Resorbable Synthetic Meshes for Abdominal Wall Defects in Preclinical Setting: A Literature Review.

BACKGROUND: Prosthetic materials for the repair of abdominal wall defects have been studied extensively to improve outcome. A new approach can be the use of a slowly resorbable synthetic mesh, which aims to combine advantages of both synthetic and biological meshes. The objective of this review is to give an overview of the physicochemical characteristics and biomechanical, histological, and macroscopic outcome (recurrence, adhesion formation) of the use of resorbable synthetic meshes, for treatment and prevention of abdominal wall hernias, based on experimental studies. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only experimental studies were included. Outcome parameters were resorption, degradation, organization of connective tissue, inflammatory response, tensile strength, and amount of adhesion formation. Surgical characteristics were taken into account as well (type of defect, clean versus contaminated model, position mesh, repair of the defect, recurrences). RESULTS: In total, eleven articles were included. Three absorbable synthetic meshes are currently available: GORE BIO-A mesh (Gore), TIGR Matrix Surgical mesh (Novus Scientific), and Phasix mesh (Bard). Two studies concluded that, despite an early transient inflammatory reaction in the first months, remodeling was good in GORE BIO-A, 6-12 mo after augmentation or suture line reinforcement with only minimal to moderate adhesions when used intraperitoneally. The TIGR Matrix Surgical mesh shows only partial remodeling with a persistent foreign body reaction after 1 y. Phasix mesh seems to perform well in extraperitoneal implantation after 1 y in two studies, although the defect was small. Only two studies directly compared two resorbable synthetic meshes under the same circumstances. The latter also included a number of animals where the meshes were used in a contaminated nonhernia model. No hernia recurrences or deaths of animals were described in all studies. CONCLUSIONS: The use of resorbable synthetic meshes in the prevention or treatment of abdominal wall defects in animal experiments with small defects in clean setting seems safe, with no serious complications related to the device during short-term follow-up. However, there is no evidence available that can support the advantages of resorbable synthetic meshes over the use of synthetic or biological meshes, mostly due to lack of good data. More experimental studies are needed, followed by randomized controlled trials and prospective registries in humans with a sufficiently long follow-up period, to reveal the potential advantages in clinical practice.

Transplantation of Adipose Tissue-Derived Stem Cell Sheet to Reduce Leakage After Partial Colectomy in A Rat Model.

Anastomotic leakage is a disastrous complication after colorectal surgery. Although current methods for leakage prevention have different levels of clinical efficacy, they are until now imperfect solutions. Stem cell therapy using ASC sheets could provide a solution to this problem. ASCs are considered as promising candidates for promoting tissue healing because of their trophic and immunomodulatory properties. Here, we provide methods to produce high-density ASC sheets, that are transplanted onto a colorectal anastomosis in a rat model to reduce the leakage. ASCs formed cell sheets in thermo-responsive culture dishes that could be easily detached. On the day of the transplantation, a partial colectomy with a 5-suture colorectal anastomosis was performed. Animals were immediately transplanted with 1 ASC sheet per rat. ASC sheets adhered spontaneously to the anastomosis without any glue, suture, or any biomaterial. Animal groups were sacrificed 3 and 7 days postoperatively. Compared to transplanted animals, the incidence of anastomotic abscesses and leakage was higher in control animals. In our model, the transplantation of ASC sheets after colorectal anastomosis was successful and associated with a lower leakage rate.

Nicotine chewing gum for the prevention of postoperative ileus after colorectal surgery: a multicenter, double-blind, randomised, controlled pilot study.

PURPOSE: When postoperative ileus is not resolved after 5 days or recurs after resolution, prolonged POI (PPOI) is diagnosed. PPOI increases discomfort, morbidity and hospitalisation length, and is mainly caused by an inflammatory response following intestinal manipulation. This response can be weakened by targeting the cholinergic anti-inflammatory pathway, with nicotine as essential regulator. Chewing gum, already known to stimulate gastrointestinal motility itself, combined with nicotine is hypothesised to improve gastrointestinal recovery and prevent PPOI. This pilot study is the first to assess efficacy and safety of nicotine gum in colorectal surgery. METHODS: Patients undergoing elective oncological colorectal surgery were enrolled in this double-blind, parallel-group, controlled trial and randomly assigned to a treatment protocol with normal or nicotine gum (2 mg). Patient reported outcomes (PROMS), clinical characteristics and blood samples were collected. Primary endpoint was defined as time to first passage of faeces and toleration of solid food for at least 24 h. RESULTS: In total, 40 patients were enrolled (20 vs. 20). In both groups, six patients developed PPOI. Time to primary endpoint (4.50 [3.00-7.25] vs. 3.50 days [3.00-4.25], p = 0.398) and length of stay (5.50 [4.00-8.50] vs. 4.50 days [4.00-6.00], p = 0.738) did not differ significantly between normal and nicotine gum. There were no differences in PROMS, inflammatory parameters and postoperative complications. CONCLUSIONS: We proved nicotine gum to be safe but ineffective in improving gastrointestinal recovery and prevention of PPOI after colorectal surgery. Other dosages and administration routes of nicotine should be tested in future research.

