Granulation tissue stageClot and exudate

WOUND HEALING PHYSIOLOGY: AN OVERVIEW

Days 3-7, Granulation tissue stageClot and exudate

Neutrophils

Hemorrhage Capillaries Necrosis of epidermis and dermis Disruption of tissue

Day 1, Inflammation

FIGURE 2.12 Healing by fi rst and secondary intention.

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tissue death [devitalization]), tissue tension or swelling (indicating tissue congestion), and sensation.

If deep tissue death occurs, the tissues can rupture and become a deep cavity. This often occurs in stage I pressure ulcers and is referred to as the erupting volcano effect. This effect is now attributed to deep tissue injury, and is mani- fested under the skin as a purple discoloration, leading to the name “purple ulcers.” Figure 2.10 shows what initially appeared to be superfi cial and partial-thickness (stages I and II) pressure ulcers, but there are also signs of purple deep discoloration in the surrounding tissues suggestive of deep tissue injury. The true degree of involvement manifested itself 3 weeks after they are fi rst diagnosed (Fig. 2.11). It is signifi cant that the manifestation doesn’t occur immediately because the staging of the ulcer will not be possible until that happens. (Chapter 3 discusses assessment of suspected deep tissue injury and staging.)

In superficial wound healing, the soft tissues usually heal by themselves over time, but intervention at this stage can hasten return to functional activities, such as work and homemaking. For example, athletes are often assessed and treated immediately for superficial soft tissue injuries, with reduced loss of playing time, less pain, and less tis- sue swelling from congestion in the tissues. Tissue swell- ing can limit functional activities, resulting in diminished mobility and placing the individual at risk for further wounding.

Partial-Thickness Wound Healing

Wounds with partial-thickness loss of the dermis heal princi- pally by epithelialization, see Figure 2.5. Epithelialization is the body’s attempt to protect itself from invasion or debris by beginning to close the wound; this process begins immediately following injury.

Epithelial cells at the wound edges, as well as from the dermal appendages—sebaceous glands, sweat glands, and hair follicles—

provide a supply of intact epithelial cells to assist in resurfacing the wound by lateral migration.^24,25 If dermal appendages are

present, islands of epidermis can appear throughout the wound surface and speed the resurfacing process. The resulting epithe- lium is often indistinguishable from the surrounding skin, and the normal function of the skin is restored. Figures 2.13 and 2.14 show a wound resurfacing from islands of epidermis. Examples of partial-thickness wounds are abrasions, skin tears, stage II pressure ulcers, and second-degree burns.

Full-Thickness or Secondary Intention Healing

Secondary intention healing is the most effective method of healing full-thickness wounds. It is necessary because, when a large amount of tissue is removed or destroyed, a gap occurs, and either the wound edges cannot be approximated or non- viable wound margins are present or both (Figure 2.15).

Wounds with a high microorganism count, debris, or skin necrosis are also left to close by secondary intention (Figure 2.16).

Full-thickness secondary intention healing princi- pally occurs by contraction, a reduction of the wound sur- face area by the drawing together of the wound edges FIGURE 2.13 Note islands of epidermal tissue which indicate probable presence of dermal appendages. (Copyright © C. Sussman.)

1

2

FIGURE 2.14 Same wound as Figure 2.13.

Note: (1) Epidermal migration from wound edges, island, and wound shape changes. (2) Progression to the acute epithelialization phase. (3) Hyperkeratotic skin changes due to old burn wounds and poor circulation.

(Copyright © C. Sussman.)

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Chronic Wound Healing

Secondary intention is the healing model associated with chronic wounds.²⁷ A chronic wound Exhibit 2.1 is defi ned as one that has “failed to proceed through an orderly and timely process to produce anatomic and functional integrity, or pro- ceeded through the repair process without establishing a sus- tained anatomic and functional result.”²⁷

Orderly refers to the progression of the wound through the biological sequences that comprise the phases of repair of acute wounds described shortly. Orderliness can be inter- rupted during any of the phases of healing, but only recently have the causative factors for these interruptions been identi- fi ed. Causative factors that affect the orderly progression of the healing process are presented in this chapter for each phase of wound healing.

Timeliness relates to the progression of the phases of repair in a manner that will heal the wound expeditiously. Timeliness is determined by the nature of the wound pathology, medi- cal status of the patient, and environmental factors.²⁷ Those wounds that do not repair themselves in an orderly and timely manner are classifi ed as chronic wounds; those that do are clas- sifi ed as acute wounds.

9/17

2

1

FIGURE 2.15 Full thickness Wound Healing by Secondary Intention.

(Copyright © B.M. Bates-Jensen.)

2

3

1 9/24

FIGURE 2.16 Same ulcer as Figure 2.15 with attributes of infection.

