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Part 1 PRINCIPLES OF MEDICINE, SURGERY, AND ANESTHESIA
CHAPTER 1 Wound Healing Vivek Shetty, DDS, Dr.Med.Dent. Charles N. Bertolami, DDS, D.Med.Sc. The healing wound is an overt expression of an intricate and tightly choreographed sequence of cellular and biochemical responses directed toward restoring tissue integrity and functional capacity following injury. Although healing culminates uneventfully in most instances, a variety of intrinsic and extrinsic factors can impede or facilitate the process. Understanding wound healing at multiple levels—bio- chemical, physiologic, cellular, and molec- ular—provides the surgeon with a framework for basing clinical decisions aimed at optimizing the healing response. Equally important it allows the surgeon to critically appraise and selectively use the growing array of biologic approaches that seek to assist healing by favorably modulating the wound microenvironment. The Healing Process The restoration of tissue integrity, whether initiated by trauma or surgery, is a phylogenetically primitive but essential defense response. Injured organisms survive only if they can repair themselves quickly and effectively. The healing response depends primarily on the type of tissue involved and the nature of the tissue disruption. When restitution occurs by means of tissue that is structurally and functionally indistinguishable from native tissue, regeneration has taken place. However, if tissue integrity is reestablished primarily through the formation of fibrotic scar tissue, then repair has occurred. Repair by scarring is the body’s version of a spot weld and the replacement tissue is coarse and has a lower cellular content than native tissue. With the exception of bone and liver, tissue disruption invariably results in repair rather than regeneration. At the cellular level the rate and quality of tissue healing depends on whether the constitutive cells are labile, stable, or permanent. Labile cells, including the keratinocytes of the epidermis and epithelial cells of the oral mucosa, divide throughout their life span. Stable cells such as fibroblasts exhibit a low rate of duplication but can undergo rapid proliferation in response to injury. For example, bone injury causes pluripotential mesenchymal cells to speedily differentiate into osteoblasts and osteoclasts. On the other hand permanent cells such as specialized nerve and cardiac muscle cells do not divide in postnatal life. The surgeon’s expectation of “normal healing” should be correspondingly realistic and based on the inherent capabilities of the injured tissue. Whereas a fibrous scar is normal for skin wounds, it is suboptimal in the context of bone healing. At a more macro level the quality of the healing response is influenced by the nature of the tissue disruption and the circumstances surrounding wound closure. Healing by first intention occurs when a clean laceration or surgical incision is closed primarily with sutures or other means and healing proceeds rapidly with no dehiscence and minimal scar formation. If conditions are less favorable, wound healing is more complicated and occurs through a protracted filling of the tissue defect with granulation and connective tissue. This process is called healing by second intention and is commonly associated with avulsive injury, local infection, or inadequate closure of the wound. For more complex wounds, the surgeon may attempt healing by third intention through a staged procedure that combines secondary healing with delayed primary closure. The avulsive or contaminated wound is débrided and allowed to granulate and heal by second intention for 5 to 7 days. Once adequate granulation tissue has formed and the risk of infection appears minimal, the wound is sutured close to heal by first intention. Wound Healing Response Injury of any kind sets into motion a complex series of closely orchestrated and temporally overlapping processes directed toward restoring the integrity of the involved tissue. The reparative processes are most commonly modeled in skin1; however, similar patterns of biochemical and cellular events occur in virtually every other tissue.2 To facilitate description, the healing continuum of coagulation, inflammation, reepithelialization, granulation
Part 1: Principles of Medicine, Surgery, and Anesthesia tissue, and matrix and tissue remodeling is typically broken down into three distinct overlapping phases: inflammatory, proliferative, and remodeling.3,4 Inflammatory Phase The inflammatory phase presages the body’s reparative response and usually lasts for 3 to 5 days. Vasoconstriction of the injured vasculature is the spontaneous tissue reaction to staunch bleeding. Tissue trauma and local bleeding activate factor XII (Hageman factor), which initiates the various effectors of the healing cascade including the complement, plasminogen, kinin, and clotting systems. Circulating platelets (thrombocytes) rapidly aggregate at the injury site and adhere to each other and the exposed vascular subendothelial collagen to form a primary platelet plug organized within a fibrin matrix. The clot secures hemostasis and provides a provisional matrix through which cells can migrate during the repair process. Additionally the clot serves as a reservoir of the cytokines and growth factors that are released as activated platelets degranulate (Figure 1-1). The bolus of secreted proteins, including interleukins, transforming growth factor ß (TGF-ß), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), maintain the wound milieu and regulate subsequent healing.1 Once hemostasis is secured the reactive vasoconstriction is replaced by a more persistent period of vasodilation that is mediated by histamine, prostaglandins, kinins, and leukotrienes. Increasing vascular permeability allows blood plasma and other cellular mediators of healing to pass through the vessel walls by diapedesis and populate the extravascular space. Corresponding clinical manifestations include swelling, redness, heat, and pain. Cytokines released into the wound provide the chemotactic cues that sequentially recruit the neutrophils and monocytes to the site of injury. Neutrophils normally begin arriving at the wound site within minutes of injury and rapidly establish themselves as the predominant cells. Migrating through the scaffolding provided by the fibrin-enriched clot, the shortlived leukocytes flood the site with proteases and cytokines to help cleanse the wound of contaminating bacteria, devitalized tissue, and degraded matrix components. Neutrophil activity is accentuated by opsonic antibodies leaking into the wound from the altered vasculature. Unless a wound is grossly infected, neutrophil infiltration ceases after a few days. However, the proinflammatory cytokines released by perishing neutrophils, including tumor necrosis factor a (TNF-a) and interleukins (IL-1a, IL-1b), continue to stimulate the inflammatory response for extended periods.5 Deployment of bloodborne monocytes to the site of injury starts peaking as the levels of neutrophils decline. Activated monocytes, now termed macrophages, continue with the wound microdébridement initiated by the neutrophils. They secrete collagenases and elastases to break down injured tissue and phagocytose bacteria and cell debris. Beyond their scavenging role the macrophages also serve as the primary source of healing mediators. Once activated, macrophages release a battery of growth factors and cytokines (TGF-a,TGF-ß1, PDGF, insulin-like growth factor [IGF]-I and -II, TNF-a, and IL-1) at the