Principal investigator: Monica Wiig
Flexor tendon surgery. Prevention of adhesion formations.
The main objective of our research is to develop a novel drug for the prevention of post-surgical adhesion formation to benefit the patients and the society. To do that we need to understand the mechanism of how adhesions develop and parallel work with the development of new drugs to prevent adhesion formation. Adhesions comprise scar-tissue that connects anatomic structures that should not normally be connected. Such adhesions develop when the body’s repair mechanisms respond to tissue injury as the result of surgery, trauma or infection. Adhesions form after almost any type of surgery and are a significant source of post-surgical complications. In addition, adhesions prolong subsequent surgery and constitute a considerable burden on the healthcare systems. The inflammatory response following flexor tendon repair surgery results in the formation of peritendinous adhesions between the tendon and tendon sheath or adjacent tissues. Adhesions restrict the gliding function of the tendon and limit the range of motion of the injured digit. The formation of adhesions has long been recognized as a particular problem for zone I and II flexor tendon injuries and inhibition of adhesion formation is considered to improve outcome with respect to range of motion. Other surgical specialities associated with complications related to adhesion formation include; shoulder, knee, abdominal, gynaecological, sinus, cardiac and peripheral nerve surgery.
The process of tendon healing is complex and involves both extrinsic and intrinsic mechanisms. The balance between intrinsic and extrinsic healing components may determine the ultimate tendon strength and extent of adhesion formation and is therefore of interest to characterize further. In a rabbit model of flexor tendon injury, we have identified tissue- and temporalspecific aspects to the flexor tendon healing process for factors involved in remodelling, inflammatory response and fibrosis. We have also studied changes in mRNA expression of neuropeptides and factors involved in angiogenesis.
Recently, a new therapeutic option has emerged in the form of a synthetic peptide (PXL01) structurally derived from human lactoferrin. We have demonstrated the anti-adhesion effect of PXL01 in experimental models, and the peptide has been shown to be safe in a recently conducted Phase I study. PXL01 exhibits broadspectrum antimicrobial properties and is shown to down-regulate inflammatory cytokines. PXL01 also inhibits plasminogen activator inhibitor type 1 (PAI-1), which is expected to increase the fibrinolytic activity after surgery and is suggested to be an additional mechanism for these peptides to reduce excessive scarring It is presently unclear, though, which of these activities that are important for the observed anti-adhesion effect in vivo.
The work plan is to use the animal model that we have developed and used in earlier studies. The rabbit model is highly relevant for the human situation, regarding the anatomy, biochemistry and molecular biology of the tendons, tendon sheath etc.
During the healing process after surgery the formation of adhesions between the tendon and the tendon sheath makes the tendon unable to move freely in the sheath and the following decreased mobility of the digit can be measured biomechanically and we can thereby grade the adhesion formations.
We will also look at the mechanism of action for the test substance by extract and measure mRNA for different inflammatory cytokines and genes participating in the fibrinolytic process in the tendon and tendon sheath at different time points after surgery.
During 2011 we started a clinical trial as a multi centres study. The hypothesis is that the test substance, PLX01, inhibits the formation of adhesions and thereby increases the mobility after trauma and surgery.
Members of the group during 2010
Ylva Gollbo Foucard