Spring-mediated Distraction Enterogenesis Research Articles

Spring-mediated distraction enterogenesis may alter the course of adaptation in porcine short bowel syndrome

IntroductionSevere forms of short bowel syndrome (SBS) resulting in chronic intestinal failure (IF) have limited therapeutic options, all of which are associated with significant morbidities. Spring-mediated distraction enterogenesis (SMDE) uses an intraluminal self-expanding spring to generate mechanical force to induce intestinal stretching and sustained axial growth, providing a promising novel approach for patients with SBS. Previous studies have established this method to be safe and effective in small and large animal models. However, SMDE has previously not been implemented in a large, clinically relevant animal model.MethodsJuvenile mini-Yucatan pigs with 75% of their small intestine resected had intraluminal springs placed after an initial adaptive period. Morphological and histological assessments were performed on SMDE segments compared to the control region of the intestine undergoing normal adaptive responses to resection.ResultsWhile the initial histologic adaptive response observed following resection was attenuated after a month, the SMDE segments instead augmented these adaptive changes. Specifically, intestinal length increased 2-fold in SMDE segments, and the widths of the epithelial, muscularis, and serosal layers were enhanced in SMDE compared with control segments of the same animal. This data suggests that morphologic intestinal adaptation may be enhanced with SMDE in the setting of SBS.DiscussionHere we demonstrate the successful and reproducible implementation of SMDE in a large animal model in the setting of prior intestinal resection, making SMDE a viable and novel approach for SBS to be explored further.

Stem cell activation during distraction enterogenesis in the murine colon.

Short bowel syndrome (SBS) is a devastating disease. We have proposed spring-mediated distraction enterogenesis for intestinal lengthening. Colonic lengthening is a potential treatment option for SBS to enhance fluid absorption capacity. We hypothesized that intraluminal spring-mediated colonic lengthening is associated with stem cell proliferation. C57BL/6 mice underwent placement of a gelatin-encapsulated compressed or uncompressed nitinol spring in a cecal segment. Animals were given clear liquid diet until postoperative day (POD) 7, followed by regular diet until POD 14. Cecal lengths were measured at euthanasia, and tissue was formalin fixed for histological processing. For Lgr5-GFP mice, immunohistochemistry against GFP was performed to localize Lgr5+ cells within crypts. Significant cecal lengthening with compressed springs and shortening with uncompressed springs were observed on POD 7 and 14. Mucosa of the compressed spring group was significantly thicker on POD 14. The density of Lgr5+ cells within the crypts in the compressed spring groups was higher than that in the uncompressed spring groups on both POD 7 and 14. Expandable springs can be used to lengthen the colon in the mouse model. Colonic lengthening was associated with gradual mucosal thickening and correlated with an increased density of stem cells within the crypts.

The effect of spring diameter on porcine ileal distraction enterogenesis.

Spring-mediated distraction enterogenesis has proven to be successful for intestinal lengthening. We aimed to evaluate the effect of spring diameter mismatch on intestinal adaptation. Juvenile mini-Yucatan pigs underwent placement of compressed nitinol springs with diameter of 10, 11, or 12mm into the ileal lumen. Pigs were euthanized on postoperative day 7. The lengths, histology, total area of blood vessels, and enteric ganglia were evaluated. All spring groups exhibited significant ileal lengthening. Across the different diameters, spring-expanded segments were similar in terms of ileal lengthening, crypt height, muscular thickness, blood vessels, and enteric ganglia area. Spring-mediated distraction enterogenesis is successful in the porcine ileum. A smaller diameter spring is as effective as a larger diameter spring in lengthening the ileum. Springs of varying diameters result in comparable structural changes in the ileum.