wound site, further amplifying and perpetuating the action of the chemical and cellular mediators released previously by degranulating platelets and neu- trophils.6 Macrophages influence all phases of early wound healing by regulating local tissue remodeling by proteolytic enzymes (eg, matrix metalloproteases and collagenases), inducing formation of new extracellular matrix, and modulating angiogenesis and fibroplasia through local production of cytokines such as throm- bospondin-1 and IL-1b. The centrality of Platelet plug FGF-2 MMP PDGFPDGF TGF-3 TGF-2 TGF-1 TGF-1 TGF-1 Macrophage Fibrin clot Growth factors Blood vessel Blood vessel Epidermis Epidermis Dermis Dermis Fibroblast Fibroblast Fat FIGURE 1-1 Immediately following wounding, platelets facilitate the formation of a blood clot that secures hemostasis and provides a temporary matrix for cell migration. Cytokines released by activated macrophages and fibroblasts initiate the formation of granulation tissue by degrading extracellular matrix and promoting development of new blood vessels. Cellular interactions are potentiated by reciprocal signaling between the epidermis and dermal fibroblasts through growth factors, MMPs, and members of the TGF-ßfamily. FGF = fibroblast growth factor; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; TGF-ß= transforming growth factor beta. Adapted from Bissell MJ and Radisky D.70
macrophage function to early wound healing is underscored by the consistent finding that macrophage-depleted animal wounds demonstrate diminished fibroplasia and defective repair. Although the numbers and activity of the macrophages taper off by the fifth post injury day, they continue to modulate the wound healing process until repair is complete. Proliferative Phase The cytokines and growth factors secreted during the inflammatory phase stimulate the succeeding proliferative phase (Figure 1-2).7 Starting as early as the third day post injury and lasting up to 3 weeks, the proliferative phase is distinguished by the formation of pink granular tissue (granulation tissue) containing inflammatory cells, fibroblasts, and budding vasculature enclosed in a loose matrix. An essential first step is the establishment of a local microcirculation to supply the oxygen and nutrients necessary for the elevated metabolic needs of regenerating tissues. The generation of new capillary blood vessels (angiogenesis) from the interrupted vasculature is driven by wound hypoxia as well as with native growth factors, particularly VEGF, fibroblast growth factor 2 (FGF-2), and TNF-ß (see Figure 1-2). Around the same time, matrix-generating fibroblasts migrate into the wound in response to the cytokines and growth factors released by inflammatory cells and wounded tissue. The fibroblasts start synthesizing new extracellular matrix (ECM) and immature collagen (Type III). The scaffold of collagen fibers serves to support the newly formed blood vessels supplying the wound. Stimulated fibroblasts also secrete a range of growth factors, thereby producing a feedback loop and sustaining the repair process. Collagen deposition rapidly increases the tensile strength of the wound and decreases the reliance on closure material to hold the wound edges together. Once adequate collagen and ECM have been generated, Wound Healing MMPs Fibrin clot Blood vessel Blood vessel Epidermis Epidermis Dermis Dermis Fibroblast Fat u-PA t-PA FIGURE 1-2 The cytokine cascade mediates the succedent proliferative phase. This phase is distinguished by the establishment of local microcirculation and formation of extracellular matrix and immature collagen. Epidermal cells migrate laterally below the fibrin clot, and granulation tissue begins to organize below the epithelium. MMPs = matrix metalloproteinases; t-PA = tissue plasminogen activator; u-PA = urinary plasminogen activator. Adapted from Bissell MJ and Radisky D.70 matrix synthesis dissipates, evidencing the highly precise spatial and temporal regulation of normal healing. At the surface of the dermal wound new epithelium forms to seal off the denuded wound surface. Epidermal cells originating from the wound margins undergo a proliferative burst and begin to resurface the wound above the basement membrane. The process of reepithelialization progresses more rapidly in oral mucosal wounds in contrast to the skin. In a mucosal wound the epithelial cells migrate directly onto the moist exposed surface of the fibrin clot instead of under the dry exudate (scab) of the dermis. Once the epithelial edges meet, contact inhibition halts further lateral proliferation. Reepithelialization is facilitated by underlying contractile connective tissue, which shrinks in size to draw the wound margins toward one another. Wound contraction is driven by a proportion of the fibroblasts that transform into myofibroblasts and generate strong contractile forces. The extent of wound contraction depends on the depth of the wound and its location. In some instances the forces of wound contracture are capable of deforming osseous structures. Remodeling Phase The proliferative phase is progressively replaced by an extended period of progressive remodeling and strengthening of the immature scar tissue. The remodel- ing/maturation phase can last for several years and involves a finely choreographed balance between matrix degradation and formation. As the metabolic demands of the healing wound decrease, the rich network of capillaries begins to regress. Under the general direction of the cytokines and growth factors, the collagenous matrix is continually degraded, resynthesized, reorganized, and stabilized by molecular crosslinking into a scar. The fibroblasts start to disappear and the collagen Type III deposited during the granulation phase is gradually replaced by stronger Type I collagen. Correspondingly the tensile strength of the scar tissue
Part 1: Principles of Medicine, Surgery, and Anesthesia gradually increases and eventually approaches about 80% of the original strength. Homeostasis of scar collagen and ECM is regulated to a large extent by serine proteases and matrix metalloproteinases (MMPs) under the control of the regulatory cytokines. Tissue inhibitors of the MMPS afford a natural counterbalance to the MMPs and provide tight control of proteolytic activity within the scar. Any disruption of this orderly balance can lead to excess or inadequate matrix degradation and result in either an exuberant scar or wound dehiscence. Specialized Healing Nerve Injury to the nerves innervating the orofacial region may range from simple contusion to complete interruption of the nerve. The healing response depends on injury severity and extent of the injury.8–10 Neuropraxia represents the mildest form of nerve injury and is a transient interruption of nerve conduction without loss of axonal continuity. The continuity of the epineural sheath and the axons is maintained and morphologic alterations are minor. Recovery of the functional deficit is spontaneous and usually complete within 3 to 4 weeks. If there is a physical disruption of one or more axons without injury to stromal tissue, the injury is described as axonotmesis. Whereas individual axons are severed, the investing Schwann cells and connective tissue elements remain intact. The nature and extent of the ensuing sensory or motor deficit relates to the number and type of injured axons. Morphologic changes are manifest as degeneration of the axoplasm and associated structures distal to the site of injury and partly proximal to the injury. Recovery of the functional deficit depends on the degree of the damage. Complete