WOUND HEALING

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Matrix Synthesis and Remodeling

In addition to epithelialization, contraction contributes to the successful closure of full-thickness wounds.

Contraction is defi ned as a process whereby both dermis and epidermis bordering a full-thickness skin defi cit
are drawn from all sides centripetally over the exposed wound bed.

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This usually occurs during the second

week following injury. Wound contraction not only accelerates closure, but also enhances the cosmetic appear-
ance and strength of the scar because proportionally less wound area must be covered by newly formed inferior
quality epithelium, which is fragile and lacks normal nervous, glandular, follicular, and vascular components
(see Figures 4.12 and 1.7b). For this reason, a high degree of contraction is a desired feature of wound repair, at
least in the horse.

A number of theories have been proposed to explain wound contraction; however, most authorities agree

that it involves a fi nely orchestrated interaction of ECM, cytokines/growth factors, and cells, in particular a
specialized fi broblast phenotype: the myofi broblast. These are the most abundant cellular elements of healthy
granulation tissue and are aligned within the wound along the lines of contraction. The most striking feature
of the myofi broblasts is a well-developed alpha smooth muscle actin (

α-SMA) microfi lamentous system, arranged

parallel to the cell’s long axis and in continuity with ECM components via various integrins. In addition to these
cell-substratum links, intercellular connections such as gap junctions and hemidesmosomes ensure that neigh-
boring cells exert tension on one another. Factors producing and regulating contraction are presently unknown,
but appear to include various cytokines/growth factors.

Wound contraction is divided into three phases. An initial lag phase (wherein skin edges retract and the

wound area increases temporarily for 5 to 10 days) occurs prior to signifi cant fi broblastic invasion into the
wound, which is a prerequisite for contraction. Subsequently a period of rapid contraction is followed by one
of slow contraction as the wound approaches complete closure. The number of myofi broblasts found in a wound
appears proportional to the need for contraction; thus, as repair progresses and the rate of contraction slows,
this number decreases accordingly.

During wound contraction, the surrounding skin stretches by intussusceptive growth and the wound takes

on a stellate appearance. Contraction ceases in response to one of three events: the wound edges meet and
contact inhibition halts both the processes of epithelialization and contraction; tension in the surrounding
skin becomes equal to or greater than the contractile force generated by the

α-SMA of the myofi broblasts;

or, in the case of chronic wounds, a low myofi broblast count in the granulation tissue may result in failure
of wound contraction despite laxity in the surrounding skin. In the latter case, the granulation tissue is pale
and consists primarily of collagen and ground substance. Wound contraction is greater in regions of the
body with loose skin than in regions where skin is under tension, such as the distal aspect of horse limbs.
Although it is speculated that the shape of the wound may infl uence the process of contraction, this does not
appear relevant in wounds at the distal extremities of horse limbs where skin is tightly stretched and not easily
moved.

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As contraction concludes, myofi broblasts disappear, either by reverting to a quiescent fi broblast phenotype

or by apoptosis,

10

primarily in response to reduced tension within the ECM.

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The myofi broblast persists in

fi brotic lesions where it may be involved in further ECM accumulation and pathologic contracture, a condition
leading to signifi cant morbidity, particularly when it involves joints or body orifi ces, but is rarely encountered
in the horse.

The conversion of ECM from granulation to scar tissue constitutes the fi nal phase of wound repair and

consists of connective tissue synthesis, lysis, and remodeling, also referred to as maturation. Proteoglycans
replace hyaluronan during the second week of repair, support the deposition and aggregation of collagen fi bers,
and provide the mature matrix with better resilience. Collagen macromolecules provide the wound tensile
strength as their deposition peaks within the fi rst week in primary wound repair and between 7 and 14 days
in second intention healing. Although this corresponds to the period of most rapid gain in strength, only 20%
of the fi nal strength of the wound is achieved in the fi rst 3 weeks of repair. At this time, collagen synthesis is
balanced by collagen lysis, which normally prevents accumulation of excessive amounts of collagen and forma-
tion of pathologic scars.

The balance between synthesis and degradation determines the overall strength of a healing wound at a

particular time. The fi rst newly deposited collagen tends to be oriented randomly and therefore provides little
tensile strength, whereas during remodeling the fi bers reform along lines of stress and therefore resist dehiscence
more effectively. Cross-linking in the later formed collagen is also more effective, although never to the same