Note change in color of granulation tissue from red to dusky pink.

(Copyright © B.M. Bates-Jensen.)

(Figures 2.17– 2.19). This results in scar tissue formation. In this process, the anatomic structure of the scar tissue does not replicate that of the tissue being replaced (e.g., muscles, tendons, or nerves); thus, original tissue function is lost. In addition, the surface tissue will not be equal in elasticity or tensile strength to the original.²⁴ Sometimes, defects are too large or will result in suboptimal reconstruction of the skin defect if surgically closed by primary intention. Then healing by secondary intention is preferred.

If a wound is located in an area where contraction will produce disfi guring or nonfunctional deformities, the process of healing by secondary intention can be allowed initially, in order to develop a strong, healthy wound bed.

Then it is interrupted, and a skin graft is placed on the granulating wound bed. Autologous skin transplants are taken from the person’s own body and grafted to the wound surface. Donor sites are chosen from appropri- ate body surfaces. Skin grafts are divided into two main categories: full-thickness skin grafts (FTSGs) and split thickness skin grafts (STSGs). STSGs are thin (0.008–

0.018 mm). FTSGs are thicker (0.018–0.030 mm). Both include the epidermis and FTSGs include the dermis as well. STSGs include only part of the dermis. The donor site then becomes a secondary wound, which will need to heal. FTSGs are used to correct defects when cosmesis is a primary concern and the defect to be corrected is not too large. STSGs are used if cosmesis is not a concern or if FTSG is precluded. Skin grafting is used for nonhealing cutaneous ulcers, to replace tissue in full-thickness burns and for reconstruction of skin after removal of malignan- cies.²⁶ Chapter 8 covers surgical wounds and grafts and Chapter 15 grafts and burns.

Healing of full-thickness wounds by secondary inten- tion involves a process that is divided into four overlapping phases of repair: infl ammation, epithelialization, prolifera- tion, and remodeling. Each of these phases will be discussed in detail later in this chapter.

EXHIBIT 2.1

Examples of Chronic Wounds

● Ischemic arterial ulcers

● Diabetic vascular and neuropathic ulcers

● Venous ulcers

● Vasculitic ulcers

● Rheumatoid ulcers

● Pressure ulcers

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1/16 AL

FIGURE 2.19 Same wound as in Figures 2.17 and 2.18. Note sustained wound contraction and progression of epithelialization and prolifera- tive phase. (Copyright © C. Sussman.)

RESEARCH WISDOM

HA is a gel that is degraded in vivo and breaks down rap- idly when applied to wounds. A wound dressing called Hyaff (ConvaTec, a Bristol Myers Squibb company, Princeton, NJ) has recently been produced from HA. When applied to the wound, this dressing creates an HA-rich tissue interface and moist wound environment conducive to granulation and healing (see Chapter 20).³⁷

10/2 – AL

FIGURE 2.17 Epidermal ridge formation with rolled edges. (Copyright

© C. Sussman.)

11/20 – AL

FIGURE 2.18 This is the same wound as Figure 2.17 that is progressing through the proliferative phase. It is contracting and changing size and shape. (Copyright © C. Sussman.)

Fetal Wound Healing

Researchers are studying what can be learned from fetal wound healing that will be useful in promoting improved wound heal- ing. It has been known for some time that fetuses who undergo surgery in utero do not form scars.^28–30 Fetal wounds are con- tinually bathed in amniotic fl uid, which has a rich content of HA and fi bronectin, as well as growth factors crucial to fetal development. HA is a key structural and functional component of the ECM, which fosters an environment that promotes cell proliferation and tissue regeneration and repair.^25,31 HA is laid down in the matrix of both fetal and adult wounds, but its sus- tained deposition is unique to fetal wounds. Many questions remain to be answered regarding fetal wound healing. There are many differences between fetal development and adult repair and regeneration. For example, the transplacental circulation provides a partial pressure of oxygen of 20 mm Hg, which is markedly lower than that in adults, signifying that the fetus lives in a hypoxic environment.³² This is in marked contrast to the adult environment, where oxygen is a critical factor in pre- vention of infection and in the repair process. There are also differences in the fetal and adult immune systems, the histology

of fetal skin during development, the function of adult versus fetal fi broblasts in collagen synthesis, the absence of myofi bro- blasts, and the absence of an infl ammatory phase.^33,34

An example of the effects of HA and amniotic fl uid on healing of surgical wounds was reported by Byl et al. in two studies.^35,36 Amniotic fl uid, HA, and normal saline were applied to con- trolled incisional wounds. The surgeons were blinded to the fl uids applied. Incisions treated with HA and amniotic fl uid both healed faster than the saline-treated wounds; in fact, they appeared to close within minutes of application. The healing was quicker, and the quality of the scar was better in the HA and amniotic fl uid incisions than in the saline-treated incisions. The tensile strengths of the wounds treated with amniotic fl uid and HA were slightly weaker than those of the saline-treated group at the end of 1 week; however, after 2 weeks, all groups had equal tensile strength.

