Wound Healing and Repair

RV M Ollero MD. Fatima University Medical Center

Wound Healing and Repair

INTRODUCTION
complex & dynamic process of restoring cellular structures & tissue layers
3 distinct phases of wound healing
inflammatory phase
proliferative phase remodeling phase

Wound Healing and Repair

Within these 3 broad phases is a complex and coordinated series of events that includes
chemotaxis phagocytosis neocollagenesis collagen degradation collagen remodeling

Wound Healing and Repair

vital to the wound healing milieu - in addition
Angiogenesis
Epithelization production of new glycosaminoglycans (GAGs) proteoglycans

culmination of these biological processes results in the replacement of normal skin structures with fibroblastic mediated scar tissue

Wound Healing and Repair

process can go away and produce an exuberance of fibroblastic proliferation
resultant hypertrophic scar
confined to the wound site

Wound Healing and Repair

Further exuberance
result in keloid formation
scar production extends beyond the area of the original insult

Conversely - insufficient healing

result in atrophic scar formation

TYPES OF WOUND HEALING

various categories of wound healing have been described
ultimate outcome of any healing process
repair of a tissue defect

3 main categories of wound healing

Primary healing Delayed primary healing

healing by Secondary intention

TYPES OF WOUND HEALING

Even though different categories exist, the interactions of cellular and extracellular constituents are similar A fourth category is healing that transpires with wounds that are only partial skin thickness

Category 1
Primary wound healing or healing by first intention
occurs within hours of repairing a fullthickness surgical incision

result in the mortality of a minimal number of cellular constituents

Category 2
Delayed primary wound healing
wound edges are not reapproximated immediately
desired in the case of contaminated wounds

Category 2
Delayed primary wound healing
fourth day
phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring Foreign materials are walled off by macrophages
may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes
granuloma

wound is closed surgically at this juncture incomplete "cleansing" of wound

chronic inflammation can ensue
resulting in prominent scarring

Category 3
Secondary healing or healing by secondary intention
a full-thickness wound is allowed to close and heal results in an inflammatory response that is more intense than with primary wound healing larger quantity of granulomatous tissue is fabricated because of the need for wound closure

Category 3
results in pronounced contraction of wounds Fibroblastic differentiation into myofibroblasts - resemble contractile smooth muscle
believed to contribute to wound contraction myofibroblasts are maximally present in the wound from the 10th-21st days

Category 4
Epithelization
process by which epithelial cells migrate and replicate via mitosis and traverse the wound
occurs as part of the phases of wound healing

partial thickness wounds (epidermis and superficial dermis) epithelization is the predominant method by which healing occurs Wound contracture is not a common component
epidermis or epidermis and superficial dermis are involved

OVERVIEW OF WOUND HEALING

The amalgam of coordinated events that constitute the process of wound healing is quite complex.

Steps in the procession of wound healing

Inflammation

Fibroblastic phase
scar maturation

wound contracture
process that occurs throughout the healing process commencing in the fibroblastic stage

Inflammatory phase
occurs immediately following the injury

lasts approximately 6 days

Fibroblastic phase
occurs at the termination of the inflammatory phase can last up to 4 weeks

Scar maturation
begins at the fourth week

can last for years

OVERVIEW OF WOUND HEALING

An analogous system depicts the 4 phases
hemostasis inflammation

granulation
remodeling in a continuous symbiotic process

SEQUENCE OF EVENTS IN WOUND HEALING

Following tissue injury - incision
initial response - bleeding

Cascade of vasoconstriction and coagulation commences with clotted blood immediately impregnating the wound, leading to hemostasis, and with dehydration - scab forms Influx of inflammatory cells
release of cellular substances and mediators

Angiogenesis and re-epithelization occur

deposition of new cellular and extracellular components ensues

Initial phase Hemostasis

Following vasoconstriction

platelets adhere to damaged endothelium

discharge adenosine diphosphate (ADP)

promotes thrombocyte clumping

dams the wound

Initial phase - Hemostasis

Inflammatory phase - initiated by the release of numerous cytokines by platelets Alpha granules liberate
platelet-derived growth factor (PDGF), platelet factor IV, and transforming growth factor beta (TGF-b)

vasoactive amines such as histamine and serotonin are released from dense bodies found in thrombocytes