Effects of adipose stem cell sheets on colon anastomotic leakage in an experimental model: Proof of principle.

The most dreaded complication of colorectal surgery is anastomotic leakage. Adipose tissue-derived stem cell sheets (ASC sheets) prepared from temperature-responsive culture surfaces can be easily transplanted onto tissues. These sheets are proposed to improve cell transplant efficiency and enhance wound healing. The aim of this study was to investigate whether application of ASC sheets could prevent leakage of sutured colorectal anastomoses. Insufficient suturing of colorectal anastomoses was performed in Wistar rats to create a colorectal anastomotic leakage model. Rats were randomized to ASC sheet application or control group. Leakage, abscess formation, adhesion formation, anastomotic bursting pressure (ABP), and histology were evaluated on postoperative day 3 or 7. ASC sheet application significantly reduced anastomotic leakage compared to controls, without increased adhesion formation. ASC sheet transplantation resulted in more CD3+ T-cells and CD163+ anti-inflammatory macrophages at the anastomotic site than the control group. ABP, vessel density and collagen deposition were not different between groups. Using cell sheet technology, we generated ASC sheets that prevented disruption of sutured colorectal anastomoses as shown by reduced leakage. Increased numbers of anti-inflammatory macrophages and T-cells might have contributed to this positive effect.

Reinforcement of the colon anastomosis with cyanoacrylate glue: a porcine model.

BACKGROUND: Previous experimental studies on cyanoacrylate (CA) glue for the prevention of colorectal anastomotic leakage (AL) have shown promising results. The aim of this study was to investigate the effect of CA in prevention of leakage in a porcine model of ischemic colorectal AL. METHODS: Twenty-four animals were divided into four groups of six: (1)ischemic anastomosis with sufficient suture (ISCH), (2)ischemic anastomosis with sufficient suture and CA reinforcement (CA-ISCH), (3)ischemic anastomosis with insufficient suture (ISCH-AI), and (4)ischemic anastomosis with insufficient suture and CA reinforcement (CA-ISCH-AI). In CA groups, N-butyl-2-cyanoacrylate was applied between the colon ends. Anastomotic bursting pressure, abscess formation, and adhesion formation were evaluated on postoperative day 7. Tissue samples were obtained for histologic evaluation of foreign body reaction. RESULTS: The AL rate was 4 of 6 (67%) in the ISCH-AI group compared with none in the other three groups. The ISCH and ISCH-AI groups had significantly higher AL scores compared with the CA groups. The mean anastomotic bursting pressure was 167 ± 54 mm Hg in the ISCH-group versus 213 ± 43 mm Hg in the CA-ISCH-group (P = nonsignificant) and 145 ± 102 mm Hg in the ISCH-AI group versus 187 ± 19 mm Hg in the CA-ISCH-AI group (P = nonsignificant). The average adhesion score was significantly higher in the ISCH group than in the CA-ISCH group (4.2 ± 1.3 versus 1.7 ± 0.82; P = 0.019). Stricture of the anastomosis occurred only in the non-CA groups (3/12, 25%). CONCLUSIONS: Anastomotic reinforcement with CA is effective and safe to prevent leakage in a high-risk colorectal anastomosis in a porcine model.

Impact of tissue adhesives on the prevention of anastomotic leakage of colonic anastomoses: an in vivo study.

