature and this was confirmed by CT imaging with 3D reconstruction. Mesenteric sample taken from the distracted segment had a fourfold increase in the volume of microvasculature versus controls. CONCLUSION: Enterogenesis results not only in increased bowel length, but also significant increase in the mesenteric microvascularity. Presumably, this sustains the lengthened segment after application of longitudinal forces.

Flow through a mechanical distraction enterogenesis device: a pilot test.

BACKGROUND: We tested the coupling portion of a prototype intraluminal distraction enterogenesis device to allow flow-through of simulated enteric contents (SEC) in both pig and human jejunum. MATERIALS AND METHODS: SEC was made using 80% corn syrup. Ten-cm pig and human intestinal segments had a spoke-shaped 2.2 cm coupling adaptor sutured in place, intraluminally. The adaptor had a flow-through area of 33.6 mm(2). SEC was pumped into the proximal part of the intestinal segment at 0.083 mL/s. The times to first passage of SEC through the coupler (first drop), 10 mL, and 20 mL of SEC eluted from the distal end were recorded. RESULTS: Mean time to first drop elution was 155 ± 38 s with pig, and 149 ± 22 s with human bowel (P = 0.8). This corresponded to a hydrostatic pressure of 37.5 mmHg before the initial drop passed through. Mean flow rates were 0.094 mL/s in pig bowel and 0.084 mL/s in human bowel (P = 0.09). To account for occlusion from luminal debris, a 75% occlusion of coupler holes was studied in the smaller pig bowel to investigate if reductions in flow-through area could be tolerated. Mean time to first drop increased slightly to 171 ± 15 s, but the elution rate stayed the same (P = 0.5). CONCLUSIONS: After a physiologic level of initial pressure buildup allowing the first drop of SEC to pass the coupling adaptor, our prototype intestinal coupling adaptor did not obstruct flow-through of SEC, even after a 75% decrease in flow-through area. This type of attachment represents a viable approach to placing a device in-continuity without obstructing flow of enteric contents.

Application of distractive forces to the small intestine: defining safe limits.

BACKGROUND: Distraction enterogenesis is a novel method for increasing small bowel length by the application of linearly directed forces. However, the magnitude of distractive forces that human and animal small bowel can safely withstand is unknown. METHODS: Acute ex vivo force-displacement curves for human (n = 5) and pig (n = 6) small intestine (with and without mesentery) were made by applying increasing amounts of distractive forces to bowel immersed in normal saline (39°C). Progressive load was applied until gross disruption of the tissue was detected, or the applied force reached 1000 gram-force (gf). Histology was used to detect evidence of load-induced damage. In vivo blood flow to pig bowel with distractive loads (30-200 gf) was measured by laser Doppler. RESULTS: The relationship between the level of force and degree of displacement was linear. The presence of a mesentery increased stiffness of pig bowel, but did not affect human bowel. Gross tissue disruption in pig and human tissue was seen at forces between 235 and 295 gf, respectively. However, in grossly undamaged areas, histology was unchanged even after application of higher loads. With in vivo testing, mesenteric blood flow was present up to 200 gf; however, blood flow to the bowel wall was reduced to undetectable levels at loads exceeding 100 gf. CONCLUSIONS: While whole bowel tissue may tolerate greater applied loads, blood flow to the bowel wall was compromised at loads over 100 gf, suggesting that any higher forces place the bowel at risk for ischemia. These measurements will help guide the clinical application of distraction enterogenesis.

Enterogenesis in a clinically feasible model of mechanical small-bowel lengthening.

BACKGROUND: Recent work indicates that mechanical force induces small-bowel growth, although methods reported do not have direct clinical application. We report a clinically feasible technique of enterogenesis and describe intestinal function in this model. METHODS: Using a pig model (n = 11), we stretched isolated small intestinal segments mechanically for 7 days in vivo with an intraluminal device. Control segments were not stretched. Morphology, histology, and epithelial proliferation were assessed. Absorption and epithelial barrier function were examined in an Ussing chamber. RESULTS: Stretch segments were significantly longer than Control segments and had nearly 2-fold greater surface area (P < .001). Mucosal thickness was much greater in Stretch than Control segments (772 +/- 134 vs. 647 +/- 75 microm, P = .02). Although villus height was reduced in Stretch and Control segments (353 +/- 76 vs. 324 +/- 76 microm, P = .6) versus native jejunum (522 +/- 87, P < .0005), crypt depth was increased dramatically in Stretch (450 +/- 95 microm) versus Control segments (341 +/- 64, P = .005). This observation was accompanied by a 2-fold increase in cellular proliferation (26.3 +/- 3.8 vs 12.1 +/- 6.6 % bromodeoxyuridine+, P < .05). Barrier function was intact ([3H]-mannitol permeation, 0.16 +/- 0.08%, vs native jejunum, 0.17 +/- 0.08%, P = .81). Glucose-mediated sodium transport was similar in Stretch versus native jejunum segments (60.0 +/- 23.5 vs 82.3 +/- 47.3 microA/cm2, P = .31), as was carbachol-induced chloride transport (82.4 +/- 72.2 vs 57.2 +/- 33.4 microA/cm2, P = .54) and alanine absorption (16.46 +/- 12.94 vs 23.53 +/- 21.31 microA/cm2, P = .53). CONCLUSIONS: Mechanical stretching induces small intestinal growth, while maintaining function. Epithelial architecture does change, such that a decrease in villus height is offset by a marked increase in crypt depth and a 2-fold increase in epithelial proliferation. Epithelial barrier and absorptive functions remain intact. The device described may have direct clinical applicability.

