Friday, October 12, 2012


                The inflammatory and repair processes are no longer simple events to describe in light of the increased knowledge in this field. The review that follows is only a brief resume of the salient events associated with tissue repair, particularly concerning the soft tissues. For further information, the reader is referred to recent reviews listed at the end of the paper.
               Wound healing refers to the body’s replacement of destroyed tissue by living tissue and comprises two essential components – Regeneration and Repair. The differentiation between the two is based on the resultant tissue. In regeneration, specialized tissues are replaced by the proliferation of surrounding undamaged specialized cells. In repair, lost tissue is replaced by granulation tissue which matures to form scar tissue. This review concentrates on the events and processes associated with the repair process.
               Probably the most straightforward way to describe the healing process is to divide it up into broad stages which are not mutually exclusive and overlap considerably. There are several different ways to “divide up” the entire process, but the allocation of 4 phases is common and will be adopted here – these being Bleeding, Inflammation, Proliferation and Remodeling.

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Bleeding Phase
             This is a relatively short lived phase, and will occur following injury, trauma, or other similar insult. Clearly if there has been no overt injury, this will be of little or no importance, but following soft tissue injury, there will have been some bleeding. The normal time for bleeding to stop will vary with the nature of the injury and the nature of the tissue in question. The more vascular tissues (e.g. muscle) will bleed for longer and there will be a greater escape of blood into the tissues. Other tissues (e.g. ligament) will bleed less (both in terms of duration and volume). It is normally cited that the interval between injury and end of bleeding is a matter of a few hours (6-8 hours is often quoted) though this of course is the average patient. Some tissues will continue to bleed for a significantly longer period, albeit at a significantly reduced rate. A crush type injury to a more vascular tissue – like muscle – could still be bleeding (minimally) 24 hours or more post trauma.

Inflammatory Phase
             The inflammatory phase is an essential component of the tissue repair process and is best regarded in this way rather than as an “inappropriate reaction” to injury. The inflammatory phase has a rapid onset (few hours) and swiftly increases in magnitude to its maximal reaction (2-3 days) before gradually resolving (over the next couple of weeks). It can result in several outcomes (see below) but in terms of tissue repair, it is normal and essential.

Proliferation Phase
              The proliferation phase essentially involved the generation of the repair material, which for the majority of musculoskeletal injuries, involved the production of scar (collagen) material. The proliferation 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 (the more vascular the tissue, the shorter the time taken to reach peak proliferative 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 final project (a high quality and functional scar) is not achieved until later in the overall repair process. It is usually considered that proliferation runs from the first day or two post-injury through to its peak at 2-3 weeks and decreases thereafter through to a matter of several months post trauma.

Remodeling Phase
               The remodeling phase is an essential component of tissue repair and is often overlooked in terms of its importance. It is neither swift nor highly reactive, but does result in an organized and functional scar which is capable of behaving in a similar way to the parent tissue (that which it is repairing). The remodeling phase has been widely quoted as starting at around the same time as the peak of the proliferative phase (2-3 weeks post injury), but more recent evidence would support the proposal that the remodeling phase actually starts rather earlier than this, and it would be reasonable to consider the start point at around 1-2 weeks.
               The final outcome of these combined events is that the damaged tissue will be repaired with a scar which is not “like for like” replacement of the original, but does provide a functional, long-term “mend” which is capable of enabling quality recovery from injury. For most patients, this is a process that will occur without the need for drugs, therapy or other intervention. It is designed to happen, and for those patients in whom problems are realized, or in whom that magnitude of the damage is sufficient, some ‘help” may be required to facilitate the process. It would be difficult to argue that therapy is “essential” in some sense. The body has an intricately complex and balanced mechanism through which these events are controlled. It is possible however, that in cases of inhibited response, delayed reactions or repeated trauma, therapeutic intervention is of value.
               It would also be difficult to argue that there was any need to change the process of tissue repair. If there is an efficient (usually) system through which tissue repair is initiated and controlled, why would there be any reason to change it? The more logical approach would be to facilitate or promote the normality of tissue repair, and thereby enhance the sequence of events that take the tissues from their injured to their “normal” state.

Inflammatory Reaction
               Inflammation is a normal and necessary prerequisite to healing. Following the tissue bleeding which clearly will vary in extent depending on the nature of the wound, a number of substances will remain in the tissues which make a contribution to the later phases. Fibrin and fibronectin form a substratum which is hospitable to the adhesion of various cells.
               Complex chemically mediated amplification cascade that is responsible for both the initiation and control of the inflammatory response can be started by numerous events, one of which is trauma. Mechanical irritation, thermal or chemical insult, and a wide variety of immune responses are some of the alternative initiators, and for a wide range of patients experiencing an inflammatory response in the musculoskeletal tissues, these are more readily identified causes.
               There are two essential elements to the inflammatory events, namely the vascular and cellular cascades. Importantly, these occur in parallel and are significantly interlinked. The chemical mediators that make an active contribution to this process are myriad. In recent years, the identification of numerous “growth factors” have led to several important discoveries and potential new treatment lines.

