Chapter 6: Wound Healing

Acute Wound

An acute wound results from the sudden loss of anatomic structure in tissue following the transfer of kinetic, chemical, or thermal energy. Functionally, an acute wound should pass predictably through the phases of wound healing to result in complete and sustained repair. Acute wounds typically occur in recently uninjured and otherwise normal tissue. Acute wound healing is timely and reliable, completing the entire process within 6-12 weeks. Most surgical wounds are acute wounds.

Chronic Wound

Wound healing fails in a chronic wound. The process of tissue repair is prolonged and pathologic. The usual mechanism is dysregulation of one of the phases of normal acute wound healing. Most often, healing arrest occurs in an inflammatory phase. This prolonged inflammatory phase may be due to wound infection or another form of chronic irritation. Tissue and wound hypoxia is the other important mechanism for the development of a chronic wound. Failed epithelialization due to repeat trauma or desiccation may also result in a chronic partial thickness wound. Surgeons may sharply convert a chronic wound into an acute wound.

Clinical Wound Healing

Surgeons often describe wound healing as primary or secondary. Primary healing occurs when tissue is cleanly incised and anatomically reapproximated. It is also referred to as healing by primary intention, and tissue repair usually proceeds without complication. Secondary healing occurs in wounds left open through the formation of granulation tissue and eventual coverage of the defect by migration of epithelial cells. Granulation tissue is composed of new capillaries, fibroblasts, and a provisional extracellular matrix that forms at the base of the early wound. This process is also referred to as healing by secondary intention. Most infected wounds and burns heal in this manner. Primary healing is simpler and requires less time and tissue synthesis than secondary healing. A wound healing primarily repairs a smaller volume than an open wound healing secondarily. The principles of primary and secondary healing are combined in delayed primary closure, when a wound is left open to heal under a carefully maintained, moist wound healing environment for approximately 5 days and is then closed as if primarily. Wounds treated with delayed primary closure are less likely to become infected than if closed immediately because bacterial balance is achieved and oxygen requirements are optimized through capillary formation in the granulation tissue.

The Mechanism of Wound Healing

The complex process of wound healing normally proceeds from coagulation and inflammation through fibroplasia, matrix deposition, angiogenesis, epithelialization, collagen maturation, and finally wound contraction (Figure 6–1). Wound healing signals include peptide growth factors, complement, cytokine inflammatory mediators, and metabolic signals such as hypoxia and accumulated lactate. Many of these cellular signaling pathways are redundant and pleiotropic.

A. Hemostasis and Inflammation

Following injury, a wound must stop bleeding in order to heal and for the injured host to survive. It is therefore not surprising that cellular and molecular elements involved in hemostasis also signal tissue repair. Immediately after injury, the coagulation products fibrin, fibrinopeptides, thrombin split products, and complement components attract inflammatory cells into the wound. Platelets activated by thrombin release insulinlike growth factor 1 (IGF-1), transforming growth factor α (TGF-α), transforming growth factor β (TGF-β), and platelet-derived growth factor (PDGF), which attract leukocytes, particularly macrophages, and fibroblasts into the wound. Damaged endothelial cells respond to a signal cascade involving the complement products C5a, tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and interleukin-8 (IL-8), and express receptors for integrin molecules on the cell membranes of leukocytes. Circulating leukocytes then adhere to the endothelium and migrate into the wounded tissue. Interleukins and other inflammatory components, such as histamine, serotonin, and bradykinin, cause vessels first to constrict for hemostasis and later to dilate, becoming porous so that blood plasma and leukocytes can migrate into the injured area.

The very early wound inflammatory cells increase metabolic demand. Since the local microvasculature is damaged, a local energy sink results, and Pao₂ falls while CO₂ accumulates. Lactate in particular plays a critical role, since its source is mainly aerobic, and its level is tightly regulated by tissue oxygen levels. Oxidative stress is an important signal for tissue repair. These conditions trigger reparative processes and stimulate their propagation.

Macrophages assume a dominant role in the synthesis of wound healing molecules as coagulation-mediated tissue repair signals fall. Importantly, macrophages, stimulated by fibrin, continue to release large quantities of lactate. This process continues even as oxygen levels begin to rise, thereby maintaining the “environment of injury.” Lactate alone stimulates angiogenesis and collagen deposition through the sustained production of growth factors. Unless the wound becomes infected, the granulocyte population that dominated the first days diminishes. Macrophages now cover the injured surface. Fibroblasts begin to organize, mixed with buds of new blood vessels. It has been shown that circulating stem cells, such as bone marrow–derived mesenchymal stem cells, contribute fibroblasts to the healing wound, but the extent of this process is as yet unknown.

B. Fibroplasia and Matrix Synthesis

Fibroplasia

Throughout wound healing, fibroplasia (the replication of fibroblasts) is stimulated by multiple mechanisms, starting with PDGF, IGF-1, and TGF-β released by platelets and later by the continual release of numerous peptide growth factors from macrophages and even fibroblasts within the wound. Growth factors and cytokines shown to stimulate fibroplasia and wound healing include fibroblast growth factor (FGF), IGF-1, vascular endothelial growth factor (VEGF), IL-1, IL-2, IL-8, PDGF, TGF-α, TGF-β, and TNF-α. Dividing fibroblasts localize near the wound edge, an active tissue repair environment with tissue oxygen tensions of approximately 40 mm Hg in normally healing wounds. In cell culture, this Pao₂ is optimum for fibroblast replication. Smooth muscle cells are also likely progenitors because fibroblasts seem to migrate from the adventitia and media of wound vessels. Lipocytes, pericytes, and other cell sources may exist for terminal differentiation into repair fibroblasts.