Generation of Porcine Ileum Through Spring-Mediated Mechanical Distraction

IntroductionShort bowel syndrome is a devastating gastrointestinal disorder in which decreased bowel length results in inadequate absorption causing nutritional deficiencies. Current treatment options are accompanied by significant morbidity. We have proposed spring-mediated distraction enterogenesis as a method to lengthen bowel with success seen in porcine jejunum. We hypothesize that spring-mediated distraction enterogenesis can be demonstrated in porcine ileum with preservation of ileal structure and function. Materials and methodsLaparotomy was performed on juvenile female mini-Yucatan pigs and a gelatin-encapsulated compressed nitinol spring was inserted into the ileal lumen and affixed proximally and distally. A control segment distal to the spring segment was marked with sutures. Postoperatively, pigs were placed on a liquid diet and euthanized on postoperative day 7. Spring and control segments were measured and processed for immunohistochemistry to evaluate for the presence of vitamin B12–intrinsic factor cotransporter, chromogranin A-producing cells, and 5-HT producing cells. ResultsAll seven pigs survived to postoperative day 7 with no adverse effects. On average, pigs gained 84.3 ± 66.4 g/d. Spring segments lengthened 1.5 ± 0.7 cm with a relative lengthening by 128% ± 56%, which was statistically significant when compared to control (P < 0.01). The average density of chromogranin-A cells in control compared to spring segments was not significantly changed (2.9 ± 1.1 cells/mm versus 3.2 ± 1.2 cells/mm, P = 0.17). Both vitamin B12–intrinsic factor cotransporter and 5-HT producing cells were present in both control and lengthened ileum. ConclusionsIntraluminal nitinol springs significantly lengthened porcine ileum. The increase in density of enteroendocrine cells may indicate enhanced endocrine function of the lengthened ileum.

Mechanical lengthening of porcine small intestine with decreased forces

Introductionshort bowel syndrome is marked by inadequate intestinal surface area to absorb nutrients. Current treatments are focused on medical management and surgical reconfiguration of the dilated intestine. We propose the use of spring-mediated distraction enterogenesis as a novel intervention to increase intestinal length. Given our previous success lengthening intestinal segments using springs with spring constant ~7 N/m that exerts 0.46 N or higher, we sought to determine the minimal force needed to lengthen porcine small intestinal segments, and to explore effects on intestine over time. MethodsJuvenile Yucatan pigs underwent laparotomy with enterotomy to introduce nitinol springs intraluminally (n = 21 springs). Bowel segments (control, spring-distracted) were retrieved on post-operative day (POD) 7 and 14, and lengths measured. Thickness of cross-sectional intestinal layers were measured using H&E, and submucosal collagen fiber orientation measured using trichrome stained sections. Resultsall pigs survived to POD7 and 14. Spring constants of at least 2 N/m exerting a minimum force of 0.10 N significantly lengthened intestinal segments (p <0.0001). The stronger the spring force, the greater the induced thickness of various intestinal layers at POD7 and 14. Collagen fiber orientation was also more disordered because of stronger springs. Conclusiona spring constant of approximately 2 N/m exerting 0.10 N and greater significantly lengthens intestinal segments and stimulates intestinal structural changes at POD7 and 14. This suggests a decreased force is capable of inducing spring-mediated distraction enterogenesis.

Biomechanical Force Prediction for Lengthening of Small Intestine during Distraction Enterogenesis.

Distraction enterogenesis has been extensively studied as a potential treatment for short bowel syndrome, which is the most common form of intestinal failure. Different strategies including parenteral nutrition and surgical lengthening to manage patients with short bowel syndrome are associated with high complication rates. More recently, self-expanding springs have been used to lengthen the small intestine using an intraluminal axial mechanical force, where this biomechanical force stimulates the growth and elongation of the small intestine. Differences in physical characteristics of patients with short bowel syndrome would require a different mechanical force—this is crucial in order to achieve an efficient and safe lengthening outcome. In this study, we aimed to predict the required mechanical force for each potential intestinal size. Based on our previous experimental observations and computational findings, we integrated our experimental measurements of patient biometrics along with mechanical characterization of the soft tissue into our numerical simulations to develop a series of computational models. These computational models can predict the required mechanical force for any potential patient where this can be advantageous in predicting an individual’s tissue response to spring-mediated distraction enterogenesis and can be used toward a safe delivery of the mechanical force.

