Epithelialization Contraction

The processes of epithelialization and contraction of the wound also occur during the proliferative phase. Epithelialization is the process where neighboring basal epithelial cells proliferate and begin to move into the wound from the edges to establish a barrier to fluid-loss and infection as they layer out across a wound surface. As the leading edges of these migrating cells contact one another, they undergo contact inhibition to arrest further migration and then proceed to reestablish a true multilayered epidermal layer. Epithelial buds also form from intact epithelial appendages in the middle of the wound, such as hair follicles and sweat glands. Well-approximated surgical wounds reepithelialize as rapidly as 24-48 hours and heal by the process called primary intention. Contraction on the other hand is the process where wound edges are mechanically approximated by contractile forces generated by special fibroblast called myofibroblasts, which have rudimentary actin-myosin machinery. The process where wounds undergo healing mainly by contraction is called secondary intention and occurs normally at a rate of just under 1 mm/day. Evidence of contraction can be seen clinically at approximately one week post-injury. In approximated surgical wounds, contraction contributes little to the healing process. Coverage of wounds with split-thickness or full-thickness skin grafts and delayed primary closure of a wound are techniques that are able to minimize excessive contraction of wounds, which can result in scar contractures if joints are involved.

Remodeling

The remodeling phase begins after collagen production/degradation has equilibrated (though both process continue at accelerated rates), usually some three weeks after the inflammatory phase began. Collagen synthesis reaches its maximum rate at close to one week while levels in the wound elevate for up to three to four weeks

before reaching equilibrium. The net synthesis of collagen however, persists for up to 4-5 weeks. Characteristic of the remodeling phase is the reorientation and cross-linking of the collagen fibers into more organized patterns and the replacement of immature type III collagen with type I collagen fibers. Cross-linking of collagen is what increases the bursting strength of the scar. The strength of wounds increases linearly by approximately 3% at one week, 50% strength is achieved after six weeks, and a maximum strength of up to 70-80% of prewounded tissue is achieved at three months.

Collagen

Collagen is the dominant fiber present in connective tissue and is largely responsible for the tensile strength of wounds. In its mature form it has a complex three-dimensional structure of three peptide chains each twisted in a right-handed helix with the complex of the three chains then arranged in a left-handed superhelical formation. The collagen molecule is secreted by activated fibroblasts and is characterized by a repeating sequence of glycine (gly)-X-Y with X usually being proline, and Y usually being hydroxyproline or hydroxylysine. The hydroxylation of lysine is important for the covalent cross-linking of fibers and is facilitated by the enzyme lysyl oxidase. Ehlers-Danlos syndrome is a genetic defect involving inadequate production of lysyl oxidase (an enzyme involved in the cross-linking process), which produces defective or weak collagen and is associated with poor wound healing. Failure to hydroxylate proline affects collagen transport out of the cells. Vitamin C is a cofactor necessary for these hydroxylations of collagen residues, and its absence produces the clinical condition of scurvy with its associated deficient, defective, and weak collagen. Hypoxia or corticosteroid administration also retard hydroxylation and produce similarly defective collagen. A series of post-translational steps produces the procollagen molecule, which is the secretory form, with its characteristic N and C terminal propeptides. Once in the ECM, specific N and C terminal pro-teinases remove the terminal peptides and allow the organization of collagen into fibrils to begin.

Once relieved of its terminal proteins, collagen assumes a complex structure of three polypeptide chains in a helical formation that are covalently-bonded to each other to form a tropocollagen molecule. Tropocollagen molecules subsequently aggregate to form collagen filaments, fibrils, and eventually the macromolecular collagen fibers.

Close to 20 different collagen molecules have been identified and characterized. Type I collagen makes up over 90% of the collagen in the body and is the dominant type in mature wounds. Type III collagen is also a key in early wound healing, composing up to a third of all wound collagen during the granulation tissue of the fibroblastic phase, before being replaced during the remodeling phase to restore the normal 4:1 ratio between types I and III collagen that exist in normal skin and mature wounds.

Growth Factors in Wound Healing

Growth factors are hormone-like proteins that affect metabolism, growth, and differentiation of cells during all three phases of wound healing. Multiple cell lines and function secrete them by paracrine, endocrine, intercrine, and autocrine mechanisms to alternately stimulate or inhibit the processes of wound healing by interacting with unique cell-surface receptors. Signal transduction is accomplished by various

Table 6.1. Major growth factors in wound healing

Factor Source Function

PDGF Platelets, macophages, Fibroblast and smooth muscle fibroblasts, endothelial cells chemotaxis proliferation, collagen synthesis