Matrix synthesis

Fibroblasts secrete the collagen and proteoglycans of the connective tissue matrix that hold wound edges together and embed cells of the healing wound matrix. These extracellular molecules assume polymeric forms and become the physical basis of wound strength (Figure 6–2). Collagen synthesis is not a constitutive property of fibroblasts but must be signaled. The mechanisms that regulate the stimulation and synthesis of collagen are multifactorial and include both growth factors and metabolic inputs such as lactate. The collagen gene promoter has regulatory binding sites to stress corticoids, the TGF-β signaling pathway, and retinoids, which control collagen gene expression. Other growth factors regulate glycosaminoglycans, tissue inhibitors of metalloproteinase (TIMP), and fibronectin synthesis. The accumulation of lactate in the extracellular environment is shown to directly stimulate transcription of collagen genes as well as posttranslational processing of collagen peptides. It is clear that the redox state and energy stores of repair cells occupying the wound regulate collagen synthesis.

The increase in collagen messenger RNA (mRNA) leads to an increased procollagen peptide. This, however, is not sufficient to increase collagen deposition because procollagen peptide cannot be transported from the cell to the extracellular space until, in a posttranslational step, a proportion of its proline amino acids are hydroxylated. In this reaction, catalyzed by prolyl hydroxylase, an oxygen atom derived from dissolved O₂ is inserted (as a hydroxyl group) into selected collagen prolines in the presence of the cofactors ascorbic acid, iron, and α-ketoglutarate. Thus, accumulation of lactate, or any other process that decreases the nicotinamide adenine dinucleotide (NAD⁺) pool, leads to production of collagen mRNAs, increased collagen peptide synthesis, and (provided enough ascorbate and oxygen is present) increased posttranslational modification and secretion of collagen monomers into the extracellular space.

Another enzyme, lysyl hydroxylase, hydroxylates many of the procollagen lysines. A lysyl-to-lysyl covalent link then occurs between collagen molecules, maximizing mature collagen fiber strength. This process, too, requires adequate amounts of ascorbate and oxygen. These oxygenase reactions (and therefore collagen deposition) are rate limited by tissue oxygen level, Pao₂. The rates are half-maximal at about 20 mm Hg and maximal at about 200 mm Hg. Hydroxylation can be “forced” to supernormal rates by tissue hyperoxia. Collagen deposition, wound strength, and angiogenesis rates may be increased and accelerated as tissue Pao₂ is elevated.

C. Angiogenesis

Angiogenesis is required for wound healing. It is clinically evident about 4 days following injury but begins earlier when new capillaries sprout from preexisting venules and grow toward the injury in response to chemoattractants released by platelets and macrophages. In primarily closed wounds, budding vessels soon meet and fuse with counterparts migrating from the other side of the wound, establishing blood flow across the wound. In wounds left open, newly forming capillaries connect with adjacent capillaries migrating in the same direction, and granulation tissue forms. Numerous growth factors and cytokines are observed to stimulate angiogenesis, but animal experiments indicate that the dominant angiogenic stimulants in wounds are derived first from platelets in response to coagulation and then from macrophages in response to hypoxia or high lactate, fibrin, and its products.

D. Epithelialization

Epithelial cells respond to several of the same stimuli as fibroblasts and endothelial cells within the mesenchymal area of a wound. A variety of growth factors also regulate epithelial cell replication. TGF-α and keratinocyte growth factor (KGF), for instance, are potent epithelial cell mitogens. TGF-β tends to inhibit epithelial cells from differentiating and thus may potentiate and perpetuate mitogenesis, though it is itself not a mitogen for these cells. During wound healing, mitoses appear in the epithelium a few cells away from the wound edge. The new cells migrate over the cells at the edge and into the unhealed area and anchor to the first unepithelialized matrix position encountered. The Pao₂ on the underside of the cell at the anchor point is usually low. Low Pao₂ stimulates squamous epithelial cells to produce TGF-β, likely suppressing terminal differentiation and again supporting further mitosis. This process of epidermal-mesenchymal communication repeats itself until the wound is closed.

Squamous epithelialization and differentiation proceed maximally when surface wounds are kept moist. It is clear that even short periods of drying impair the process, and therefore wounds should not be allowed to desiccate. The exudates from acute, uninfected superficial wounds also contain growth factors and lactate, and therefore recapitulate the growth environment found at the base of the wound.