transection of the nerve trunk is referred to as neurotmesis and spontaneous recovery from this type of injury is rare. Histologically, changes of degeneration are evident in all axons adjacent to the site of injury.11 Shortly after nerve severance, the investing Schwann cells begin to undergo a series of cellular changes called wallerian degeneration. The degeneration is evident in all axons of the distal nerve segment and in a few nodes of the proximal segment. Within 78 hours injured axons start breaking up and are phagocytosed by adjacent Schwann cells and by macrophages that migrate into the zone of injury. Once the axonal debris has been cleared, Schwann cell outgrowths attempt to connect the proximal stump with the distal nerve stump. Surviving Schwann cells proliferate to form a band (Büngner’s band) that will accept regenerating axonal sprouts from the proximal stump. The proliferating Schwann cells also promote nerve regeneration by secreting numerous neurotrophic factors that coordinate cellular repair as well as cell adhesion molecules that direct axonal growth. In the absence of surgical realignment or approximation of the nerve stumps, proliferating Schwann cells and outgrowing axonal sprouts may align within the randomly organized fibrin clot to form a disorganized mass termed neuroma. The rate and extent of nerve regeneration depend on several factors including type of injury, age, state of tissue nutrition, and the nerves involved. Although the regeneration rate for peripheral nerves varies considerably, it is generally considered to approximate 1 mm/d. The regeneration phase lasts up to 3 months and ends on contact with the end-organ by a thin myelinated axon. In the concluding maturation phase both the diameter and performance of the regenerating nerve fiber increase. Bone The process of bone healing after a fracture has many features similar to that of skin healing except that it also involves calcification of the connective tissue matrix. Bone is a biologically privileged tissue in that it heals by regeneration rather than repair. Left alone, fractured bone is capable of restoring itself spontaneously through sequential tissue formation and differentiation, a process also referred to as indirect healing. As in skin the interfragmentary thrombus that forms shortly after injury staunches bleeding from ruptured vessels in the haversian canals, marrow, and periosteum. Necrotic material at the fracture site elicits an immediate and intense acute inflammatory response which attracts the polymorphonuclear leukocytes and subsequently macrophages to the fracture site. The organizing hematoma serves as a fibrin scaffold over which reparative cells can migrate and perform their function. Invading inflammatory cells and the succeeding pluripotential mesenchymal cells begin to rapidly produce a soft fracture callus that fills up interfragmentary gaps. Comprised of fibrous tissue, cartilage, and young immature fiber bone, the soft compliant callus acts as a biologic splint by binding the severed bone segments and damping interfragmentary motion. An orderly progression of tissue differentiation and maturation eventually leads to fracture consolidation and restoration of bone continuity. More commonly the surgeon chooses to facilitate an abbreviated callus-free bone healing termed direct healing (Figure 1-3). The displaced bone segments are surgically manipulated into an acceptable alignment and rigidly stabilized through the use of internal fixation devices. The resulting anatomic reduction is usually a combination of small interfragmentary gaps separated by contact areas. Ingrowth of mesenchymal cells and blood vessels starts shortly thereafter, and activated osteoblasts start depositing osteoid on the surface of the fragment ends. In contact zones where the fracture ends are closely apposed, the fracture line is filled concentrically by lamellar bone. Larger gaps are filled through a succession of fibrous
Wound Healing7tissue,fibrocartilage,and woven bone.Inthe absence ofany microinstability at thefracture site,direct healing takes placewithout any callus formation. Subsequent bone remodeling eventual- ly restores the original shape and internalarchitecture ofthe fractured bone.Func- tional sculpting and remodeling oftheprimitive bone tissue is carried out by atemporary team ofjuxtaposed osteoclastsand osteoblasts called the basic multicellu- lar unit (BMU).The osteoblasts developfrom pluripotent mesenchymal stem cellswhereas multicellular osteoclasts arise froma monocyte/macrophage lineage.12Thedevelopment and differentiation oftheBMUs are controlled by locally secretedgrowth factors,cytokines,and mechanicalsignals.As osteoclasts at the leading edge ofthe BMUs excavate bone through prote- olytic digestion,active osteoblasts move in, secreting layers ofosteoid and slowly refill- ing the cavity.The osteoid begins to miner- alize when it is about 6 µm thick.Osteo- clasts reaching the end oftheir lifespan of2 weeks die and are removed by phagocytes. The majority (up to 65%) ofthe remodel- ing osteoblasts also die within 3 monthsand the remainder are entombed inside themineralized matrix as osteocytes. While the primitive bone mineralizes, remodeling BMUs cut their way throughthe reparative tissue and replace it withmature bone.The “grain”ofthe new bonetissue starts paralleling local compressionand tension strains.Consequently theshape and strength ofthe reparative bonetissue changes to accommodate greaterfunctional loading.Tissue-level strainsproduced by functional loading play animportant role in the remodeling oftheregenerate bone.Whereas low levels oftis- sue strain (~2,000 microstrains) are con- sidered physiologic and necessary for celldifferentiation and callus remodeling, high strain levels (> 2,000 microstrains) begin to adversely affect osteoblastic dif- ferentiation and bone matrix forma- tion.13,14Ifthere is excess interfragmentarymotion,bone regenerates primarilythrough endochondral ossification or theformation ofa cartilaginous callus that isgradually replaced by new bone.In con- trast osseous healing across stabilized frac- ture segments occurs primarily throughintramembranous ossification.Major fac- tors determining the mechanical milieu ofa healing fracture include the fracture con- figuration,the accuracy offracture reduc- tion,the stability afforded by the selectedfixation device,and the degree and natureofmicrostrains provoked by function.Ifafracture fixation device is incapable ofsta- bilizing the fracture,the interfragmentarymicroinstability provokes osteoclasticresorption ofthe fracture surfaces andresults in a widening ofthe fracture gap. Although bone union may be ultimatelyachieved through secondary healing bycallus production and endochondral ossi- fication,the healing is protracted.Fibroushealing and nonunions are clinical mani- festations ofexcessive microstrains inter- fering with the cellular healing process. Extraction Wounds The healing ofan extraction socket is a spe- cialized example ofhealing by secondintention.15Immediately after the removalofthe tooth from the socket,blood fills theextraction site.Both intrinsic and extrinsicpathways ofthe clotting cascade are activat- ed.The resultant fibrin meshwork contain- ing entrapped red blood cells seals offtheGap healingContact healingOsteoblastBasic multicellular unit OsteoclastOsteocyteBlood vesselFIGURE1-3Direct bone healing facilitated by a lag screw.The fracture site shows both gap healing and contact healing.The internal archi- tecture ofbone is restored eventually by the action ofbasic multicellular units.
