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TISSUE REPAIR


esting recent study (13) demonstrated the relationship between mechanical stretching and the production of various mediators – leukotriene B4 and prostaglandin E2 – in human tendon fibroblasts.


Vascular events The vascular events involve an essential combination of a vasodila- tory response with increased flow volume (although at a lower velocity) and a vasopermeability (increased leakiness) of the ves- sels. These processes are initiated and controlled by a wide array of cytokines and mediators released in cascades. The combined events result in an increase in local flow, production of exudates and a sta- bilisation of the area. As we know, the external signs of the inflam- matory process are largely a result of these events (heat, redness, swelling, pain).


The flow and pressure changes in the vessels allows fluid and the smaller solutes to pass into the tissue spaces as the vessels show a marked increase in permeability to plasma proteins (14,15).


The effect of the exudate is to dilute any irritant substances in the damaged area. Due to the high fibrinogen content of the fluid, a fibrin clot can also form, providing an initial union between the surrounding intact tissues and a meshwork which can trap foreign particles and debris. The meshwork also serves as an aid to phago- cytic activity (see Figure 2). Mast cells in the damaged region release hyaluronic acid and other proteoglycans which bind with the exudate fluid and create a gel which limits local fluid flow, and further traps various particles and debris (16).


Cellular events The early cellular response in the damaged tissue is the attraction and stimulation of a range of phagocytic white blood cells (PMNs). There are a wide range of mediators that initiate and control these events. The role of these cells is essentially debris removal (assum- ing that there is no infection) - to remove the debris and enable the construction of a repair onto a sound foundation rather than build the scar on top of the debris.


Dead and dying cells, fibrin mesh and clot residue all need to be removed. As a ‘bonus’, one of the chemicals released as an end prod- uct of phagocytosis is lactic acid which is one of the stimulants of proliferation – the next sequence of events in the repair process.


KEY POINT


There is scope for the relationship between exercise, lactate production and stimulation of proliferative events to be explored further.


The inflammatory events therefore result in a vascular response, a cellular and fluid exudate, with resulting oedema and phagocytic activation. The complex interaction of the chemical mediators not only stimulates various components of the inflammatory phase, but also stimulates the proliferative phase that follows. The course of the inflammatory response will depend upon the number of cells destroyed, the original cause of the process and the tissue condi- tion at the time of insult. Much as the process has been considered to be disadvantageous, it is in fact both essential and a normal component of repair. The evidence would suggest that without it, repair itself will progress less efficiently, and inhibition of the


10


inflammatory events can lead to inhibition of the repair stages to follow (17-19).


Several recent papers have considered the role of inflammation in relation to tendon injury, tendinopathy and associated problems (20-22). The conflicting views on whether there is (or is not) an inflammatory event in this tissue are well considered in these papers.


Proliferation phase The proliferative phase essentially involves the generation of the repair material, which for the majority of musculoskeletal injuries, involves the production of scar (collagen) material. The prolifera- tive phase has a rapid onset (24-48 hours) but takes considerably longer to reach its peak reactivity, which is usually between 2-3 weeks post injury (21) - the more vascular the tissue, the shorter the time taken to reach peak production. This peak in activity does not represent the time at which scar production is complete, but the time phase during which the bulk of the scar material is formed. The production of a high quality and functional scar is not achieved until later in the overall repair process. In general terms it is usu- ally considered that proliferation runs from the first day or two post-injury through to its peak at 2-3 weeks and decreases there- after through to a matter of several months post-trauma.


The repair process restores tissue continuity by the initial deposi- tion of granulation tissue which matures to form scar tissue. Repair tissue is a connective tissue, distinct right from the onset in sev- eral ways from the connective tissue native to the site (23). Interesting recent developments have identified that in muscle there is a degree of regenerative activity post-trauma, linked to the activation of a mechanosensitive growth factor and subsequent activation of muscle satellite (stem) cells (5). A range of growth factors have been identified as being active in the processes of proliferation, leading again to some new potential treatments (24).


KEY POINT


Blaney Davidson et al (25) have identified for example that there is a relationship between a growth factor (TGF- β) and the capacity of cartilage to repair, and that it is associated (in an animal model at least) with aging whilst Molloy et al (9) have provided a useful review of the role of various growth factors following tendon injury.


Two fundamental processes involved in the repair are fibroplasia and angiogenesis (Figure 3). The function of the fibroblast is to repair the connective tissue (26). Fibroblasts appear to migrate to the area from surrounding tissue. Fibroblastic activation is chemi- cally mediated, and a wide range of such mediators have been iden- tified, including various factors released from the macrophages (eg. MDGFs) during the inflammatory stage. Fibroblasts migrate into the wounded area and proliferate within the first few days after the tis- sue damage. Fibroblastic production of new collagen required to effect the repair is oxygen dependent and low tissue oxygenation will limit the efficacy of the process. Fibroblasts not only produce the required collagen, but also the glycosaminoglycans and proteo- glycans needed for the ‘ground substance’. The bonding of the triple helix collagen molecules and their relative lubrication will influence


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