BACKGROUND: Tissue adhesives (TA) may be useful to strengthen colorectal anastomoses, thereby preventing anastomotic leakage (AL). Previous studies have identified cyanoacrylate (CA) TAs as the most promising colonic anastomotic sealants. This study investigates the protective effects of sealing colonic anastomoses with various CAs. MATERIALS AND METHODS: Fifty-five Wistar rats underwent laparotomy and transection of the proximal colon. An anastomosis was created with 4 interrupted sutures followed by either application of Histoacryl Flexible, Omnex, Glubran 2, or no TA seal. An additional control group was included with a 12-suture anastomosis and no TA seal. After 7 days, the rats were sacrificed and scored for the presence of AL as the main outcome. Secondary outcomes were the occurrence of bowel obstruction, adhesions, and anastomotic bursting pressure. Histological evaluation was performed. RESULTS: The highest AL rate was found in the Glubran 2 group (7/11), followed by the 4-sutures group without TA (5/11), and the Omnex group (5/11). Histoacryl Flexible showed the lowest AL rate (2/11). In the control group, only one rat showed signs of AL. Histologically, the highest influx of inflammatory cells was found in the 4-suture group without TA and for Omnex and Glubran 2. Histoacryl Flexible caused more mature collagen deposition when compared to the other TA groups. CONCLUSIONS: Histoacryl Flexible showed the lowest leakage rate compared to the other TA groups and to the 4-suture control group. Glubran 2 showed the highest AL rate and a high inflammatory response. Histoacryl Flexible was associated with the presence of more mature collagen and seems to promote anastomotic healing.

In vitro modulation of the behavior of adhering macrophages by medications is biomaterial-dependent.

After implantation of a biomaterial, an inflammatory response involving macrophages is induced. The behavior of macrophages depends on their phenotype, and by directing macrophage polarization unwanted effects may be avoided. In this study, the possibility to modulate the behavior of macrophages activated by biomaterials was assessed in an in vitro model. Primary human monocytes were seeded on polyethylene terephthalate, polypropylene and polylactic acid yarns, and treated with medications frequently used by patients: rapamycin, dexamethasone, celecoxib or pravastatin. Modulation of the adhering macrophages with rapamycin resulted in a generally pro-inflammatory effect. Dexamethasone caused an overall anti-inflammatory effect on the macrophages cultured on either material, while celecoxib only affected macrophages adhering to polyethylene terephthalate and polylactic acid. Pravastatin increased the pro-inflammatory genes of macrophages cultured on polypropylene and polylactic acid. Pairwise comparison revealed that macrophages adhering to polylactic acid seemed to be more susceptible to phenotype modulation than when adhering to polypropylene or polyethylene terephthalate. The data show that macrophages activated by the biomaterials can be modulated, yet the degree of the modulatory capacity depends on the type of material. Combined, this model provides insights into the possibility of using a medication in combination with a biomaterial to direct macrophage behavior and thereby possibly avoid unwanted effects after implantation.

Is the intraoperative air leak test effective in the prevention of colorectal anastomotic leakage? A systematic review and meta-analysis.

OBJECTIVE: The intra-operative air leak test (ALT) is a common intraoperative test used to identify mechanically insufficient anastomosis. This meta-analysis aims to determine whether ALT aids to the reduction of postoperative colorectal anastomotic leakage (CAL). METHODS: A literature search was performed to select studies in acknowledged databases. Full text articles targeting ALT during colorectal surgery were included. Quality assessment, risk of bias, and the level-of-evidence of the inclusions were evaluated. ALT methodology, ALT(+) (i.e., leak observed during the test) rate, and postoperative CAL rate of the included studies were subsequently analyzed. RESULTS: Twenty studies were included for analysis, in which we found substantial risks of bias. A lower CAL rate was observed in patients who underwent ALT than those did not; however, the difference was not significant (p = 0.15). The intraoperative ALT(+) rate greatly varied among the included studies from 1.5 to 24.7 %. ALT(+) patients possessed a significantly higher CAL rate than the ALT(-) patients (11.4 vs. 4.2 %, p < 0.001). CONCLUSIONS: Based on the available evidence, performing an ALT with the reported methodology has not significantly reduced the clinical CAL rate but remains necessary due to a higher risk of CAL in ALT(+) cases. Unfortunately, additional repairs under current methods may not effectively decrease this risk. Results of this review urge a standardization of ALT methodology and effective methods to repair ALT(+) anastomoses.

Cytokines as Early Markers of Colorectal Anastomotic Leakage: A Systematic Review and Meta-Analysis.

