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Lee KB, Chon SJ, Kim S, Kim DY, Park CW, Shin SJ, Kim SM, Lee KH, Ji YI. Using Type I Collagen Gel to Prevent Postoperative Intrauterine Adhesion: A Multicenter Retrospective Study. J Clin Med 2023; 12:jcm12113764. [PMID: 37297959 DOI: 10.3390/jcm12113764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/24/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
We evaluated the clinical outcomes of using type 1 collagen gel after therapeutic resectoscopy; overall, 150 women aged > 20 who planned to undergo therapeutic resectoscopy were enrolled. The patients were randomly assigned to either of the anti-adhesive treatment groups: the type 1 collagen gel (Collabarrier®) (study group; N = 75) or the sodium hyaluronate and sodium carboxymethylcellulose gel group (control group; N = 75) after resectoscopy. One month after applying anti-adhesive materials, postoperative intrauterine adhesions were evaluated using second-look hysteroscopy; the incidence rate of postoperative intrauterine adhesions examined through second-look hysteroscopy showed no significant differences between the groups. There were no statistical differences between the frequency and mean scores of the type and intensity of adhesions in both groups. Finally, no significant differences in adverse events, serious adverse events, adverse device effects, and serious adverse device effects were noted between the two groups; type 1 collagen gel can be effectively and safely used in intrauterine surgery to minimize postoperative adhesions, thereby eventually decreasing the prevalence of infertility, secondary amenorrhea, and recurrent pregnancy loss in reproductive women.
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Affiliation(s)
- Kwang Beom Lee
- Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea
| | - Seung Joo Chon
- Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea
| | - Sunghoon Kim
- Department of Obstetrics and Gynecology, Women's Cancer Clinic, Institute of Women's Life Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Dae Yeon Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Chan Woo Park
- Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University School of Medicine, Seoul 13496, Republic of Korea
| | - So Jin Shin
- Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
| | - Seok Mo Kim
- Department of Obstetrics and Gynecology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Ki Hwan Lee
- Department of Obstetrics and Gynecology, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon 34134, Republic of Korea
| | - Yong Il Ji
- Department of Obstetrics and Gynecology, Inje University, Haeundae Paik Hospital, Busan 48108, Republic of Korea
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Kim JK, Lee CR, Kang SW, Jeong JJ, Nam KH, Cho SR, Jo S, Kim EY, Yun JS, Park HJ, Kim MS, Kim K, Lee S, Bae JS, Jun SY, Park J, Kim JS. Efficacy and safety of temperature-sensitive acellular dermal matrix in prevention of postoperative adhesion after thyroidectomy: A randomized, multicenter, double-blind, non-inferiority study. PLoS One 2022; 17:e0273215. [PMID: 36121791 PMCID: PMC9484646 DOI: 10.1371/journal.pone.0273215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/14/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction MegaShield® is a newly developed temperature-sensitive anti-adhesive containing micronized acellular dermal matrix. The aim of this study was to investigate the efficacy and safety of MegaShield® compared with Guardix-SG® in the prevention of adhesions in patients undergoing bilateral total thyroidectomy. Method We conducted a multicenter trial between October 2018 and March 2020 in patients undergoing total thyroidectomy. The patients were randomly assigned to either the MegaShield® group or the Guardix-SG® group. The primary outcome was the esophageal movement using marshmallow six weeks after the surgery and the secondary outcome was the assessed adhesion score. The safety assessment was also evaluated. Results The study included 70 patients each in the MegaShield® and control (Guardix-SG®) groups. Baseline clinical characteristics, the mean score of marshmallow esophagography, and the sum of adhesion scores were not statistically different between the two groups. Inferiority test demonstrated that the efficacy of MegaShield® is not inferior to that of Guardix-SG®. There were no device-related complications in both groups. Conclusion The efficacy and safety of MegaShield® were not inferior than those of Guardix-SG®. MegaShield® demonstrated the potential of ADM as a potential future anti-adhesive agent. Trial registration The name of trial registry CRIS (Clinical Research Information Service) https://cris.nih.go.kr/cris/index.jsp. (The full trial protocol can be accessed) Registration number: KCT0003204.
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Affiliation(s)
- Jin Kyong Kim
- Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Cho Rok Lee
- Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Sang-Wook Kang
- Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Ju Jeong
- Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Kee-Hyun Nam
- Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- * E-mail:
| | - Sung-Rae Cho
- Department and Research Institute of Rehabilitation Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seongmoon Jo
- Department and Research Institute of Rehabilitation Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Young Kim
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji-Sup Yun
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Jin Park
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mi Sung Kim
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwangsoon Kim
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sohee Lee
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ja Seong Bae
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - So Yeon Jun
- Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jihye Park
- Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Soo Kim
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Lee SB, Gwark SC, Kang CM, Sohn G, Kim J, Chung IY, Lee JW, Kim HJ, Ko BS, Ahn SH, Kim W, Do J, Jeon JY, Kim J, Um E, in Yoon T, Jung SU, Han M, Son BH. The effects of poloxamer and sodium alginate mixture (Guardix-SG®) on range of motion after axillary lymph node dissection: A single-center, prospective, randomized, double-blind pilot study. PLoS One 2020; 15:e0238284. [PMID: 32966294 PMCID: PMC7510996 DOI: 10.1371/journal.pone.0238284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 03/11/2020] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Restricted shoulder mobility is a major upper extremity dysfunction associated with lower quality of life and disability after breast cancer surgery. We hypothesized that a poloxamer and sodium alginate mixture (Guardix-SG®) applied after axillary lymph node dissection (ALND) would significantly improve shoulder range of motion (ROM) in patients with breast cancer. METHODS We conducted a double-blind, randomized, prospective study to evaluate the clinical efficacy and safety of Guardix-SG® for the prevention of upper extremity dysfunction after ALND. The primary outcome measure was shoulder ROM at baseline (T0) and 3 (T1), 6 (T2), and 12 months (T3) after surgery. Secondary outcome measures were the Disabilities of the Arm, Shoulder, and Hand score(DASH), pain associated with movement, which was assessed using a numeric rating scale, and lymphedema assessed using body composition analyzer. RESULTS A total of 83 women with breast cancer were randomly assigned to either the Guardix-SG® group or the control group. In the Guardix-SG® group (n = 37), Guardix-SG® was applied to the axillary region after ALND. In the control group (n = 46), ALND was performed without using Guardix-SG®. Comparing ROM for shoulder flexion before surgery (178.2°) and 12 months after surgery (172.3°), that was restored 12 months after surgery in the Guardix-SG® group, and there was no statistically significant difference between that at before surgery and 12 months after surgery (p = 0.182). No adverse effect was observed in either group. CONCLUSIONS The results of this study have shown that Guardix-SG® help improve shoulder ROM without causing adverse effects in patients who underwent breast cancer surgery. However, there was no statistically significant difference from the control group. A further large-scale study is needed to obtain a more conclusive conclusion. TRIAL REGISTRATION CRISKCT0003386; https://cris.nih.go.kr (20181207).
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Affiliation(s)
- Sae Byul Lee
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sung-chan Gwark
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Cheol Min Kang
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Guiyun Sohn
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jisun Kim
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Il Yong Chung
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jong Won Lee
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Hee Jeong Kim
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Beom Seok Ko
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sei-Hyun Ahn
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Won Kim
- Department of Rehabilitation Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Junghwa Do
- Department of Rehabilitation Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jae Yong Jeon
- Department of Rehabilitation Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jinsung Kim
- Division of Breast Surgery, Department of Surgery, Ulsan University Hospital, Ulsan, Korea
| | - Eunhae Um
- Department of Surgery, Inje University Ilsan Paik Hospital, Goyang-si, Gyeonggi-do, Korea
| | - Tae in Yoon
- Division of Breast Surgery, Department of Surgery, Dongnam institute of Radiological and medical science, Busan, Korea
| | - Sung-ui Jung
- Division of Breast Surgery, Department of Surgery, Kosin University Gospel Hospital, Busan, Korea
| | - Minkyu Han
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, Korea
| | - Byung Ho Son
- Division of Breast Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Kim SG, Song KY, Lee HH, Kim EY, Lee JH, Jeon HM, Jeon KH, Jin HM, Kim DJ, Kim W, Yoo HM, Kim JG, Park CH. Efficacy of an antiadhesive agent for the prevention of intra-abdominal adhesions after radical gastrectomy: A prospective randomized, multicenter trial. Medicine (Baltimore) 2019; 98:e15141. [PMID: 31083151 PMCID: PMC6531037 DOI: 10.1097/md.0000000000015141] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Guardix-SG is a poloxamer-based antiadhesive agent. The aim of this study was to investigate its efficacy in preventing abdominal adhesions in gastric cancer patients undergoing gastrectomy. Few clinical studies have reported that antiadhesive agent reduces the incidence of adhesion after gastrectomy. METHODS We conducted a multicenter trial from June 2013 and August 2015 in patients with gastric adenocarcinoma undergoing radical gastrectomy. Patients were randomly assigned to the Guardix treatment or control group. Postoperative adhesions were diagnosed based on postoperative symptoms, plain x-ray films, and computed tomography. The primary endpoint of the study was the incidence of small bowel obstruction in the first postoperative year. The secondary end-point was the safety of Guardix-SG. RESULTS The study included 109 patients in the Guardix group and 105 patients in the control group. The groups were similarly matched with pathological stage, operation type, anastomosis method, midline incision length, and the extent of lymph node dissection. Eight in the Guardix group and 21 in the control group experienced intestinal obstruction during the 1-year follow-up period. The cumulative incidence of small bowel obstruction was significantly lower in the Guardix group compared to that seen in the control group (4.7% vs 8.6% at 6 months and 7.3% vs 20% at 1 year; P = .007, log-rank test). There were no differences in postoperative complications and adverse events. CONCLUSION Guardix-SG significantly decreased the incidence of intestinal obstruction without affecting the incidence of postoperative complications.