TGF-ß Macrophages, platelets, fibroblasts Potent collagen synthesis inducer, stimulates wound contraction, stimulates angiogenesis TGF-a Macrophages, platelets, Stimulates proliferation of epithelial, keratinocytes endothelial, and fibroblast cells. A very potent angiogenesis stimulator. EGF Macrophages, platelets, Similar to TGF-a keratinocytes

IL-1 Macrophages, PMNs Inflamatory cell stimulation chemotaxis, collagenase synthesis TNF Macrophages, lymphocytes Fibroblast stimulation, collagen synthesis, angiogenesis FGF Macrophages, endothelial cells Angiogenesis, collagen synthesis, wound contraction, ECM synthesis second messenger systems including tyrosine kinases, G-proteins, DAG/IP-3, and protein kinase C which all serve to alter gene expression and stimulate protein synthesis. An absolute or relative deficiency of growth factors in a wound may contribute to wound failure and production of the chronic wound environment. A summary of the major identified growth factors is included in the Figure 6.1 below (Table 6.1).

Chronic Wounds

The chronic wound is one that fails to proceed thru the normal progression of wound healing in a timely fashion. Characteristic of chronic wound healing is prolific granulation tissue deposition with significant fibrosis/scar formation of the tissue. Granulation tissue is a rich collection of capillary buds interspaced with multiple cell lines including fibroblasts and inflamatory cells. As healing progresses granulation tissue normally undergoes apoptosis to an avascular and acellular collagen matrix. Persistence of granulation tissues results in hypercellular tissue with eventual hypertrophic scar formation.

A large number of identifiable factors predictably will impair, delay, or prevent satisfactory resolution of a wound. These factors are summarized in Table 6.2A and Table 6.2B.

A special group of problem wounds worth noting include venous stasis wounds and pressure sores. Venous ulcers result from progressive lower extremity venous valvular failure with resultant edema formation, microcirculatory occlusion, and perivascular fibrin cuffing. Eventually breakdown of the overlying skin results from the hypoxic state and frequently troublesome relapsing wounds develop. In addition, stasis ulcers have a relative deficiency of growth factors due to decreased breakdown by proteinases and by the sequestering of growth factors in the perivascular fibrin cuffs. Surgical treatment by skin grafting the wound or ligation of subfascial

Table 6.2A. Factors affecting wound healing

Radiation

Malnutrition

Aging

Infection

Hypoxia

Radiation produces both endothelial cell and fibroblast cell injury, affecting both perfusions of the tissue as well as affecting collagen and ECM secretion. Decreased infiltration by inflamatory cells also lowers available cytokine amounts, and impairs all phases of healing to some degree.

Low protein states affect available amino acids available for collagen synthesis. Fatty acid and carbohydrate deficiencies retard wound healing in part by stimulating protein breakdown to supply calories.

Characterized by a linear decrease across the board in the wound healing processes (contraction, epithelialization, cell migration, collagen/ECM synthesis)

Heavily colonized wounds demonstrate prolonged inflammatory phases and decreased fibroblast proliferation and function

A multifactoral process contributed to by smoking, diabetes, peripheral vascular disease, edema, and radiation. Hypoxic tissue is prone to infection and heals poorly. The increased intercapillary distance in wounds requires higher tissue P02to drive oxygen into healing areas. Oxygen is necessary for epitheliazation, collagen synthesis, and bacterial destruction by oxygen generated free radicals.

Steroids

Diabetes

Affects DNA synthesis during the inflamatory phase by downregulating DNA synthesis of inflamatory cytokines. This effect is blunted somewhat by dietary supplementation with Vitamin A (10-25K international units Q day)

Affects the inflammatory process as well as damages regional microcirculation

Smoking Lowers tissue PO2 by its vasoconstrictive properties and contributes to atherosclerosis. Smokers also have elevated carboxyhemoglobin levels.

NSAIDS Decrease collagen formation

Chemotherapy Decrease collagen synthesis and fibroblast proliferation

perforating veins (the Linton procedure) has been for the most part unsuccessful, although they do have some proponents. Sensible and cost-effective strategies for treating stasis ulcers include fitted or off-the-shelf compression garments and leg elevation with the hope of eventual spontaneous secondary healing. A useful technique for assisting healing in noninfected stasis ulcers is the weekly application of Unna-boot™ wraps, a commercially available semi-rigid gauze impregnated with zinc oxide paste, which serves to assist with the calf-muscle pump for venous return as well as to allow prolonged contact with the zinc paste, which may serve to

Table 6.2B. Vitamin and mineral deficiency

Vitamin C Cofactor for lysyl hydroxylase (collagen hydroxylation)

Vitamin A Cofactor for epitheliazation and collagen synthesis

Vitamin E Strong antioxidant effects

Zinc Cofactor for DNA synthesis

Copper Cofactor for lysyl oxidase (collagen cross-linking)

Vitamin B6 Cofactor for collagen cross-linking promote healing. Oral pentoxyifylline is an agent that has shown promise as an adjunct to compression treatment, facilitating healing by some as yet unknown mechanism.

