Tissue repair consists of a complex series of tissue and cellular reactions that allow the body to carry out a functional recovery of the tissues that have been damaged. There is a large literature on tissue repair and there are several topics that have aroused great interest over time and are above all that concerning the growth factors that influence and control the various processes and what concerns the angiogenic role as an essential component of repair.

PHASES OF TISSUE REPAIR

The tissue repair process is complex and unquestionably efficient. Its division into phases serves to help understand such an event with such a complex series of events. In reality these events overlap, follow each other and are largely independent. In the literature there are several disputes about the timing of each event, due to the fact that in some subjects, in relation to the extent of the damage, they will move more easily, and in others less.


  • Bleeding phase: This is a relatively short phase that occurs immediately following injury, trauma or other similar insults. If there has been damage to the soft tissues, there will be bleeding. The normal time for bleeding to stop varies based on the nature of the injury and the nature of the tissue in question. The more vascularized a tissue (for example a muscle) the longer it will bleed and there will be more blood loss in the tissues. The less vascularized the tissue (eg ligament) the less blood there will be (both in terms of duration and volume). It is normally considered that the interval between the injury and the end of bleeding is in terms of a few hours (6-8 hours on average). Some tissues will continue to bleed for a significantly long period, albeit in a significantly unimportant manner. An injury to more vascularized tissue, such as muscle, may still bleed 24 hours or more after the injury. Any surgery that had the ability to increase blood flow during this period would be inappropriate. Short cold applications can be very effective if the cold source is not left in place for a time which then results in a vasodilator response. Recently, more and more attention has been placed on the ability of cold therapies to reduce the amount of secondary dead cells due to local hypoxia.


  • Inflammatory phase: The inflammatory phase is an essential component of the tissue repair process. The inflammatory phase has a rapid onset (a few hours) and gently decreases in size from its maximum reaction (2-3 days) before gradually resolving (over the next two weeks). The complex chemically mediated cascade that is responsible for both promoting and controlling the inflammatory response can be promoted by numerous events, one of which is trauma. Mechanical irritation, thermal or chemical insult, and a large variety of immune responses are just some of the alternative initiators, and for a large number of patients who experience an inflammatory response in musculoskeletal tissues, these are more readily identified as causes. There are two essential elements in inflammatory events, and they are the vascular cascade and the cell cascade. A key point is that these happen in parallel and are significantly correlated. The chemical mediators that actively contribute to this process are manifold. In recent years, the identification of numerous growth factors have led to important discoveries and potential new lines of treatment. Some of these mediators directly contribute to perceived pain at the injury site, such as interleukin-1 and tumor necrosis factor-alpha released by macrophages. A very interesting recent study demonstrated the relationships between mechanical stretching and the production of different mediators (leukotriene B4 and prostaglandins n E2) in human tendon fibroblasts.


  • Vascular Events: Vascular events involve an essential combination of a vasodilatory response with increased volume of flow (however at a slow rate) and vasopermeability (increased fragility) of the vessels. These processes are promoted and controlled by a large array of cytokines and cascade-released mediators. The combined events result in an increase in local flow, exudate production and stabilization of the area. As is well known, the external signs of the inflammatory process are largely a result of these events (heat, redness, swelling, pain). The flow and pressure variation in the vessels allows fluid and small solutes to pass into the intertissue spaces as the vessels show an increase in permeability to plastic proteins. The purpose of the exudate is to dilute any irritating substance in the damaged area. Thanks to the high content of fibrinogen in the fluid, a fibrin coating can form which provides an initial union between the surrounding intact tissues and a texture that can trap foreign particles and debris. The plot also serves as an aid to phagocyte activity. The mast cells in the injured region release hyaluronic acid and other proteoglycans which envelop the exudate and create a gel that limits the local fluid flow, and later traps various particles and debris.


  • Cellular events: The first cellular response in the injured tissue is the attraction and stimulation of a range of phagocytes with white blood cells. There is a wide range of mediators who promote and control these events. The role of these cells is essentially the removal of debris (assuming there is no infection), to remove the debris and allow the construction of a shelter, a basal layer, rather than building the scar over the debris. Dead and dying cells, fibrin texture and residual coating all need to be removed. As a 'bonus' one of the chemical agents released as the end product of phagocytosis is lactic acid which is one of the proliferation stimulants - the next sequence in the repair process. However, the inflammatory events are the result of a vascular response, a fluid and cellular exudate, with edema and activation of phagocytes. The complex interaction of chemical mediators not only stimulates the various components of the inflammatory phase, but also stimulates the proliferative phase that follows. The course of the inflammatory response will depend on the number of cells destroyed, the original cause of the process and the condition of the tissue at the time of the insult.