E. Collagen Fiber Remodeling and Wound Contraction

Remodeling of the wound extracellular matrix is also a well-regulated process. First, fibroblasts replace the provisional fibrin matrix with collagen monomers. Extracellular enzymes, some of which are Pao₂-dependent, quickly polymerize these monomers, initially in a pattern that is more random than in uninjured tissue, predisposing early wound to mechanical failure. Progressively, the very early provisional matrix is replaced with a more mature one by forming larger, better organized, stronger, and more durable collagen fibers. The very early wound provisional matrix usually mechanically fails within the matrix itself (days 0-5). Next, mechanical failure occurs at the matrix-tissue interface or fusion point (Figure 6–3). The mechanism for connecting the wound matrix to the uninjured tissue border is poorly understood.

Reorganization of the new matrix is an important feature of healing, and fibroblasts and leukocytes secrete collagenases that ensure the lytic component. Turnover occurs rapidly at first and then more slowly. Even in simple wounds, wound matrix turnover can be detected chemically for as long as 18 months. Healing is successful when a net excess of matrix is deposited despite concomitant lysis. Lysis, in contrast to anabolic synthesis, is less dependent upon energy and nutrition. If synthesis is impaired, however, lysis weakens wounds.

During rapid turnover, wounds normally gain strength and durability but are vulnerable to contraction or stretching. Fibroblasts exert the force for contraction. Fibroblasts attach to collagen and each other and pull the collagen network together when the cell membranes shorten as the fibroblasts migrate. The wound myofibroblast, a specialized phenotype, expresses intracellular actin filaments that also contribute force to fibroblast-mediated wound contraction. The collagen fibers are then fixed in the packed positions by a variety of cross-linking mechanisms. Both open and closed wounds tend to contract if not subjected to a superior counterforce. The phenomenon is best seen in surface wounds, which may close 90% or more by contraction alone in loose skin. For example, the residual of a large open wound on the back of the neck may be only a small area of epithelialization. On the back, the buttock, or the neck, this is often a beneficial process, whereas in the face and around joints, the results may be disabling or disfiguring. Pathological wound contraction is usually termed a contracture or a stricture. Skin grafts, especially thick ones, may minimize or prevent disabling wound contractures. Dynamic splints, passive or active stretching, or insertion of flaps containing dermis and subdermis also counteract contraction. Prevention of a stricture often depends on ensuring that opposing tissue edges are well perfused so that healing can proceed quickly to completion and contraction stops. Healing wounds may also stretch during active turnover when tension overcomes contraction. This may account for the laxity of scars in ligaments of injured but unsplinted joints and the tendency for incisional hernia formation in abdominal wounds of obese patients.

F. Healing of Specialized Tissues

Tissue other than skin heals generally by the same fundamental pathways. Although tissue structure may be specialized, the initial repair processes are shared. It does appear that the rate and efficiency of wound healing in different tissue types depends in large part on total collagen content, collagen organization, and blood supply.

Gastrointestinal tract

The rate of repair varies from one part of the intestine to the other in proportion to blood supply. Anastomoses of the colon and esophagus heal least reliably and are most likely to leak, whereas failure of stomach or small intestine anastomoses is rare. Intestinal anastomoses regain strength rapidly when compared to skin wounds. After 1 week, bursting strength may exceed the uninjured surrounding intestine. However, the surrounding intestine also participates in the reaction to injury, initially losing collagen by lysis, and as a result may lose strength. For this reason, leakage can occur a few millimeters from the anastomosis. A tight suture line causing ischemia will exacerbate this surgical problem.

The mesothelial cell lining of the peritoneum also is important for healing in the abdomen and GI tract. The esophagus and retroperitoneal colon lack a serosal mesothelial lining, which may contribute to failed wound healing. There is evidence that mesothelial cells signal the repair of peritoneal linings and are a source of repair cells.

Comorbidities that delay collagen synthesis or stimulate collagen lysis are likely to increase the risk of perforation and leakage. The danger of leakage is greatest from the fourth to seventh days, when tensile strength normally would rise rapidly but may be impeded by impaired collagen deposition or increased lysis. Local infection, which most often occurs near esophageal and colonic anastomoses, promotes lysis and delays synthesis, thus increasing the likelihood of perforation.

Bone

Bone healing is controlled by many of the same mechanisms that control soft tissue healing. It too occurs in predictable, morphologic stages: inflammation, fibroplasia, and remodeling. The duration of each stage varies depending on the location and extent of the fracture.

Injury (fracture) causes hematoma formation from the damaged blood vessels of the periosteum, endosteum, and surrounding tissues. Within hours, an inflammatory infiltrate of neutrophils and macrophages is recruited into the hematoma as in soft tissue injuries. Monocytes and granulocytes debride and digest necrotic tissue and debris, including bone, on the fracture surface. This process continues for days to weeks depending on the amount of necrotic tissue. As inflammation progresses to fibroplasia, the hematoma is progressively replaced by granulation tissue that can form bone. This bone wound tissue, known as callus, develops from both sides of the fracture and is composed of fibroblasts, endothelial cells, and bone-forming cells (chondroblasts, osteoblasts). As macrophages (osteoclasts) phagocytose the hematoma and injured tissue, fibroblasts (osteocytes) deposit a collagenous matrix, and chondroblasts deposit proteoglycans in a process called enchondral bone formation. This step, prominent in some bones, is then converted to bone as osteoblasts condense hydroxyapatite crystals at specific points on the collagen fibers. Endothelial cells form a vasculature structure characteristic of uninjured bone. Eventually the fibrovascular callus is completely replaced by new bone. Unlike healing of soft tissue, bone healing has features of regeneration, and bone often heals without leaving a scar.