Purpose. Colorectal anastomotic leakage (CAL) is one of the most severe complications after colorectal surgery. This meta-analysis evaluates whether systemic or peritoneal inflammatory cytokines may contribute to early detection of CAL. Methods. Systematic literature search was performed in the acknowledged medical databases according to the PRISMA guidelines to identify studies evaluating systemic and peritoneal levels of TNF, IL-1ß, IL-6, and IL-10 for early detection of CAL. Means and standard deviations of systemic and peritoneal cytokine levels were extracted, respectively, for patients with and without CAL. The meta-analysis of the mean differences was carried out for each postoperative day using Review Manager. Results. Seven articles were included. The meta-analysis was performed with 5 articles evaluating peritoneal cytokine levels. Peritoneal levels of IL-6 were significantly higher in patients with CAL compared to patients without CAL on postoperative days 1, 2, and 3 (P < 0.05). Similar results were found for peritoneal levels of TNF but on postoperative days 3, 4, and 5 (P < 0.05). The articles regarding systemic cytokine levels did not report any significant difference accordingly. Conclusion. Increased postoperative levels of peritoneal IL-6 and TNF are significantly associated with CAL and may contribute to its early detection.

Postoperative Hemodynamic Index Measurement With Miniaturized Dynamic Light Scattering Predicts Colorectal Anastomotic Healing.

INTRODUCTION: Perioperative bowel perfusion (local hemodynamic index [LHI]) was measured with a miniaturized dynamic light scattering (mDLS) device, aiming to determine whether anastomotic perfusion correlates with the anastomotic healing process and whether LHI measurement assists in the detection of anastomotic leakage (AL) in colorectal surgery. METHODS: A partial colectomy was performed in 21 male Wistar rats. Colonic and anastomotic LHIs were recorded during operation. On postoperative day (POD) 3, the rats were examined for AL manifestations. Anastomotic LHI was recorded before determining the anastomotic bursting pressure (ABP). The postoperative LHI measurements were repeated in 15 other rats with experimental colitis. Clinical manifestations and anastomotic LHI were also determined on POD3. Diagnostic value of LHI measurement was analyzed with the combined data from both experiments. RESULTS: Intraoperative LHI measurement showed no correlation with the ABP on POD3. Postoperative anastomotic LHI on POD3 was significantly correlated with ABP in the normal rats (R(2) = 0.52; P < .001) and in the rats with colitis (R(2) = 0.63; P = .0012). Anastomotic LHI on POD3 had high accuracy for identifying ABP <50 mm Hg (Area under the curve = 0.86; standard error = 0.065; P < .001). A cutoff point of 1236 yielded a sensitivity of 100% and a specificity of 65%. On POD3, rats with LHIs <1236 had significantly higher dehiscence rates (40% vs 0%), more weight loss, higher abscess severity, and lower ABPs (P < .05); worse anastomotic inflammation and collagen deposition were also found in the histological examination. CONCLUSION: Our data suggest that postoperative evaluation of anastomotic microcirculation with the mDLS device assists in the detection of AL in colorectal surgery.

Reducing colorectal anastomotic leakage with tissue adhesive in experimental inflammatory bowel disease.

BACKGROUND: Anastomotic leakage after gastrointestinal surgery remains a challenging clinical problem. This study aimed to investigate the effectiveness of TissuCol (fibrin glue), Histoacryl Flex (n-butyl-2-cyanoacrylate), and Duraseal (polyethylene glycol) on colorectal anastomotic healing during experimental colitis. METHODS: We first performed colectomy 7 days after 10 mg trinitrobenzene sulfonic acid (TNBS)-induced colitis to validate a rat TNBS-colitis-colectomy model. Subsequently, this TNBS-colitis-colectomy model was used in 73 Wistar rats that were stratified into a colitis group (CG, no adhesive), a TissuCol group (TG), a Histoacryl group (HG), and a Duraseal group (DG). Anastomotic sealant was applied with one adhesive after constructing an end-to-end hand-sewn anastomosis. Clinical manifestations, anastomotic bursting pressure, and immunohistochemistry of macrophage type-one (M1) and type-two (M2) was performed on postoperative day (POD)3 or POD7. RESULTS: TNBS-caused mucosal and submucosal colon damage and compromised anastomotic healing (i.e., abscess formation and low anastomotic bursting pressure). On POD3, higher severity of abscesses was seen in CG. Average anastomotic bursting pressure was 53.2 ± 35.5 mm Hg in CG, which was significantly lower than HG (134.4 ± 27.5 mm Hg) and DG (95.1 ± 54.3 mm Hg) but not TG (83.4 ± 46.7 mm Hg). Furthermore, a significantly higher M2/M1 index was found in HG. On POD7, abscesses were only seen in CG (6/9) but not in other groups; HG had the lowest severity of adhesion. CONCLUSIONS: We describe the first surgical IBD model by performing colectomy in rats with TNBS-induced colitis, which causes intra-abdominal abscess formation and compromises anastomotic healing. Anastomotic sealing with Histoacryl Flex prevents these complications in this model. Alternative activation of macrophages seems to be involved in its influence on anastomotic healing.

