Page 21 - ISAKOS Newsletter 2016 Volume 1

Genetics and Pathogenesis of Rotator Cuff Healing: The Race is Long!
Carina Cohen, MD
Federal University of São Paulo, BRAZIL
Degenerative rotator cuff tears are a frequent cause of shoulder pain that may lead to severe impairment of function, therefore rotator cuff repair is a very commonly performed orthopedic procedure. However, re-tear rates after the tendon repair is high, reported to be around 20% and even greater than 90% in massive tears. Not all repaired tendons heal completely but residual defects or retears after repair can be asymptomatic.
There are multiple factors that affect the outcome of cuff tearing and healing process. We will review the pathogenesis and genetic factors involved in rotator cuff tears to look for solutions that address the biological aspects of the disease.
The normal bone-to-tendon interface involves the interdigitation of layers of intact, oriented Type I collagenous fibers to a continuous insertion on the humerus. Longitudinally, there are four distinct zones of tissue: tendon, nonmineralized fibrocartilage, mineralized fibrocartilage, and bone. When the tendons within the rotator cuff begin to degenerate, the collagenous fibers undergo hyaline and myxoid degeneration, and the bone undergoes chondroid metaplasia. Inflammation, calcification, vascular proliferation, and fatty infiltration are also present. These degenerative changes are often macroscopically visible at the site of rupture during surgical repair and are also present throughout the damaged tendon suggesting the degenerative process happens not only locally.
In normal bone-to-tendon healing and also after surgical repair there are three stages (inflammatory, repair stage, and remodeling), however the four fibrocartilagenous zones are not recreated since the bone and tendon are joined by a layer of fibrovascular scar tissue predominated by Type III collagen. This tissue is weaker than the original insertion site which makes repairs prone to failure. Tissue healing in adults with a competent immune system is characterized by fibrosis rather than regeneration of normal tissue structure and composition due to a number of inflammatory mediators (such as cytokines) and pathways that affect the process.
Growth factors are a group of cytokines that have been implicated in the repair stage of natural bone-to-tendon healing, such as the cytokines basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), platelet- derived growth factor β (PDGF- β) and transforming growth factor beta (TGF-β. In general, these growth factors induce mitosis, extracellular matrix production, neovascularization, cell maturation, and differentiation. Research has focused on their ability to augment rotator cuff repairs showing that several growth factors are capable of increasing the strength of repairs in animal models. However, the strengthening is accomplished through the production of more scar tissue, as opposed to regeneration of native tissue so is not clear whether it really improves quality.
Although many growth factors and cellular processes have been identified in the normal bone-to-tendon healing process, each growth factor has a multitude of functions and interactions, and it is unlikely a great change will be observed through application of individual growth factors. Therefore, there is a great amount of interest in the creation of “platelet- rich plasma” (PRP) by centrifuging autologous blood to purify a dense, suturable plasma matrix. PRP includes high platelet concentration that provides a release of many growth factors and bioactive molecules identified previously as crucial in normal bone-to-tendon healing: TGF-β, bFGF, PDGF, vascular endothelial growth factor, connective tissue growth factor, and epidermal growth factor.
The safety of PRP augmentation to rotator cuff repair has been investigated but PRP has yet to prove itself as a useful augment to rotator cuff repair. There are 16 controlled studies about PRP, but is very hard to compare them as they have different study designs, tear sizes, surgical technique of cuff repair (double row, single row, transosseous repair), biologic characteristics of PRP (presence or absence of white cells and whether it is used activated by trombin or in the inactivated form), devices used (since different devices produce different concentrations), and method used for application – either by direct injection or by incorporation of platelet rich fibrin matrix into the repair.
The latest Cochrane systematic review and meta-analysis found no benefit attributable to PRP for short-, medium-, or long-term function. It showed improvement in Constant Score at one year follow-up but not statistically significant. Short-term improvements in pain were identified but the effect sizes were small, and unlikely to be clinically important. Based on this review, PRP use is currently unsupported. These results are similar to other previous systematic reviews and meta-analyses on this subject. Growth factor therapy for rotator cuff repairs remains a promising therapy for the future; however, much work needs to be done to optimize its effectiveness. The optimal timing and vehicle for growth factor delivery have remained elusive.
CURRENT CONCEPTS
ISAKOS NEWSLETTER 2016: Volume I 19