Wound Healing

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Practical Urology: EssEntial PrinciPlEs and PracticE

In addition to furthering the inflammatory

Proliferation

process, local vasodilation is responsible for

the typical erythema that accompanies acute

Wound healing events during this phase of

injury.With the release of these chemotatic sub-

wound healing include mesenchymal cell

stances, leukocytes (neutrophils, monocytes,

chemotaxis and proliferation (fibroplasia),

macrophages, and lymphocytes) are drawn into

angiogenesis, and epithelialization.9 This phase

the wound.

of wound healing begins with a provisional

Neutrophils phagocytize necrotic debris, for-

matrix of fibrin and fibronectin being formed.

eign material, and bacteria.4 They are the domi-

The matrix consists of a papillary bed, fibro-

nant white blood cell early in wound healing.

blasts, macrophages, and a loose arrangement of

After phagocytosis and digestion, neutrophils

collagen, fibronectin, and bacteria. Macrophages

either die (releasing free oxygen radicals and

are the principal cell in the initial matrix; how-

destructive enzymes) or are engulfed by mac-

ever, fibroblasts quickly increase in numbers

rophages.5 The release of free oxygen radicals

during this phase of healing. Fibroblasts are

and enzymes by the destruction of neutrophils

normally located in the dermis and are often

can prolong the inflammatory reaction (oxi-

damaged by the initial insult. Fibroblasts, medi-

dizing stress). Areas of encapsulated chronic

ated by cytokines, quickly become the most

inflammation, which are termed granulomas,

dominant cell in the proliferative phase. PDGF,

may develop as a result of ongoing release of

fibronectin, and EGF are chemotactic for both

these enzymes and subsequent continued gen-

fibroblasts and smooth muscle cells.10

eration of free oxygen radicals. The recruitment

Fibroblasts divide and produce the compo-

of macrophages to safely remove neutro-

nents of the extracellular matrix.8 The extracel-

phils from a wound may help prevent chronic

lular matrix contains collagen, proteoglycans,

inflammation.

and attachment proteins such as fibronectin.

Macrophages are central to wound healing.6

Over this phase,the amount of collagen increases

Following the first 24–48 h, they become the

to become the primary structural element in the

prevailing white blood cells in the wound. As a

wound matrix. Collagen is synthesized pri-

response to chemotatic agents (like TGF-b), cir-

marily by fibroblasts in a complex process that

culating monocytes and tissue macrophages

begins 3–5 days after injury.11 Procollagen, the

migrate to the wound. They engulf necrotic tis-

precursor of collagen is formed within fibro-

sue and bacteria as well as remove the remain-

blasts and released.It is composed of long chains

ing neutrophils preventing ongoing release of

which are linked together in a helical configura-

inflammatory mediators. Additionally, mac-

tion and cleaved by proteases to form collagen.12

rophages release many different growth factors

TGF-b increases collagen synthesis and gluco-

and cytokines. This allows for fibroblast prolif-

corticoids interfere with wound healing during

eration, angiogenesis, extracellular matrix pro-

this step by decreasing collagen synthesis. As

duction, and the recruitment of additional

collagen matures, cross-linking occurs between

leukocytes. For example, Interleukin-1 (IL-1) is

chains of collagen to form larger collagen fibrils.

secreted by macrophages, causing lymphocyte

Vitamin C is a necessary nutrient in hydroxyla-

activation and is chiefly responsible for the

tion, which stabilizes and cross-links collagen.

febrile response as a result of circulating IL-1

The increased cross-linking increases the tensile

reaching the hypothalamus.7 Activated mono-

strength of the wound. Collagen synthesis is

cytes and macrophages stimulate collagen pro-

dependent both on local oxygen and vascular

duction and release matrix metalloproteinases

supply.

(MMPs) – including collagenases – aiding in

Angiogenesis is stimulated by high lactate

breaking down and repairing damaged tissue

levels, an acidic pH, and decreased oxygen

matrix. In order for there to be orderly progress

tension in the tissue.9 Fibroblast growth fac-

of wound healing, a balance between MMPs and

tor (FGF) and vascular endothelial growth

tissue inhibitory metalloproteinases (TIMPs)

factor (VEGF) are important factors in angio-

must exist.8 If not the effect of MMPs may extend

genesis. The epithelial cells secrete VEGF in

to adjacent uninjured tissues. Repair of the

response to hypoxia signaling to fibroblasts to

wound begins in the proliferative phase of

stimulate angiogenesis. The subsequent rele-

wound healing.

ase of growth factors from the macrophages

Regeneration of the epithelium is important

to seal the wound and prevent further water loss.

The two layers of the skin are the epidermis and

the dermis. The epidermis is multilayered. The

stratum corneum, the most superficial layer of

epidermis, consists primarily of dead cells and

keratin. The deeper epidermal layer is composed

of a protective layer of the skin which provides

protection from water loss. The dermis too is

multilayered, consisting of a superficial layer,

the periadnexal in areas where adnexal struc-

tures are absent, and the deep or reticular layer

Figure 19.1. cross-section of the skin (reprinted with permis-

containing the majority of collagen content and

the lymphatics (Fig. 19.1).

sion from Jordan and Mccraw15.copyright © american Urological

association Education and research, inc).

The first step in epithelialization is the for-

mation of the clot to seal the wound. This pro-

being anchored to dermis, epithelial cells pro-

tects against bacterial invasion as well as

prevents fluid loss. Initially, the epithelial cells

vide little strength.

migrate across the wound and can completely

The definition of wound contraction is the

cover a surgically coapted wound in 18–24 h. 14

movement of tissue toward the center of the

Epithelial cells migrate from epithelium. This

wound. This should not be confused with wound

can be from the wound edge or in partial thick-

contracture,which is physically constrained joint

ness wounds – from epithelial appendages

motion as a result of wound contraction. Wound

(e.g., hair follicles, sweat and sebaceous

contraction typically begins 4–5 days after injury

glands). As epithelial cells cross the wound and

and will continue for 12–15 days.9 The rate of

contact each other, the speed of migration

movement varies by the type of tissue and how

slows and is stopped by contact inhibition.

much laxity exists at the point of contraction.

Epithelial cell migration is decreased by bacte-

Contraction is mediated by fibroblasts and myo-

ria, large amounts of exudate, and necrotic

fibroblasts, which act similarly to smooth muscle

tissue. Reestablishment of a mature epithelial

cells. Pharmaceuticals (e.g., colchicine) that

layer is an important component of scar reso-

inhibit microtubules (tubulin) minimize wound

lution. In full thickness injuries, epithelializa-

contraction implicating the important role of

tion occurs from the edge of the wound at a

microtubules in this phase of wound healing.

rate of 1–2 mm per day.14 Regenerated epithe-

The process of wound contraction requires cell

lium does not retain all the features of normal

division and is inhibited by local radiation and

epithelium. It has fewer basal cells and the

systemic chemotherapy drugs.

interface between dermis and epidermis is

In those areas with more elastic skin wounds,

abnormal as rete pegs are absent. Without

wound contraction can be augmented greatly by