Mesenteric neovascularization during spring-mediated intestinal lengthening

BackgroundShort gut syndrome, a condition characterized by inadequate absorption of nutrients owing to decreased bowel length, has minimal avenues for treatment. We have proposed spring-mediated distraction enterogenesis to lengthen bowel in porcine jejunum as a treatment for short gut. We aim to evaluate the extent of mesenteric neovascularization in segments of lengthened bowel via spring-mediated enterogenesis. MethodsFemale juvenile Yucatan pigs underwent laparotomy and insertion of gelatin-encapsulated compressed nitinol springs, held in place with plication sutures, into the jejunum. At surgery and sacrifice, macroscopic mesenteric blood vessels were counted between the plication sites. Histologic samples of the mesentery were obtained to evaluate microscopic vasculature. ResultsA statistically significant increase in macroscopic mesenteric blood vessels was seen after intestinal lengthening (before: 1.9 ± 0.7 vessels, after: 4.7 ± 1.2 vessels, p = 0.001). A statistical significance is also seen in the density of arterioles (control: 3.0 ± 3.0 vessels/mm, spring: 7.0 ± 9.0 vessels/mm, p = 0.01) and venules (control: 4.0 ± 3.0 vessels/mm, spring: 8.0 ± 8.0 vessels/mm, p = 0.003). ConclusionIntestinal segments lengthened by intraluminal springs demonstrated total greater number of macroscopic vessels and microscopic blood vessels per length of mesentery as compared to control. This suggests local changes within the mesentery to recruit blood supply to growing intestine. Level of evidenceN/A Type of studyTreatment study.

Biomechanics of small intestine during distraction enterogenesis with an intraluminal spring

During recent years, distraction enterogenesis has been extensively studied as a treatment for short bowel syndrome, which is the most common cause of intestinal failure. Although different strategies such as parenteral nutrition and surgical lengthening have been used to manage the difficulties that patients with SBS deal with, these treatments are associated with high complication rates. Distraction enterogenesis uses mechanical force to increase the length and stimulate growth of the small intestine. In this study we combine in vivo experiments with computational modeling to explore the biomechanics of spring dependent distraction enterogenesis. We hypothesize that the self-expanding spring provides mechanical force for elastic tissue lengthening and triggers cellular proliferation. The additional growth of the intestine suggests signaling between mechanical stress and tissue response. We developed a computational modeling platform to test the correlation of applied mechanical force and tissue growth. We further validated our computational models with experimental measurements using spring-mediated distraction enterogenesis in a porcine model. This modeling platform can incorporate patient biometrics to estimate an individual's tissue response to spring mediated distraction enterogenesis.

Intestinal lengthening via multiple in-continuity springs

BackgroundShort bowel syndrome is a debilitating condition with few effective treatments. Spring-mediated distraction enterogenesis can be used to lengthen intestine. The purpose of this study is to determine whether multiple springs in series can safely increase the total amount of lengthening. MethodsJuvenile mini-Yucatan pigs each received three nitinol springs placed within their jejunum. Plication was used to narrow the intestine around each spring to secure them. Compressed springs were used in the experimental group, while uncompressed springs were used in the control group. The intestine was examined 3 weeks later for lengthening and histologic changes. ResultsAll pigs tolerated diets postoperatively with continued weight gain, and no dilation or obstruction of the intestine was observed. Segments of intestine that contained compressed springs had a significant increase in length from 2.5 cm to 3.9 ± 0.2 cm per spring, compared to segments containing control springs that showed no change (p < 0.001). ConclusionsIntestinal plication can be safely used to secure multiple springs in series to achieve intestinal lengthening without compromising intestinal function. Using several springs at once allows for a greater amount of total lengthening. This is a promising model that has potential in the treatment of short bowel syndrome.

Three-dimensionally printed surface features to anchor endoluminal spring for distraction enterogenesis.

Spring-mediated distraction enterogenesis has been studied as a novel treatment for short bowel syndrome (SBS). Previous approaches are limited by multiple surgeries to restore intestinal continuity. Purely endoluminal devices require a period of intestinal attachment for enterogenesis. The purpose of this study is to modify the device to prevent premature spring migration in a porcine model. Two models were created in juvenile mini-Yucatan pigs for the placement of three-dimensionally printed springs. (1) Two Roux-en-y jejunojenostomies with two Roux limbs were made. A spring with bidirectional hooked surface features was placed in one Roux limb and a spring with smooth surface was placed in the other Roux limb. (2) The in-continuity model had both hooked and smooth surface springs placed directly in intestinal continuity. Spring location was evaluated by weekly radiographs, and the intestine was retrieved after 2 to 4 weeks. Springs with smooth surfaces migrated between 1 to 3 weeks after placement in both porcine models. Springs with bidirectional hooked surface features were anchored to the intestine for up to 4 weeks without migration. Histologically, the jejunal architecture showed significantly increased crypt depth and muscularis thickness compared to normal jejunum. Bidirectional features printed on springs prevented the premature migration of endoluminal springs. These novel spring anchors allowed for their endoluminal placement without any sutures. This approach may lead to the endoscopic placement of the device for patients with SBS.