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Affiliation(s)
- Sung Geun Kim
- Division of Gastrointestinal Surgery, Department of Surgery, St. Paul's Hospital
| | - Kyo Young Song
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital
| | - Han Hong Lee
- Division of Gastrointestinal Surgery, Department of Surgery, Uijeongbu St. Mary's Hospital
| | - Eun Young Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital
| | - Jun Hyun Lee
- Division of Gastrointestinal Surgery, Department of Surgery, Bucheon St. Mary's Hospital
| | - Hae Myung Jeon
- Division of Gastrointestinal Surgery, Department of Surgery, Uijeongbu St. Mary's Hospital
| | - Kyung Hwa Jeon
- Division of Gastrointestinal Surgery, Department of Surgery, St. Vincent's Hospital
| | - Hyung Min Jin
- Division of Gastrointestinal Surgery, Department of Surgery, St. Vincent's Hospital
| | - Dong Jin Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Yeouido St. Mary's Hospital
| | - Wook Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Yeouido St. Mary's Hospital
| | - Han Mo Yoo
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital
| | - Jeong Gu Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Korea
| | - Cho Hyun Park
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital
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Biocompatible, drug-loaded anti-adhesion barrier using visible-light curable furfuryl gelatin derivative. Int J Biol Macromol 2018; 120:915-920. [DOI: 10.1016/j.ijbiomac.2018.07.180] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 07/11/2018] [Accepted: 07/29/2018] [Indexed: 11/23/2022]
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Choi GJ, Park HK, Kim DS, Lee D, Kang H. Effect of statins on experimental postoperative adhesion: a systematic review and meta-analysis. Sci Rep 2018; 8:14754. [PMID: 30283040 PMCID: PMC6170439 DOI: 10.1038/s41598-018-33145-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 09/24/2018] [Indexed: 12/14/2022] Open
Abstract
Adhesion is a significant concern after surgery. Many researchers studied the anti-adhesive effect of statin, of which results were inconsistent. Thus, we purposed to perform a systematic review and meta-analysis to evaluate the effect of statins on postoperative adhesion in an experimental study. A comprehensive search was conducted using MEDLINE, EMBASE, and Google Scholar to identify animal studies that investigated the postoperative anti-adhesive effect of statins applied at the surgical area. Primary outcome measure was gross adhesion score. Secondary outcomes included microscopic adhesion score and tissue plasminogen activator (t-PA) activity. Totally, 298 rats from 9 animal studies (172 rats received statin therapy and 126 rats received placebo or no treatment) were included in the final analysis. The combined results showed that gross and microscopic adhesion scores were significantly lower in the statin group in comparison to the control group (standardized mean difference [SMD] = 1.65, 95% confidence interval [CI]: 1.02 to 2.28, Pchi2 < 0.001, I2 = 77.9%; SMD = 1.90, 95% CI: 1.10 to 2.79, Pchi2 < 0.001, I2 = 84.5%, respectively). However, there was no evidence of a difference in t-PA activity (SMD = -3.43, 95% CI: -7.95 to 1.09, Pchi2 < 0.001, I2 = 95.5%). In conclusion, statins were effective in preventing postoperative adhesion, as assessed based on gross and microscopic adhesion scores in rats.
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Affiliation(s)
- Geun Joo Choi
- Department of Anesthesiology and Pain Medicine, College of Medicine, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06911, Republic of Korea
| | - Hee Kyung Park
- Department of Biomedical Engineering, School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06911, Republic of Korea
| | - Dong Su Kim
- Department of Biomedical Engineering, School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06911, Republic of Korea
| | - Donghyun Lee
- Department of Biomedical Engineering, School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06911, Republic of Korea.
| | - Hyun Kang
- Department of Anesthesiology and Pain Medicine, College of Medicine, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06911, Republic of Korea.
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Kim SW, Kim JW, Noh SH, Kim EH, Ito Y, Nah JW, Son TI. Application of visible light curable furfuryl-low molecular chitosan derivative as an anti-adhesion agent. J IND ENG CHEM 2018. [DOI: 10.1016/j.jiec.2018.06.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Cil ATB, Aydogdu IO. Effect of Fat Graftıng on Postoperatıve Intraabdomınal Adhesions on a Rat Model. Arch Med Res 2018; 49:235-239. [DOI: 10.1016/j.arcmed.2018.09.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 09/07/2018] [Accepted: 09/19/2018] [Indexed: 12/23/2022]
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Liu Z, Cheng S, Gu C, Pei H, Hong X. Effect of Hydrogen-Rich Saline on Postoperative Intra-Abdominal Adhesion Bands Formation in Mice. Med Sci Monit 2017; 23:5363-5373. [PMID: 29127274 PMCID: PMC5695092 DOI: 10.12659/msm.904669] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background Postsurgical peritoneal adhesions (PPAs) are pathologic fibrous bands within the peritoneal cavity. The aim of this study was to investigate the protective effect of hydrogen-rich saline (HRS) on PPAs formation in mice. Material/Methods Adhesions were induced in mice using the cecum rubbing model. The mice were allocated into 4 groups: control sham group without cecum rubbing; PPA group with saline applied intraperitoneally (i.p.) daily after cecum rubbing; PPA+HRS (5) group with 5 ml/kg of HRS applied i.p. daily after cecum rubbing; and PPA+HRS (10) group with 10 ml/kg of HRS applied i.p. daily after cecum rubbing. On the 1st, 3rd, and 7th days after the operation, mice were killed and pathological adhesion bands were quantified to detect the effect of HRS on PPAs formation. Results HRS did not affect PPAs formation on the 1st day, but did make a significant reduction on the 3rd and 7th days. A significant increase of t-PA and decrease of TGF-β1 and PAI-1 in the peritoneal fluids were observed in the HRS-treated groups. The levels of MDA and MPO in the HRS-treated groups were significantly lower than those in the PPA group. TNF-α and IL-6 levels in HRS-treated groups significantly decreased compared with those in the PPA group on postoperative day 3 and 7. Moreover, HRS decreased the mRNA levels of pro-inflammatory cytokines and TGF-β1 expression in the postsurgical adhesion bands. Conclusions These results showed that HRS had therapeutic potential for preventing PPAs formation, possibly through balancing the expression of TGF-β1, t-PA, and PAI-1, and inhibiting oxidative stress and inflammation.
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Affiliation(s)
- Zhong Liu
- Department of Emergency Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland)
| | - Sanfang Cheng
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland)
| | - Changwei Gu
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland)
| | - Honghong Pei
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland)
| | - Xin Hong
- Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland)
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Strowitzki MJ, Ritter AS, Radhakrishnan P, Harnoss JM, Opitz VM, Biller M, Wehrmann J, Keppler U, Scheer J, Wallwiener M, Schmidt T, Ulrich A, Schneider M. Pharmacological HIF-inhibition attenuates postoperative adhesion formation. Sci Rep 2017; 7:13151. [PMID: 29030625 PMCID: PMC5640636 DOI: 10.1038/s41598-017-13638-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 09/29/2017] [Indexed: 02/06/2023] Open
Abstract
Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.