Vascular Events
               In addition to the vascular changes associated with the bleeding, there are also marked changes in the state of the intact vessels. There are changes in the caliber of the blood vessels, changes in the vessel wall and in the flow of blood through the vessels. Vasodilation follows an initial but brief vasoconstruction and persists for the duration of the inflammatory response. Flow increases through the main channels and additionally previously dormant capillaries are opened to increase the volume through the capillary bed. The cause of this dilation is primarily by chemical means (histamine, prostaglandins and complement cascade components C3 and C5) while the axon reflex and autonomic system exert additional influences. There is an initial increase in velocity of the blood followed by prolonged slowing of the stream. The white cells marginate, platelets adhere to the vessel walls and the endothelial cells swell. In addition to the vasodilation response, there is an increase in the vasopermeability of the local vessels (also mediated by numerous of the chemical mediators), and thus the combination of the vasodilation and vasopermeability response is that there is an increased flow through vessels which are more “leaky”, resulting in an increased exudate production.
               The flow and pressure changes in the vessels allow fluid and the smaller solutes to pass into the tissue spaces. This can occur both at the arterial and venous ends of the capillary network as the increased hydrostatic pressure is sufficient to overcome the osmotic pressure of the plasma proteins. The vessels show a marked increase in permeability to plasma proteins. There are several phases to the permeability changes but essentially, there is a separation of the endothelial cells, particularly of the venules, and an increased escape of protein rich plasma to the interstitial tissue spaces. The chemical mediators responsible for the permeability changes include histamine, serotonin (5-HT), bradykinin and leukotreines together with a potentiating effect from the prostaglandins.
               The effect of the exudate is to dilute any irritant substances in the damaged area and 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 phagocytic activity. 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.

Cellular Events
                The cellular components of the inflammatory response include the early emigration (within minutes) of the neutrophils (polymorohonucleocytes or PMN’s) from the vessels. This is followed by several other species leaving the main flow, including monocytes, lymphocytes, eosinophils, basophils and smaller numbers of red cells (though these leave the vessel passively rather than the active emigration of the while cells). Monocytes, once in the tissue spaces become macrophages. The main groups of chemical mediators responsible for chemotaxis are some components of the complement cascade, lymphokines, factors released from the mast cells in the damaged tissue.
               The PMN escapees act as early debriders of the wound. Numerous chemical mediators have been identified as having a chemotactic role, for example, PDGF (platelet derived growth factor) released from damaged platelets in the area. Components of the complement cascade (C3a and C5a), leukotreines (released from a variety of white cells, macrophages and mast cells) and lymphokines (released from polymorphs) have been identified.
               These cells exhibit a strong phagocytic activity and are responsible for the essential tissue debridement role. Dead and dying cells, fibrin mesh and clot reside all need to be removed. As a “bonus”, one of the chemicals released as an end product of phagocytosis is lactic acid which is one of the stimulants of proliferation – the next sequence of events in the repair process.
               The inflammatory response therefore results 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 carious components of the inflammatory phase, but also stimulates the proliferative phase. The course of the inflammatory response will depend upon the number of cells destroyed, the original causation of the process and the tissue condition at the time of insult.

Inflammatory Outcomes
Resolution is a possible outcome at this stage on condition that less than a critical number of cells have been destroyed. For more patients that come to our attention, this is an unlikely scenario.
               Suppuration, in the presence of infective microorganisms will result in pus formation. Pus consists of dead cell debris, living, dead and dying polymorphs suspended in the inflammatory exudate. Clearly the presence of an infection will delay the healing of a wound.
               Chronic inflammation does not necessarily imply inflammation of long duration, and may follow a transient or prolonged acute inflammatory stage. Essentially there are two forms of chronic inflammation: either the chronic reaction supervenes on the acute reaction or may in fact develop slowly with no initial acute phase. Chronic supervening on acute almost always involves some suppuration while chronic ab initio can have many causes including local irritants, poor circulation, some micro-organisms or immune disturbances. Chronic inflammation is usually more productive than exudative – it produces more fibrous material than inflammatory exudate. Frequently there is some tissue destruction, inflammation and attempted healing occurring simultaneously.
               Healing by fibrosis will most likely be taking place in the tissue repair scenario considered here. The fibrin deposits from the inflammatory stage will be partly removed by the fibrinolytic enzymes and will be gradually replaced by granulation tissue which becomes organized to form the scar tissue. Macrophages are largely responsible for the removal of the fibrin, allowing capillary budding and fibroblastic activity to proceed (proliferation). The greater the volume of damaged tissue, the greater the extent of, and the greater the density of, the resulting scar tissue. Chronic inflammation is usually accompanied by some fibrosis even in the absence of significant tissue destruction. The effects of acute inflammation are largely beneficial. The fluid exudate dilutes the toxins and escaped blood products include antibodies (and systemic drugs). The fibrinogen forms fibrin clots providing a mechanical barrier to the spread of micro-organisms (if present) and additionally assist phagocytosis. The gel-like consistency of the inflammatory exudate also makes a positive contribution by preventing the spread of the inflammatory mediators to surrounding, intact tissues.

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