James W. Burns

Reduction of postsurgical adhesion formation in the rabbit uterine horn model with use of hyaluronate/ carboxymethylcellulose gel

OBJECTIVE To assess the efficacy of a bioabsorbable gel for reducing primary postoperative adhesions. DESIGN A randomized, prospective, blinded study. SETTING Academic research environment. ANIMALS Forty-one New Zealand Rabbits. INTERVENTION(S) A chemically modified hyaluronate and carboxymethylcellulose (HA/CMC) gel formulation was applied to a bilateral uterine horn injury. Postoperative adhesions were assessed at a second-look laparoscopy. MAIN OUTCOME MEASURE(S) The uterine horn model was shown to be adhesiogenic, with 29 (70%) of 42 untreated uterine horns found to have adhesions. After gel treatment, 22 (55%) of 40 uterine horns were free of adhesions compared with 12 (30%) of 42 controls. RESULT(S) Animals treated with HA/CMC gel had significantly reduced postsurgical adhesion scores when compared with controls. CONCLUSION(S) Treatment of injured uterine horn with HA/CMC gel resulted in a significant reduction in postoperative surgical adhesions.

A hyaluronate based gel for the prevention of postsurgical adhesions : evaluation in two animal species

OBJECTIVE To assess in two animal surgery models, the efficacy of a bioabsorbable gel to prevent postoperative adhesions. DESIGN A randomized, prospective, blinded study using animal abdominal surgery models. SETTING Two animals species with surgical traumas to induce adhesion formation. INTERVENTIONS A chemically modified hyaluronate and carboxymethylcellulose-based gel formulation. MAIN OUTCOME MEASURES The number of animals with no adhesions, mean number of adhesions, and total adhesion score. RESULTS Treatment with the bioabsorbable gel increased the number of animals without any adhesion by 70% in a rat cecal abrasion model and by > 90% in a rabbit sidewall defect-bowel abrasion model when compared with nontreatment control animals. Other outcome measures showed similar efficacy. CONCLUSION The modified hyaluronate-carboxymethylcellulose gel was effective in two animal species after surgery in the abdominal cavity. The gel appears to act as a physical barrier between damaged peritoneal tissue and may be appropriate for human clinical trials in open and laparoscopic surgical procedures.

Efficacy of hyaluronic acid/nonsteroidal anti-inflammatory drug systems in preventing postsurgical tendon adhesions

Tendon adhesion is acknowledged to be a function of both an overwhelming inflammatory response at the surgical site and the loss of physical separation that is normally present between the tendons and the synovial sheath. Adhesions bind the flexor tendons to each other and to surrounding structures, interfering with their normal gliding function. The clinical result of adhesion formation following flexor tendon surgery is poor digital function. This study investigated the effect of intraoperative treatments of high viscosity absorbable gels made of various combinations of hyaluronic acid and nonsteroidal anti-inflammatory drugs, on adhesion formation in a leghorn chicken flexor tendon model. Forty-eight mature, white leghorn chickens were used to verify the surgical model and to test five different gel treatments. The gels were formed from: 2% sodium hyaluronate in phosphate buffered saline alone or combined with 1 mg/mL tolmetin sodium; 1 mg/mL naproxen sodium; 0.216 g/mL calcium acetate; or 0.216 g/mL calcium acetate plus 1 mg/mL naproxen sodium. The gels were applied by injecting 0.2 mL of the specified composition into the intrasheath space near the conclusion of the surgical procedure. Gross and histological evaluations were conducted to analyze the efficacy. All of the treatments significant reduced the extent and severity of postsurgical tendon adhesion in this animal model as compared with the control (no gel treatment) (p < 0.05). The combination of naproxen sodium and calcium acetate in a high viscosity sodium hyaluronate carrier was the most effective composition. The combination of a high viscosity gel and nonsteroidal anti-inflammatory drugs appears to maintain the natural separation between the tendons and their sheaths and decrease the tissue inflammatory response through mediating two of the major stimuli in adhesion formation.

Role of transforming growth factor beta-1 in peritonitis-induced adhesions.