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Affiliation(s)
- Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Alina S Ritter
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Praveen Radhakrishnan
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jonathan M Harnoss
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.,Cancer Immunology, Genentech, Inc., South San Francisco, USA
| | - Vanessa M Opitz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Marvin Biller
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Julian Wehrmann
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Ulrich Keppler
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jana Scheer
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Markus Wallwiener
- Department of General Gynaecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
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11
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Peritoneal adhesion prevention with a biodegradable and injectable N,O-carboxymethyl chitosan-aldehyde hyaluronic acid hydrogel in a rat repeated-injury model. Sci Rep 2016; 6:37600. [PMID: 27869192 PMCID: PMC5116612 DOI: 10.1038/srep37600] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 11/01/2016] [Indexed: 02/05/2023] Open
Abstract
Postoperative peritoneal adhesion is one of the serious issues because it induces severe clinical disorders. In this study, we prepared biodegradable and injectable hydrogel composed of N,O-carboxymethyl chitosan (NOCC) and aldehyde hyaluronic acid (AHA), and assessed its anti-adhesion effect in a rigorous and severe recurrent adhesion model which is closer to clinical conditions. The flexible hydrogel, which gelated in 66 seconds at 37 °C, was cross-linked by the schiff base derived from the amino groups of NOCC and aldehyde groups in AHA. In vitro cytotoxicity test showed the hydrogel was non-toxic. In vitro and in vivo degradation examinations demonstrated the biodegradable and biocompatibility properties of the hydrogel. The hydrogel discs could prevent the invasion of fibroblasts, whereas fibroblasts encapsulated in the porous 3-dimensional hydrogels could grow and proliferate well. Furthermore, the hydrogel was applied to evaluate the anti-adhesion efficacy in a more rigorous recurrent adhesion model. Compared with normal saline group and commercial hyaluronic acid (HA) hydrogel, the NOCC-AHA hydrogel exhibited significant reduction of peritoneal adhesion. Compared to control group, the blood and abdominal lavage level of tPA was increased in NOCC-AHA hydrogel group. These findings suggested that NOCC-AHA hydrogel had a great potential to serve as an anti-adhesion candidate.
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Farhat YM, Al-Maliki AA, Easa A, O'Keefe RJ, Schwarz EM, Awad HA. TGF-β1 Suppresses Plasmin and MMP Activity in Flexor Tendon Cells via PAI-1: Implications for Scarless Flexor Tendon Repair. J Cell Physiol 2015; 230:318-26. [PMID: 24962629 DOI: 10.1002/jcp.24707] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 06/20/2014] [Indexed: 01/07/2023]
Abstract
Flexor tendon injuries caused by deep lacerations to the hands are a challenging problem as they often result in debilitating adhesions that prevent the movement of the afflicted fingers. Evidence exists that tendon adhesions as well as scarring throughout the body are largely precipitated by the pleiotropic growth factor, Transforming Growth Factor Beta 1(TGF-β1), but the effects of TGF-β1 are poorly understood in tendon healing. Using an in vitro model of tendon healing, we previously found that TGF-β1 causes gene expression changes in tenocytes that are consistent with scar tissue and adhesion formation, including upregulation of the anti-fibrinolytic protein, PAI-1. Therefore, we hypothesized that TGF-β1 contributes to scarring and adhesions by reducing the activity of proteases responsible for ECM degradation and remodeling, such as plasmin and MMPs, via upregulation of PAI-1. To test our hypothesis, we examined the effects of TGF-β1 on the protease activity of tendon cells. We found that flexor tendon tenocytes treated with TGF-β1 had significantly reduced levels of active MMP-2 and plasmin. Interestingly, the effects of TGF-β1 on protease activity were completely abolished in tendon cells from homozygous plasminogen activator inhibitor 1 (PAI-1) knockout (KO) mice, which are unable to express PAI-1. Our findings support the hypothesis that TGF-β1 induces PAI-1, which suppresses plasmin and plasmin-mediated MMP activity, and provide evidence that PAI-1 may be a novel therapeutic target for preventing adhesions and promoting a scarless, regenerative repair of flexor tendon injuries.
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Affiliation(s)
- Youssef M Farhat
- Department of Biomedical Engineering, 601 Elmwood Ave, Rochester, New York.,The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York
| | - Alaa A Al-Maliki
- The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York
| | - Anas Easa
- The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York
| | - Regis J O'Keefe
- The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.,Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York
| | - Edward M Schwarz
- The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.,Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York
| | - Hani A Awad
- Department of Biomedical Engineering, 601 Elmwood Ave, Rochester, New York.,The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.,Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York
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Beyene RT, Kavalukas SL, Barbul A. Intra-abdominal adhesions: Anatomy, physiology, pathophysiology, and treatment. Curr Probl Surg 2015; 52:271-319. [PMID: 26258583 DOI: 10.1067/j.cpsurg.2015.05.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 05/12/2015] [Indexed: 12/18/2022]
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Qin F, Ma Y, Li X, Wang X, Wei Y, Hou C, Lin S, Hou L, Wang C. Efficacy and mechanism of tanshinone IIA liquid nanoparticles in preventing experimental postoperative peritoneal adhesions in vivo and in vitro. Int J Nanomedicine 2015; 10:3699-716. [PMID: 26056449 PMCID: PMC4445949 DOI: 10.2147/ijn.s81650] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Up to 90% of patients develop adhesion following laparotomy. Upregulating fibrinolysis within the peritoneum reduces adhesions. Tanshinone IIA (Tan IIA) promotes fibrinolysis in hepatic fibrosis and the cardiovascular system and may play a role in preventing adhesions. We report preparation and characterization of liquid nanoparticles of Tan IIA for intravenous administration and investigate its feasibility in clinical practice. Tan IIA liquid nanoparticles (Tan IIA-NPs) were prepared using the emulsion/solvent evaporation method. Adhesions were induced in Sprague–Dawley rats by injuring the parietal peritoneum and cecum, followed by intravenous administration of various Tan IIA-NP dosages. The adhesion scores for each group were collected 7 days after the initial laparotomy. The activity of tissue-type plasminogen activator (tPA) was measured from the peritoneal lavage fluid. The messenger RNA and protein expression levels of plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TGF-β1 and collagen I expressions were measured immunohistochemically in the ischemic tissues. The effects of Tan IIA-NPs and free-Tan IIA on tPA and PAI-1 were measured in vitro in TGF-β1-induced HMrSV5 cells. Tan IIA-NPs exhibited small particle size, high encapsulation efficiency, good stability for storage, and safety for intravenous administration. Tan IIA-NPs were effective in preventing adhesion. Tan IIA-NPs increased tPA activity in peritoneal lavage fluid, and tPA mRNA and protein expression, and decreased PAI-1 mRNA and protein expression in the ischemic tissues. Moreover, Tan IIA-NPs decreased TGF-β1 and collagen I expressions in the ischemic tissues. Tan IIA-NPs administered via tail veins upregulated fibrinolysis in the peritoneum. In vitro studies showed that these effects may be mediated by the TGF-β signal pathway.
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Affiliation(s)
- Fei Qin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yun Ma
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiao Li
- Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Xian Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuanyi Wei
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chuqi Hou
- Department of Pharmacology, Southern Medical University, Guangzhou, People's Republic of China
| | - Si Lin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Lianbing Hou
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chengxi Wang
- Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
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Application of hyaluronic acid/sodium alginate-based microparticles to prevent tissue adhesion in a rabbit model. Surg Today 2015; 46:501-8. [DOI: 10.1007/s00595-015-1186-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/16/2015] [Indexed: 01/17/2023]
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16
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Inagaki NF, Inagaki FF, Kokudo N, Miyajima A. Cell-based therapy for preventing postoperative adhesion and promoting regeneration after hepatectomy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:524-30. [PMID: 25877017 DOI: 10.1002/jhbp.247] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 03/12/2015] [Indexed: 12/31/2022]
Abstract
Postoperative adhesion is a critical clinical issue after almost all abdominal or pelvic surgeries including liver surgery. Postoperative adhesion causes several complications, such as small bowel obstruction and chronic abdominal pain. Furthermore, it makes reoperation much more difficult, leading to increased mortality and morbidity rate. Postoperative adhesion is particularly problematic for repeated hepatectomy, since hepatic malignant neoplasm recurs frequently and repeated hepatectomy is widely used as one of the most curative treatments. Several treatments to reduce postoperative adhesion have been developed, which include laparoscopic surgery, administration of pharmacological agents and use of prophylactic barrier materials. However, none of them are optimal. We have proposed a novel treatment using a cell sheet of fetal liver mesothelial cells (FL-MCs) to prevent postoperative adhesion in a novel mouse model. Besides adhesion, repeated hepatectomy has another serious problem; although the liver has a remarkable ability to regenerate, the recovery of liver mass and function of the remnant liver after multiple repeated hepatectomy is limited. The FL-MC cell sheet enhances proliferation of hepatocytes after hepatectomy by providing growth factors for hepatocytes. Thus the FL-MC sheet could simultaneously solve the two problems associated with repeated hepatectomy.