Bone healing also depends on blood supply. Following injury, the ends of fractured bone are avascular. Osteocyte and blood vessel lacunae become vacant for several millimeters from the fracture. New blood vessels must sprout from preexisting ones and migrate into the area of injury. As new blood vessels cross the bone ends, they are preceded by osteoclasts just as macrophages precede them in soft tissue repair. In bone, this unit is called the cutting cone because it bores its way through bone in the process of connecting with other vessels. Excessive movement of the bone ends during this revascularization stage will break the delicate new vessels and delay healing. Osteomyelitis originates most often in ischemic bone fragments. Hyperoxygenation optimizes fracture healing and aids in the cure (and potentially the prevention) of osteomyelitis. Acute or chronic hypoxia slows bone repair.

Bone repair may occur through primary or secondary intention. Primary repair can occur only when the fracture is stable and aligned, and its surfaces closely apposed. This is the goal of rigid plate fixation or rod fixation of fractures. When these conditions are met, capillaries can grow across the fracture and rapidly reestablish a vascular supply. Little or no callus forms. Secondary repair with callus formation is more common. Once the fracture has been bridged, the new bone remodels in response to the mechanical stresses upon it, with restoration to normal or near-normal strength. During this process, as in soft tissue, preexisting bone and its vascular network are simultaneously removed and replaced. Increased bone turnover may be detected as long as 10 years after injury. Although remodeling is efficient, it cannot correct deformities of angulation or rotation in misaligned fractures. Careful fracture reduction is still important.

Bone repair can be manipulated. Electrical stimulation, growth factors, and distraction osteogenesis are three tools for this purpose. Electrical currents applied directly (through implanted electrodes) or induced by external alternating electromagnetic fields accelerate repair by inducing new bone formation in much the same way as small piezoelectric currents produced by mechanical deformation of intact bone controls remodeling along lines of stress. Electrical stimulation has been used successfully to treat nonunion of bone (where new bone formation between bone ends fails, often requiring long periods of bed rest). Bone morphogenetic protein (BMP)-impregnated implants have accelerated bone healing in animals and have been used with encouraging results to treat large bony defects and nonunions, including during spinal fusion.

The Ilizarov technique, linear distraction osteogenesis, can lengthen bones, stimulate bone growth across a defect, or correct defects of angulation. The Ilizarov device is an external fixator attached to the bones through metal pins or wires. A surgical break is created and then slowly pulled apart (1 mm/d) or slowly reangulated. The vascular supply and subsequent new bone formation migrate along with the moving segment of bone.

Effect of Tissue Hypoxia

Impaired perfusion and inadequate oxygenation are the most frequent causes of healing failure. Oxygen is required for successful inflammation, bactericidal activity, angiogenesis, epithelialization, and matrix (collagen) deposition. The critical collagen oxygenases involved have Km values for oxygen of about 20 mm Hg and maximums of about 200 mm Hg, meaning that reaction rates are regulated by Pao₂ and blood perfusion throughout the entire physiologic range. The Pao₂ of wound fluid in human incisions is about 30-40 mm Hg, suggesting that these enzymes normally function just beyond half capacity. Wound Pao₂ is depressed by hypovolemia, catecholamine infusion, stress, fear, or cold. Under ideal conditions, wound fluid Pao₂ can be raised above 100 mm Hg by improved perfusion and breathing of oxygen. Human healing is profoundly influenced by local blood supply, vasoconstriction, and all other factors that govern perfusion and blood oxygenation. Wounds in well-vascularized tissues (eg, head, anus) heal rapidly and are remarkably resistant to infection (Figure 6–4).

Dysregulated Inflammation During Impaired Wound Healing

Molecular growth signals and lytic enzymes released by inflammatory cells are necessary for repair. Inhibited or excessive inflammatory responses lead to wound complications. Failure to heal is common in patients taking anti-inflammatory corticosteroids, immune suppressants, or cancer chemotherapeutic agents that inhibit inflammatory cells. Open wounds are more effected than primarily repaired wounds. Anti-inflammatory drugs impair the wound less after the third day of healing, as the normal level of inflammation in wound healing is reduced. Inflammation may also be excessive. Increased wound inflammation (eg, in response to infection and endotoxin or foreign bodies like mesh implants during hernia repair) can stimulate inflammatory cells to produce cytolytic cytokines and excessive proteases with the consequence of pathologic lysis of newly formed tissue. A pathological cycle of wound healing may ensue and result in an impaired quantity and quality of wound scar.

Impaired Healing Due to Malnutrition

Malnutrition impairs healing, since healing depends on nucleic acid and protein synthesis, cell replication, specific organ function (liver, heart, lungs), and extracellular matrix production. Weight loss and protein depletion have been shown experimentally and clinically to be risk factors for poor healing. Deficient healing is seen mainly in patients with acute malnutrition (ie, in the weeks just before or after an injury or operation). Even a few days of starvation measurably impairs healing, and an equally short period of repletion can reverse the deficit. Wound complications increase in severe malnutrition. A period of preoperative corrective nutrition is generally helpful for patients who have recently lost 10% or more of their body weight.

