Innovative approaches for induction of gastrointestinal anastomotic healing: an update on experimental and clinical aspects.

PURPOSE: In most cases, traditional techniques to perform an anastomosis following gastrointestinal resections lead to successful healing. However, despite focused research in the field, in certain high-risk situations leakage rates remain almost unchanged. Here, additional techniques may help the surgeon to protect the anastomosis and prevent leakage. We give an overview of some of the latest developments on experimental and clinical techniques for induction of anastomotic healing. METHODS: We performed a review of the current literature on approaches to improve anastomotic healing. RESULTS: Many promising approaches with a high clinical potential are in the developmental pipeline. Highly experimental approaches like inhibition of matrix metalloproteinases, stem cell therapy, hyperbaric oxygen therapy, induction of the hypoxic adaptive response, and the administration of growth factors are still in the preclinical phase. Other more clinical developments aim to strengthen the anastomotic suture line mechanically while shielding it from the influence of the microbiome. Among them are gluing, seaming the staple line, attachment of laminar biomaterials, and temporary intraluminal tubes. In addition, individualized bowel preparation, selectively reducing certain detrimental microbial populations could become the next stage of bowel preparation. Compression anastomoses are evolving as an equivalent technique additional to established hand-sewn and stapled anastomoses. Fluorescence angiography and flexible endoscopy could complement intraoperative quality control additionally to the air leak tests. Virtual ileostomy is a concept to prepare the bowel for the easy formation of a stoma in case of leakage. CONCLUSION: A variety of promising diagnostic and prophylactic measures that may support the surgeon in identifying high-risk anastomoses and support them according to their potential deficits is currently in development.

The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model.

OBJECTIVE: To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation. MATERIAL AND METHODS: Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined. RESULTS: Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups. CONCLUSION: Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.

The Effectiveness of Adipose Tissue-Derived Mesenchymal Stem Cells Mixed with Platelet-Rich Plasma in the Healing of Inflammatory Bowel Anastomoses: A Pre-Clinical Study in Rats.

Introduction: Multiple factors have been linked with increased risk of anastomotic leak in bowel surgery, including infections, inflammatory bowel disease, patient comorbidities and poor surgical technique. The aim of this study was to investigate the positive effect, if any, of adipose derived mesenchymal stem cells (MSCs) mixed with platelet-rich plasma (PRP) in the healing of bowel anastomoses, in an inflammatory environment after establishment of experimental colitis. Materials and Methods: Thirty-five male Wistar rats were divided into five groups of seven animals: normal controls, colitis controls, PRP, MSCs, and PRP+MSCs. All groups underwent laparotomy, one-cm segmental colectomy and anastomosis in situ. In the colitis group, colectomy was performed at the affected area. Colitis was previously established by transrectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) except for the normal controls. Post-mortem histopathological, tissue hydroxyproline and anastomotic bursting pressure (ABP) assessments were performed. The Mann-Whitney U test was used to assess statistical significance differences between groups. Results: No perioperative mortality was noted. Tissue hydroxyproline and ABP were significantly increased in the group of PRP+MSCs compared to colitis controls (p = 0.0151 and p = 0.0104, respectively). Inflammatory cell infiltration was lower and fibroblast activity higher in PRP+MSCs group, but not statistically significant (p > 0.05). Neoangiogenesis (p = 0.0073) and anastomotic area epithelialization (p = 0.0182) were significantly higher in PRP + MSCs group compared to colitis controls. Discussion: The synergistic effect of the PRP and MSCs is apparently responsible for the improved healing markers in bowel anastomoses even on inflammatory bowel. This gives hope for primary anastomoses and stoma saving in many emergency and/or elective circumstances, especially in immunocompromised or malnourished patients, even in cases with inflammation or peritonitis. Clinical studies should follow in order to support the clinical application of PRP+MSCs in gastrointestinal anastomoses.

Intestinal Anastomotic Healing: What do We Know About Processes Behind Anastomotic Complications.

Colorectal surgery has developed rapidly in the recent decades. Nevertheless, colorectal anastomotic leakage continues to appear postoperatively in unpleasant rates and leads to life-threatening conditions. The development of valid complication-preventing methods is inefficient in many aspects as we are still lacking knowledge about the basics of the process of anastomotic wound healing in the gastrointestinal tract. Without the proper understanding of the crucial mechanisms, research for prevention of anastomotic leakage is predestined to be unsuccessful. This review article discusses known pathophysiological mechanisms together with the most lately found processes to be further studied. The aim of the article is to facilitate the orientation in the topic, support the better understanding of known mechanisms and suggest promising possibilities and directions for further research.