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Affiliation(s)
- Natsuko F Inagaki
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Fuyuki F Inagaki
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsushi Miyajima
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
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Kim TH, Park JS, An SS, Kang H. Inhibition of thrombin-activated fibrinolysis inhibitor decreases postoperative adhesion. J Surg Res 2015; 193:560-6. [DOI: 10.1016/j.jss.2014.07.056] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 07/10/2014] [Accepted: 07/23/2014] [Indexed: 12/08/2022]
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Song KJ, Lee HM, Lee EJ, Kwon JH, Jo KH, Kim KS. Anti-adhesive effect of a thermosensitive poloxamer applied after the removal of nasal packing in endoscopic sinus surgery: a randomised multicentre clinical trial. Clin Otolaryngol 2014; 38:225-30. [PMID: 23745533 DOI: 10.1111/coa.12117] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2013] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To compare the efficacies of a thermosensitive poloxamer (TPX) and Merogel in preventing adhesion applied after the removal of nasal packing in endoscopic sinus surgery as a non-inferiority trial. DESIGN Randomised, multicentre, single-blind, active-controlled, matched-pair study. SETTING Yonsei University Gangnam Severance Hospital, Korea University Guro Hospital. PARTICIPANTS A total of 70 patients were enroled and underwent endoscopic sinus surgeries. Four of the patients did not complete their follow-up. Analysis of the 66 enroled patients having completed postoperative assessment was performed. The severity of rhinosinusitis was graded with a Lund-McKay CT score, and only those with bilateral disease and a CT score difference ≤2 between sinuses were included. MAIN OUTCOME MEASURES An independent rhinologist from a third institution through a blinded assessment with digital photoendoscopy of the middle meati bilaterally taken postoperatively. RESULTS In the blinded assessment, thermosensitive poloxamer (anti-adhesion rate: 92%) was similar to Merogel (anti-adhesion rate: 89%). Evaluation of the presence and grade of adhesion, oedema, and infection in the middle meatus revealed no significant differences between the thermosensitive poloxamer group and the Merogel group at all postoperative periods. CONCLUSION Anti-adhesive effects of thermosensitive poloxamer are similar to those of Merogel. Therefore, thermosensitive poloxamer can be considered a safe alternative to Merogel for preventing adhesion in patients undergoing endoscopic sinus surgeries, and further evaluation of thermosensitive poloxamer as an anti-adhesive and primary packing material compared with the control using no packing is needed.
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Affiliation(s)
- K J Song
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea
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19
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Peker K, Inal A, Sayar I, Sahin M, Gullu H, Inal DG, Isik A. Prevention of intraabdominal adhesions by local and systemic administration of immunosuppressive drugs. IRANIAN RED CRESCENT MEDICAL JOURNAL 2013; 15:e14148. [PMID: 24693396 PMCID: PMC3955511 DOI: 10.5812/ircmj.14148] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 01/14/2013] [Accepted: 05/15/2013] [Indexed: 11/21/2022]
Abstract
BACKGROUND Intraperitoneal adhesion formation is a serious postsurgical issue. Adhesions develop after damage to the peritoneum by surgery, irradiation, infection or trauma. OBJECTIVES Using a rat model, we compared the effectiveness of systemic and intraperitoneally administered common immunosuppressive drugs for prevention of postoperative intraperitoneal adhesions. MATERIALS AND METHODS Peritoneal adhesions were induced in 98 female Wistar-Albino rats by cecal abrasion and peritoneal excision. Rats were randomly separated into seven groups, each containing fourteen rats, and the standard experimental model was applied to all of rats. 14 days later, rats were euthanized, intraperitoneal adhesions were scored and tissues were examined histologically using hematoxylin/eosin and Masson's trichrome staining. RESULTS Throughout the investigation, no animal died during or after surgery. In all of experimental groups, decrease in fibrosis was statistically significant. Decrease in fibrosis was most prominently in intraperitoneal tacrolimus group (P = 0.000), and decrease was least in intraperitoneal cyclosporine group (P = 0.022). Vascular proliferation was significantly decreased in all experimental groups (P < 0.05) except for systemic tacrolimus group (P = 0.139). Most prominent reduction in vascular proliferation was in intraperitoneal tacrolimus group (P = 0.000). CONCLUSIONS Administration of immunosuppressive drugs is effective for prevention of intraperitoneal adhesions.
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Affiliation(s)
- Kemal Peker
- Department of General Surgery, Erzincan University, Erzincan, Turkey
| | - Abdullah Inal
- Department of General Surgery, Erzincan University, Erzincan, Turkey
| | - Ilyas Sayar
- Department of Pathology, Erzincan University, Erzincan, Turkey
| | - Murat Sahin
- Department of Anesthesiology & Reanimation, Erzincan University, Erzincan, Turkey
| | - Huriye Gullu
- Department of Anesthesiology & Reanimation, Erzincan University, Erzincan, Turkey
| | - Duriye Gul Inal
- Department of Anesthesiology & Reanimation, Erzincan University, Erzincan, Turkey
| | - Arda Isik
- Department of General Surgery, Erzincan University, Erzincan, Turkey
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Kucuk GO, Ertem M, Kepil N. Histopathological Response and Adhesion Formation After Omentectomy with Ultrasonic Energy, Bipolar Sealing, and Suture Ligation. Indian J Surg 2013; 77:799-804. [PMID: 27011460 DOI: 10.1007/s12262-013-1005-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 10/27/2013] [Indexed: 01/17/2023] Open
Abstract
This study was designed to evaluate the histopathological response and intra-abdominal adhesion formation after an omentectomy in rats using the bipolar vessel-sealing device, ultrasonic coagulator, and suture ligation techniques. Forty Wistar albino rats were used, divided into four random groups. The rats underwent a midline laparotomy, and a partial omentectomy was performed using a 3-0 silk suture with suture ligation in group 1, bipolar device in group 2, and ultrasonic coagulator in group 3; only a laparotomy was performed on the control group. Lateral thermal damage was examined the same day, and a piece of the omentum was left in the animals to be examined on postoperative day 15. A relaparotomy was performed to assess adhesion formation and histopathological response. In pairwise comparisons, there was no statistically significant difference among the ultrasonic device, bipolar device, and suture ligation groups in terms of microscopic adhesion scoring; however, the scores of the bipolar device and suture ligation groups were significantly higher compared with those of the control group (p < 0.01). Furthermore, the macroscopic adhesion scores were significantly lower for the ultrasonic device group when compared with those of the bipolar device and suture ligation groups (p < 0.05 and p < 0.01). The ultrasonic device seems to be superior to the bipolar device and suture ligation in terms of macroscopic adhesion formation, but no significant difference was found in terms of the histopathological response in rats following an omentectomy. Further research may be required.
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Affiliation(s)
- Gultekin Ozan Kucuk
- Department of General Surgery, Samsun Education and Research Hospital, Samsun, Turkey
| | - Metin Ertem
- Department of General Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Nuray Kepil
- Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
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21
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Kim JY, Cho WJ, Kim JH, Lim SH, Kim HJ, Lee YW, Kwon SW. Efficacy and safety of hyaluronate membrane in the rabbit cecum-abdominal wall adhesion model. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2013; 85:51-7. [PMID: 23908960 PMCID: PMC3729986 DOI: 10.4174/jkss.2013.85.2.51] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 03/29/2013] [Accepted: 05/06/2013] [Indexed: 11/30/2022]
Abstract
Purpose Tissue adhesion is a well-known postsurgical phenomenon, causing pain, functional obstruction, and difficult reoperative surgery. To overcome these problems, various synthetic and natural polymer membranes have been developed as postoperative tissue adhesion barriers. However, limitation in their use has hindered its actual application. We prepared a hyaluronate membrane (HM) to evaluate its efficacy and safety as an adhesion barrier compared to a commercialized product (Interceed, Ethicon). Methods To evaluate the antiadhesion effect, a cecum-abdominal wall abrasion model was adopted in a rabbit. The denuded cecum was covered by Interceed or HM or neither and apposed to the abdominal wall (each, n = 10). Four weeks after surgery, the level of adhesion was graded. Acute and chronic toxicity of the three groups were also evaluated. Results Blood samples drawn to evaluate acute toxicity at postoperative day 3 and 7 showed no significant difference among the three groups. The grade and area of adhesion were significantly lower in the HM compared to those of the control and Interceed at four weeks after surgery. Histologic evaluations, which was carried out to estimate tissue reactions at the site of application, as well as to assess chronic toxicity for the major organs, were not significantly different in the three groups. Conclusion This study showed that the antiadhesion efficacy of HM was superior to commercialized antiadhesion membrane, Interceed. Low inflammatory response and nontoxicity were also demonstrated. From these results, we suggest that the HM is a good candidate as a tissue adhesion barrier.
