Tendon healing: can information technology be optimised?

Free

Loading

  1. N Maffulli1,
  2. H D Moller2,
  3. C H Evansiii
  1. 1Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Staffordshire, United kingdom of great britain and northern ireland
  2. 2Orthopaedische Klinik, Medizinische Hochschule im Annastift eastward.V., Hannover, Germany
  3. 3Middle for Molecular Orthopaedics, Harvard Medical School, Boston, MA, USA
  1. Correspondence to:
 Professor Maffulli, Department of Trauma and Orthopaedic Surgery, Keele Academy School of Medicine, North Staffordshire Hospital, Thornburrow Drive, Hartshill, Stoke on Trent, Staffordshire ST4 7QB, Great britain; osa14{at}keele.air-conditioning.uk

Statistics from Altmetric.com

  • tendons
  • healing
  • growth factors
  • cytokines
  • gene therapy

Tendon disorders are a major problem in sports and occupational medicine. Tendons have the highest tensile force of all connective tissue because of a high proportion of collagen in the fibres and their closely packed parallel arrangement in the direction of force. The private collagen fibrils are arranged into fascicles which comprise blood vessels and nerve fibres. Specialised fibroblasts, tenocytes, lie within these fascicles and exhibit high structural organization.i Histologically, they announced as star shaped cells in cross sections. In longitudinal sections, they are arranged in rows following the direction of the tendon fibres. This specialised organization is related to their office, as tenocytes synthesise both fibrillar and not-fibrillar components of the extracellular matrix, and are able to reabsorb collagen fibrils.two The fascicles themselves are enclosed past epitenon. This is surrounded past the paratenon, and the potential space between them is filled by a thin, lubricating film of fluid which allows gliding of the tendon during motion.

BIOLOGY OF TENDON HEALING

Tendon healing is classically considered to occur through extrinsic and intrinsic healing. The intrinsic model produces obliteration of the tendon and its tendon sheath. Healing of the defect involves an exudative and a formative phase which, on the whole, are very similar to those associated with wound healing.iii Extrinsic healing occurs through the chemotaxis of the specialised fibroblasts into the defect from the ends of the tendon sheath.4 The process tin be divided into 3 phases: inflammation, repair, and organisation or remodelling. In the inflammatory phase, occurring three to seven days later on the injury, cells migrate from the extrinsic peritendinous tissue such as the tendon sheath, periosteum, subcutaneous tissue, and fascicles, also as from the epitenon and endotenon.5 Initially, the extrinsic response far outweighs the intrinsic one. This results in the rapid filling of the defect with granulation tissue, tissue debris, and haematoma. The migrating fibroblasts still play a phagocytic role, and are bundled in a radial fashion in relation to the direction of the fibres of the tendon.1 Biomechanical stability is given past fibrin.

The migrated fibroblasts begin to synthesise collagen around solar day five. Initially, these collagen fibres are randomly orientated. Tenocytes become the principal cell blazon, and over the next 5 weeks collagen is continuously synthesised. During the 4th week, a noticeable increase in proliferation of fibroblasts of intrinsic origin, mainly from the endotenon, takes place. These cells take over the main role in the healing process and both synthesise and reabsorb collagen. The newly formed tissue starts to mature, and the collagen fibres are increasingly orientated along the direction of force through the tendon. This phase of repair continues for two months later on the initial injury. Final stability is caused during the remodelling induced by the normal physiological use of the tendon. This further orientates the fibres into the management of force. In improver, cross linking betwixt the collagen fibrils increases the tendon tensile strength. During the repair phase, the mechanically stronger type 1 collagen is produced in preference to type 3 collagen, thus slightly altering the initial ratio of these fibres to increase the strength of the repair.6

Despite intensive remodelling over the post-obit months, complete regeneration of the tendon is never accomplished. The tissue replacing the defect remains hypercellular. The diameter of the collagen fibrils is altered, favouring thinner fibrils with reduction in the biomechanical strength of the tendon.

In tendinopathic and ruptured Achilles tendons, there is a reduction in the proportion of type ane collagen, and a significant increment in the amount of type 3 collagen,seven responsible for the reduced tensile strength of the new tissue which is due to a reduced number of cantankerous links compared with type 1 collagen.8 Recurring microinjuries lead to the development of hypertrophied biologically inferior tissue replacing the intact tendon.

