Formation and Prevention of Postoperative Abdominal Adhesions

Genevieve M. Boland; Ronald J. Weigel

doi:10.1016/j.jss.2005.12.002

The formation of postoperative abdominal adhesions is a major cause of morbidity, resulting in multiple complications many of which manifest dozens of years after the initial inciting event and add up to millions of dollars worth of hospital costs [1, 2]. The field of surgical research has been interested in finding a means of preventing the formation of postsurgical adhesions and the history of preventive strategies goes back for more than 100 years [3]. Yet, despite much interest in prevention, the formation of peritoneal adhesions continues to be a significant and common side effect of intra-abdominal surgery. Currently there are no definitive strategies that are being used to prevent the formation of peritoneal adhesions. Historically, there have been major difficulties in assessing and comparing the adhesion literature, since there has been no single consistent model of adhesion formation and no standard and reliable means of measuring adhesion formation (i.e, number, surface area, or strength of adhesions). Additionally, there has been much variability in the results from different animal models and between the different means of inducing peritoneal injury. The lack of standardization has made the comparison of studies a challenge and makes the translation of this information into reasonable clinical interventions difficult to justify. In vitro studies have been limited by the two-dimensional culture systems, which are not adequate to address the complicated three-dimensional architecture involved in the formation of fibrous bands. Recently, several models of peritoneal tissue culture have been described that may hold promise for studying the complex behavior of peritoneal cells and may be useful in addressing some of the initial basic science questions required before in vivo studies are performed [4, 5]. In order for a given intervention to be deemed successful, it must be quantifiable by some measurement of success (e.g., visual analysis via laparoscopy, ultrasonography, CT/MRI imaging, or specific serum markers). Recently, an MRI approach has shown some success in visualizing adhesions [6], potentially offering a noninvasive means of assessing postoperative adhesion formation and the success of various interventions. To date, there are no serum markers that have been directly and consistently correlated with the process of pathological wound healing and adhesion formation (e.g., transforming growth factor beta (TGF-β) isoforms, hyaluronic acid, fibronectin proteins, or fragments), and this too has limited our ability to measure and assess both healing and adhesion formation, as well as gauge the efficacy of potential preventative strategies. Finally, the field of adhesion-related research has been limited by the fact that correlating a given intervention with a decrease in morbidity and complications secondary to the presence of adhesions is very difficult, particularly since the time horizon for these types of studies is very long. With such a daunting task, it is not a mystery why the solution to this seemingly simple problem has remained illusive for so long. In terms of clinical interventions, adhesion prophylaxis is a very appealing therapeutic target since the window of time for a successful intervention is relatively small (on the order of 5-7 days). The relatively short time requirement for adhesion prevention avoids the need for ongoing treatments and minimizes concerns over the long-term side effects of various biomaterials or therapeutic drugs to be used. Applying an agent intra-abdominally at the time of operation allows one to target an intervention at the specific site of action of the pathological process and thereby avoids the difficulties of therapeutic homing or potential systemic effects since the therapies can be applied directly where needed. An optimal adhesive barrier should be easy to apply in the operating room (e.g., sprayable), have the appropriate chemical and physical properties and kinetics (e.g., dissolve after 1-2 weeks), be nontoxic and biocompatible, and contain targeted biological signals (e.g., growth factors, growth factor inhibitors, adhesive sequences, etc.). The combination of the optimal materials with specific biological targets has the potential to be a high-yield strategy when based upon an in-depth and thorough understanding of the processes at work in the postoperative abdomen. Overview of Peritoneal Healing and Adhesion Formation: Before the action of various adhesio-preventive strategies can be assessed, the key components and interactions involved in the process of peritoneal healing itself must be thoroughly understood. At the time of surgery, the initial mesothelial injury exposes a denuded and acellular surface that serves as the nidus for wound healing and/or tissue-tissue adhesion. This submesothelial damage and unveiling of the submesothial matrix occurs with simultaneous activation of the coagulation cascade and deposition of fibrin at the site of injury. Under normal conditions, this fibrinous exudate serves as a platform for appropriate healing to progress, but under certain pathologic circumstances, the deposited fibrin can instead serve as a bridge between unrelated, neighboring tissues. Within a very short period of time, the wound and its surrounding area are invaded by inflammatory cells that migrate from the peritoneal vasculature or from the peritoneal fluid itself. The inflammatory exudate is initially composed of neutrophils, but by 24 h the predominant cell has become the macrophage. Next, the injured wound surface is evenly reperitonealized by the combined effort of multiple foci of proliferating mesothelial cells. Reperitonealization continues for 7 to 10 days in which time the entire surface becomes covered by a contiguous sheet of mesothelium (as very nicely reviewed in [7]). This process differs markedly from the annular ingrowth of peripheral epithelial cells that occurs in dermal or cutaneous wound healing. Interestingly, in the abdomen, the speed of reperitonealization remains the same (7-10 days), regardless of the initial wound size since it is not limited by the rate of migration of cells from the periphery. To date, the origin of replacement mesothelial cells remains a topic of controversy, although there are several interesting theories explaining their origin. Regardless of their source, the presence of these cells at the wound site corresponds to progressive wound healing and/or fibrosis and the deposition of an extracellular matrix (ECM) composed of fibronectin, hyaluronic acid, various glycosaminoglycans (GAGs), and proteoglycans (PGs). The process of ECM deposition is directed by and maintained through the action of various growth factors and cytokines including TGF-β, EGF, VEGF, IGF, and FGF. Finally, the deposited matrix is strengthened and remodeled over time (1 week to 1 month). As the cells realign, the temporary ECM molecules are replaced by more permanent proteins such as collagens, while revascularization continues. © 2006 Elsevier Inc. All rights reserved.

Formation and Prevention of Postoperative Abdominal Adhesions

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