Geesien S. A. Boersema

The Effect of Biomaterials Used for Tissue Regeneration Purposes on Polarization of Macrophages

Abstract Activation of macrophages is critical in the acute phase of wound healing after implantation of surgical biomaterials. To understand the response of macrophages, they are often cultured in vitro on biomaterials. Since a wide range of biomaterials is currently used in the clinics, we undertook a systematic review of the macrophage polarization in response to these different surgical biomaterials in vitro. Beside the chemistry, material characteristics such as dimension, pore size, and surface topography are of great influence on the response of macrophages. The macrophage response also appears to depend on the differences in sterilization techniques that induce lasting biochemical changes or residues of chemicals and their byproducts used for sterilization. Regarding tissue-based biomaterials, macrophages on human or porcine dermis, strongly cross-linked by chemicals elicit in general a proinflammatory response with higher amounts of proinflammatory cytokines. Synthetic biomaterials such as polyethylene, polyethylene terephthalate (PET) + polyacrylamide (PAAm), PET + sodium salt of poly(acrylic acid) (PAANa), perfluoropolyether (PFPE) with large posts, PEG-g-PA, and polydioxanone (PDO) always appear to elicit an anti-inflammatory response in macrophages, irrespective of origin of the macrophages, for example, buffy coats or full blood. In conclusion, in general in vitro models contribute to evaluate the foreign body reaction on surgical biomaterials. Although it is difficult to simulate complexity of host response elicited by biomaterials, after their surgical implantation, an in vitro model gives indications of the initial foreign body response and allows the comparison of this response between biomaterials.

Emergency Laparoscopic Sigmoidectomy for Perforated Diverticulitis with Generalised Peritonitis: A Systematic Review

Background: Laparoscopic sigmoidectomy for diverticulitis has initially been confined to the elective setting. However, open acute sigmoidectomy for perforated diverticulitis is associated with high morbidity rates that might be reduced after laparoscopic surgery. The aim of this systematic review was to assess the feasibility of emergency laparoscopic sigmoidectomy for perforated diverticulitis. Methods: We performed a systematic search of PubMed, EMBASE and CENTRAL. All studies reporting on patients with perforated diverticulitis (Hinchey III-IV) treated by laparoscopic sigmoidectomy in the acute phase were included, regardless of design. Results: We included 4 case series and one cohort study (total of 104 patients) out of 1,706 references. Hartmanns procedure (HP) was performed in 84 patients and primary anastomosis in 20. The mean operating time varied between 115 and 200 min. The conversion rate varied from 0 to 19%. The mean length of hospital stay ranged between 6 and 16 days. Surgical re-intervention was necessary in 2 patients. In 20 patients operated upon without defunctioning ileostomy, no anastomotic leakage was reported. Three patients died during the postoperative period. Stoma reversal after HP was performed in 60 out of 79 evaluable patients (76%). Conclusions: Acute laparoscopic sigmoidectomy for the treatment of perforated diverticulitis is feasible in selected patients provided they are handled by experienced hands.

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.

Reducing Anastomotic Leakage by Reinforcement of Colorectal Anastomosis with Cyanoacrylate Glue

Introduction: Technical failure of sutured or stapled anastomoses may lead to anastomotic leakage, which is one of the most important complications after colorectal surgery. Cyanoacrylate glue (CA) provides strong mechanical attachment, making it a good candidate for suture reinforcement. This study aimed to demonstrate that CA is the most important factor in the strength of a sealed colorectal anastomosis, in both normal and insufficient anastomoses. Methods: Ex vivo porcine colorectal segments were resected. A 1-layer continuous anastomosis or an insufficient 6-interrupted-suture anastomosis was created, and the baseline anastomotic bursting pressure (ABP) was measured. The primary anastomosis was then reinforced either by CA or with 4 additional interrupted sutures, further inverting the anastomosis. After reinforcement a second ABP test was performed. Results: Thirty-two segments were used. Reinforcing the anastomosis by CA significantly increased ABP in both normal and insufficient anastomoses when compared to the primary anastomosis (p < 0.05 for all groups); no significant difference in ABP was found between normal and insufficient anastomosis groups after CA reinforcement. Anastomotic reinforcement with CA was not inferior to the reinforcement with sutures in both normal and insufficient anastomoses, and had significantly fewer ABP variances in normal anastomosis groups (p = 0.042). Conclusion: Reinforcing a colorectal anastomosis with CA increases its mechanical strength in both normal and technically insufficient situations, which may contribute to the reduction of anastomotic leakage. CA is promising for anastomotic reinforcement based on mechanical improvement of the anastomosis, and in vivo studies are needed to evaluate its biological effects.

