SOFT TISSUE WOUND HEALING REVIEW
Introduction
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.
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.
