Postsurgical abdominal adhesions have a great impact on the quality of life of millions of people worldwide. Small bowel obstruction and others complications of adhesions are serious, causing not only morbidity but also mortality [8, 21]. Adhesions are non-anatomic connections of fibrous tissue within normal peritoneal surfaces . It may have a potential benefit, including neovascularization of ischaemic structures such anastomoses, but it is also responsible for various clinical problems .
The abdominal formation of fibrin is a common pathophysiological pathway for adhesions. Fibrin is formed after peritoneal injury, which can cause fibrinous adhesion. If the fibrinolytic system, which results in lysis of abdominal fibrin, is not activated, the adhesions will become fibrous . This can be explained when the equilibrium between coagulation and fibrinolysis is disturbed [24–26]. Our present study confirmed this by the evidence of more collagen I fibers observed in the abdominal adhesions animal model than in the vehicle group.
Apart from the formation of fibrin, a complex interaction of biochemical components, including inflammation, fibrinolysis and wound healing, is involved in the pathological process of abdominal adhesions . For instance, initially the deposition of fibrin is regulated and maintained by growth factors and cytokines . After the first week and up to a month, the matrix is remodeled and replaced by persistent proteins, such as collagen, and revascularization occurs. Fibrinolysis stimulators, such as tissue plasminogen factor (t-PA), and urokinase and fibrinolysis inhibitors, such as plasminogen activator inhibitor type I (PAI-1), transforming growth factor (TGF)-β, a key molecular mediator of pathological fibrosis, have also been shown to play a role in adhesions pathogenesis [29, 30]. The interrelationship between all the factors remains largely unknown, therefore, identifying the effective treatment or prevention for abdominal adhesions remains a big challenge.
Numerous approaches have been used to prevent adhesions . The three main principle pathways are: (1) decreasing the trauma to the peritoneum; (2) medical intervention in the fibrin formation/degradation balance, and (3) barriers (including fluid barrier and membranes) preventing organs from bridging over to other structures in the abdomen and thereby forming adhesions. Unfortunately none of these measures have proven uniformly effective under all surgical conditions. Barrier products, including hyaluronic acid-carboxymethyl cellulose membrane have been the most clinically successful in reducing adhesions formation by preventing the close apposition of injured tissues. However, treatment with these products induced many side effects, such as postponing wound healing. Furthermore, many treated models have a high standard deviation, which makes the relevance of results with only moderate effects questionable.
Penicillamine can decrease the permeability of vessels by inhibiting aggregation of platelets, stabilizing lysosome and inhibiting releasing of lysomal enzymes. It can also attenuate immune reaction and decrease blood disk effusion and fibrin deposition by inhibiting generation of IgG and IgM and decreasing antigen-antibody complex in blood-serum, which blocks the first stage of abdominal adhesions. It is reported that D-penicillamine administration markedly reduces severe adhesions band formation without severe side effects . Therefore, we hypothesized, based on these results, that a combination of penicillamine and barrier products may be a better treatment for adhesions.
In the present study, we developed a novel penicillamine- bound membrane, which used hyaluronic acid as the ideal substrate, and then found that both penicillamine and penicillamine-bound membrane have better therapeutic effects on preventing abdominal adhesions than Dextran (Dex), sodium hyaluronate (SH) and non-penicillamine-bound membrane. Both of them did not affect wound healing. Although they decreased the breaking strength of incision insignificantly at postsurgical day 7 but, this decrease was ameliorated at postsurgical day 14. Penicillamine-bound membrane showed greater benefits than penicillamine itself in preventive effects and local administration. Recent studies investigated that penicillamine can inhibit blood vessel hyperplasia, which plays an important role in adhesions generation, by inhibiting the proliferation of endangium and smooth muscle cell, and this was confirmed by our results.