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Affiliation(s)
- Jae Young Kim
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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22
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Dinarvand P, Farhadian S, Seyedjafari E, Shafiee A, Jalali A, Sanaei-rad P, Dinarvand B, Soleimani M. Novel approach to reduce postsurgical adhesions to a minimum: Administration of losartan plus atorvastatin intraperitoneally. J Surg Res 2013; 181:91-8. [DOI: 10.1016/j.jss.2012.05.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 05/02/2012] [Accepted: 05/09/2012] [Indexed: 12/08/2022]
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Dayton MT, Dempsey DT, Larson GM, Posner AR. New paradigms in the treatment of small bowel obstruction. Curr Probl Surg 2012; 49:642-717. [PMID: 23057861 DOI: 10.1067/j.cpsurg.2012.06.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Merril T Dayton
- Department of Surgery, SUNY Buffalo, Kaleida Health System, Buffalo, NY, USA
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24
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Shimomura M, Hinoi T, Ikeda S, Adachi T, Kawaguchi Y, Tokunaga M, Sasada T, Egi H, Tanabe K, Okajima M, Ohdan H. Preservation of peritoneal fibrinolysis owing to decreased transcription of plasminogen activator inhibitor-1 in peritoneal mesothelial cells suppresses postoperative adhesion formation in laparoscopic surgery. Surgery 2012; 153:344-56. [PMID: 23218127 DOI: 10.1016/j.surg.2012.07.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 07/25/2012] [Indexed: 11/24/2022]
Abstract
BACKGROUND Postoperative adhesion formation is regulated by peritoneal fibrinolysis, which is determined by tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). This study compared peritoneal fibrinolysis and adhesion formation after laparoscopic surgery (LAP) and open surgery (OP). METHODS We divided 154 male rats into 3 groups after cecal cauterization: Control, no treatment; LAP, CO2 pneumoperitoneum at 5 mmHg for 60 minutes; and OP, laparotomy for 60 minutes. Adhesions were quantified at day 7. The activity and mRNA level of tPA and PAI-1 were determined by enzyme-linked immunosorbent assay in plasma and peritoneal lavage and by real-time polymerase chain reaction in peritoneal mesothelial cells from omentum. We also examined peritoneal fibrinolysis in human gastric cancer patients treated with LAP (n = 14) or OP (n = 10). RESULTS In the animal study, adhesion scores, PAI-1 activity in peritoneal lavage fluid, and PAI-1 mRNA levels in peritoneal mesothelium were significantly greater in the OP group than the control and LAP groups. In the human study, postoperative PAI-1 mRNA levels were significantly greater in the OP group than the LAP group. Additionally, PAI-1 mRNA levels and subsequent adhesion formation were induced by prolonged operative time in the OP group, but not the LAP group. CONCLUSION Preservation of peritoneal fibrinolysis owing to decreased PAI-1 expression at the transcriptional level in peritoneal mesothelial cells is associated with suppression of postoperative adhesion formation in LAP. PAI-1 mRNA levels and subsequent adhesion formation were not induced by prolonged operative time in LAP. These results highlight the less invasiveness nature of LAP.
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Affiliation(s)
- Manabu Shimomura
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Fjellström O, Deinum J, Sjögren T, Johansson C, Geschwindner S, Nerme V, Legnehed A, McPheat J, Olsson K, Bodin C, Paunovic A, Gustafsson D. Characterization of a small molecule inhibitor of plasminogen activator inhibitor type 1 that accelerates the transition into the latent conformation. J Biol Chem 2012; 288:873-85. [PMID: 23155046 DOI: 10.1074/jbc.m112.371732] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A novel class of small molecule inhibitors for plasminogen activator inhibitor type 1 (PAI-1), represented by AZ3976, was identified in a high throughput screening campaign. AZ3976 displayed an IC(50) value of 26 μm in an enzymatic chromogenic assay. In a plasma clot lysis assay, the compound was active with an IC(50) of 16 μm. Surprisingly, AZ3976 did not bind to active PAI-1 but bound to latent PAI-1 with a K(D) of 0.29 μm at 35 °C and a binding stoichiometry of 0.94, as measured by isothermal calorimetry. Reversible binding was confirmed by surface plasmon resonance direct binding experiments. The x-ray structure of AZ3976 in complex with latent PAI-1 was determined at 2.4 Å resolution. The inhibitor was bound in the flexible joint region with the entrance to the cavity located between α-helix D and β-strand 2A. A set of surface plasmon resonance experiments revealed that AZ3976 inhibited PAI-1 by enhancing the latency transition of active PAI-1. Because AZ3976 only had measurable affinity for latent PAI-1, we propose that its mechanism of inhibition is based on binding to a small fraction in equilibrium with active PAI-1, a latent-like prelatent form, from which latent PAI-1 is then generated more rapidly. This mode of action, with induced accelerated latency transition of active PAI-1 may, together with supporting x-ray data, provide improved opportunities for small molecule drug design in the hunt for therapeutically useful PAI-1 inhibitors.
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Affiliation(s)
- Ola Fjellström
- Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
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Andrews S, Ford D, Martin P. Knockdown of osteopontin reduces the inflammatory response and subsequent size of postsurgical adhesions in a murine model. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1165-72. [PMID: 22858059 DOI: 10.1016/j.ajpath.2012.06.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Revised: 05/28/2012] [Accepted: 06/20/2012] [Indexed: 01/08/2023]
Abstract
Adhesions between organs after abdominal surgery remain a significant unresolved clinical problem, causing considerable postoperative morbidity. Osteopontin (OPN) is a cytokine up-regulated after cell injury and tissue repair. Our previous studies have shown that blocking OPN expression at sites of cutaneous wounding resulted in reduced granulation tissue and scarring. We hypothesize that it may be possible to similarly reduce inflammation-associated fibrosis that causes small-bowel adhesions after abdominal surgery. By using a mouse model, we deliver OPN antisense oligodeoxynucleotides via Pluronic gel to the surface of injured, juxtaposed small bowel and show a significant reduction of inflammatory cell influx to the developing adhesion and a dramatic reduction in the resulting adhesion size. A significant reduction in α-smooth muscle actin expression and collagen deposition within the mature adhesion is also demonstrated. We see no impact on mortality, and the healing of serosal injury to intact bowel appeared normal given the reduced inflammatory response. Our studies suggest that dampening OPN levels might be a potentially important target for anti-adhesion therapeutics.
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Affiliation(s)
- Stuart Andrews
- Department of Physiology/Pharmacology, University of Bristol, Bristol, United Kingdom.
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Atta HM. Prevention of peritoneal adhesions: a promising role for gene therapy. World J Gastroenterol 2011; 17:5049-58. [PMID: 22171139 PMCID: PMC3235588 DOI: 10.3748/wjg.v17.i46.5049] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2011] [Revised: 07/14/2011] [Accepted: 07/21/2011] [Indexed: 02/06/2023] Open
Abstract
Adhesions are the most frequent complication of abdominopelvic surgery, yet the extent of the problem, and its serious consequences, has not been adequately recognized. Adhesions evolved as a life-saving mechanism to limit the spread of intraperitoneal inflammatory conditions. Three different pathophysiological mechanisms can independently trigger adhesion formation. Mesothelial cell injury and loss during operations, tissue hypoxia and inflammation each promotes adhesion formation separately, and potentiate the effect of each other. Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation. This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions. It explores the promising role of combinatorial gene therapy and vector modifications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field.
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Kim KI, Na HN, Ito Y, Son TI. Synthesis of visible light-induced cross-linkable chitosan as an anti-adhesive agent. Macromol Res 2011. [DOI: 10.1007/s13233-011-0303-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Matsuzaki S, Botchorishvili R, Jardon K, Maleysson E, Canis M, Mage G. Impact of intraperitoneal pressure and duration of surgery on levels of tissue plasminogen activator and plasminogen activator inhibitor-1 mRNA in peritoneal tissues during laparoscopic surgery. Hum Reprod 2011; 26:1073-81. [PMID: 21393301 DOI: 10.1093/humrep/der055] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Our objective was to evaluate the impact of intraperitoneal pressure (IPP) and duration of a CO(2) pneumoperitoneum on the peritoneal fibrinolytic system during laparoscopic surgery. METHODS Human study: Patients undergoing laparoscopic surgery were divided into two groups: low (8 mmHg, n= 32) or standard (12 mmHg, n= 36) IPP. Normal peritoneum was collected from the parietal wall at the beginning of surgery and every 60 min thereafter. Mouse study: Mice were divided into three groups: low (2 mmHg) or high (8 mmHg) IPP or laparotomy. Peritoneal tissue was collected at 0, 4, 8, 24, 48 and 72 h, and 5 and 7 days after surgery. Real-time RT-PCR was performed in humans and mice to measure the levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA in peritoneal tissues. RESULTS Human study: The tPA/PAI-1 mRNA ratio was significantly decreased in the 12 mmHg group at 1 h [P < 0.0001 versus matched initial peritoneal biopsies (MI)]. The tPA/PAI-1 mRNA ratio decreased in both groups at 2 h (P < .0.01 versus MI). Mouse study: The tPA/PAI-1 ratio was decreased at 0 h, and the difference was significant at 4 h in both the laparotomy (P < 0.001 versus controls, 0 h, 5 and 7 days) and high-IPP (P < 0.0001 versus 0, 48 and 72 h, 5 and 7 days) groups. No changes in tPA/PAI-1 ratio were observed in the low-IPP group. CONCLUSIONS A low IPP and shorter duration of surgery appear to minimally impact the fibrinolytic system during a CO₂ pneumoperitoneum.
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Affiliation(s)
- Sachiko Matsuzaki
- Chirurgie Gynécologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.