Four Phases of Wound Healing

The physiological process of acute wound healing includes four phases: infl ammation, epithelialization, proliferation, and remodeling. Rather than a series of distinct steps, these phases have been described as a cascade of overlapping events that occurs in a reasonably predictable fashion. A diagram by Hunt and Van Winkle¹ (Figure 2.20) features infl ammation the central activity of wound healing—in its center. On either side are proliferation and epithelialization—the concurrent events that occur as a consequence of injury. The lower portion of the diagram represents the coming together of the phases, leading to the remodeling phase of wound healing. The interpreta- tion of this diagram is that the four phases occur in an orderly,

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FIGURE 2.20 Diagram of wound repair. (Reprinted with permission from Hunt TK, Van Winkle W. Fundamentals of Wound Management in Surgery, Wound Healing: Normal Repair. South Plainfi eld, NJ: Chirurgecom, Inc, 1976.)

Term Defi nition (Reference)

Angiogenesis Development of new blood vessels in injured tissues. Function of endothelial cells.

Apoptosis A mechanism for cell deletion in the regulation of cell populations, as of B and T lymphocytes fol- lowing cytokine depletion. Often used synonymously with programmed cell death.

Basement membrane Thin layer of extracellular material found between the layers of the epithelia or between the epi- thelia and connective tissue. Also called basal lamina.³⁹

Chemoattractants Cause cell migration.

Chemotaxis Attraction of a cell in response to a chemical signal.

Chronic wound Wound that has “failed to proceed through an orderly and timely process to produce anatomic and functional integrity, or proceeded through the repair process without establishing a sustained anatomic and functional result.”²⁷

Collagenases Enzymes that cleave (break) the bonds of the polypeptide chains in collagen at specifi c sites, aid- ing in its resorption during periods of connective tissue growth or repair.³⁹

Complement system Eleven proteins found in plasma with specifi c purpose of combating bacterial contamination. Also chemotactic for phagocytes; substances most responsible for acute infl ammation.²⁴

ECM Intricate system of GAGs and proteins secreted by cells; provides the framework for tissues.³⁹ Terminology Associated with Wound Healing Physiology

2.1

TABLE

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Term Defi nition (Reference)

Free radicals Highly reactive molecular species that have at least one unpaired electron in the outer shell. Attempt to react with other molecules to achieve an electrically more stable state in which the electron is paired with another. Important for normal cell functions, including metabolism and defense against infection.⁷⁴ Galvanotaxis Attraction of a cell in response to an electrical signal.

GAGs Polysaccharides that contain amino acids, sugars, and glycoprotein. Termed proteoglycans.⁹⁷ Growth factors (GFs) Extracellular polypeptides—proteins able to affect cell reproduction, movement, and function. Term

encompasses items c, d, and e, below. Regulators of the wound healing cascade. May be defi cient in chronic wounds.³⁹

a. Autocrine stimulation GF produced by a cell acting on itself.

b. Paracrine stimulation GF produced by one cell type acting on another in the local area.

c. Endocrine stimulation GF produced by one cell type acting on distant cells.

d. Cytokines Refers to diverse group of polypeptides and glycoproteins that are important mediators of infl ammation.

Anti-infl ammatory cytokines inhibit production of proinfl ammatory cytokines, counter their action or both e. Interleukins (ILs) A group of proinfl ammatory cytokines

f. Colony-stimulating factor Term for GF used by hematologists.¹²⁰

Hemostasis Coagulation to stop bleeding and initiate the wound healing process.

Hydroxyproline (HoPro) A polypeptide chain of insoluble collagen.

Integrins Regulate a wide range of cellular functions during growth, development, differentiation, and the immune response. Serve a critical function in cell adhesion and signaling during wound healing, where they are fundamental to reepithelialization and granulation tissue formation.⁹⁴

Ligand A molecule that binds to another molecule, used especially to refer to a small molecule that binds spe- cifi cally to a larger molecule.¹²¹

MMPs Proteolytic enzymes that degrade proteins and ECM macromolecules. MMPs have the ability to degrade a variety of ECM components, which is of benefi t in the developmental and remodeling pro- cesses in healthy tissues.⁹⁴ Synthesized and secreted by multiple cell types involved in wound healing in response to biochemical signals.

Mitogens Cause cell growth.

Mitogenic Causing mitosis or cellular proliferation.

Neovascularization Development of new blood vessels; another term for angiogenesis.

