Biologics for tendon repair

Abstract

Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.

Keywords: Cell-based therapy; Embryonic stem cells; Gene therapy; Growth Factors; Mesenchymal stem cells; Natural biomaterials; Tendon; Tendon repair; Tendon-derived cells.

Fig. 1

A schematic drawing of basic tendon structure. The collagen molecules are organized hierarchically in fibrils, fibers and fascicles. The cellular content is dominated by the tenocytes, which are terminally differentiated cells. Tendons contain stem and progenitor cell populations, whose exact location is still debated (therefore indicated with a?). Different sheets, endotenon and epitenon (loose connective tissues), and paratenon (fatty areolar tissue) are shown as well as blood vessels and nerves. Based on [227].

Fig. 2

The tendon repair process in humans. The healing of ruptured tendons passes through three main phases containing distinctive cell and molecular cascades. These phases overlap and their duration depends upon the location and severity of the tendon injury. Currently, the tendon research field is actively exploring the use of growth factors, genes, stem cells and biomaterials, alone or in various combinations, for enhancing tendon healing. Mostly, the appropriate times of application are in the first two stages (indicated by white arrows), and depend on the type of growth factors, genes, stem cells or biomaterials implemented. Based on [47].

Fig. 3

Key molecular, cellular and matrix changes occurring during the three main phases of tendon repair. Each healing stage is characterized by involvement of different growth factors, activation of certain cell types and production of essential matrix proteins, which collectively contribute to the replacement of the initial fibrous tissue with more a tendonous regenerate. Based on [45,46].

Fig. 4

Studies on the use of biologics for tendon repair. Article counts were carried out after searching in PubMed using the following key words: tendon repair/healing in combination with growth factors, stem cells, biomaterials and gene therapy. The articles include in vivo and in vitro studies, and some articles scored in more then one category. The search results demonstrate that in the last decade the tendon research field has progressively expanded as represented by the continuous increase in the number of articles focusing on different strategies for enhancing tendon tissue healing. Such cumulative efforts may lead to the development of efficient biologics for tendon repair.