Development of an endoluminal intestinal attachment for a clinically applicable distraction enterogenesis device.

PURPOSE: Previous methods of distraction enterogenesis have relied upon blind-ending intestinal segments or transmural device fixation, requiring multiple operations and potential bowel injury. We hypothesized that using a novel attachment would allow reversible device coupling to the luminal bowel surface, achieving effective endoluminal distraction. METHODS: A telescopic hydraulic device was designed with latex balloon attachments covered with high-friction mesh and a dilating fenestrated elastic mask (DFM attachment), allowing mesh-to-mucosa contact only with inflation. Yorkshire pigs underwent jejunal Roux-en-Y limb creation and device placement via jejunostomy. Devices underwent 3 cycles of balloon inflation and hydraulic extension/retraction per day for 7 days and then explanted and studied for efficacy. RESULTS: DFM attachment allowed reversible, high-strength endoluminal coupling without tissue injury or reduction in bowel perfusion. After 7 day implant, distracted bowel achieved a 44 ± 2% increase in length vs. fed, nondistracted bowel, corresponding to a gain of 7.1 ± 0.3 cm. Distracted bowel demonstrated increased epithelial cell proliferation vs. control bowel. Attachment sites demonstrated villus flattening, increased crypt depth, thicker muscularis mucosa, and unchanged muscularis propria thickness vs. CONCLUSION: Novel high-strength, reversible attachments enabled fully endoluminal distraction enterogenesis, achieving length gains comparable to open surgical techniques. This approach may allow development of clinically applicable technology for SBS treatment.

Development of an endoluminal intestinal lengthening device using a geometric intestinal attachment approach.

BACKGROUND: Distraction enterogenesis may provide a novel therapy for short bowel syndrome. Previously described methods have relied on isolated intestinal segments or transmural fixation because of ineffective endoluminal attachment. We hypothesized that a novel approach of geometric coupling between a tapering device and the mesenteric curvature would allow trans-stomal distraction enterogenesis. METHODS: A catheter device was designed with tapering stiffness, consisting of a stiff catheter with a taper to a flexible latex tip to prevent perforation. Yorkshire pigs underwent creation of a jejunal Roux limb with device placed via jejunostomy. Intestinal attachment was achieved without a substantial decrease in bowel perfusion as measured by laser Doppler. An external clamp was secured at the stoma to provide external fixation of the device. The catheter was advanced 1 cm/day for either 7 or 14 days before explant. RESULTS: After 7 days, the distracted segment achieved a mean ± SD increase in length of 37 ± 6% versus fed, nondistracted bowel, corresponding to an absolute gain of 10.6 ± 1.7 cm (1.5 cm/day). After 14 days, the Roux limb achieved an 80 ± 2% increase in length versus fed control bowel, corresponding to an absolute gain of 16.8 ± 3.0 cm (1.2 cm/day). No perforation or stoma-related complication occurred. CONCLUSION: We describe a novel catheter device with tapering stiffness allowing for endoluminal distraction enterogenesis via geometric coupling. This approach may allow development of clinically applicable technology for the treatment of patients with short bowel syndrome.

Mechanical Extension Implants for Short-Bowel Syndrome.

Short-bowel syndrome (SBS) is a rare, potentially lethal medical condition where the small intestine is far shorter than required for proper nutrient absorption. Current treatment, including nutritional, hormone-based, and surgical modification, have limited success resulting in 30% to 50% mortality rates. Recent advances in mechanotransduction, stressing the bowel to induce growth, show great promise; but for successful clinical use, more sophisticated devices that can be implanted are required. This paper presents two novel devices that are capable of the long-term gentle stressing. A prototype of each device was designed to fit inside a short section of bowel and slowly extend, allowing the bowel section to grow approximately double its initial length. The first device achieves this through a dual concentric hydraulic piston that generated almost 2-fold growth of a pig small intestine. For a fully implantable extender, a second device was developed based upon a shape memory alloy actuated linear ratchet. The proof-of-concept prototype demonstrated significant force generation and almost double extension when tested on the benchtop and inside an ex-vivo section of pig bowel. This work provides the first steps in the development of an implantable extender for treatment of SBS.