Lgr5 Stem Cell Proliferation from Spring-Mediated Distraction Enterogenesis in a Mouse Model

Lgr5 Stem Cell Proliferation from Spring-Mediated Distraction Enterogenesis in a Mouse Model

Spring-Mediated Intestinal Lengthening in a Porcine Model

Introduction: Spring-mediated distraction enterogenesis has been shown to increase the length of an intestinal segment and continues to be investigated as a possible treatment for short bowel syndrome. Both metal (nitinol) and biodegradable (polycaprolactone, PCL) springs have been used in rats to triple the length of a segment of intestine.[1][2][3][4] We describe our experiences with adapting spring-mediated intestinal lengthening to a pig model with the intention of creating a minimally invasive, completely endoluminal spring device for clinical application. Methods: Juvenile mini-Yucatan pigs underwent laparotomy for spring placement within the jejunum. Various configurations of intestinal lengthening were tested as follows: PCL spring placed in an isolated segment, PCL spring in de-functional Roux-en-y segments, PCL spring within in-continuity bowel secured either with external sutures or internal high friction surface adhesive, and 3D printed nylon springs with surface hooks within in-continuity bowel (Figures 1 and 2). Bowel segments were measured and marked intra-operatively and re-examined 1–4 weeks after spring placement. Results: In the subset of pigs that had springs placed in isolated jejunum, the spring segments had a 2.2-fold increase in length relative to the starting length of the segment. In the Roux-en-y model the PCL springs resulted in a 2-fold increase in length. In the subset of pigs that had PCL springs placed in-continuity 5 out of 12 springs detached prematurely and were passed without causing an obstruction. The remaining 7 springs resulted in a 1.5-fold increase in length. In the subset of pigs with 3D-printed springs placed in-continuity the intestine showed a 1.4-fold increase in length.FIGURE 1: Different configuration to test intestinal lengthening. A) Jejunal isolated segment model. B) De-functional Roux-en-Y with PCL anchor. C) Jejunal incontiinuity model.FIGURE 2: Different seft-expandable springs. A) PCL spring. B) PCL spring with high-surface adhesive. C) 3D-printed nylon spring with surface hooks.Conclusion: Spring-mediated intestinal lengthening can be achieved in a pig model. While the greatest amount of lengthening is possible in an isolated-segment model, this has little clinical applicability. Despite a decrease in the amount of lengthening achieved with the in-continuity model, the ability to repeat this process without further surgical interventions may ultimately allow for clinically significant intestinal lengthening in patients with short bowel syndrome. Sun West Company.

Spring-mediated distraction enterogenesis in-continuity

PurposeDistraction enterogenesis has been investigated as a novel treatment for patients with short bowel syndrome (SBS) but has been limited by loss of intestinal length during restoration and need for multiple bowel surgeries. The feasibility of in-continuity, spring-mediated intestinal lengthening has yet to be demonstrated. MethodsJuvenile mini-Yucatan pigs underwent in-continuity placement of polycaprolactone (PCL) degradable springs within jejunum. Methods used to anchor the spring ends to the intestine included full-thickness sutures and a high-friction surface spring. Spring constant (k) was 6–15N/m. Bowel was examined for length and presence of spring at 1 to 4weeks. ResultsAnimals tolerated in-continuity lengthening without bowel obstruction for up to 29days. In-continuity jejunum with springs demonstrated intestinal lengthening by 1.47-fold ±0.11. Five springs had detached prematurely, and lengthening could not be assessed. Histologically, in-continuity jejunum showed significantly increased crypt depth and muscularis thickness in comparison to normal jejunum. ConclusionSelf-expanding endoluminal springs placed in continuity could lengthen intestine without obstruction in a porcine model. This is the first study showing safety and efficacy of a self-expanding endoluminal device for distraction enterogenesis. This is proof-of-concept that in-continuity spring lengthening is feasible and demonstrates its therapeutic potential in SBS. Level of evidenceLevel 3.