Scar Formation Versus Regeneration

In excessive healing or proliferative scarring, it is as if the equilibrium point between collagen deposition and collagen lysis is never reached. It is unclear why some wounds seem to continue in the dysregulated repair process. Upregulation of fibroplastic growth factors like TGF-β is implicated during hypertrophic or keloid scar formation. Because the mechanism of excessive scar formation is unknown, there is no universally accepted treatment regimen. In a recent meta-analysis of pathologic scar treatments, the mean amount of improvement to be expected was only 60%. Hypertrophic scars are generally self-limited, are related to residual inflammation, and may regress after a year or so. Keloids by definition extend beyond the borders of the wound and are most common in pigmented skin. The last areas of a burn to heal are the most often hypertrophic, possibly due to traction, reinjury, and tension. Immune mechanisms may also contribute to pathological scar. Prolonged inflammatory reactions potentiate scar. Therapy includes intralesional injection of anti-inflammatory steroids and dressing with Silastic sheets, which are shown to increase protease-based lytic activity in the scar. Excessive or hypertrophic scarring is rare in burn injuries that heal within 21 days. Pressure garments or compression dressings are effective in decreasing scarring in burn injuries that require more than 21 days to heal. The exact mechanism by which pressure is effective is unknown.

Impediments to wound healing may be broadly categorized as those local to the wound, and those that are systemic comorbidities and diseases. Often, a clinical intervention is possible to minimize or eliminate these obstacles to tissue repair (Table 6–1).

Acute Wounds

Acute wounds express normal wound healing pathways and are expected to heal. Over days and weeks, the undisturbed acute wound can be observed to progress reliably through the phases of hemostasis, normal inflammation, normal fibroplasia, and ultimately scar maturation with epithelialization. The most common acute wound complications are pain, infection, mechanical dehiscence, and hypertrophic scar.

Chronic Wounds & Decubiti

A. Chronic Wounds

Chronically unhealed wounds, especially on the lower extremity, are common in the setting of vascular, immunologic, and neurologic disease. Venous ulcers, largely of the lower leg, reflect poor perfusion and perivascular leakage of plasma into tissue. The extravasation of plasma proteins into the soft tissue stimulates chronic inflammation. This is the result of venous hypertension produced by incompetent venous valves. Most venous ulcers will heal if the venous congestion and edema are relieved by leg elevation, compression stockings, or surgical procedures that eliminate or repair incompetent veins or their valves.

Arterial or ischemic ulcers, which tend to occur on the lateral ankle or foot, are best treated by revascularization. Hyperbaric oxygen, which provides a temporary source of enhanced oxygenation that stimulates angiogenesis, is an effective though expensive alternative when revascularization is not possible. Useful information can be obtained by transcutaneous oximetry. Tissues with a low Pao₂ will not heal spontaneously. However, if oxygen tension can be raised into a relatively normal range by oxygen administration even intermittently, the wound may respond to oxygen therapy.

Sensory loss, especially of the feet, can lead to ulceration. Bony deformities due to chronic fractures, like the Charcot deformity, cause pathologic pressure on wounded tissue. Ulcers in patients with diabetes mellitus may have two causes. Patients with neuropathic ulcers usually have good circulation, and their lesions will heal if protected from trauma by off-loading, special shoes, or splints. Recurrences are common, however. Diabetics with ischemic disease, whether they have neuropathy or not, are at risk for gangrene, and they frequently require amputation when revascularization is not possible.

In pyoderma gangrenosum, granulomatous inflammation, with or without arteritis, causes skin necrosis, possibly by a mechanism involving excess cytokine release. These ulcers are associated with inflammatory bowel disease and certain types of arthritis and chondritis. Corticosteroids or other anti-inflammatory drugs are helpful. However, anti-inflammatory corticosteroids can also contribute to poor healing by inhibiting cytokine release and collagen synthesis.

B. Decubiti

Decubitus ulcers can be major complications of immobilization. The morbidity of decubitus ulcers lengthens hospital stays and increases health care costs. They result from prolonged pressure that reduces tissue blood supply, irritative or contaminated injections, and prolonged contact with moisture, urine, or feces. Most patients who develop decubitus ulcers are also poorly nourished. Pressure ulcers are common in paraplegics, immobile elderly patients following fractures, and intensive care unit patients. The ulcers vary in depth and often extend from skin to a bony pressure point such as the greater trochanter, the sacrum, the heels, or the head. Most decubitus ulcers are preventable. Hospital-acquired ulcers are nearly always the result of immobilization, unprotected positioning on operating tables, and ill-fitting casts or other orthopedic appliances.

Wound Infection

A wound infection results when bacterial proliferation and invasion overcomes wound immune defense mechanisms. When an imbalance in this quantitative equilibrium results in infection, a delay in wound healing occurs. Therefore, prevention and treatment of wound infection involves maintenance or reestablishment of the balanced equilibrium.