  • Proliferative phase: The proliferative phase essentially involves the production of shelter material, which for the majority of musculoskeletal injuries involves the production of scar (collagen). The proliferative phase has a rapid onset (24-48 hours) but takes much longer to reach peak reactivity, which is usually 2-3 weeks after injury, the more vascularized the tissue, the less time it takes to reach the peak of production. This peak in activity does not represent the time at which scar production is complete, but the 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. Generally speaking, proliferation is normally considered to start from the first day or two after injury towards the peak at 2-3 weeks and decrease immediately thereafter over a period of several months after the injury. The repair process restores tissue continuity from the initial deposit of granular tissue that matures to form scar tissue. The shelter tissue is connective tissue, well distinguished from that which forms in different ways from the original connective tissue. Interesting recent studies have identified that there is a degree of post-traumatic regenerative activity in the muscle, related to the activation of mechanosensitive growth factors and consequent activation of satellite muscle cells. A number of growth factors have been identified as active in proliferation processes, again leading to some new potential treatments. Two fundamental processes are involved in the repair and are fibroplasia and angiogenesis. The function of the fibroblast is to repair the connective tissue. Fibroblasts migrate to the area from surrounding tissues. Fibroclastic activation is chemically mediated, and the large amount of some mediators has been identified, including various factors released by macrophages during the inflammatory stage. Fibroblasts migrate to the injured area and proliferate in the first few days after tissue damage. The fibroblastic production of new collagen, required as a repairing effect, is oxygen-dependent and poor tissue oxygenation will limit the effectiveness of the process. Fibroblasts not only produce the required collagen, but also the glycosaminoglycans and proteoglycans necessary for the base matter. The bonds of the triple helix collagen molecules and their relative lubrication will affect the mobility and extensibility of the scar tissue. Angiogenesis (the formation of new local blood vessels in the lesion area) is essential due to the fact that the production of collagen from fibroblasts is inhibited in conditions of poor oxygenation. Angiogenesis results in an increase in local flow and an increase in the availability of oxygen, which allows the fibroblasts to generate their product. A large number of mediators are able to influence these events, and interestingly a number of stimulants (including ultrasound, electrical stimulation and exercise) have been shown to stimulate this normal reaction. Myofibroblasts are derived from fibroblasts activated by a number of chemical mediators, and are responsible for the contraction of the wound and the rapid strengthening of the shelter. These pull the bridges of the wounds together, especially in skin lesions, reducing the size of the final scar. Granular-scar tissue matures with lymphatic development (roughly like capillary development), nerve fibers and invasion of mast cells. Collagen fibers are oriented in response to local stress providing traction force in desired directions. When the granular tissue matures, there is a devascularization process with obliteration of the lumen of the vessels.


  • Remodeling Phase: The remodeling phase is an essential component of tissue repair and is often overlooked in terms of importance. It is neither low nor highly reactive, but results in a functional and organized scar that is able to behave in a similar way to the parent tissue (which is being repaired). The remodeling phase has a more extensible overlap with the proliferative phase mentioned above, and is considered to begin in the first week after the injury, and the scar is remodeled as it is built rather than after the event. The remodeling phase primarily involves the newly deposited collagen and the associated extracellular matrix. The initial collagen deposition produces relatively weak fibrils with random orientation. As collagen matures, it becomes much more oriented in line with local stresses. A percentage of the original collagen (Type III) is reabsorbed (by the action of collagenase) and replaced with Type I collagen with more cross links and more traction force. Collagen synthesis and lysis both occur in large quantities in a normal wound, compared to uninjured tissue as old fibrous tissue is removed and new scar tissue is deposited. However, the scar that matures is a dynamic system rather than a static system. There are important factors that influence the course of this long phase, including physical stress. A final remodeling can continue for months, and even beyond a year after the wound has healed.


  • Cytokines, growth factors and tissue repair: Recently published studies concern the influence of a significant amount of cytokines and growth factors in various aspects of the repair process. This is supporting the possibility that future manual treatments could be openly used to influence these mediators and even influence the repair process. The damaged tissue will be repaired with a scar that is not only a replacement for the original tissue, but provides a functional, long-term adjustment that is capable of allowing for quality repair from the injury.

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