Part 1: Principles of Medicine, Surgery, and Anesthesia torn blood vessels and reduces the size of the extraction wound. Organization of the clot begins within the first 24 to 48 hours with engorgement and dilation of blood vessels within the periodontal ligament remnants, followed by leukocytic migration and formation of a fibrin layer. In the first week the clot forms a temporary scaffold upon which inflammatory cells migrate. Epithelium at the wound periphery grows over the surface of the organizing clot. Osteoclasts accumulate along the alveolar bone crest setting the stage for active crestal resorption. Angiogenesis proceeds in the remnants of the periodontal ligaments. In the second week the clot continues to get organized through fibroplasia and new blood vessels that begin to penetrate towards the center of the clot. Trabeculae of osteoid slowly extend into the clot from the alveolus, and osteoclastic resorption of the cortical margin of the alveolar socket is more distinct. By the third week the extraction socket is filled with granulation tissue and poorly calcified bone forms at the wound perimeter. The surface of the wound is completely reepithelialized with minimal or no scar formation. Active bone remodeling by deposition and resorption continues for several more weeks. Radiographic evidence of bone formation does not become apparent until the sixth to eighth weeks following tooth extraction. Due to the ongoing process of bone remodeling the final healing product of the extraction site may not be discernible on radiographs after 4 to 6 months. Occasionally the blood clot fails to form or may disintegrate, causing a localized alveolar osteitis. In such instances healing is delayed considerably and the socket fills gradually. In the absence of a healthy granulation tissue matrix, the apposition of regenerate bone to remaining alveolar bone takes place at a much slower rate. Compared to a normal socket the infected socket remains open or partially covered with hyperplastic epithelium for extended periods. Skin Grafts Skin grafts may be either full thickness or split thickness.16 A full-thickness graft is composed of epidermis and the entire dermis; a split-thickness graft is composed of the epidermis and varying amounts of dermis. Depending on the amount of underlying dermis included, split-thickness grafts are described as thin, intermediate, or thick.17 Following grafting, nutritional support for a free skin graft is initially provided by plasma that exudes from the dilated capillaries of the host bed. A fibrin clot forms at the graft-host interface, fixing the graft to the host bed. Host leukocytes infiltrate into the graft through the lower layers of the graft. Graft survival depends on the ingrowth of blood vessels from the host into the graft (neovascularization) and direct anastomoses between the graft and the host vasculature (inosculation). Endothelial capillary buds from the host site invade the graft, reaching the dermoepidermal junction by 48 hours. Concomitantly vascular connections are established between host and graft vessels. However, only a few of the ingrowing capillaries succeed in developing a functional anastomosis. Formation of vascular connections between the recipient bed and transplant is signaled by the pink appearance of the graft, which appears between the third and fifth day postgrafting. Fibroblasts from the recipient bed begin to invade the layer of fibrin and leukocytes by the fourth day after transplantation. The fibrin clot is slowly resorbed and organized as fibroblastic infiltration continues. By the ninth day the new blood vessels and fibroblasts have achieved a firm union, anchoring the deep layers of the graft to the host bed. Reinnervation of the skin graft occurs by nerve fibers entering the graft through its base and sides. The fibers follow the vacated neurilemmal cell sheaths to reconstruct the innervation pattern of the donor skin. Recovery of sensation usually begins within 2 months after transplanta- tion.Grafts rarely attain the sensory qualities of normal skin, because the extent of re-innervation depends on how accessible the neurilemmal sheaths are to the entering nerve fibers. The clinical performance of the grafts depends on their relative thickness. As split-thickness grafts are thinner than full-thickness grafts, they are susceptible to trauma and undergo considerable contraction; however, they have greater survival rates clinically. Full-thickness skin grafts do not “take” as well and are slow to revascularize. Nevertheless full-thickness grafts are less susceptible to trauma and undergo minimal shrinkage. Wound Healing Complications Healing in the orofacial region is often considered a natural and uneventful process and seldom intrudes into the sur- geon’s consciousness. However, this changes when complications arise and encumber the wound healing continuum. Most wound healing complications manifest in the early postsurgical period although some may manifest much later. The two problems most commonly encountered by the surgeon are wound infection and dehiscence; proliferative healing is less typical. Wound Infection Infections complicating surgical outcomes usually result from gross bacterial contamination of susceptible wounds. All wounds are intrinsically contaminated by bacteria; however, this must be distinguished from true wound infection where the bacterial burden of replicating microorganisms actually impairs healing.18 Experimental studies have demonstrated that regardless of the type of infecting microorganism, wound infection occurs when there are more than 1 × 105 organisms per gram of tissue.19,20 Beyond relative numbers, the pathogenicity of the infecting microorganisms as well as host response factors determine whether wound healing is impaired.