The design, development, and in vivo performance of intestinal anastomosis ring fabricated by magnesium­zinc­strontium alloy.

In the current work, an intestinal anastomosis ring made of magnesium­zinc­strontium (Mg-Zn-Sr) alloy was developed and fabricated in order to take advantages of the appropriate biocompatibility and degradability of Mg-based alloys. As-fabricated anastomosis rings were implanted into the intestinal tracts of Bama miniature pigs to evaluate their biological performance in vivo. At the injury site, the formation of edema and granulation tissue was observed for 2 weeks after surgery. Till week 4, the edema transformed to firm scar tissue, which reached the healing standard of intestinal tissue. The levels of biochemical indicators such as blood routine, liver and kidney functions as well as electrolytes were all under normal conditions, indicating that the implantation of Mg alloy did not have remarkable influence on the blood system as well as liver and kidney functions. Pathological results revealed that no obvious abnormality was found in heart, liver, spleen, lung, kidney and brain tissues. The Mg ions were found to be excreted from the body through urine. The intestinal anastomosis ring could be discharged through excretion around 2 weeks after surgery, of which the surface was corroded and covered by a layer of Ca- and P-containing minerals. According to histological images, a mild inflammatory response was noticed on week 2. At this stage, dilated and congested capillaries were found in the muscular layer. Moreover, the mucosal layer and villi at the injury site were disordered. Till week 4, the muscular and mucosal layer were similar to their healthy counterparts even though the villi were slightly shorter than normal ones. Together, the results indicate that Mg-Zn-Sr alloy is a promising candidate for the fabrication of biodegradable intestinal anastomosis ring.

Treat-to-target in Crohn's disease: Will transmural healing become a therapeutic endpoint?

Crohn's disease (CD) represents a chronic transmural inflammatory condition of the gastrointestinal tract, which usually leads to structural damage and significant disability. Deep remission - defined by both clinical and endoscopic remission, signifying mucosal healing - represents the current endpoint in the treat-to-target strategy, significantly improving patients' long-term outcomes. Transmural healing (TH) could be a more effective target, but this possibility remains unclear. This narrative review aims to critically review and summarize the available literature relating TH to long-term outcomes, being the first of its kind and to the best of the author's knowledge. A systematic literature search (from inception to March 31 2018) was performed, using multiple databases, and identifying seven full-text manuscripts. In those studies, long-term favorable outcomes (≥ 52 wk) included sustained clinical remission, as well as fewer therapeutic changes, CD-related hospitalizations, and surgeries. Despite heterogeneous design and methodological limitations, six of the studies demonstrated that TH or intestinal healing (TH plus mucosal healing) were predictive for the aforementioned favorable outcomes. Therefore, TH may become a reasonable therapeutic target and be included in the concept of deep remission. Further prospective, well-designed, multicenter trials aiming to better define the role of TH in personalized therapy for CD and to determine the long-term influence of TH on bowel damage and disability are warranted.

Effect of Humira® on Intestinal Anastomotic Response in Rabbits.

AIM: The aim of this study was to compare the strength and degree of inflammation in small intestinal anastomoses in rabbits after repeated preoperative treatment with the TNF-α antibody, adalimumab (Humira®), compared to placebo. METHOD: Thirty-three New Zealand white female rabbits were randomized to three weeks of weekly subcutaneous injections of adalimumab (n = 24) or placebo (n = 9). After this treatment regime, two end to end anastomoses were performed in the ileum. Following euthanasia on postoperative day 5 the anastomoses were evaluated for minimal tensile strength (MITS) and histological parameters of wound healing using a modified Verhofstad Scale. RESULTS: There were no statistically significant differences between the adalimumab and placebo groups in terms of MITS or histological parameters. Multiple regression analyzes revealed that there was no association between MITS and treatment, numbers of sutures, length of surgery, preoperative weight gain, postoperative weight loss or histological score. On the day of surgery the median serum concentration of adalimumab was 5.4 µg/ml (3.4-8.6). CONCLUSION: Repeated preoperative treatment with adalimumab had no significant influence on MITS or histological score in anastomoses in the small intestine of the rabbits.