A number of very expensive topical growth factors (notably PDGF) and wound dressings have been marketed over the years with claims of facilitating closure of stasis ulcers, but to date these have been both disappointing clinically and economically unfeasible, and in general do not play a role in how most of these wounds are treated. In the future, as the etiology and biochemistry of these wounds is better understood, we can expect more successful chemical adjuncts for routine clinical use that demonstrate in vivo efficacy.

Pressure ulcers are a group of wounds that frequently occur in a wide variety of patient populations including the elderly, debilitated, paralyzed, or nonambulatory groups. The common etiology is sustained pressure over a bony prominence resulting in microcirculatory compromise. This can occur and produce tissue necrosis with sustained pressures as low as 25 mm Hg for durations as short as two hours. Frequent sites for pressure ulcers include the sacral/ischial/trochanteric region, posterior scalp, posterior heels, metatarsal heads in diabetics, and on extremities with casts on. The most important strategy for treating pressure sores is prevention. Frequent turning and repositioning of bedridden patients is mandatory and serves to eliminate the majority of avoidable pressure sores. Treatment of existing wounds also involves avoiding pressure to the area, as well as local wound care with dressing changes and sharp debridement of devitalized tissues.

In dealing with a presumed venous stasis ulcer, one should not overlook the possibility that the etiology is ischemic or some combination of arterial insufficiency and venous stasis. A pulse exam should be done just as with peripheral vascular disease (PVD) and vascular noninvasive studies (i.e., ABI's with segmental limb pressures) and possibly arteriograms should be obtained in those without palpable distal pulses who are surgical candidates. The use of transcutaneous oxygen probes has also been reported to be of use in assessing these wounds, with a TCPO2 of less than 30 predicting failure of spontaneous healing due to depressed fibroblast function. Nonhealing wounds in the face of PVD merit referral to a vascular surgeon for a potential revascularization.

Wound Dressings

An important technique of local wound care involves the use of saline-moistened dressing changes. As the moist gauze is applied to the wound and proceeds to dry out, necrotic material and debris in the wound adhere to it and are removed as the dressing is changed (i.e., "wet to dry" dressings). Frequent dressing changes (3 or 4 times daily) can serve to mechanically debride heavily colonized wounds but should not replace sharp debridement of grossly nonviable tissue. A variety of antimicrobial

Table 6.3.

Topical antimicrobials

Agent

Comment

Notable Side-Effects

Bacitracin Betadine solution

0.025% Sodium Hypocholorite (Dakin's Solution)

Silver Sulfadiazine (Silvadene™)

0.5% Silver Nitrate

™afenide (Sulfamylon)

Gram positive coverage only

Broad spectrum but short acting due to rapid dilution in the wound. Colloidal or gel preparations are signifigantly longer acting.

Bacteriacidal to all fungi and bacterial species. The single best agent for lowering bacterial counts.

Broad spectrum. Penetrates eschar poorly.

Broad-spectrum bacteriostatic agent with the exception of Klebsiella and Enterobacter species. Penetrates eschar poorly. Painless on application.

Broad spectrum except for fungus and MRSA. Very good eschar penetration. Painful during application.

Toxic to fibroblasts at higher concentrations. Contraindicated in patients with iodine allergies.

Associated with transient neutropenia. Contraindicated in patients with sulfur or silver allergies.

Associated with electrolyte abnormalities (hyponatremia and hypochloremia) and rarely methemogolbinemia.

Can cause a metabolic acidosis (due to carbonic anhydrase inhibition), is painful on application, and lacks antifungal coverage.

Polymyxin

Gram negative coverage only.

solutions can be used instead of saline, each of which has their own advantages and spectrum of activity. One should also familiarize oneself with some of the common side effects of these agents in order to recognize potential life-threatening complications (see Table 6.3).

Care must be taken when using moistened gauze dressing changes to avoid either macerating or drying out the wound excessively. A common strategy to prevent irreversibly desiccating the tissue is to change the dressing before it dries out completely (i.e., "wet to moist" dressings). To avoid maceration, the wet dressing should not be over moistened and have minimal contact with surrounding normal tissue by securing it in a fashion that it does not shift in and out of the wound. A useful strategy in wounds not requiring further debridement is to discontinue dressing changes and place Silvadene™ cream on the wound once or twice daily to both continue antimicrobial effects and to perpetuate a moist environment.