The continual presence of a bacterial infection stimulates the host immune defenses leading to the production of inflammatory mediators, such as prostaglandins and thromboxane. Neutrophils migrating into the wound release cytotoxic enzymes and free oxygen radicals. Thrombosis and vasoconstrictive metabolites cause wound hypoxia, leading to enhanced bacterial proliferation and continued tissue damage. Bacteria destroyed by host defense mechanisms provoke varying degrees of inflammation by releasing neutrophil proteases and endotoxins. Newly formed cells and their collagen matrix are vulnerable to these breakdown products of wound infection, and the resulting cell and collagen lysis contribute to impaired healing. Clinical manifestations of wound infection include the classic signs and symptoms of local infection: erythema, warmth, swelling, pain, and accompanying odor and pus. Inadequate tissue perfusion and oxygenation of the wound further compromise healing by allowing bacteria to proliferate and establish infection. Failure to follow aseptic technique is a frequent reason for the introduction of virulent microorganisms into the wound. Transformation of contaminated wounds into infected wounds is also facilitated by excessive tissue trauma, remnant necrotic tissue, foreign bodies, or compromised host defenses. The most important factor in minimizing the risk of infection is meticulous surgical technique, including thorough débridement, adequate hemostasis, and elimination of dead space. Careful technique must be augmented by proper postoperative care, with an emphasis on keeping the wound site clean and protecting it from trauma. Wound Dehiscence Partial or total separation of the wound margins may manifest within the first week after surgery. Most instances of wound dehiscence result from tissue failure rather than improper suturing techniques. The dehisced wound may be closed again or left to heal by secondary intention, depending upon the extent of the disruption and the surgeon’s assessment of the clinical situation. Proliferative Scarring Some patients may go on to develop aberrant scar tissue at the site of their skin injury. The two common forms of hyperproliferative healing, hypertrophic scars and keloids, are characterized by hypervascularity and hypercellularity. Distinctive features include excessive scarring, persistent inflammation, and an overproduction of extracellular matrix components, including glycosaminoglycans and collagen Type I.21 Despite their overt resemblance, hypertrophic scars and keloids do have some clinical dissimilarities. In general, hypertrophic scars arise shortly after the injury, tend to be circumscribed within the boundaries of the wound, and eventually recede. Keloids, on the other hand, manifest months after the injury, grow beyond the wound boundaries, and rarely subside. There is a clear familial and racial predilection for keloid formation, and susceptible individuals usually develop keloids on their face, ear lobes, and anterior chest. Although processes leading to hypertrophic scar and keloid formation are not yet clarified, altered apoptotic behavior is believed to be a significant factor. Ordinarily, apoptosis or programmed cell death is responsible for the removal of inflammatory cells as healing proceeds and for the evolution of granulation tissue into scar. Dysregulation in apoptosis results in excessive scarring, inflammation, and an overproduction of extracellular matrix components. Both keloids and hypertrophic scars demonstrate sustained elevation of growth factors including TGF-ß , platelet-derived growth factor, IL-1, and IGF-I.22 The growth factors, in turn, increase the numbers of local fibroblasts and prompt exces- Wound Healing sive production of collagen and extracellular matrix. Additionally, proliferative scar tissue exhibits increased numbers of neoangiogenesis-promoting vasoactive mediators as well as histamine-secreting mast cells capable of stimulating fibrous tissue growth. Although there is no effective therapy for keloids, the more common methods for preventing or treating these lesions focus on inhibiting protein synthesis. These agents, primarily corticosteroids, are injected into the scar to decrease fibroblast proliferation, decrease angiogenesis, and inhibit collagen synthesis and extracellular matrix protein synthesis. Optimizing Wound Healing At its very essence the wound represents an extreme disruption of the cellular microenvironment. Restoration of constant internal conditions or homeostasis at the cellular level is a constant undertow of the healing response. A variety of local and systemic factors can impede healing, and the informed surgeon can anticipate and, where possible, proactively address these barriers to healing so that wound repair can progress normally.23 Tissue Trauma Minimizing surgical trauma to the tissues helps promote faster healing and should be a central consideration at every stage of the surgical procedure, from placement of the incision to suturing of the wound. Properly planned, the surgical incision is just long enough to allow optimum exposure and adequate operating space. The incision should be made with one clean consistent stroke of evenly applied pressure. Sharp tissue dissection and carefully placed retractors further minimize tissue injury. Sutures are useful for holding the severed tissues in apposition until the wound has healed enough. However, sutures should be used judiciously as they have the ability to add to the risk of infection and are capable of strangulating the tissues if applied too tightly.