Phagocytosis Ingestion, destruction, and digestion of cellular particulate matter.³⁹ Proteases Proteolytic enzymes that degrade proteins.³⁹

Substrates Substances acted upon by an enzyme, such as substances necessary for new tissue growth: protein, vitamin C, zinc.

Tensile strength The most longitudinal stress that a substance can withstand without tearing apart.

TIMPs Secreted proteins that are widely distributed in tissues and fl uids and serve as specifi c inhibitors for the MMPs. Synthesized and secreted by same multiple cell types as MMPs.⁵²

Terminology Associated with Wound Healing Physiology (continued ) 2.1

TABLE

overlapping fashion. Incidentally, the literature identifi es either three or four phases of repair, depending on whether epithe- lialization is included as part of proliferation or as a separate phase. The wound healing model used in this text is based on four phases.

The biologic repair process is the same for all acute wounds, open or closed, regardless of etiology. However, the sequence of repair is completed more quickly in primary healing and when involvement is limited to superfi cial and partial-thickness skin.

Slower healing occurs when there is full-thickness skin loss

extending into and through the subcutaneous tissue.³⁸ Table 2.1 defi nes key terminology associated with wound healing physiology to facilitate understanding.

Attributes that distinguish the healing of chronic wounds from that of acute wounds are continually being studied. Thus, after we explain the process of normal wound healing in a particular phase in each of the sections that follow, we go on to discuss the attri- butes and processes that may be responsible for chronic wound healing in that phase. Table 2.2 summarizes factors and their effects on chronic wound healing during each phase of repair.

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Summary of Factors and Effects during Each Phase of Wound Healing in Chronic Wounds 2.2

TABLE

Chronic Infl ammatory Phase

Chronic Epithelialization

Phase Chronic Proliferative Phase Chronic Remodeling Phase

Different stimulus of repair Diminished keratinocyte migration due to

Different composition of fi bronectin:

Imbalance of collagen synthesis and degradation:

a. From within a. Lack of moist environment

a. Partially degraded into fragments

a. Impaired scar tensile strength

b. Gradual b. Lack of oxygen b. Fragments may perpetuate

activity of matrix proteases

b. Overproduction of collagen: hypertrophic scarring

c. Slowed c. Lack of nutritious tissue base

c. Inhibit healing c. Imbalance of fi brotic and antifi brotic cytokines:

hypergranulation d. Lack of stimulation by

appropriate cytokine Inadequate perfusion and

oxygenation:

Keratinocyte migration obstructed by wound edges that are

Excess activity of proteases causes:

Hyperoxygenation:

a. Muted phase process a. Rolled a. Accelerated rate of

connective tissue breakdown

a. Hypertrophy of granulation tissue b. Ischemic tissue barrier to

angiogenesis

b. Thickened b. Destruction of polypeptide- signaling molecules

b. Impediment to epidermal cell migration

c. Nonproductive c. Production of

metalloproteinases that do not lyse collagen

Free radicals and oxygen reperfusion injury:

Keratinocyte migration slowed due to

Chronic wound fl uid inhibition of: Impairment of scar tensile strength:

a. Large production of free radicals

a. Large gap a. Cellular proliferation:

endothelial cells, keratinocytes, fi broblasts

a. Wound breakdown

b. Disruption in normal defense against free radicals

b. Slow fi lling of “dead space”

b. Cell adhesion b. Dehiscence c. Capillary plugging by

neutrophils

Repeated trauma and infection:

a. Increases the presence of proinfl ammatory cytokines b. Increases the presence

of tissue inhibitors (metalloproteinases) c. Lowers the level of growth

factors

Impediments to wound healing:

a. Elevated levels of MMPs b. Imbalance between levels

of MMPs and their inhibitors (TIMPs)

Large tissue defect:

a. Prolongs proliferation of tissue to fi ll the space

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Summary of Factors and Effects during Each Phase of Wound Healing in Chronic Wounds (continued ) 2.2

TABLE

Chronic Infl ammatory Phase

Chronic Epithelialization

Phase Chronic Proliferative Phase Chronic Remodeling Phase

Substrates relationship to stalling or plateauing:

a. Inadequate substrates b. Bacterial competition for

substrates necessary for tissue repair

c. Continued lysis of new growth faster than synthesis of new material

Long-term wound hypoxia effects:

a. Negative effect on collagen production

b. Decreased fi broblast proliferation

c. Decreased tissue growth Impaired wound contraction:

a. Wound remains large b. Delayed reepithelialization

Adapted from Bates-Jensen B. A Quantitative Analysis of Wound Characteristics as Early Predictors of Healing in Pressure Sores. Dissertation Abstracts International, Volume 59, Number 11, University of California, Los Angeles; 1999, with permission.