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Viable cryopreserved umbilical tissue (vCUT) reduces post-operative adhesions in a rabbit abdominal adhesion model.

ABSTRACT: Post-operative adhesions, a common complication of surgery, cause pain, impair organ functionality, and often require additional surgical interventions. Control of inflammation, protection of injured tissue, and rapid tissue repair are critical for adhesion prevention. Adhesion barriers are biomaterials used to prevent adhesions by physical separation of opposing injured tissues. Current adhesion barriers have poor anti-inflammatory and tissue regenerative properties. Umbilical cord tissue (UT), a part of the placenta, is inherently soft, conforming, biocompatible, and biodegradable, with antimicrobial, anti-inflammatory, and antifibrotic properties, making it an attractive alternative to currently available adhesion barriers. While use of fresh tissue is preferable, availability and short storage time limit its clinical use. A viable cryopreserved UT (vCUT) "point of care" allograft has recently become available. vCUT retains the extracellular matrix, growth factors, and native viable cells with the added advantage of a long shelf life at -80 °C. In this study, vCUT's anti-adhesion property was evaluated in a rabbit abdominal adhesion model. The cecum was abraded on two opposing sides, and vCUT was sutured to the abdominal wall on the treatment side; whereas the contralateral side of the abdomen served as an internal untreated control. Gross and histological evaluation was performed at 7, 28, and 67 days post-surgery. No adhesions were detectable on the vCUT treated side at all time points. Histological scores for adhesion, inflammation, and fibrosis were lower on the vCUT treated side as compared to the control side. In conclusion, the data supports the use of vCUT as an adhesion barrier in surgical procedures.

SUBMITTER: Dhall S

PROVIDER: S-EPMC6351431 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Viable cryopreserved umbilical tissue (vCUT) reduces post-operative adhesions in a rabbit abdominal adhesion model.

Dhall Sandeep S Coksaygan Turhan T Hoffman Tyler T Moorman Matthew M Lerch Anne A Kuang Jin-Qiang JQ Sathyamoorthy Malathi M Danilkovitch Alla A

Bioactive materials 20181010 1

Post-operative adhesions, a common complication of surgery, cause pain, impair organ functionality, and often require additional surgical interventions. Control of inflammation, protection of injured tissue, and rapid tissue repair are critical for adhesion prevention. Adhesion barriers are biomaterials used to prevent adhesions by physical separation of opposing injured tissues. Current adhesion barriers have poor anti-inflammatory and tissue regenerative properties. Umbilical cord tissue (UT), ...[more]

PMID: 30723842

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Project description:PurposeFibrin clot is essential for post-operative abdominal adhesion formation. Fucoidans, sulfated polysaccharides, inhibit fibrin clot formation. In addition, they inhibit inflammation and fibrosis, which also play important roles in adhesion formation. The purpose of this study was to evaluate fucoidans' potential for inhibiting post-operative abdominal adhesions and measure their effects on systemic coagulation parameters when administered intraperitoneally (IP).Methods and materialsFemale Sprague Dawley rats were studied. A 2.5x2.5cm full thickness segment of abdominal wall was excised. The skin edges were approximated. This model induces extensive adhesions and allows objective quantitation. Three fucoidans were evaluated- Sigma Fucoidan Crude (SFC), Fucus vesiculosis 95% (Sigma) and, Peridan. One protocol involved continuous infusion into the abdomen from a subcutaneous osmotic pump. Alternatively, boluses of the solutions were injected IP at the end of the operation. Rats were sacrificed a week later. Adhesion extent was scored. Systemic coagulation effects of fucoidans were also evaluated. INR and aPTT were measured following IP injection of the fucoidan solutions and after 7 days of continuous infusion.ResultsAnimals given a continuous infusion of either SFC or Peridan yielded adhesion reduction of 80 to 90% from control. Bolus Peridan had no discernable influence on adhesion formation, but a single bolus of SFC caused significant adhesion reductions. Peridan resulted in prompt aPTT elevations which fell to nearly normal by 5 hours. The maximum peak value after SFC injection was seen in 15 hours. The maximal INR elevations were around 2. Measurement of INR and aPTT after a week of continuous infusion of either Peridan or SFC, were always in the normal control range. The third agent, Sigma, frequently yielded intraperitoneal infection found at autopsy.ConclusionsThese findings indicate that selected fucoidans infused intraperitoneally for a week after abdominal operations reduce adhesion extent by up to 90%.