Part 1: Principles of Medicine, Surgery, and Anesthesia Hemostasis and Wound Débridement Bleeding from a transected vessel or diffuse oozing from the denuded surfaces interfere with the surgeon’s view of underlying structures. Achieving complete hemostasis before wound closure helps prevent the formation of a hematoma postoperatively. The collection of blood or serum at the wound site provides an ideal medium for the growth of microorganisms that cause infection. Additionally, hematomas can result in necrosis of overlying flaps. However, hemostatic techniques must not be used too aggressively during surgery as the resulting tissue damage can prolong healing time. Postoperatively the surgeon may insert a drain or apply a pressure dressing to help eliminate dead space in the wound. Devitalized tissue and foreign bodies in a healing wound act as a haven for bacteria and shield them from the body’s defenses.23 The dead cells and cellular debris of necrotic tissue have been shown to reduce host immune defenses and encourage active infection. A necrotic burden allowed to persist in the wound can prolong the inflammatory response, mechanically obstruct the process of wound healing, and impede reepithelialization. Dirt and tar located in traumatic wounds not only jeopardize healing but may result in a “tattoo” deformity. By removing dead and devitalized tissue, and any foreign material from a wound, débridement helps to reduce the number of microbes, toxins, and other substances that inhibit healing. The surgeon should also keep in mind that prosthetic grafts and implants, despite refinements in biocompatibility, can incite varying degrees of foreign body reaction and adversely impact the healing process. Tissue Perfusion Poor tissue perfusion is one of the main barriers to healing inasmuch as tissue oxygen tension drives the healing response.24,25 Oxygen is necessary for hydroxylation of proline and lysine, the polymerization and cross-linking of procollagen strands, collagen transport, fibroblast and endothelial cell replication, effective leukocyte killing, angiogenesis, and many other processes. Relative hypoxia in the region of injury stimulates a fibroblastic response and helps mobilize other cellular elements of repair.26 However, very low oxygen levels act together with the lactic acid produced by infecting bacteria to lower tissue pH and contribute to tissue breakdown. Cell lysis follows, with releases of proteases and glycosidases and subsequent digestion of extracellular matrix.27 Impaired local circulation also hinders delivery of nutrients, oxygen, and antibodies to the wound. Neutrophils are affected because they require a minimal level of oxygen tension to exert their bactericidal effect. Delayed movement of neutrophils, opsonins, and the other mediators of inflammation to the wound site further diminishes the effectiveness of the phagocytic defense system and allows colonizing bacteria to proliferate. Collagen synthesis is dependent on oxygen delivery to the site, which in turn affects wound tensile strength. Most healing problems associated with diabetes mellitus, irradiation, small vessel atherosclerosis, chronic infection, and altered cardiopulmonary status can be attributed to local tissue ischemia. Wound microcirculation after surgery determines the wound’s ability to resist the inevitable bacterial contamination.28 Tissue rendered ischemic by rough handling, or desiccated by cautery or prolonged air drying, tends to be poorly perfused and susceptible to infection. Similarly, tissue ischemia produced by tight or improperly placed sutures, poorly designed flaps, hypovolemia, anemia, and peripheral vascular disease, all adversely affect wound healing. Smoking is a common contributor to decreased tissue oxygenation.29 After every cigarette the peripheral vasoconstriction can last up to an hour; thus, a pack-a-day smoker remains tissue hypoxic for most part of each day. Smoking also increases carboxyhemoglobin, increases platelet aggregation, increases blood viscosity, decreases collagen deposition, and decreases prostacyclin formation, all of which negatively affect wound healing. Patient optimization, in the case of smokers, may require that the patient abstain from smoking for a minimum of 1 week before and after surgical procedures. Another way of improving tissue oxygenation is the use of systemic hyperbaric oxygen (HBO) therapy to induce the growth of new blood vessels and facilitate increased flow of oxygenated blood to the wound. Diabetes Numerous studies have demonstrated that the higher incidence of wound infection associated with diabetes has less to do with the patient having diabetes and more to do with hyperglycemia. Simply put, a patient with well-controlled diabetes may not be at a greater risk for wound healing problems than a nondiabetic patient. Tissue hyperglycemia impacts every aspect of wound healing by adversely affecting the immune system including neutrophil and lymphocyte function, chemotaxis, and phagocytosis.30 Uncontrolled blood glucose hinders red blood cell permeability and impairs blood flow through the critical small vessels at the wound surface. The hemoglobin release of oxygen is impaired, resulting in oxygen and nutrient deficiency in the healing wound. The wound ischemia and impaired recruitment of cells resulting from the small vessel occlusive disease renders the wound vulnerable to bacterial and fungal infections. Immunocompromise The immune response directs the healing response and protects the wound from infection. In the absence of an adequate immune response, surgical outcomes are
often compromised. An important assessment parameter is total lymphocyte count. A mild deficit is a lymphocytic level between 1,200 and 1,800, and levels below 800 are considered severe total lymphocyte deficits. Patients with debilitated immune response include human immunodeficiency virus (HIV)-infected patients in advanced stages of the disease, patients on immunosuppressive therapy, and those taking high-dose steroids for extended periods.31 Studies indicate that HIVinfected patients with CD4 counts of less than 50 cells/mm3 are at significant risk of poor wound outcome.32 Although newer immunosuppressive drugs, such as cyclosporine, have no apparent effect on wound healing, other medications can retard the healing process both in rate and quality by altering both the inflammatory reaction and the cell metabolism. The use of steroids, such as prednisone, is a typical example of how suppression of the innate inflammatory process also increases wound healing complications. Exogenous corticosteroids diminish prolyl hydroxylase and lysyl oxidase activity, depressing fibroplasias, collagen formation, and neovascularity.33 Fibroblasts reach the site in a delayed fashion and wound strength is decreased by as much as 30%. Epithelialization and wound contraction are also impaired. The inhibitory effects of glucocorticosteriods can be attenuated to some extent by vitamin A given concurrently. Most antineoplastic agents exert their cytotoxic effect by interfering with DNA or RNA production. The reduction in protein synthesis or cell division reveals itself as impaired proliferation of fibroblasts and collagen formation. Attendant neutropenia also predisposes to wound infection by prolonging the inflammatory phase of wound healing. Because of their deleterious effect on wound healing, administration of antineoplastic drugs should be restricted, when possible, until such time that the potential for healing complications has passed. Radiation Injury Therapeutic radiation for head and neck tumors inevitably produces collateral