Colorectal anastomotic leakage caused by insufficient suturing after partial colectomy: a new experimental model.

BACKGROUND: Colorectal anastomotic leakage (CAL) is the most important complication of colorectal surgery, accounting for one third of post-operative deaths. To prevent it, many interventions have been tested in animal models, mostly rats. However, few of these models have been validated. We aimed to develop a reproducible rat CAL model by creating an anastomosis with insufficient suturing after partial colectomy. METHODS: To establish the number of sutures that would create an appropriate leakage rate for research (20%-50%), partial colectomy was performed in 60 Wistar rats using a 12-suture anastomosis in the control group and an anastomosis with insufficient suturing in the experimental group, starting with five sutures. Seven days later, the rats were examined for the occurrence and severity of CAL, the presence of adhesions, and anastomotic bursting pressure. When an acceptable leakage rate was achieved, the experimental and control studies were repeated twice to confirm the adequacy of the chosen technique. RESULTS: On day 7, five-suture and 12-suture anastomoses had leakage rates of 50% vs. 30%, 44.4% vs. 20%, and 50% vs. 20%, respectively, in the various series. Overall, the five-suture group had a significantly higher CAL rate than did the 12-suture group (48.3% vs. 23.3%; p=0.045). It also had higher CAL severity and more adhesions (p for both<0.05). The bursting pressure of these anastomoses was significantly lower than that in the 12-suture group (116.8±58.9 mm Hg vs. 150.4±50.3 mm Hg; p=0.041). CONCLUSION: Anastomosis with five sutures after partial colectomy provides a suitable rat CAL model. Its future applications may help to improve the consistency of CAL studies.

The prevention of colorectal anastomotic leakage with tissue adhesives in a contaminated environment is associated with the presence of anti-inflammatory macrophages.

BACKGROUND: Colorectal anastomoses created in a contaminated environment result in a high leakage rate. This study investigated whether using anastomotic sealants (TissuCol(®), Histoacryl(®) Flex, and Duraseal(®)) prevents leakage in a rat peritonitis model. STUDY DESIGN: Sixty-seven Wistar rats were divided into control and experimental groups (TissuCol, Histoacryl, and Duraseal groups). Peritonitis was induced 1 day before surgery with the cecal ligation puncture model. On day 0, colonic anastomosis was constructed with sutures and then sealed with no adhesive (control group) or one select adhesive (experimental groups). Bursting pressure, abscess formation, and adhesion severity were evaluated on day 3 or day 14. Hematoxylin and eosin staining and immunohistochemical staining for CD4, CD8, CD206, and iNOS were performed. RESULTS: On day 3, bursting pressures of the TissuCol group (120.1 ± 25.3 mmHg), Histoacryl group (117.3 ± 20.2 mmHg), and Duraseal group (123.6 ± 35.4 mmHg) were significantly higher than the that of the control group (24.4 ± 31.7 mmHg, p < 0.001). Abscesses around the anastomosis were found in the control group (6/7) and Duraseal group (2/9) but not in the TissuCol group or Histoacryl group. A higher number of CD206+ cells (M2 macrophages), a lower number of iNOS+ cells (M1 macrophages), a higher M2/M1 index, and a higher CD4+/CD8+ index were seen at the anastomotic site in all experimental groups compared with the control group on day 3. On day 14, abscesses were only found in the control group. Adhesion severity in the Duraseal group was significantly lower than that in the control group (p = 0.001). CONCLUSIONS: Anastomotic sealing using TissuCol(®), Histoacryl(®) Flex, or Duraseal(®) seems to be an effective and safe option to prevent leakage in contaminated colorectal surgery. The presence of large numbers of anti-inflammatory macrophages seems to be involved in preventing the leakage.