Project description:BackgroundIntra-abdominal adhesions develop after nearly every abdominal surgery, commonly causing female infertility, chronic pelvic pain, and small bowel obstruction. Pentoxifylline (PTX) is a methylxanthine compound with immunomodulatory and antifibrotic properties. The aim of this study was to investigate whether PTX can reduce post-operative intra-abdominal adhesion formation via collagen deposition, tissue plasminogen activator (tPA) level, inflammation, angiogenesis, and fibrosis.MethodsSeventy male BALB/c mice were randomized into one of three groups: (1) sham group without peritoneal adhesion model; (2) peritoneal adhesion model (PA group); (3) peritoneal adhesion model with PTX (100 mg/kg/day i.p.) administration was started on preoperative day 2 and continued daily (PA + PTX group). On postoperative day 3 and day 7, adhesions were assessed using the Lauder scoring system. Parietal peritoneum was obtained for histological evaluation with hematoxylin and eosin (HE) and picrosirius red staining. Fibrinolysis was analyzed by tPA protein levels in the peritoneum by ELISA. Immunohistological analysis was also conducted using markers for angiogenesis (ki67+/CD31+), inflammation (F4/80+) and fibrosis (FSP-1+ and α-SMA+). All the comparisons were made by comparing the PA group with the PTX treated PA group, and p < 0.05 was considered statistically significant.ResultsIntra-abdominal adhesions were markedly reduced by PTX treatment. Compared with the PA group, PTX treatment had lower adhesion scores than the PA group on both day 3 and day 7 (p < 0.05). Histological evaluations found that PTX treatment reduced collagen deposition and adhesion thickening. ELISA analysis showed that PTX treatment significantly increased the level of tPA in the peritoneum. In addition, in the immunohistological analysis, PTX treatment was found to significantly decrease the number of ki67+/CD31+ cells at the site of adhesion. Finally, we also observed that in the PTX treated group, there was a reduction in the expression of F4/80+, FSP-1+, and α-SMA+ cells at the site of adhesion.ConclusionPTX may decrease intra-abdominal adhesion formation via increasing peritoneal fibrinolytic activity, suppressing angiogenesis, decreasing collagen synthesis, and reducing peritoneal fibrosis. Our findings suggest that PTX can be used to decrease post-operative intra-abdominal adhesion formation.

Project description:Post-operative abdominal adhesions are the leading cause of bowel obstruction and a major cause of chronic pain and infertility. Further, adhesion formation complicates any re-operative strategy, increasing the length of surgery and rendering a safe minimally invasive approach impossible. Despite the prevalence of abdominal adhesions, which form following 50-90% of abdominal operations, no proven preventative or treatment strategy has been developed. Our group previously established a mouse model to study adhesive disease in vivo and explored adhesion biology across mouse and human tissues. We established that adhesions derive primarily from the visceral peritoneum, are composed of poly-clonally proliferating tissue-resident fibroblasts, and identified that modulation of JUN signaling regulates abdominal adhesiogenesis following surgery. We identified a small molecule JUN inhibitor (T-5224) that decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with anti-adhesion properties for intra-peritoneal delivery and sustained-release for post-operative adhesion prevention. We extensively characterized this novel therapeutic system, and found it to be safe, systemically well-tolerated, and efficacious in reducing adhesions in our mouse model. Furthermore, this therapeutic system minimizes not only the quantity of adhesions that form, but also limits the maturation of adhesion fibrosis at an ultrastructural level. Critical towards clinical translation, we developed a large mammal (porcine) preclinical model of adhesions with bowel resection and showed that the T-5224-hydrogel therapeutic provides robust adhesion prevention without deleterious effects on bowel anastomosis or abdominal wall (laparotomy) wound healing. At a single-cell transcriptomic level, treated fibroblasts in our pig model show decreased JUN and associated pathway signaling. Adhesion biology shares close similarities across surgical sites (e.g. thoracic, joint space, neurological); as such, this formulation has significant potential for applicability across the body. Material properties of the T-5224-hydrogel formulation, such as shear-thinning and self-healing, also facilitate ease of open or minimally invasive application. Therefore, these results are promising for immediate and high-impact translation to patient care to address a common, unmet clinical need.

Dataset Information

Viable cryopreserved umbilical tissue (vCUT) reduces post-operative adhesions in a rabbit abdominal adhesion model.

Publications

Viable cryopreserved umbilical tissue (vCUT) reduces post-operative adhesions in a rabbit abdominal adhesion model.

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