Initial phase - Hemostasis

PDGF is chemotactic for fibroblasts

TGF-b, is a potent modulator of fibroblastic mitosis

leading to prolific collagen fibril construction in later phases

Initial phase - Hemostasis

Fibrinogen is cleaved into fibrin and the framework for completion of the coagulation process is formed Fibrin provides the structural support for cellular constituents of inflammation process starts immediately after the insult and may continue for a few days

Second phase Inflammation

Within the first 6-8 hours - next phase of the healing process is underway polymorphonuclear leukocytes (PMNs) engorging the wound

TGF-b facilitates PMN migration from surrounding blood vessels where they extrude themselves from these vessels
these cells "cleanse" the wound clearing it of debris

Second phase Inflammation

PMNs attain their maximal numbers in 24-48 hours and commence their departure by hour 72 Other chemotactic agents are released
fibroblastic growth factor (FGF) transforming growth factors (TGF-b and TGF-a) PDGF plasma-activated complements C3a and C5a (anaphylactic toxins)

Second phase Inflammation

They are sequestered by macrophages or interred within the scab or eschar

Second phase Inflammation

As the process continues, monocytes exude from the vessels
macrophages continue the cleansing process manufacture various growth factors during days 3-4 orchestrate the multiplication of endothelial cells with the sprouting of new blood vessels

duplication of smooth muscle cells

creation of the milieu created by the fibroblast

Second phase Inflammation

factors influencing the wound healing process (secreted by macrophages)
TGFs cytokines

interleukin-1 (IL-1)
tumor necrosis factor (TNF) PDGF

Third phase - Granulation

consists of different subphases

subphases do not happen in discrete time frames but constitute an overall and ongoing process

Subphases of Granulation Phase

fibroplasia matrix deposition angiogenesis re-epithelialization

Third phase - Granulation

day 5-7,
Migration of fibroblasts into the wound
laying down new collagen
subtypes I and III

Early in normal wound healing

type III collagen predominates but is later replaced by type I collagen

Third phase - Granulation

Tropocollagen
precursor of all collagen types transformed within the cell's rough endoplasmic reticulum, where proline and lysine are hydroxylated

Disulfide bonds are established

allowing 3 tropocollagen strands to form a triple lefthanded triple helix - procollagen

As the procollagen is secreted into the extracellular space

peptidases in the cell wall cleave terminal peptide chains creating true collagen fibrils

Third phase - Granulation

The wound is suffused with GAGs and fibronectin produced by fibroblasts
GAGs include
heparan sulfate hyaluronic acid

chondroitin sulfate
keratan sulfate

Proteoglycans are GAGs that are bonded covalently to a protein core and contribute to matrix deposition

Third phase - Granulation

Angiogenesis
product of parent vessel offshoots

formation of new vasculature

requires extracellular matrix and basement membrane degradation followed by migration, mitosis, and maturation of endothelial cells

Basic FGF and vascular endothelial growth factor

believed to modulate angiogenesis

Third phase - Granulation

Re-epithelization occurs with the migration of cells from the periphery of the wound and adnexal structures process commences with the spreading of cells within 24 hours Division of peripheral cells occurs in hours 48-72
resulting in a thin epithelial cell layer bridges the wound

Third phase - Granulation

Epidermal growth factors
believed to play a key role in this aspect of wound healing

succession of subphases can last up to 4 weeks in the clean and uncontaminated wound

Fourth phase - Remodeling

After the third week

wound undergoes constant alterations - remodeling

can last for years after the initial injury occurred

Collagen is degraded and deposited in an equilibrium-producing fashion

resulting in no change in the amount of collagen present in the wound

Fourth phase - Remodeling

collagen deposition in normal wound healing
peak by the third week after the wound is created

Contraction of the wound is an ongoing process resulting in part from the proliferation of the specialized fibroblasts
myofibroblasts
resemble contractile smooth muscle cells

Wound contraction occurs to a greater extent with secondary healing than with primary healing

Fourth phase - Remodeling

Maximal tensile strength of the wound
achieved by the 12th week

ultimate resultant scar

has only 80% of the tensile strength of the original skin