Peritonitis is a major cause of intra-abdominal adhesion formation. The overexpression of transforming growth factor beta-l (TGF-Pl), a potent mitogen, chemoattractant, and stimulant for collagen synthesis by fibroblasts, has been linked to tissue fibrosis at various sites throughout the body including peritoneal adhesion formation. Hence we hypothesized that the mechanism(s) involved in peritonitis-induced adhesion formation may be mediated through the upregulation of TGF-β expression. Peritonitis was induced in rats by cecal ligation and puncture, while a control group underwent sham operation. Adhesions were scored and harvested from both groups at 0,6 and 12 hours and at 1,2,4, 7, and 28 days. Tissue expression of TGF-PI mRNA was determined by quantitative reverse transcription-polymerase chain reaction and TGF-β protein was localized by immunohistochemical analysis. Serum and peritoneal fluid TGF-β concentrations were quantified by enzyme-linked immunosorbent assay. Compared with sham operation, peritonitis was associated with a significantly greater incidence of abdominal adhesions and a significant increase in the levels of TGF-β 1 mRNA expression at days 2,4, and 7. Immunostaining intensity of TGF-β in adhesions from the peritonitis group also steadily rose through day 7. In peritoneal fluid, the ratio of active:total TGF-βl was significantly increased in the peritonitis group on days 1, 2, and 4 compared with the sham group. These results suggest that peritonitis is associated with the upregulation of TGF-βl, a mechanism that may exacerbate adhesion formation.

Expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in serosal tissue of intraperitoneal organs and adhesions

OBJECTIVE To compare expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in serosal tissue of intraperitoneal organs and adhesions. DESIGN Prospective and cross-sectional study. SETTING Academic research centers. PATIENT(S) Patients undergoing abdominal or pelvic surgery. INTERVENTION(S) MMP-1 and TIMP-1 expression. MAIN OUTCOME MEASURE(S) Expression of messenger ribonucleic acid (mRNA) and protein was measured by using quantitative reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. RESULT(S) Serosal tissue of intraperitoneal organs and adhesions express MMP-1 and TIMP-1 mRNA and protein at levels that are consistently varied with 10- to 10,000-fold and 2- to 10-fold higher TIMP, mRNA and protein, respectively. Parietal peritoneum, fallopian tubes and ovaries express higher MMP-1 mRNA levels compared with uterus and adhesions; the lowest expression is found in small and large bowels, subcutaneous tissue. and omentum. Expression of TIMP-1 mRNA was less variable; the highest level was found in the uterus and the lowest in subcutaneous tissue and small bowels. There was less variability in MMP-1 and TIMP-1 protein content than mRNA expression; ovaries and adhesions contained the highest MMP-1 and TIMP-1 levels, respectively, and peritoneum contained the lowest. The MMP-1 and TIMP-1 content and ratios further indicate limited MMP-1 proteolytic activity. Although tissues from premenopausal women express more MMP-1 and TIMP-1, expression did not differ by sex or age. CONCLUSION(S) Because MMP-1 and TIMP-1 expression varies consistently among the serosal tissues of peritoneal organs and adhesions, and because tissue injury alters their expression, site-specific variations in expression of these substances may predispose a particular organ to develop more adhesions.

Matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in peritoneal fluids and sera and correlation with peritoneal adhesions

OBJECTIVE To assess the presence of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in peritoneal fluid and serum of subjects with and without adhesions. DESIGN Cross-sectional study. SETTING Academic research centers. PATIENT(S) Sixty-three patients who underwent abdominal/pelvic surgery. INTERVENTION(S) MMP-1, TIMP-1, and MMP-1-TIMP-1 complex content. MAIN OUTCOME MEASURE(S) ELISA. RESULT(S) Peritoneal fluids (PF) and sera of subjects with and without peritoneal adhesions contain MMP-1, TIMP-1, and MMP-1-TIMP-1 complex at varying levels with 10- to 100-fold higher TIMP-1 than MMP-1. Compared with serum, PF contains a lower level of MMP-1 in subjects with mild adhesions and without adhesions, higher TIMP-1 in subjects with extensive adhesions, and lower MMP-1-TIMP-1 complex in subjects with moderate adhesions. However, the serum and PF content of MMP-1, TIMP-1, and MMP-1-TIMP-1 complex was not statistically different among subjects with or without adhesions, with the exception of TIMP-1 in PF of subjects with extensive adhesions. MMP1-TIMP-1 ratio indicates that a major portion of MMP-1 is in complex with TIMP-1. There was no age- or gender-dependent difference in MMP-1 and TIMP-1 content in serum or PF. CONCLUSION(S) Despite differences in MMP-1 and TIMP-1 levels in serum and PF of subjects with extensive and moderate adhesions, there is no correlation between MMP-1 and TIMP-1, with the exception of higher TIMP-1 in PF of subjects with extensive adhesions.

