The term tissue repair is intended to refer to series of events which starts with damage to the skin, to varying depths, and ends with restructuring the actual skin.
This series of events is very complex and involves a high number of both cells and molecules.
Simplifying the explanation, it is usual to divide the reparative process into phrases even if in actual fact there are not really any interactions between one phase and the next; in actual fact the various phases are superimposed.
The phases we can define are as follows:

• exudative or inflammatory phase
• proliferative phase
• reparative or remodelling phase

If, for any reason, there is any hindrance to the progress of the various phases or one of these halts then we will be left with a chronic situation, i.e. failure to cure or delay in curing the ulcerative wound, and we will find ourselves no longer faced with physiological tissue repair but with pathological tissue repair.

Exudative or inflammatory phase
The principal task of this phase is detersion of the wound which has been created, followed by filling up the cavity which is produced.
At the beginning the platelets are involved: by joining to each other (aggregation) they form the first "plug" which occludes the bleeding vessels by releasing certain substances (thromboxane, PAF, PDGF) capable of calling in specialist cells to the site of the wound.
Then in this phase the fibrinogen transforms into fibrin which, acting as a net, imprisons white corpuscles, red corpuscles, platelets and other cells; this agglomerate will be used as another "plug" to stop the blood flowing out of the vessels and to fill up the ulcer.
The fibrin produced in this area finally has the function of "guiding" the cells which are involved in the actual tissue reconstruction: the fibroblasts.
This initial event is followed by the arrival of the neutrophil granulocytes (cells which belong to the family of white corpuscles); these are drawn into the wound by the substances released slightly earlier by other cells and their principal function is that of "cleaning" the wound of detritus, bacteria and any foreign bodies.
This function also continues with the release of enzymes with a digestive function (elastases, proteases and collagenases).
Finally, still in this first phase, we see the arrival of the macrophages, also summonsed by special substances (chemiotactants).
This population of cells not only advances the work of cleaning up already started by the neutrophil granulocytes but acts on the fibroblasts releasing substances which stimulate tissue repair (growth factors).
The macrophages also release substances which have a vasoactive action, i.e. they determine vasodilation, causing the typical reddening and swelling of the perilesional skin (inflammation).

Proliferative phase
This is the specific way in which the granulation tissue forms, given this name because the bed of the wound is populated by "red granular foci" centrally consisting of blood vessels (which is why they are red) and peripherally by collagen, fibroblasts and yet other cells.
In this phase it is really the macrophages which direct operations by secreting substances, called growth factors, which stimulate the formation of new blood vessels (angiogenesis), the proliferation of fibroblasts and the concurrent deposition of protein material.
Stimulated in this way, the fibroblasts produce collagen and proteoglycans and in this phase we can see the vessels migrating from the periphery to the centre of the ulcer as well as the underlying migration of keratinocytes.
The keratinocytes are the most superficial cells of the skin and by sliding on top of each other they attempt to cover up the ulcerative wound once good granulation tissue has been created on its bed.
These more superficial cells stop migrating when they receive a signal, determined by physical contact, which is activated as soon as the cells from one manage to "touch" the cells on the opposite edge (this mechanism is called contact inhibition).
In the meantime something is also happening "below": this is the filling of the "hole" by means of the granulation tissue extending from the periphery to the centre and from the bottom to the top.

Reparative or remodelling phase
This stage is characterised by the prevalence of phenomena of deposition and differentiation of collagen in comparison with angiogenesis.
In fact in this phase we see the transition from one type of collagen to another, contraction of the wound and reorganisation of the extracellular matrix.
Re-epithelisation also ends (i.e. the sliding movement of the keratinocytes) with activation of contact inhibition.
It is important to emphasise that for some years there will be continuous reorganisation of the repaired tissue, even when objectively the wound appears to be completely healed (reorganisation of fibrils and agglomerates of collagen and contraction of the extracellular matrix).

Why an ulcerative wounds may not heal
Providing a response to this question is relatively simple, but it is less simple to accurately identify the specific reasons why the wound is not healing in each patient.
Very generally speaking we can state that an ulcerative wound may not heal, or its cure may be delayed, because of local or systemic factors.
More specifically the local factors may be the presence of an infection, of necrotic tissue, foreign bodies or detritus, of an arteriopathy which creates ischaemia locally, of repeated traumas (thinking, for example, of neuropathic plantar ulcers for which no off-bearing device has been used).
It is obvious that if we wish to cure a wound we must not only acknowledge the presence of one or more of these factors but we must also eliminate it (revascularisation of an ischaemic foot, treat an infected foot with antibiotics, take the load off a neuropathic plantar ulcer by using an appropriate orthesis).
On the other hand, with regard to systemic factors, we can list inadequate control of diabetes (hyperglycaemia), malnutrition which is not infrequent in elderly patients, the use of drugs which impede normal tissue repair (steroids, antiblastics, etc).
We should also emphasise that defining an ulcerative wound which does not heal (non healing ulcer) as a "difficult wound" may often not be exactly correct.
Even today we see patients being admitted with ulcers of the foot dating back for years for whom failed healing has to be ascribed to failure to supply off-bearing apparatus, incorrect treatment of the underlying osteomyelitis or concurrent arteriopathy ( Figure 46).

The figure ( Figure 43) shows the case of a patient treated for months with autologous grafts, with platelet gel and with advanced dressing for an ulcer termed as "difficult": the caption explains what the real "difficulty" consists of.