Wounds containing more than 10⁵ bacteria/gram of tissue or any tissue level of β-hemolytic streptococci are at high risk for wound infection if closed by direct wound edge approximation, skin graft, pedicled, or free flap. Clean-contaminated and contaminated wounds result in high rates of postoperative infection (6%-15%), while clean cases have lower infection rates (1%-3%). When wounds are considered at risk for having a significant bacterial bioburden (clean-contaminated or contaminated cases), prophylactic operative antibiotics reduce wound infection rates. Wounds following clean cases with negligible bacterial bioburden do not clearly benefit from prophylactic antibiotics except when implanted prosthetic materials are used.

Mechanical Wound Failure

Mechanical factors play an important and often underappreciated role in acute wound healing. Primary closure of an incision stabilizes distractive forces to allow wound healing and an optimized anatomic result (Figure 6–5). Cellular studies confirm that mechanical load forces are an important signal for acute wound repair. When anatomic stability of a wound is achieved, a particular suture material or suturing technique is of secondary importance. The increased use of foreign material implants, like meshes for hernia repair, are suggested to manipulate the mechanical environment of the acute wound, even to the point of promoting “tension-free” wound healing. Negative pressure wound therapy is increasingly applied to stabilize acute wounds and to support acute wound healing. Mechanical microdeformation of repair cells in the wound bed is thought to stimulate acute wound healing.

Mechanical signaling pathways are important for the regulation of tissue repair, especially in load-bearing structures like the abdominal wall and Achilles tendon. From this perspective, the midline fascia behaves more like a ligament or tendon than skin, for example. It is observed that scars placed under mechanical loads ultimately will assume the morphology and function of tendons and, conversely, that incisions placed under “low” loads organize scars with reduced tensile strengths. The empiric observation that a suture length (SL)–wound length (WL) ratio of 4:1 results in the most reliable midline abdominal wall closure may reflect the technique resulting in establishing the optimal acute wound healing–load set point for the abdominal wall. When a laparotomy wound mechanically fails, a fundamental repair signal may be lost, contributing to the biology of hernia formation. Clinically, laparotomy dehiscence of only 12 mm on postoperative day 30 predicts a 94% incisional hernia rate after 3 years.

Acute Wounds

A. Sutures

The ideal suture material is flexible, strong, easily tied, and securely knotted. It stimulates little tissue reaction and does not serve as a nidus for infection.

Silk is an animal protein but is relatively inert in human tissue. It is commonly used because of its track record and favorable handling characteristics. It loses strength over long periods and is unsuitable for suturing arteries to plastic grafts or for insertion of prosthetic cardiac valves. Silk sutures are multifilament, providing mechanical immune barriers for bacteria. Occasionally, silk sutures form a focus for small abscesses that migrate and “spit” through the skin, forming small sinuses that will not heal until the suture is removed.

Synthetic nonabsorbable sutures are generally inert polymers that retain strength. However, their handling characteristics are not as good as those of silk, and they must usually be knotted at least four times, resulting in increased amounts of retained foreign material. Multifilament plastic sutures may also become infected and migrate to the surface like silk sutures. Monofilament plastics will not harbor bacteria. Nylon monofilament is extremely nonreactive, but it is difficult to tie. Monofilament polypropylene is intermediate in these properties. Vascular anastomoses to prosthetic vascular grafts rely indefinitely on the strength of sutures; therefore, use of absorbable sutures may lead to aneurysm formation.

Synthetic absorbable sutures are strong, have predictable rates of loss of tensile strength, incite a minimal inflammatory reaction, and have special usefulness in gastrointestinal, urologic, and gynecologic operations that are contaminated. Polyglycolic acid and polyglactin retain tensile strength longer in gastrointestinal anastomoses. Polydioxanone sulfate and polyglycolate are monofilament and lose about half their strength in 50 days, thus solving the problem of premature breakage in fascial closures. Poliglecaprone monofilament synthetic sutures have faster reabsorption, retaining 50% tensile strength at 7 days and 0% at 21 days. This suture is suitable for low-load soft tissue approximation but is not intended for fascial closure.

Stainless steel wire is inert and maintains strength for a long time. It is difficult to tie and may have to be removed late postoperatively because of pain. It does not harbor bacteria, and it can be left in granulating wounds, when necessary, and will be covered by granulation tissue without causing abscesses. However, sinuses due to motion are fairly common.

Catgut (now made from the submucosa of bovine intestine) will eventually resorb, but the resorption time is highly variable. It stimulates a considerable inflammatory reaction and tends to potentiate infections. Catgut also loses strength rapidly and unpredictably in the intestine and in infected wounds as a consequence of acid and enzyme hydrolysis.

Staples, whether for internal use or skin closure, are mainly steel-tantalum alloys that incite a minimal tissue reaction. The technique of staple placement is different from that of sutures, but the same basic rules pertain. There are no real differences in the healing that follows sutured or stapled closures. Stapling devices tend to minimize errors in technique, but at the same time, they do not offer a feel for tissue and have limited ability to accommodate to exceptional circumstances. Staples are preferable to sutures for skin closure, since they do not provide a conduit for contaminating organisms. There is no reliable evidence that absorbable sutures lead to more incisional hernias or gastrointestinal anastomotic leaks.

Surgical glues or tissue adhesives are now established as safe and effective for the repair of small skin incisions. The most common forms are cyanoacrylate-based glues. Tissue adhesives are often less painful than sutures or staples, and the seal can serve as the wound dressing as well.