CYTOKINETIC MODULATION OF TENDON HEALING

Growth factors and other cytokines play a cardinal role in the embryonic differentiation of tissue and in the healing of tissues.9 Growth factors stimulate cell proliferation and chemotaxis, and aid angiogenesis, influencing cell differentiation. They regulate cellular constructed and secretory activity of components of extracellular matrix. Finally, they influence the process of wound healing.

In the normal flexor tendon of the canis familiaris, the levels of bones fibroblast growth factor are college than the levels of platelet derived growth cistron (PDGF). In injured tendons, the converse is true.x Nether the influence of PDGF, chemotaxis and the rate of proliferation of fibroblasts and collagen synthesis are increased.11 Fibroblasts of the patellar tendon show increased proliferation in vitro after the administration of basic fibroblast growth factor.12 In addition, an angiogenic effect is evident.13 During the embryogenesis of tendon, os morphogenic proteins (BMP), specially BMP 12 and 13, cause increased expression of elastin and collagen type 1. Besides, animal studies have shown that BMP 12 exerts a positive effect on the healing processes of the patellar tendon.14

The growth factors of the transforming growth gene β superfamily induce an increase in mRNA expression of type one collagen and fibronectin in prison cell culture experiments.xv

Loftier expression of collagen type ane seems to be essential to achieve faster healing of tendons. Consequently, in that location should be a shift from the initial production of collagen type iii to type 1 early in the healing process. The afore mentioned growth factors could potentially be used to influence the processes of regeneration of tendons therapeutically. However, it is unlikely that a unmarried growth factor will give a positive result. The interaction of many factors present in the right concentration at the correct fourth dimension will exist necessary.

Cistron THERAPY TO PROVIDE GROWTH FACTORS

Growth factors have a limited biological half life. Given the complexity of the healing process of tendons, a single awarding of growth factors is unlikely to be successful. As there is no bioavailability of oral proteins, repeated local injections would be necessary to maintain levels in the therapeutic range. This tin can exist technically difficult in operatively treated tendons. The transfer of genes for the relevant growth factors seems an elegant culling.xvi After cellular uptake and expression of genes, a high level of the mediators can be locally produced and secreted.

To achieve this goal, vectors are used enabling the uptake and expression of genes into target cells. Vectors tin be broadly grouped into viral and non-viral. Viral vectors are viruses deprived of their ability to replicate, into which the required genetic cloth tin be inserted. They are constructive, every bit the introduction of their genetic textile into host cells forms function of their normal life wheel. Not-viral vectors take specific characteristics that enable penetration of the nucleus—for example, liposomal transport. The genes are released in the vicinity of the target cells without systemic dilution.

There are two master strategies for transfer using vectors. In in vivo transfer, the vectors are applied directly to the relevant tissue. In vitro transfer involves removal of cells from the trunk, the gene transfer in vitro, and subsequent culture of these cells before they are reintroduced into the target site. Direct transfer is less invasive and technically easier, and can exist started during treatment of the acute phase of the injury. A disadvantage is the non-specific infection of cells during the injection process. In addition, owing to the amount of extracellular matrix nowadays, a vector with high transgenic activity is necessary to be able to transfer the gene to enough cells.

Indirect transfer of genes is safer. The relevant cell type is isolated and genetically modified. Before reintroduction into the body, cells can exist selected and tested for quality. Attributable to the work involved in this technique, information technology would be more suitable for the treatment of degenerative processes rather than acute injuries. The first studies on the feasibility of this procedure take been conducted using marker genes.17 The main factor used, lacZ, codes for the bacterial β galactosidase which is not present in eukaryotic cells.

The add-on of a suitable substrate changes the staining properties of the cells that limited the new gene, enabling the effectiveness of transmission and the duration of expression of the strange cistron to exist ascertained. With the vectors currently available, the gene is expressed for half dozen to 8 weeks in tendon tissue.xviii Using this strategy, the transfer and expression of the PDGF gene into the patellar tendon of rats pb to an increment in angiogenesis and collagen synthesis in the tendon over 4 weeks. Gene expression of this duration could influence the whole healing procedure of tendons and could be the first of an optimised healing process.