The goal of a wound dressing on colonized wounds should be to both protect the wound from the environment and to assist in lowering the bacterial count of the wound. Surveillance of bacterial growth in the wound is critical before performing any type of wound closure, be it by primary closure, skin grafting, occlusive dressing, or flap coverage. Simple swab cultures of the wound are a cost-effective way of determining a rough estimate of bacterial colonization, but quantitative tissue culture from wound biopsy is the gold-standard prior to performing closure or coverage planning. Bacterial counts greater than 105 colony-forming units (CFU) have been reliably shown to predict failure of grafts, flaps, or primary closure. Special attention should be paid to cultures that reveal beta-hemolytic Streptococcus, which can cause wound failure with as few as 100 CFU.

Occlusive dressings provide a moist environment favorable to more rapid epitheliazation. These types of dressings require close surveillance for development of infection under them and are more useful for fresh wounds that have had little chance to develop bacterial colonization. Suspicion of infection requires removing the occlusive dressing and using dressing changes or topical antimicrobial therapy. Occlusive dressings can be particularly useful for small cuts and scrapes, as well as for superficial burns and as a dressing on donor sites from skin grafts.

A recent advance in wound dressing is widespread adoption of the vacuum-assisted closure device (VAC™). This device employs an open-cell foam sponge placed in the wound that's covered with an occlusive dressing and then put to a powerful vacuum pump. When a proper seal is created, a form-fitting dressing is created. The VAC works by evacuating excess fluid and by facilitating removal of both bacteria and metalloproteinases (a group of enzymes that degrade growth factors) in the wound. The subatmospheric pressures generated also serves to physically facilitate contracture of the wound. Edema is deleterious because it serves as both a diffusion barrier to nutrients and as a diluent of locally produced antibacterial sebaceous gland secretions.

Advantages of the VAC wound dressing include not only faster epithelialization and wound contraction, but they also simplify care by requiring less frequent dressing changes (Q2-3 days) in clean wounds. VAC's have been used on many complex wounds including sacral decubs, perineal wounds, open abdominal wounds, and as a bolster for skin grafts. VAC dressings have also been applied to colonized wounds and have been effective clinically in decreasing bacterial loads. If used in this way however, the sponge may need to be replaced as frequent as twice-daily to survey for underlying infection and assist in debridement. At present, prudent recommendations for VAC dressing application should probably be limited to clean or lightly-colonized wounds.

Nutritional Support

An important and frequently overlooked source of wound failure is malnutrition. A thorough assessment by a clinical dietician should be obtained for any patient where nutritional status is in question. General recommendations for caloric needs start with approximately 25-35 kcal/kg/day of nonprotein calories (fats + carbohydrates) and 1-1.5 gm/kg/day of protein. Other than clues on physical exam, a history of alcohol abuse and serum albumin < 3.0 may suggest chronic malnutrition. An important and convenient serial test to follow for improvement is the protein, prealbumin, which has a half-life of just less than one week, as opposed to several weeks for albumin. An increasing prealbumin, checked weekly, is highly suggestive a patient in positive nitrogen balance.

A recent advance in nutritional support for wound healing involves supplementing the patient with the anabolic steroid, Oxandrin™ (oxandrolone). Taken as an oral supplement (10 mg twice daily), Oxandrin has shown exciting potential in the

treatment of large burns by blunting the protein wasting associated with the hyper-metabolic state post-burn. Clinically faster reepitheliazation of skin graft donor sites and the maintenance of lean body mass have reflected this. Results have also been reported in assisting closure of some chronic wounds.

A number of vitamin, electrolyte, and trace element deficiencies may impair healing. In patients with a normal, well-balanced diet, it will be rare that significant nutritional deficiencies will exist. However, in the hospitalized patient, a number of clinical deficiencies of these substrates may present. Supplementation with an oral or IV multivitamin is a cheap method of treating or prophylaxing against occult deficiencies. Additional dosing of supplemental zinc sulfate and vitamins A, C, and E are advocated by some for wound healing in larger or chronic wounds. Excess dosing of fat-soluble vitamins (A,D,E, and K) can lead to systemic toxicity, however.

References

1. Steed DL. The Role of growth factors in wound healing. Surg Clin North Am 1997; 77(3):575-586.

2. Stadelmann WK, Digenis AG, Tobin GR. Impediments to wound healing. Am J Surg 1998; 176(Suppl 2A):39S-47S.

3. Eaglstein WH, Falanga V. Chronic Wounds. Surg Clin North Am 1997; 77(3):689-700.

4. Clark RA. Wound Repair: Overview and General Considerations. The Molecular and Cellular Biology of Wound Repair. 2nd ed. New York: Plenum Press, 1996.

5. Brew EC, Mitchel MB, Harken AH. Fibroblast growth factors in operative wound healing. J Am Coll Surg 1995; 180:499.

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