Effects of a hyaluronan-based membrane (Seprafilm) on intraperitoneally disseminated human colon cancer cell growth in a nude mouse model.

AbstractPURPOSE: The purpose of this study was to examine whether a hyaluronan-based membrane (Seprafilm® Adhesion Barrier) could affect growth and metastasis of colon cancer in a human xenograft/nude mouse model. METHODS: Male athymic (nude) mice underwent a midline abdominal incision followed by an intraperitoneal inoculation of KM12-L4 human colon cancer cells. Seprafilm® membrane was placed under the incision or on the right lateral abdominal wall; control groups received no Seprafilm® membrane. In another group, Vicryl™ mesh was placed on the right lateral abdominal wall and removed after 1 minute to control for surgical trauma associated with biomaterial placement. RESULTS: Intraperitoneal Seprafilm® did not affect human colon cancer tumor metastasis, including the liver, spleen, and mesenteric lymph nodes. The application of a biomaterial such as Seprafilm® or Vicryl™ mesh to the peritoneal sidewall away from the midline wound was associated with an increased rate of local tumor growth. This was likely because of the local trauma of biomaterial placement in the nude mouse model and not because of the presence of a foreign material. CONCLUSIONS: Our study suggests that Seprafilm® does not affect tumor metastasis. Additionally, placement of biomaterials may cause local trauma that stimulates the formation of localized sidewall tumors in the nude mouse model. Further studies in other animal models and ultimately, in humans are required to unambiguously understand the safety of Seprafilm® and other biomaterials in cancer patients.

Biology takes centre stage

Traditionally, biomaterials have functioned primarily as implants, with only basic understanding of their interactions with the body apart from biocompatibility. A new generation of biomaterials will actively make use of interactions with biological functions, promising new capabilities and therapeutic products.

Effects of hyaluronic acid/carboxymethylcellulose gel on bowel anastomoses in the New Zealand white rabbit

Intra-abdominal adhesions form in more than 90% of patients undergoing major abdominal surgery and can lead to significant complications. Application of a bioresorbable gel consisting of chemically modified hyaluronic acid (HA) and carboxymethylcellulose (CMC) has shown promise as a means of preventing intra-abdominal adhesions, but there have been concerns that the presence of the gel might interfere with the integrity and healing of bowel anastomoses. We tested the effects of HA/CMC gel on adhesion formation and anastomotic healing in 60 New Zealand white rabbits after transection and complete (100%) or incomplete (90%) anastomosis of the ileum. Half of the animals underwent application of HA/CMC gel and half served as control subjects. Animals were killed at 4, 7, or 14 days after surgery. Anastomotic adhesions were scored in a blinded fashion. Integrity of the anastomosis was tested by measuring bursting pressure at the anastomotic site and in an adjacent section of intact bowel. With complete anastomosis, HA/CMC gel significantly reduced adhesion formation at 7 and 14 days after surgery (P<0.05), but gel application did not inhibit adhesion formation when the anastomosis was incomplete. Anastomosed segments of bowel burst at a lower pressure than intact bowel 4 days after surgery, but bursting pressures were normal at 7 and 14 days. Burst pressures of anastomoses receiving an application of HA/CMC gel were nearly identical to control anastomoses at all three time points. HA/CMC gel did not interfere with the normal healing process of bowel anastomoses. Furthermore, HA/CMC gel decreased adhesion formation after complete anastomoses, yet it did not affect adhesion formation in the presence of anastomotic disruption.

Plasminogen-Activator Inhibitor-1 (PAI-1) Remains Elevated After Surgery and Is Not Correlated with Postoperative Adhesion Score

PAI-1 plays a role in maintaining hemostasis between fibrin formation and lysis. It has been shown to be elevated in inflamed human peritoneum when compared with controls. The purpose of this investigation is to determine if PAI-1 is elevated after surgery and if any correlation with adhesion formation exists.