Clinical Endpoint, Early Detection, and Differential Diagnosis of Postoperative Ileus: A Systematic Review of the Literature

Background: This systematic review summarizes evidence regarding clinical endpoints, early detection, and differential diagnosis of postoperative ileus (POI). Methods: Using MEDLINE, EMBASE, Cochrane, and Web-of-Science, we identified 2,084 articles. Risk of bias and level of evidence (LOE) of the included articles were determined, and relevant results were summarized. Results: Eleven articles were included, most of which with substantial risks of bias. Bowel motility studies revealed that defecation together with solid food tolerance is the most representative clinical endpoint of POI (LOE: 2b); other clinical signs (e.g. bowel sounds, passage of flatus) did not correlate with a full recovery of bowel motility. Inflammatory parameters including interleukin (IL)-6, IL-1, and TNF-α might assist in an early detection of prolonged POI (LOE: 4). Clinical manifestations (e.g. nausea, vomiting, abdominal distension, bowel sounds, flatus) and X-ray examinations provided limited aid to the differential diagnosis of POI, while CT with Gastrografin had the best specificity and sensitivity (both 100%; LOE: 1c). Conclusions: Postoperative defecation together with tolerance of solid food intake seems to be the best clinical endpoint of POI. CT has the best differential diagnostic value between POI and other complications. Prospective studies with a high LOE are in great need.

Critical analysis of cyanoacrylate in intestinal and colorectal anastomosis.

BACKGROUND Although cyanoacrylate glue (CA) has been widely used in various kinds of medical applications, its application in gastrointestinal anastomosis remains limited, and outcomes of experimental studies have not been satisfactory. This systematic review summarizes research regarding CA application in intestinal and colorectal anastomosis, and correlates methodological aspects to experimental outcomes. METHODS A systematic literature search was performed using Medline, Embase, Cochrane, and Web-of-Science libraries. Articles were selected if CA was applied to intestinal or colorectal anastomoses. Included articles were categorized according to CA molecular structure; the method details in each study were extracted and analyzed. RESULTS Twenty-two articles were included. More than half of the inclusions reported positive outcomes (seven articles) or neutral outcomes (eight articles). Analysis of the methods revealed that methodological details such as CA dosage, time of polymerization were not consistently reported. Porcine studies, inverted anastomosis, and n-butyl-cyanoacrylate studies showed more positive outcomes; everted anastomosis, and oversized sutures might negatively influence the outcomes. CONCLUSIONS Owing to the positive outcome from the porcine studies, application of CA in gastrointestinal (GI) anastomosis still seems promising. To achieve a better consistency, more methodological details need to be provided in future studies. Optimizing the dosage of CA, choice of animal model, inverted anastomosis construction, and other method details may improve intestinal and colorectal anastomoses with CA application in future studies.

Nicotine gum chewing: A novel strategy to shorten duration of postoperative ileus via vagus nerve activation

Postoperative ileus (POI) is a transit cessation of bowel motility after surgery. Substantial evidences suggest that gum chewing accelerate the recovery of bowel motility after surgery. Perioperative nicotine administration reduces postoperative opioid use and prevents postoperative nausea and vomiting. Nicotine gum chewing combines stimulation of the cephalic-vagal reflex by gum chewing, and activation of the cholinergic anti-inflammatory pathway by nicotine administration. We therefore hypothesized that nicotine gum chewing reduces POI and improves patient outcomes such as shortening the length of hospitalization as well as saving medical costs. As nicotine gum is commercially available, inexpensive, and has been in use for many years without any severe side effects, it may have a wide clinical application in POI prevention.

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-1β, 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 (R2 = 0.52; P < .001) and in the rats with colitis (R2 = 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.

The yet-to-be discovered mechanism of anastomotic leakage — Comment to: Lack of evidence for tissue hypoxia as a contributing factor in anastomotic leak following colon anastomosis and segmental devascularization in rats

Dear Editor: We read the paper from Shakhsheer et al. with great interests, which reported that tissue hypoxia was not a distinctive feature of anastomotic leak [1]. Our previous study on the same topic have reported similar findings that anastomotic healing was not associated with intraoperative anastomotic perfusion [2]. We believe that these experimental data are of interests and importance not only to the translational research field but also to the clinical surgeons, especially when many intraoperative perfusion measurement devices have been introduced to clinical practice nowadays and colonic cutting-edges are often altered based on the test results. Given the fact that no solid clinical evidence (i.e., randomized controlled trials) is yet available to demonstrate whether those interventions do prevent colorectal anastomotic leaks or not, these experimental data undoubtedly raise the question of the Byet-to-be discovered mechanism^ of how intraoperative tissue hypoxia influence colonic anastomotic healing. However, we also would like to raise our concerns regarding whether the animal model used in this study is appropriate to demonstrate the author’s original hypothesis. This is because many previous studies have reported that segmental devascularization may not have significant influences that are comparable to clinical outcomes (e.g., leak rate).We therefore chose to ligate the whole ileocolic artery to assure colon hypoxia in our previous study investigating the effectiveness of hyperbaric oxygen therapy in ischemic colonic anastomosis [3], and significantly higher mortality rate and leak rate were observed in the ischemic group in that study. Those data suggest that such model may be of better representativeness and should be considered as a candidate in the future translational studies focusing on ischemic colorectal anastomosis. We would like to congratulate the authors for their detailed analysis and investigation of the undiscovered mechanism. Acknowledging that the solid evidence regarding clinical effectiveness of intraoperative perfusion measurement are still awaited, we should be highly aware of the authors’ results. However, one cannot overemphasize the importance of blood supply in colorectal anastomosis. More research is still of request; more patients will benefit from the research in the future.