damage in adjacent tissue and reduces its capacity for regeneration and repair. The pathologic processes of radiation injury start right away; however, the clinical and histologic features may not become apparent for weeks, months, or even years after treatment.34 The cellular and molecular responses to tissue irradiation are immediate, dose dependent, and can cause both early and late consequences.35 DNA damage from ionizing radiation leads to mitotic cell death in the first cell division after irradiation or within the first few divisions. Early acute changes are observed within a few weeks of treatment and primarily involve cells with a high turnover rate. The common symptoms of oral mucositis and dermatitis result from loss of functional cells and temporary lack of replacement from the pools of rapidly proliferating cells. The inflammatory response is largely mediated by cytokines activated by the radiation injury. Overall the response has the features of wound healing; waves of cytokines are produced in an attempt to heal the radiation injury. The cytokines lead to an adaptive response in the surrounding tissue, cause cellular infiltration, and promote collagen deposition. Damage to local vasculature is exacerbated by leukocyte adhesion to endothelial cells and the formation of thrombi that block the vascular lumen, further depriving the cells that depend on the vessels. The acute symptoms eventually start to subside as the constitutive cells gradually recover their proliferative abilities. However, these early symptoms may not be apparent in some tissues such as bone, where cumulative progressive effects of radiation can precipitate acute breakdown of tissue many years after therapy. The late effects of radiation are permanent and directly related to higher doses.36 Collagen hyalinizes and the tissues become increas- Wound Healing ingly fibrotic and hypoxic due to obliterative vasculitis, and the tissue susceptibility to infection increases correspondingly. Once these changes occur they are irreversible and do not change with time. Hence, the surgeon must always anticipate the possibility of a complicated healing following surgery or traumatic injury in irradiated tissue. Wound dehiscence is common and the wound heals slowly or incompletely. Even minor trauma may result in ulceration and colonization by opportunistic bacteria. If the patient cannot mount an effective inflammatory response, progressive necrosis of the tissues may follow. Healing can be achieved only by excising all nonvital tissue and covering the bed with a well-vascularized graft. Due to the relative hypoxia at the irradiated site, tissue with intact blood supply needs to be brought in to provide both oxygen and the cells necessary for inflammation and healing. The progressive obliteration of blood vessels makes bone particularly vulnerable. Following trauma or disintegration of the soft tissue cover due to inflammatory reaction, healing does not occur because irradiated marrow cannot form granulation tissue. In such instances the avascular bone needs to be removed down to the healthy portion to allow healing to proceed. Hyperbaric Oxygen Therapy HBO therapy is based on the concept that low tissue oxygen tension, typically a partial pressure of oxygen (PO2) of 5 to 20 mm Hg, leads to anaerobic cellular metabolism, increase in tissue lactate, and a decrease in pH, all of which inhibit wound healing.64 HBO therapy entails the patient lying in a hyperbaric chamber and breathing 100% oxygen at 2.0 to 2.4 atmospheres for 1 to 2 hours. The HBO therapy is repeated daily for 3 to 10 weeks. HBO increases the quantity of dissolved oxygen and the driving pressure for oxygen diffusion into the tissue. Correspondingly the oxygen diffusion distance
Part 1: Principles of Medicine, Surgery, and Anesthesia is increased threefold to fourfold, and wound PO2 ultimately reaches 800 to 1,100 mm Hg. The therapy stimulates the growth of fibroblasts and vascular endothelial cells, increases tissue vascularization, enhances the killing ability of leukocytes, and is lethal for anaerobic bacteria. Clinical studies suggest that HBO therapy can be an effective adjunct in the management of diabetic wounds.65 Animal studies indicate that HBO therapy could be beneficial in the treatment of osteomyelitis and soft tissue infections.66,67 Adverse effects of HBO therapy are barotraumas of the ear, seizure, and pulmonary oxygen toxicity. However, in the absence of controlled scientific studies with well-defined end points, HBO therapy remains a controversial aspect of surgical practice.68,69 Age In general wound healing is faster in the young and protracted in the elderly. The decline in healing response results from the gradual reduction of tissue metabolism as one ages, which may itself be a manifestation of decreased circulatory efficiency. The major components of the healing response in aging skin or mucosa are deficient or damaged with progressive injuries.37 As a result, free oxidative radicals continue to accumulate and are harmful to the dermal enzymes responsible for the integrity of the dermal or mucosal composition. In addition the regional vascular support may be subjected to extrinsic deterioration and systemic disease decompensation, resulting in poor perfusion capability.38 However, in the absence of compromising systemic conditions, differences in healing as a function of age seem to be small. Nutrition Adequate nutrition is important for normal repair.39 In malnourished patients fibroplasia is delayed, angiogenesis decreased, and wound healing and remodeling prolonged. Dietary protein has received special emphasis with respect to healing. Amino acids are critical for wound healing with methionine, histidine, and arginine playing important roles. Nutritional deficiencies severe enough to lower serum albumin to < 2 g/dL are associated with a prolonged inflammatory phase, decreased fibroplasia, and impaired neovascularization, collagen synthesis, and wound remodeling. As long as a state of protein catabolism exists, the wound will be very slow to heal. Methionine appears to be the key amino acid in wound healing. It is metabolized to cysteine, which plays a vital role in the inflammatory, proliferative, and remodeling phases of wound healing. tein. Serum prealbumin is commonly used as an assessment parameter for pro- 40,41 Contrary to serum albumin, which has a very long half-life of about 20 days, prealbumin has a shorter halflife of only 2 days. As such it provides a more rapid assessment ability. Normal serum prealbumin is about 22.5 mg/dL, a level below 17 mg/dL is considered a mild deficit, and a severe deficit would be below 11 mg/dL. As part of the perioperative optimization process, malnourished patients may be provided with solutions that have been supplemented with amino acids such as glutamine to promote improved mucosal structure and function and to enhance whole-body nitrogen kinetics. An absence of essential building blocks obviously thwarts normal repair, but the reverse is not necessarily true. Whereas a minimum protein intake is important for healing, a high protein diet does not shorten the time required for healing. Several vitamins and trace minerals play a significant role in wound healing.42 Vitamin A stimulates fibroplasia, collagen cross-linking, and epithelialization, and will restimulate these processes in the steroidretarded wound. Vitamin C deficiency impairs collagen synthesis by fibroblasts, because it is an important cofactor, along with a-ketoglutarate and ferrous iron, in the hydroxylation process of proline and lysine. Healing wounds appear to be more sensitive to