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Ward BC, Panitch A. Abdominal Adhesions: Current and Novel Therapies. J Surg Res 2011; 165:91-111. [DOI: 10.1016/j.jss.2009.09.015] [Citation(s) in RCA: 174] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Revised: 08/17/2009] [Accepted: 09/04/2009] [Indexed: 12/20/2022]
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Na HN, Kim KI, Han JH, Lee JG, Son TI, Han DK, Ito Y, Song KS, Jang EC. Synthesis of O-carboxylated low molecular chitosan with azido phenyl group: Its application for adhesion prevention. Macromol Res 2010. [DOI: 10.1007/s13233-010-1007-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Tokinaga Y, Kimoto Y, Ogawa K, Mizumoto K, Tange K, Hatano Y. Reduction of adhesion formation by an angiotensin type 1 receptor antagonist. Langenbecks Arch Surg 2010; 396:127-32. [DOI: 10.1007/s00423-010-0665-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Accepted: 06/10/2010] [Indexed: 01/07/2023]
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Tepetes K, Asprodini EK, Christodoulidis G, Spyridakis M, Kouvaras E, Hatzitheofilou K. Prevention of postoperative adhesion formation by individual and combined administration of 4 per cent icodextrin and dimetindene maleate. Br J Surg 2009; 96:1476-1483. [PMID: 19918860 DOI: 10.1002/bjs.6746] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND To date, no single method has been successful in eliminating peritoneal adhesion formation after major abdominal surgery. This study evaluated the individual and possible synergistic effect of a local intraperitoneal barrier, 4 per cent icodextrin, and an intravenously administered antihistamine drug, dimetindene maleate, in the prevention of adhesion development following surgical trauma. METHODS De novo experimental adhesions were induced by standardized trauma of the peritoneum and large bowel in 120 New Zealand White rabbits. The animals were randomized into four groups receiving intraperitoneal saline, intraperitoneal 4 per cent icodextrin (60 ml), intravenous dimetindene maleate (0.1 mg/kg) and 4 per cent icodextrin-dimetindene in combination (n = 30 per group). Ten days later, adhesion scores and incidence were assessed by two independent surgeons. and surface area by computer-aided planimetry. RESULTS Treatment with either icodextrin or dimetindene maleate significantly reduced adhesion scores and increased the incidence of adhesion-free animals in an equipotent manner. The effect of combined treatment on severity, incidence and surface area of adhesions was more pronounced than that of each drug administered separately. CONCLUSION Combined administration of 4 per cent icodextrin and dimetindene maleate may be used safely and efficaciously to prevent surgically induced adhesions.
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Affiliation(s)
- K Tepetes
- Department of General Surgery, Larissa University Hospital, Larissa, Greece.
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Whang SH, Astudillo JA, Sporn E, Bachman SL, Miedema BW, Davis W, Thaler K. In search of the best peritoneal adhesion model: comparison of different techniques in a rat model. J Surg Res 2009; 167:245-50. [PMID: 20304431 DOI: 10.1016/j.jss.2009.06.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Revised: 05/21/2009] [Accepted: 06/12/2009] [Indexed: 11/26/2022]
Abstract
BACKGROUND Adhesion-related complications after abdominal surgery result in significant morbidity and costs. Results from animal studies investigating prevention or treatment of adhesions are limited due to lack of consistency in existing animal models. The aim of this study was to compare quality and quantity of adhesions in four different models and to find the best model. MATERIALS AND METHODS This study was approved by the University of Missouri Animal Care and Use Committee (ACUC). Forty female rats were randomly assigned to four different groups of 10 animals each. Adhesion created was performed utilizing the four techniques: Group 1 - parietal peritoneum excision (PPE), Group 2 - parietal peritoneum abrasion (PPA), Group 3 - peritoneal button creation (PBC), and Group 4 - cecal abrasion (CA). Rats were allowed to recover and necropsy was performed on postoperative d 14. Adhesions were scored by an established quantitative and qualitative scoring systems. The midline incision served as the control in each animal. RESULTS The four groups were not equal with respect to both quantity score (P<0.001) and quality score (P=0.042). The PBC group had the highest quantity of adhesions. The highest quality of adhesion was seen in the PPE group. A multivariate analysis carried out to quantify the performance of each model clearly demonstrated that PBC exhibited the best results in terms of both quantity and quality. CONCLUSIONS The button technique (PBC) is most consistent and reproducible technique for an intra-abdominal adhesion model. This model can help in the study and development of substances to prevent adhesion formation in the future.
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Affiliation(s)
- Susan H Whang
- Department of General Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
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Klass BR, Rolfe KJ, Grobbelaar AO. In vitro flexor tendon cell response to TGF-beta1: a gene expression study. J Hand Surg Am 2009; 34:495-503. [PMID: 19258148 DOI: 10.1016/j.jhsa.2008.10.032] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2008] [Revised: 10/26/2008] [Accepted: 10/29/2008] [Indexed: 02/02/2023]
Abstract
PURPOSE Adhesion formation around zone II flexor tendon repairs remains an important clinical challenge. Tendon healing is complex, and when uncontrolled it may lead to adhesion formation. Transforming growth factor-beta1 (TGF-beta1) is a multipotent growth factor known to be involved in wound healing and scar formation. It has also been shown to have a role in both tendon healing and adhesion formation. METHODS Uninjured rabbit flexor tendons were divided into endotenon, epitenon, and sheath cells and cultured separately. The in vitro effect of TGF-beta1 gene expression was determined on quiescent tendon cells using real-time polymerase chain reaction for collagen type 1, collagen type 3, fibronectin, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (t-PA). RESULTS Endotenon-derived cells showed a statistically significant down-regulation of collagen type I gene expression in response to TGF-beta1 compared with untreated endotenon cells and with both epitenon and sheath cells at a number of time points. However, endotenon cells showed an increase in collagen type 3 gene expression compared with untreated cells and epitenon cells. All cells showed a statistically significant increase in fibronectin in the later time points compared with the untreated cells. Endotenon-derived cells showed an early increase in PAI-1, whereas sheath cells showed a later increase. CONCLUSIONS We have shown that cells cultured from 3 separate parts of the flexor tendon-sheath complex respond in different ways when stimulated with TGF-beta1. The down-regulation of collagen types 1 and 3 in endotenon cells may give further insight into the effects of TGF-beta1 in tendon healing. Also, the upregulation of fibronectin and PAI-1, combined with a down-regulation of tissue plasminogen activator, could explain the association of TGF-beta1 with tendon adhesion formation. Treatments aimed at improving tendon healing and the prevention of adhesions may arise from modification of the effects of TGF-beta1.
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Affiliation(s)
- B R Klass
- Department of Plastic and Reconstructive Surgery, Royal Free Hospital, London, UK.
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Yilmaz B, Aksakal O, Gungor T, Sirvan L, Sut N, Kelekci S, Soysal S, Mollamahmutoglu L. Metformin and atorvastatin reduce adhesion formation in a rat uterine horn model. Reprod Biomed Online 2009; 18:436-42. [DOI: 10.1016/s1472-6483(10)60106-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Lee YW, Chu B, Lee YG, Kim NH, Kim JH, Kim KI, Kwon SW. Efficacy and Safety of the Electrospun Nanofibrous Adhesion Barrier for Laparoscopic Surgery in a Rabbit Model. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2009. [DOI: 10.4174/jkss.2009.76.2.73] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
| | | | | | | | | | - Kwang Il Kim
- Department of Patholgogy, College of Medicine, Pochon CHA University, Seongnam, Korea
| | - Sung Won Kwon
- Department of General Surgery, College of Medicine, Pochon CHA University, Seongnam, Korea
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Reed KL, Stucchi AF, Leeman SE, Becker JM. Inhibitory Effects of a Neurokinin-1 Receptor Antagonist on Postoperative Peritoneal Adhesion Formation. Ann N Y Acad Sci 2008; 1144:116-26. [DOI: 10.1196/annals.1418.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Lim R, Morrill JM, Prushik SG, Reed KL, Gower AC, Leeman SE, Stucchi AF, Becker JM. An FDA approved neurokinin-1 receptor antagonist is effective in reducing intraabdominal adhesions when administered intraperitoneally, but not orally. J Gastrointest Surg 2008; 12:1754-61. [PMID: 18709513 DOI: 10.1007/s11605-008-0634-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Accepted: 07/16/2008] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Postoperative adhesions pose a continued healthcare problem. We previously demonstrated that intraperitoneal (i.p.) administration of a neurokinin-1 receptor antagonist (NK-1RA) at surgery reduces intraabdominal adhesions in rats. The NK-1RA aprepitant (Emend, Merck) is clinically approved for preventing postoperative nausea and vomiting; however, its effects on adhesion formation are unknown. Thus, we determined the effects of i.p. and oral administration of aprepitant on adhesion formation in a rat model. METHODS Adhesions were surgically induced in rats that were randomized to receive either one or five oral preoperative doses or a single intraoperative i.p. dose of aprepitant (50 mg/kg). Adhesions were scored at 7 days. In similar experiments using i.p. dosing, animals were sacrificed at 24 h and peritoneal fluid, and tissue were collected to assess fibrinolytic activity and tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels, respectively. RESULTS I.p. aprepitant reduced adhesion formation by 33% (p < 0.05) compared with controls while oral aprepitant had no effect. Compared to controls i.p. aprepitant reduced tPA activity by 55% (p < 0.05), increased PAI-1 mRNA levels by 140% (p < 0.05), and had no affect on tPA mRNA levels. CONCLUSION These data suggest that aprepitant maybe a useful pharmacologic agent for reducing adhesion formation clinically.
