ORIGINAL ARTICLES A Novel Polypeptide Derived From Human Lactoferrin in Sodium Hyaluronate Prevents Postsurgical Adhesion Formation in the Rat Elin Nilsson, MSc,* Camilla Bjo ¨rn, MSc,* Veronika Sjo ¨strand, MSc,* Kerstin Lindgren, BSc,* Mattias Mu ¨nnich, MSc,* Inger Mattsby-Baltzer, PhD,† Marie-Louise Ivarsson, MD, PhD,‡ Kjell Olmarker, MD, PhD,*§ and Margit Mahlapuu, PhD* Objective: The objective of the study was to evaluate whether a peptide derived from human lactoferrin, PXL01 could act safely to reduce the formation of peritoneal adhesions in the rat model and to map the molecular mechanisms of its action. Summary Background Data: Adhesion formation is a significant problem within every surgical discipline causing suffering for the patients and major cost for the society. For many decades, attempts have been made to reduce postsurgical adhesions by reducing surgical trauma. It is now believed that major improvements in adhesion prevention will only be reached by devel- oping dedicated antiscarring products, which are administrated in connection to the surgical intervention. Methods: Anti-inflammatory as well as fibrinolytic activities of PXL01 were studied in relevant human cell lines. Using the sidewall defect-cecum abrasion model in the rat, the adhesion prevention properties of PXL01 formulated in sodium hyaluronate were evaluated. Large bowel anastomosis healing model in the rat was applied to study if PXL01 would have any negative effects on intestine healing. Results: PXL01 exhibits an inhibitory effect on the most important hall- marks of scar formation by reducing infections, prohibiting inflammation, and promoting fibrinolysis. PXL01 formulated in sodium hyaluronate mark- edly reduced formation of peritoneal adhesions in rat without any adverse effects on wound healing. Conclusions: A new class of synthetically derived water soluble low molecular weight peptide compound, PXL01 showed marked reduction of peritoneal adhesion formation in an animal model without any negative effects on healing. On the basis of these data, a comprehensive adhesion prevention regimen in clinical situation is expected. (Ann Surg 2009;250: 1021–1028) P eritoneal adhesions are fibrous tissue connections forming be- tween abdominal structures after surgical trauma or other types of injury. General abdominal, vascular, gynecological, urological, and orthopedic surgery may lead to adhesion formation in up to 95% of the patients. 1–3 Postsurgical adhesions are considered the main cause of small bowel obstruction, 4 a well-known etiology of sec- ondary infertility in females 5 as well as a possible cause of postop- erative pain. 6 More than 30% of the individuals undergoing lower abdominal surgery are readmitted for disorders related to adhesion formation at some period during their life time. 1,2 For many decades, attempts have been made to reduce post- surgical adhesions by reducing surgical trauma (avoiding desicca- tion, gentle tissue handling, and meticulous hemostasis) as well as by avoiding contamination of the abdominal cavity with foreign materials (using starch-free gloves, lint-free gauze, and absorbable sutures). 3,7,8 Importantly, the laparoscopic techniques have shown not to be sufficient to overcome the problem of postoperative adhesion formation. 9,10 Thus, intraperitoneal adhesions remain a major clinical issue, and it is now believed that future improvements may only be marginally influenced through superior surgical tech- nique. Instead, the focus is to develop dedicated products for prevention of adhesion formation, which are administrated in con- nection to the surgical intervention. Most of the therapeutic strategies tested in prevention of adhesions are medical device products. Different types of physical barriers have been evaluated, where the biodegradable films applied during the intervention are used to keep the injured abdominal surfaces separated during the critical period of peritoneal healing. The 2 most widely used adhesion-reducing barriers are Seprafilm (Genzyme, Cambridge, MA) and Interceed (Johnson & Johnson MedicalInc., Arlington, TX). Seprafilm, composed of sodium hyal- uronic acid and carboxymethylcellulose (CMC), forms a viscous gel approximately 24 to 48 hours after application, and is slowly resorbed within 1 week. 11,12 Seprafilm has been shown to reduce postsurgical adhesion in clinical situation. 13–15 However, the device is difficult to apply, as it adheres to gloves and organs, and as it is brittle. 16 Additionally, Seprafilm increases the risk of sequelae associated with anastomosic leakage and is not compatible with laparoscopic procedures. 17 Interceed, composed of oxidized regen- erated cellulose, is transformed into a gelatinous mass covering the injured peritoneum and has shown efficacy in adhesion-prevention in several clinical studies. 18 –20 However, application of Interceed requires complete hemostasis as even small amounts of intraperito- neal bleeding negates any beneficial effect of this barrier. 16 A general limitation of using the physical barriers is the site-specificity of the product, requiring the surgeon to predict where adhesions will occur and where they would most likely cause clinical problems. As an alternative to physical barriers, different fluids for intra-abdominal instillation such as icodextrin (Adept, Baxter Healthcare Corporation, IL) or lactated Ringers’s solution, have been administrated after the surgery in volumes sufficient to allow floatation of the abdominal structures and thus preventing the injured surfaces from adhering to each other. 17,21–24 However, it has been shown that laparoscopically instilled fluids are absorbed more rapidly from the abdominal cavity than the time required for peri- toneal healing. 25 A limited number of pharmacologically active compounds have been tested for prevention of postsurgical adhesions. For From the *PharmaSurgics AB, Gothenburg, Sweden; †Department of Infectious Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ‡Department of Surgery, Sahlgrenska University Hospital/O ¨ stra, University of Gothenburg, Gothenburg, Sweden; and §Division of Orthopae- dics, Department of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. The authors Elin Nilsson and Camilla Bjorn contributed equally to the work in this manuscript. Supported by Pharmasurgics AB, Gothenburg, Sweden. All authors are founders or employees of Pharmasurgis AB, Gothenburg, Sweden except for M-L Ivarsson who received no benefits in the preparation of this study. Reprints: Margit Mahlapuu, PhD, Pharmasurgics AB, Arvid Wallgrens Backe 20, 413 46 Go ¨teborg, Sweden. E-mail: margit.mahlapuu@pharmasurgics.se. Copyright © 2009 by Lippincott Williams & Wilkins ISSN: 0003-4932/09/25006-1021 DOI: 10.1097/SLA.0b013e3181b246a7 Annals of Surgery • Volume 250, Number 6, December 2009 www.annalsofsurgery.com | 1021