ascorbate deficiency than uninjured tissue. Increased rates of collagen turnover persist for a long time, and healed wounds may rupture when the individual becomes scorbutic. Local antibacterial defenses are also impaired because ascorbic acid is also necessary for neutrophil superoxide production. The B-complex vitamins and cobalt are essential cofactors in antibody formation, white blood cell function, and bacterial resistance. Depleted serum levels of micronutrients, including magnesium, copper, calcium, iron, and zinc, affect collagen synthesis.43 Copper is essential for covalent cross-linking of collagen whereas calcium is required for the normal function of granulocyte collagenase and other collagenases at the wound milieu. Zinc deficiency retards both fibroplasia and reepithelialization; cells migrate normally but do not undergo mitosis.44 Numerous enzymes are zinc dependent, particularly DNA polymerase and reverse transcriptase. On the other hand, exceeding the zinc levels can exert a distinctly harmful effect on healing by inhibiting macrophage migration and interfering with collagen cross-linking. Advances in Wound Care An increased understanding of the wound healing processes has generated heightened interest in manipulating the wound microenvironment to facilitate healing. Traditional passive ways of treating surgical wounds are rapidly giving way to approaches that actively modulate wound healing. Therapeutic interventions range from treatments that selectively jumpstart the wound into the healing cascade, to methods that mechanically protect the wound or increase oxygenation and perfusion of the local tissues.45,46 Growth Factors Through their central ability to orchestrate the various cellular activities that underscore inflammation and healing,
cytokines have profound effects on cell proliferation, migration, and extracellular matrix synthesis.47 Accordingly newer interventions seek to control or modulate the wound healing process by selectively inhibiting or enhancing the tissue levels of the appropriate cytokines. The more common clinical approach has been to apply exogenous growth factors, such as PGDF, angiogenesis factor, epidermal growth factor (EGF), TGF, bFGF, and IL-1, directly to the wound. However, the potential of these extrinsic agents has not yet been realized clinically and may relate to figuring out which growth factors to put into the wound, and when and at what dose. To date only a single growth factor, recombinant human platelet-derived growth factor-BB (PDGF-BB), has been approved by the United States Food and Drug Administration for the treatment of cutaneous ulcers, specifically diabetic foot ulcers. Results from several controlled clinical trials show that PDGF-BB gel was effective in healing diabetic ulcers in lower extremities and significantly decreased healing time when compared to the placebo group.48,49 More recently, recombinant human keratinocyte growth factor 2 (KGF2) has been shown to accelerate wound healing in experimental animal models. It enhanced both the formation of granulation tissue in rabbits and wound closure of the human meshed skin graft explanted on athymic nude rats.50,51Experimental studies suggest potential for the use of growth factors in facilitating peripheral nerve healing. Several growth factors belonging to the neurotrophin family have been implicated in the maintenance and repair of nerves. Nerve growth factor (NGF), synthesized by Schwann cells distal to the site of injury, aids in the survival and development of sensory nerves. This finding has led some investigators to suggest that exogenous NGF application may assist in peripheral nerve regeneration following injury.52 Newer neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3 as well as ciliary neurotrophic factor appear to support the growth of sensory, sympathetic, and motor neurons in vitro.53–55 Insulinlike growth factors have demonstrated similar neurotrophic properties.56 Although most of the investigations hitherto have been experimental, increasing sophistication in the dosing, combinations, and delivery of neurotropic growth factors will lead to greater clinical application. Osteoinductive growth factors hold special appeal to surgeons for their ability to promote the formation of new bone. Of the multiple osteoinductive cytokines, the bone morphogenetic proteins (BMPs) belonging to the TGF-ß superfamily have received the greatest attention. Advances in recombinant DNA techniques now allow the production of these biomolecules in quantities large enough for routine clinical applications. In particular, recombinant human bone morphogenetic protein-2 (rhBMP-2) and rhBMP-7 have been studied extensively for their ability to induce undifferentiated mesenchymal cells to differentiate into osteoblasts (osteoinduction). Yasko and colleagues used a rat segmental femoral defect model to show that rhBMP-2 can produce 100% union rates when combined with bone marrow.57 The union rate achieved with the combination approach was three times higher than that achieved with autologous cancellous bone graft alone. Similarly, Toriumi and colleagues showed that rhBMP-2 could heal mandibular defects with bone formed by the intramembranous pathway.58 The widespread application of osteoinductive cytokines depends in large part on a better understanding of the complex interaction of growth factors and the concentrations necessary to achieve specific effects. Gene Therapy The application of gene therapy to wound healing has been driven by the desire to selectively express a growth factor for controlled periods of time at the site of tissue injury.59 Unlike the diffuse effects of a Wound Healing bolus of exogenously applied growth factor, gene transfer permits targeted, consistent, local delivery of peptides in high concentrations to the wound environment. Genes encoding for select growth factors are delivered to the site of injury using a variety of viral, chemical, electrical, or mechanical methods.60 Cellular expression of the proteins encoded by the nucleic acids help modulate healing by regulating local events such as cell proliferation, cell migration, and the formation of extracellular matrix. The more popular methods for transfecting wounds involve the in vivo use of adenoviral vectors. Existing gene therapy technology is capable of expressing a number of modulatory proteins at the physiologic or supraphysiologic range for up to 2 weeks. Numerous experimental studies have demonstrated the use of gene therapy in stimulating bone formation and regeneration. Mesenchymal cells transfected with adenovirus-hBMP-2 cDNA have been shown to be capable of forming bone when injected intramuscularly in the thighs of rodents.61,62 Similarly bone marrow cells transfected ex vivo with hBMP-2 cDNA have been shown to heal femoral defects.63 Using osteoprogenitor cells for the expression of bone-promoting osteogenic factors enables the cells to not only express bone growth promoting factors, but also to respond, differentiate, and participate in the bone formation process. These early studies suggest that advances in gene therapy technology can be used to facilitate healing of bone and other tissues and may lead to better and less invasive reconstructive procedures in the near future. Dermal and Mucosal Substitutes Immediate wound coverage is critical for accelerated wound healing. The coverage protects the wound from water loss, drying, and mechanical injury. Although autologous grafts remain the standard for replacing dermal mucosal surfaces, a number of bioengineered substitutes are finding their
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