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Affiliation(s)
- Rizal Lim
- Department of Surgery, Boston University School of Medicine, 88 East Newton St. C500, Boston, MA 02118, USA
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Abstract
Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging field.
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Wasserberg N, Nunoo-Mensah JW, Ruiz P, Tzakis AG. The effect of immunosuppression on peritoneal adhesions formation after small bowel transplantation in rats. J Surg Res 2007; 141:294-298. [PMID: 17543342 DOI: 10.1016/j.jss.2006.12.541] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2006] [Revised: 12/07/2006] [Accepted: 12/08/2006] [Indexed: 01/11/2023]
Abstract
BACKGROUND The reported incidence of adhesion related small bowel obstruction after abdominal organ transplantation is considerably lower than other abdominal procedures. The purpose of the study was to investigate the influence of immunosuppression on peritoneal adhesion formation after intestinal transplantation in rats. METHODS Four groups of rats (n = 6) underwent small bowel intestinal transplantation in syngeneic (Groups A, B) and allogeneic (Groups C, D) combinations. Groups B and D received tacrolimus immunosuppression 1 mg/kg/d. Animals were euthanized on postoperative day 7, and the total adhesion score (TAS), tissue hydroxyproline content (HPC), TGF-beta mRNA expression levels and histology were examined. RESULTS All of the animals in Group C showed severe histological (Grade III) acute cellular rejection. There were no histological signs of rejection in Group D. A significant reduction in TAS was observed in tacrolimus treated animals in both syngeneic and allogeneic combinations (Groups B and D), compared with controls (Groups A and C) (P < 0.001 and P < 0.01, respectively). TAS results correlated with the differences in TGF-beta levels that showed significant reduction when each immunosuppressed group was compared with its nontreated counterpart, i.e., (Groups B versus A, P < 0.05, and Groups D versus C, P < 0.01). TGF-beta levels were significantly high in the rejection group (C) and correlated with the intense adhesion formation that was demonstrated in that group. Group C was also the only group in which a significant elevation in HPC was demonstrated (P < 0.001). CONCLUSION Intense adhesion formation occurs during early posttransplant acute rejection. Postsurgical adhesion formation is significantly reduced in immunosuppressed rats after intestinal transplantation.
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Affiliation(s)
- Nir Wasserberg
- Department of Surgery, University of Miami School of Medicine, Miami, Florida, USA.
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Segura T, Schmokel H, Hubbell JA. RNA interference targeting hypoxia inducible factor 1alpha reduces post-operative adhesions in rats. J Surg Res 2007; 141:162-70. [PMID: 17561118 DOI: 10.1016/j.jss.2006.07.045] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2006] [Revised: 07/24/2006] [Accepted: 07/31/2006] [Indexed: 01/17/2023]
Abstract
BACKGROUND To investigate the use of RNA interference mediated gene down-regulation targeting hypoxia inducible factor 1alpha (HIF-1alpha) and plasminogen activator inhibitor 1 (PAI-1) in an effort to prevent abdominal adhesion formation. MATERIALS AND METHODS Real time PCR and a PAI-1 protein activity assay were used in vitro to determine the efficacy of small interfering RNAs (siRNAs). For in vivo experiments, 57 white female rats were operated to generate ischemic and serosal injury to the uterine horns, and treated with saline, siRNA(Lamin A/C) (negative control), siRNA(HIF-1alpha), siRNA(PAI-1), or siRNA(HIF-1alpha) plus siRNA(PAI-1). The cationic polyer poly(ethylenimine) (PEI) was used as the delivery vehicle for all siRNAs delivered in vivo. Adhesions were analyzed by a blinded surgeon 8 days post-surgery. RESULTS After in vitro transfection with siRNA, at least 69% gene down-regulation was obtained for all siRNAs tested. In vitro siRNA-mediated down-regulation of HIF-1alpha, PAI-1 or their simultaneous delivery resulted in a significant decrease of PAI-1 protein activity (at least P < 0.05). Administration of 4 nmol siRNA(HIF-1alpha)/PEI complexes after injury to the uterine horns achieved a statistical reduction of post-operative adhesion formation with a reduction by 52% (P < 0.05). Delivery of 4 nmol siRNA(PAI-1)/PEI complexes and the simultaneous delivery of 2 nmol siRNA(HIF-1alpha) plus 2 nmol siRNA(PAI-1), resulted in a reduction of abdominal adhesion by 36% and 42%, respectively, with the reduction being statistically significant when compared directly to the saline control (P < 0.01). CONCLUSION These data show that administration of siRNA/PEI complexes within the peritoneal cavity can be used to prevent post-operative abdominopelvic adhesions.
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Affiliation(s)
- Tatiana Segura
- Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Bioengineering and Institute of Chemical Sciences and Engineering, Lausanne, Switzerland
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Tingstedt B, Isaksson K, Andersson E, Andersson R. Prevention of Abdominal Adhesions – Present State and What’s beyond the Horizon? Eur Surg Res 2007; 39:259-68. [DOI: 10.1159/000102591] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Accepted: 02/27/2007] [Indexed: 11/19/2022]
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Aarons CB, Cohen PA, Gower A, Reed KL, Leeman SE, Stucchi AF, Becker JM. Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity. Ann Surg 2007; 245:176-84. [PMID: 17245169 PMCID: PMC1876993 DOI: 10.1097/01.sla.0000236627.07927.7c] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES The aims of this study were to determine if statins reduce adhesion formation in vivo and to identify the mechanism of action in vitro. BACKGROUND : Intraperitoneal adhesions develop in up to 95% of patients following laparotomy. Adhesions are reduced by mechanisms that up-regulate fibrinolysis within the peritoneum. Statins promote fibrinolysis in the cardiovascular system and may play a role in the prevention of adhesions. METHODS Adhesions were induced in rats (n = 102) using our previously described ischemic button model. Rats received vehicle (controls), lovastatin (30 mg/kg), or atorvastatin (30 mg/kg) as a single intraperitoneal dose at the time of laparotomy. Animals were killed and adhesions were quantified at day 7. Peritoneal fluid and tissue were collected at day 1 to measure tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) by real-time PCR and ELISA. To assess the effects of statins on wound healing, burst pressures were measured in anastomoses of the colon. The effects of lovastatin on tPA and PAI-1 production were measured in vitro in human mesothelial cells (HMC) in the presence or absence of mevalonate (MVA), geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), all intermediates in the cholesterol pathway downstream of HMG-CoA. The effect of a Rho protein inhibitor, exoenzyme C3 transferase, on tPA production was also determined. RESULTS Lovastatin and atorvastatin reduced adhesion formation by 26% and 58%, respectively (P < 0.05), without affecting anastomotic burst pressure. At 24 hours, tPA mRNA levels in peritoneal tissue and tPA activity in peritoneal fluid from lovastatin-treated animals were increased by 57% and 379%, respectively (P < 0.05), while PAI-1 levels were unchanged. HMC incubated with either lovastatin or atorvastatin showed concentration-dependent increases in tPA production and decreases in PAI-1 production (P < 0.05). These lovastatin-induced changes in tPA and PAI-1 production were significantly reversed by the addition of MVA, GGPP, and FPP. The Rho protein inhibitor increased tPA production and rescued tPA production from the inhibitory effect of GGPP. CONCLUSION These data suggest that statins administered within the peritoneum can up-regulate local fibrinolysis, while the in vitro studies show that this effect may be mediated, in part, by intermediates of the cholesterol biosynthetic pathway that regulate Rho protein signaling.