In summary, tendon healing, fifty-fifty when successful, does non result in normal tendon. Mostly, the event is functionally satisfactory despite morphological differences and biomechanical weakness compared with a normal tendon. The therapeutic use of growth factors by gene transfer seems promising in the quest to produce a new tendon that is biologically, biomechanically, biochemically, and physiologically "normal".

REFERENCES

  1. ↵

    Maffulli N, Benazzo F. Bones sciences of tendons. Sports Medicine and Arthroscopy Review 2000;8:1–five.

  2. ↵

    Birk DE, Zycband EI, Woodruff Southward, et al. Collagen fibrillogenesis in situ: fibril segments become long fibrils as the developing tendon matures. Developmental Dynamics 1997;208:291–8.

  3. ↵

    Gigante A, Specchia N, Rapali S, et al. Fibrillogenesis in tendon healing: an experimental written report. Bollettino della Societa' Italiana di Biologia Sperimentale 1996;72:203–ten.

  4. ↵

    Wang ED. Tendon repair. Journal of Hand Therapy 1998;11:105–ten.

  5. ↵

    Reddy GK, Stehno-Bittel Fifty, Enwemeka CS. Matrix remodeling in healing rabbit Achilles tendon. Wound Repair and Regeneration 1999;7:518–27.

  6. ↵

    A comparison of the size distribution of collagen fibrils in connective tissues every bit a function of age and a possible relation between fibril size distribution and mechanical properties. Proc R Soc Lond B Biol Sci 1978;203:305–21.

  7. ↵

    Maffulli N, Ewen SW, Waterston SW, et al. Tenocytes from ruptured and tendinopathic achilles tendons produce greater quantities of type III collagen than tenocytes from normal achilles tendons. An in vitro model of human tendon healing. Am J Sports Med 2000;28:499–505.

  8. ↵

    Jozsa L, Reffy A, Kannus P, et al. Pathological alterations in human being tendons. Arch Orthop Trauma Surg 1990;110:15–21.

  9. ↵

    Grotendorst GR. Growth factors equally regulators of wound repair. Int J Tissue React 1988;x:337–44.

  10. ↵

    Duffy FJ Jr, Seiler JG, Gelberman RH, et al. Growth factors and canine flexor tendon healing: initial studies in uninjured and repair models. J Manus Surg [Am] 1995;20:645–9.

  11. ↵

    Pierce GF, Tarpley JE, Tseng J, et al. Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds. J Clin Invest 1995;96:1336–50.

  12. ↵

    Chan BP, Chan KM, Maffulli N, et al. Effect of basic fibroblast growth factor. An in vitro written report of tendon healing. Clin Orthop 1997;342:239–47.

  13. ↵

    Gabra Due north, Khayat A, Calabresi P, et al. Detection of elevated bones fibroblast growth factor during early hours of in vitro angiogenesis using a fast ELISA immunoassay. Biochem Biophys Res Commun 1994;205:1423–30.

  14. ↵

    Enzura Y, Rosen 5, Nifuji A. Induction of hypertrophy in healing patellar tendon by implantation of human recombinant BMP 12. J Bone Miner Res 1996;11:401

  15. ↵

    Ignotz RA, Massague J. Transforming growth cistron-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 1986;261:4337–45.

  16. ↵

    Moller Hard disk, Evans CD, Robins PD, et al. Factor therapy in orthopaedic sports medicine. In: Chan KM, Fu FH, Maffulli N, et al, eds. Controversies in orthopaedic sports medicine. Hog Kong: Williams and Wilkins, 1988:577–88.

  17. ↵

    Lou J, Manske PR, Aoki M, et al. Adenovirus-mediated gene transfer into tendon and tendon sheath. J Orthop Res 1996;14:513–17.

  18. ↵

    Nakamura N, Shino M, Natsuume T, et al. Early on biological result of in vivo factor transfer of platelet-derived growth factor (PDGF)-B into healing patellar ligament. Gene Therapy 1998;5:1165–70.

View Abstract

Request Permissions

If you wish to reuse any or all of this article please use the link beneath which will take you to the Copyright Clearance Centre'south RightsLink service. You will be able to get a quick toll and instant permission to reuse the content in many different ways.

Copyright information:

Copyright 2002 British Periodical of Sports Medicine