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      Biologics for tendon repair ☆

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          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.

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          Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.

          Yanming Bi, Driss Ehirchiou, Tina Kilts … (2007)
          The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
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            Structure of the tendon connective tissue.

            P Kannus (2000)
            Tendons consist of collagen (mostly type I collagen) and elastin embedded in a proteoglycan-water matrix with collagen accounting for 65-80% and elastin approximately 1-2% of the dry mass of the tendon. These elements are produced by tenoblasts and tenocytes, which are the elongated fibroblasts and fibrocytes that lie between the collagen fibers, and are organized in a complex hierarchical scheme to form the tendon proper. Soluble tropocollagen molecules form cross-links to create insoluble collagen molecules which then aggregate progressively into microfibrils and then into electronmicroscopically clearly visible units, the collagen fibrils. A bunch of collagen fibrils forms a collagen fiber, which is the basic unit of a tendon. A fine sheath of connective tissue called endotenon invests each collagen fiber and binds fibers together. A bunch of collagen fibers forms a primary fiber bundle, and a group of primary fiber bundles forms a secondary fiber bundle. A group of secondary fiber bundles, in turn, forms a tertiary bundle, and the tertiary bundles make up the tendon. The entire tendon is surrounded by a fine connective tissue sheath called epitenon. The three-dimensional ultrastructure of tendon fibers and fiber bundles is complex. Within one collagen fiber, the fibrils are oriented not only longitudinally but also transversely and horizontally. The longitudinal fibers do not run only parallel but also cross each other, forming spirals. Some of the individual fibrils and fibril groups form spiral-type plaits. The basic function of the tendon is to transmit the force created by the muscle to the bone, and, in this way, make joint movement possible. The complex macro- and microstructure of tendons and tendon fibers make this possible. During various phases of movements, the tendons are exposed not only to longitudinal but also to transversal and rotational forces. In addition, they must be prepared to withstand direct contusions and pressures. The above-described three-dimensional internal structure of the fibers forms a buffer medium against forces of various directions, thus preventing damage and disconnection of the fibers.
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              Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.

              Melissa A Baxter, Robert Wynn, Simon Jowitt … (2004)
              Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long-term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 8710523
                Journal ID (pubmed-jr-id): 21484
                Journal ID (nlm-ta): Adv Drug Deliv Rev
                Journal ID (iso-abbrev): Adv. Drug Deliv. Rev.
                Title: Advanced drug delivery reviews
                ISSN (Print): 0169-409X
                ISSN (Electronic): 1872-8294
                Publication date Nihms-submitted: 21 July 2015
                Publication date (Electronic): 21 November 2014
                Publication date (Print): April 2015
                Publication date PMC-release: 01 April 2016
                Volume: 84
                Pages: 222-239
                Affiliations
                [a ] Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig Maximilians University, Nussbaumstr. 20, 80336 Munich, Germany
                [b ] Department of Orthopedic Surgery, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland
                [c ] Rehabilitation Medicine Research Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
                Author notes
                [* ] Corresponding author. Tel.: +49 89 44005 5486; fax: +49 89 44005 5489. denitsa.docheva@ 123456med.uni-muenchen.de (D. Docheva).
                Article
                Manuscript ID: NIHMS709062
                DOI: 10.1016/j.addr.2014.11.015
                PMC ID: 4519231
                PubMed ID: 25446135
                SO-VID: 392a6f8a-7132-4246-8e20-6f0715a88ca1
                License:

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Categories
                Subject: Article

                Keywords: tendon,tendon repair,growth factors,cell-based therapy,mesenchymal stem cells,embryonic stem cells,tendon-derived cells,natural biomaterials,gene therapy
                Data availability:
                Keywords: tendon, tendon repair, growth factors, cell-based therapy, mesenchymal stem cells, embryonic stem cells, tendon-derived cells, natural biomaterials, gene therapy

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