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Affiliation(s)
- Cary B Aarons
- Department of Surgery, Boston University School of Medicine, Boston 02118, USA
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Cahill RA, Wang JH, Redmond HP. Enteric bacteria and their antigens may stimulate postoperative peritoneal adhesion formation. Surgery 2007; 141:403-10. [PMID: 17349853 DOI: 10.1016/j.surg.2006.09.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2006] [Revised: 09/27/2006] [Accepted: 09/29/2006] [Indexed: 10/23/2022]
Abstract
BACKGROUND Intraabdominal sepsis causes exuberant inflammation, which results in dense adhesions. Translocation of enteric bacteria and/or their antigens after laparotomy may therefore also affect peritoneal healing by promoting local release of proinflammatory cytokines. Our hypothesis was that targeted counter therapy could be beneficial if such contamination was to augment postoperative adhesion formation. METHODS Two endotoxin-hyposensitive mouse strains (C3H/HeJ and C57BL/10ScCr) and their syngeneic counterparts (C3H/HeN and C57BL10/ScSn, respectively) underwent reproducible adhesion-inducing operation (AIO) (n=10/group) with sacrifice and blinded adhesion grading 14 days later. In addition, CD-1 mice were gavaged with fluorescein isothiocyanate labeled-lipopolysaccharide (FITC-LPS) prior to either AIO or sham laparotomy and had both peritoneal macrophages and circulating monocytes assessed by flow cytometry afterward. The cytokine-release response of resident peritoneal cells to LPS stimulation was assessed in vitro (murine peritoneal mast cell cultures) and in vivo (unoperated CD-1 mice administered LPS intraperitoneally [10 & 50 microg/mouse]). Finally, CD-1 mice (n=10/group) had AIO and received either bactericidal/permeability increasing protein (rBPI, 2 mg/mouse) or vehicle solution in the early postoperative period with assessment of adhesion formation 2 weeks later. RESULTS Both HeJ and ScCr mice had less adhesions than their controls (P=.0015 and .0001, respectively, Mann Whitney U test). FITC-LPS uptake by peritoneal macrophages was striking after AIO. Intraperitoneal LPS provoked significant local vascular endothelial growth factor (VEGF) release as did the process of AIO. In vitro, LPS induced significant interleukin-(IL)-6 release from isolated mast cells. Intraperitoneal administration of rBPI to CD-1 mice early after AIO markedly attenuated subsequent adhesion formation (P=.0003). CONCLUSIONS Peritoneal adhesion formation is exacerbated by peritoneal contamination due to translocation after laparotomy and may be attenuated by therapeutic antagonism.
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Affiliation(s)
- Ronan A Cahill
- Department of Academic Surgery, Cork University Hospital and N.U.I (Cork), Ireland
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Gago LA, Saed G, Elhammady E, Diamond MP. Effect of oxidized regenerated cellulose (Interceed) on the expression of tissue plasminogen activator and plasminogen activator inhibitor-1 in human peritoneal fibroblasts and mesothelial cells. Fertil Steril 2006; 86:1223-7. [PMID: 17008148 DOI: 10.1016/j.fertnstert.2006.04.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2005] [Revised: 04/11/2006] [Accepted: 04/11/2006] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To characterize the molecular changes that occur in normal fibroblasts, adhesion fibroblasts, and mesothelial cells as a result of exposure to oxidized regenerated cellulose (Interceed; Johnson & Johnson Medical, Inc., New Brunswick, NJ). DESIGN Control and Interceed-treated normal peritoneal fibroblasts, adhesion fibroblasts, and mesothelial cells in culture were assessed for messenger RNA levels of molecules known to be associated with adhesion development, using multiplex reverse transcriptase polymerase chain reaction (n = 4). SETTING University research laboratory. PATIENT(S) Normal and adhesion fibroblasts and mesothelial cells. INTERVENTION(S) Exposure of cells, normal fibroblasts, adhesion fibroblasts, and mesothelial cells to oxidized regenerated cellulose. MAIN OUTCOME MEASURE(S) Real-time reverse transcriptase polymerase chain reaction expression of messenger RNA tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and tPA-PAI-1 ratio, an indicator of overall fibrinolytic activity. RESULT(S) Interceed treatment of normal peritoneal fibroblasts, adhesion fibroblasts, and mesothelial cells results in an increased expression of tPA in mesothelial cells and an increase in the tPA-PAI-1 ratio, signifying an overall increase in fibrinolytic activity. CONCLUSION(S) Interceed, which has been shown in multiple human in vivo studies to decrease postoperative adhesion development, increases the expression of tPA and the tPA-PAI-1 ratio (an indicator of overall fibrinolytic activity), thereby promoting dissolution of fibrin and healing without adhesion development. Thus, the ability of Interceed to reduce postoperative adhesion development may be derived from both a barrier and biologic effect.
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Affiliation(s)
- L April Gago
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
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Yeo Y, Highley CB, Bellas E, Ito T, Marini R, Langer R, Kohane DS. In situ cross-linkable hyaluronic acid hydrogels prevent post-operative abdominal adhesions in a rabbit model. Biomaterials 2006; 27:4698-705. [PMID: 16750564 DOI: 10.1016/j.biomaterials.2006.04.043] [Citation(s) in RCA: 180] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2006] [Accepted: 04/28/2006] [Indexed: 11/23/2022]
Abstract
We studied the efficacy of an in situ cross-linked hyaluronic acid hydrogel (HAX) in preventing post-surgical peritoneal adhesions, using a rabbit sidewall defect-cecum abrasion model. Two cross-linkable precursors were prepared by modifying hyaluronic acid with adipic dihydrazide and aldehyde, respectively. The hydrogel precursors cross-linked to form a flexible hydrogel upon mixing. The hydrogel was biodegradable and provided a durable physical barrier, which was highly effective in reducing the formation of post-operative adhesions. Ten out of 12 animals in the untreated control group developed fibrous adhesions requiring sharp dissection, while only 2 out of 8 animals treated with HAX gels showed such adhesions, and those occurred in locations that were not covered by the hydrogel. We also studied means by which gel degradation time can be modulated by varying the precursor concentration and molecular weight.
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Affiliation(s)
- Yoon Yeo
- Department of Chemical Engineering, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, 02139, USA
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Bergström M, Falk P, Holmdahl L. Effect of acidosis on expression of mesothelial cell plasminogen activator inhibitor type-1. Surg Endosc 2006; 20:1448-52. [PMID: 16736314 DOI: 10.1007/s00464-005-0283-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2005] [Accepted: 02/15/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND Abdominal mesothelial cells are exposed to carbon dioxide during laparoscopy. Previous data indicate that carbon dioxide increases release and expression of plasminogen activator inhibitor type-1 (PAI-1) and induces acidification. METHODS To assess the impact resulting from a range of pH, human mesothelial cells were exposed to culturing media balanced to pH levels of 6.0 to 8.0 for 90 min. Samples from cell media were withdrawn at several time points. Concentrations of PAI-1 and PAI-1 activity were measured using enzyme-linked immunoassay techniques. To focus on the effect of clinically relevant pH, cells were subjected to pH 6.4 and 7.4. Samples were withdrawn for PAI-1 assessments and for PAI-1 mRNA analyses. RESULTS During exposure to various levels of pH, PAI-1 secretion and activity were variable. However, 5 h after exposure, greater concentration and activity of PAI-1 were observed in acidified cultures. More PAI-1 mRNA was isolated after exposure of cells to a pH of 6.4, apparently indicating transcriptional regulation. CONCLUSIONS Mesothelial cells seem to respond to acidification by an increased release and production of PAI-1 in vitro.
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Affiliation(s)
- M Bergström
- Department of Surgery, Sahlgrenska University Hospital, Göteborg University, S-41685, Göteborg, Sweden
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Boland GM, Weigel RJ. Formation and prevention of postoperative abdominal adhesions. J Surg Res 2006; 132:3-12. [PMID: 16457846 DOI: 10.1016/j.jss.2005.12.002] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2005] [Revised: 11/15/2005] [Accepted: 12/06/2005] [Indexed: 01/17/2023]
Affiliation(s)
- Genevieve M Boland
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Nehéz L, Vödrös D, Axelsson J, Tingstedt B, Lindman B, Andersson R. Prevention of postoperative peritoneal adhesions: effects of lysozyme, polylysine and polyglutamate versus hyaluronic acid. Scand J Gastroenterol 2005; 40:1118-1123. [PMID: 16211718 DOI: 10.1080/00365520510023332] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Intraperitoneal adhesions are an important cause of postoperative intestinal obstruction, abdominal discomfort and infertility. In the present study we hypothesized that a combination of polypeptides with different surface properties, resulting in fine disperse low-soluble complexes, could be of benefit in the prevention of abdominal adhesions. MATERIAL AND METHODS Various polypeptides including lysozyme, polyglutamate, polylysine and combinations of all three were evaluated as compared to hyaluronic acid. A standard wound on the parietal peritoneum in mice was used and the evaluated agents were administered immediately postoperatively. The extent of peritoneal adhesions to the injured area was measured and expressed as a percentage of the wound length as evaluated after 7 days. Flow cytometry was performed to evaluate the effect on peritoneal macrophage survival and phagocytic function and the Pick test was used to determine peroxide production in order to estimate toxicity and potential impairment of macrophage function caused by the chemicals. RESULTS Significant differences were seen among the treatment groups (p<0.001). Both polyglutamate and lysozyme, and polyglutamate together with polylysine significantly decreased adhesion formation as compared to hyaluronic acid. The polylysine-polyglutamate combination was still visible macroscopically on the peritoneal surface after 1 week, though not after 1 month. The polyglutamate-lysozyme mixture was less effective than these individual components alone. The chemicals did not show any toxic effects or altered function in macrophage cell culture. CONCLUSIONS Lysozyme, polyglutamate and, most effectively, a polyglutamate-polylysine combination significantly decreased experimental abdominal adhesion formation. A strong mechanical connection to the wound and prolonged attendance in the surface were noted. Peritoneal phagocyte function did not seem to be influenced by the chemicals.
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