Surgical Technique

Primarily closed wounds are of a smaller volume and heal mainly by the synthesis of a new matrix. Wound contraction and epithelialization, as in an open wound healing by secondary intent, contribute a small part to primary wound healing. An open wound, healing by secondary intent, must synthesize granulation tissue to fill in the wound bed, contract at the wound periphery, and cover the surface area with epithelial cells. Wounds heal faster following delayed primary closure than by secondary intent, as well. The mechanical load forces transmitted through a primarily reconstructed wound will stimulate repair. Successful delayed primary closure requires that the acute wound be in bacterial balance. Primary repair should approximate, but not strangulate, the incision. The type of suture material used does not matter, as long as the primary repair is anatomic and perfused.

The most important means of achieving optimal healing after operation is good surgical technique. Many cases of surgical wound failure are due to technical errors. Tissue should be protected from drying and contamination. The surgeon should use fine instruments; should perform clean, sharp dissection; and should make minimal, skillful use of electrocautery, ligatures, and sutures. All these precautions contribute to the most important goal of surgical technique, gentle handling of tissue. Anatomic tissue approximation should be achieved when possible but optimum tissue perfusion preserved.

A. Wound Closure

As with many surgical techniques, the exact method of wound closure may be less important than how well it is performed. The tearing strength of sutures in fascia is no greater than 4 kg. There is little reason to use sutures of greater strength than this. Excessively tight closure strangulates tissue, likely leading to hernia formation or infection.

The most reliable laparotomy closure uses a continuous technique at SL-WL ratio of 4:1, which allows for the normal 10% strain that occurs along the length of the incision, while maintaining mechanical integrity. A 4:1 SL-WL ratio is achieved with suture placed 1-cm deep on normal fascia (the bite) followed by 1 cm of progress. The depth of the suture-line bite must extend beyond the wound lytic zone. Normal collagen lysis occurs for approximately 5 mm perpendicular to the incision, weakening the adjacent fascia. The most common technical causes of dehiscence are an SL-WL ratio less than 4:1, infection, and excessively tight sutures. Tight suture lines impair wound perfusion and oxygen delivery that is required for wound healing. If wound healing is impaired, wider, interrupted internal retention sutures may be added, although improved outcomes are not proven (Figure 6–6).

Delayed primary closure is a technique by which the subcutaneous portion of the wound is left open for 4-5 days prior to primary repair. During the delay period, angiogenesis and fibroplasia start, and bacteria are cleared from the wound. The success of this method depends on the ability of the surgeon to detect the signs of wound infection. Merely leaving the wound open for 4 days does not guarantee that it will not become infected. Some wounds (eg, fibrin-covered or inflamed wounds) should not be closed but should be left open for secondary closure. Quantitative bacterial counts less than 10⁵ non–β-hemolytic streptococcus organisms per gram of wound tissue predict successful healing after delayed primary closure. Any level of β-hemolytic streptococcal wound infection predicts delayed wound healing.

Implantable Materials

Soft tissue prostheses reduce the incidence of wound failure and recurrence following hernia repair. The recurrence rate following inguinal hernia repairs using autologous tissues ranges from 5% to 25% in most series. The recurrence rate following primary incisional hernia repair using autologous tissues is even worse, ranging from 20% to 60%. The introduction of synthetic soft tissue prostheses to inguinal and incisional hernia repair has significantly reduced recurrence rates across general surgery. The prevailing view is that the mechanism for the reduced hernia recurrence rates is the reduction of tension along suture lines when using mesh and the replacement abnormal tissue.

No implantable prosthesis is ideal in regard to tissue compatibility, permanent fixation, and resistance to infection. Two principles are paramount: biocompatibility and a material that is incorporated into tissue. Both specific and nonspecific immune mechanisms are involved in the inflammatory reaction to foreign materials. Highly incompatible materials, such as wood splinters, elicit an acute inflammatory process that includes massive local release of proteolytic enzymes (inflammation). Consequently, the foreign body is never incorporated and instead is isolated loosely in a fibrous pocket. In less severe incompatibility, rejection is not so vigorous and proteolysis is not so prominent. Mononuclear cells and lymphocytes, the major components of wound inflammatory tissue, direct a response that creates a fibrous capsule that may be acceptable in a joint replacement but may distort a breast reconstruction (encapsulation). Newer biological prostheses are composed of acellularized tissue to abrogate the immune response. The expectation is that these materials recellularize with host cells and blood vessels during incorporation and assume a more physiological function (regeneration).

Most implants must become anchored to adjacent normal tissues through fibrous tissue ingrowth. This process requires biocompatibility and interstices large enough to permit repair fibroblast migration, just as in a wound, and to allow pedicles of vascularized tissue to enter and join similar units. In bone, this tissue incorporation imparts stability. In vascular grafts, the invading tissue supports neointima formation, which retards mural thrombosis and distal embolization. Soft tissue will grow into pores larger than about 50 μm in diameter. Of the vascular prostheses, woven Dacron is best for tissue incorporation. In bone, sintered, porous metallic surfaces are best. Large-screen polypropylene mesh can be used to support the abdominal wall or chest and is usually well incorporated into the granulation tissue that penetrates the mesh. Mesh porosity is increasingly recognized as an important design element for reliable implantation and wound healing. Microporous polytetrafluoroethylene (PTFE) sheets are often not well incorporated and are not suitable for use in infected tissues.

The implantation space remains vulnerable to infection for years and is a particular problem in implants that cross the body surface. Mesh cuffs around vascular access devices that incite incorporation have successfully forestalled infection for months, but infections that arise from bacteria entering the body along “permanently” implanted foreign bodies traversing the skin surface, such as ventricular assist devices, remain an unsolved problem.

Negative Pressure Wound Therapy

Negative pressure wound therapy (NPWT) mechanically stabilizes the distractive forces of an open acute wound and supports healing. Distractive tissue forces keep a wound open with force vectors that oppose wound contraction, thereby delaying healing. NPWT also reduces periwound edema and improves wound perfusion. NPWT may directly stimulate repair fibroblast activity through mechanical microdeformation of the cell surface.

NPWT can also stabilize a therapeutically open abdomen (laparotomy), minimizing wound size and supporting closure of the abdominal wall. Distractive force from the rectus muscle components and lateral oblique muscles acts to keep the laparotomy open, leading to incisional hernia formation and potentially loss of abdominal, peritoneal volume (domain) (Figure 6–7).

A. Chronic Wounds

The first principle in managing chronic wounds is to diagnose and treat tissue hypoxia, such as underlying circulatory disease. The second principle is never to allow open wounds to dry—that is, use moist dressings, which may also relieve pain. A third principle is to control any infection with topical or systemic antibiotics. A fourth principle is to recognize that chronically scarred or necrotic tissue is usually poorly perfused. Debridement of unhealthy tissue, often followed by skin grafting, may be required for healing. A fifth principle is to reduce autonomic vasoconstriction by means of warmth, moisture, and pain relief.

A number of growth factors have been shown to accelerate healing of acute wounds in animals. They include FGFs, TGF-β, IGF-1, PDGF, and epidermal growth factor (EGF). However, in the setting of chronic human wounds, with the perfusion problems noted above and the hostile wound environment with elevated protease levels, proof of efficacy has been difficult to develop, and no clear-cut advantage to any formulation has yet been convincingly demonstrated. The one exception is the randomized, prospective, double-blind, placebo-controlled multicenter trial by the Diabetic Ulcer Study Group, which demonstrated that daily topical application of recombinant human PDGF-BB homodimer moderately accelerated healing and resulted in more wounds that healed completely.

B. Ducubiti

The first principle is to incise and drain any infected spaces or debride necrotic tissue. Dead tissue is debrided until the exposed surfaces are viable. Sources of pressure must again be unloaded. Many will then heal spontaneously. However, deep ulcers may require surgical closure, sometimes with removal of underlying bone. The defect may require closure by judicious movement of thick, well-vascularized tissue into the affected area. Musculocutaneous flaps are the treatment of choice when chronic infection and significant tissue loss are combined. However, recurrence is common because the flaps are usually insensate.

Postoperative Care

Optimum postoperative care of the wound requires cleanliness, maintenance of a moist wound environment, protection from trauma, and support of the patient. Even closed wounds can be infected by surface contamination, particularly within the first 2-3 days. Bacteria gain entrance most easily through suture tracts. If a wound is likely to be traumatized or contaminated, it should be protected during this time. Such protection may require special dressings such as occlusive dressings or sprays and repeated cleansing.

Some mechanical stress enhances healing. Even fracture callus formation is greater if slight motion is allowed. Patients should move and stress their wounds a little. Early ambulation and return to normal activity are, in general, good for repair.

The appearance of delayed wound infections, weeks to years after operation, reinforces that all wounds are contaminated and may harbor bacteria. Most frequently, poor tissue perfusion and oxygenation of the wound during the postoperative period weakens host resistance. Regulation of perfusion is largely due to sympathetic nervous activity. The major stimuli of vasoconstriction are cold, pain, hypovolemia, cigarette smoking, and hypoxemia. Recent studies show that efforts to limit these impediments to wound healing reduce the wound infection rate by more than half. Maintenance of intraoperative normothermia and blood volume is particularly important. Appropriate assurance that peripheral perfusion is adequate is best obtained from peripheral tissues rather than urine output, central venous pressure, or wedge pressure, none of which correlate with peripheral wound tissue oxygenation. What does correlate with tissue oxygenation is the capillary refill time on the forehead or patella, which should be less than 2 and 5 seconds respectively. Collagen deposition is increased also by the addition of oxygen breathing (nasal prongs or light mask) but only in well-perfused patients.

The ideal care of the wound begins in the preoperative period and ends only months later. The patient must be prepared so that optimal conditions exist when the wound is made. Surgical technique must be clean, gentle, and skillful. Nutrition should be optimized preoperatively when possible. Cessation of cigarette smoking will improve wound outcomes. Postoperatively, wound care includes maintenance of nutrition, blood volume, oxygenation, and careful restriction of immunosuppressant drugs when possible. Although wound healing is in many ways a local phenomenon, ideal care of the wound is essentially ideal care of the patient.

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