chapter 7 wound healing of the... · during wound healing, endothelial cells released cytokines,...

Chapter 7

Wound Healing

長庚皮膚科 R2 劉人鳳2015.12.11

CHAPTER SUMMARY

Wound healing occurs in orderly, overlapping phases: the inflammatory,

the proliferative, and the remodeling phases.

The depth of the wound determines the degree of contraction and the

location and source of keratinocytes that serve as a reservoir for re-

epithelialization.

Acute wounds created by a scalpel heal faster than wounds created by

destructive or ablative methods.

長庚皮膚科 R2 劉人鳳

CHAPTER SUMMARY

Platelets are the first cell to appear in the healing process, and

macrophages are the most important cell in the healing process;

they both mediate their actions through cytokines or growth factors.

Wound healing is highly regulated by signals from the serum and

surrounding extracellular matrix.

Physicians can accelerate wound healing by

avoiding placing toxic substances on the wound

keeping the wound free of necrotic and potentially infected tissue

appropriate use of occlusive dressings to create a moist wound

environment


TYPES OF WOUNDS

Acute versus chronic wounds

Healing time

Anatomic location, shape, wound cause, patient age, and physical

condition

Ex: an elliptical wound on the face of a healthy child will likely heal faster

than a circular burn wound on an elderly person with multiple comorbidities

Patient age is a critical factor


Primary versus secondary intention healing

Acute wound heals without intervention, primarily by contraction of

myofibroblasts

Second intention healing

A surgeon directs closure of the wound

Primary intention healing


Methods of creating acute wounds

Scalpel (steel), laser (heat), liquid nitrogen (cold), or chemicals (acid)

Accidental trauma, thermal, or chemical burns

Wounds created by sharp steel (surgical incisions)

Heal faster

Healing of traumatic wounds may be slowed

• foreign substances prolongation of the inflammatory phase


PHASES OF WOUND HEALING

Inflammatory phase

Inflammatory phase

Local vasodilatation, blood and fluid leakage into the extravascular space,

and blocking of lymphatic drainage

rubor (redness), tumor (swelling), calor (heat), dolor (pain), and functio

laesa (loss of function)

Usually lasts 24–48 h, may persist for up to 2 weeks (chronic inflammation)


Inflammatory phase

Tissue injury blood vessel disruption and bleeding activates

keratinocytes release interleukin1 (IL1)

Platelets

Homeostasis

Release of important mediators: platelet derived growth factor (PDGF),

epidermal growth factor (EGF), and TGFβ1.

Leukocytes, mast cells, basophils, and eosinophils

Monocytes Macrophages: phagocytosis, initiation of formation of

granulation tissue


https://www.studyblue.com/notes/note/n/31-

hemostasisthrombosis/deck/2392686


Inflammatory phase -- Vascular

response

Initially, vasoconstriction hemostasis

Histamine is released into the area from mast cells, basophils, and platelets

vasodilatation and increased permeability

Hemostasis:

development of a fibrin clot

coagulation


http://www.pharmacology2000.com/Coagulation/coagulation1.htm


Inflammatory phase -- Cellular

response

Leukocytes – Neutrophils

Within 1 hr of the onset of inflammation

endothelium of the venules covered with neutrophils = Margination

Inflammation persists, neutrophils (days)

macrophages (tissue-derived monocytes)

Chemotactic factors from

Mast cells -- TNF, histamine, proteases, leukotrienes, and cytokines (interleukins)

Coagulation cascade (fibrinogen, FDP) -- kallikrein, fibrinopeptides


Leukocytes – Monocytes,

Macrophages

Phagocytosis Chronic inflammation

angiogenesis and granulation tissue

formation ~ Proliferative phase

Fibroblasts; Collagen deposition

Produce growth factors: PDGF, fibroblast

growth factor (FGF), vascular endothelial

growth factor (VEGF), TGF-β, and TGF-α

Cell migration, proliferation, and matrix

production


Mast cells

Trigger inflammation, vasodilatation and increased vascular permeability

• histamine and TNF

Regulate hemostasis

• platelet-activating factor (PAF), heparin, tryptase, chymase, and t-

plasminogen activator (tPA)

Recruit leukocytes

• TNF, histamine, proteases, leukotrienes, and cytokines (interleukins)

Angiogenesis, extracellular matrix deposition, and remodeling

• histamine, heparin, cytokines, and growth factors


Inflammatory phase -- Chemical

mediators of inflammation

Histamine

Mast cells (mainly), blood platelets and basophils

H1 receptor dilatation of arterioles and increase permeability

Heparin: anticoagulation during early phase

Serotonin

Platelets and mast cells

Potent vasoconstrictors

Fibroblast proliferation and the cross-linking of collagen molecules

Kinins

Brdykinin, released from plasma protein

Vasodilatation

Rapidly destroyed with limited activity長庚皮膚科 R2 劉人鳳

Prostaglandins

Prostaglandin E2 (PGE2): increase vascular permeability, attract leukocytes

Sensitize pain receptors (proinflammatory) or as inhibitors

Synthesis of mucopolysaccharides

Inhibited by steroids or NSAIDs in chronic inflammation

Complement system

Ag – Ab – complement cascade of sequential

reaction facilitate phagocytosis


Growth factors


Inflammatory phase –

Chronic inflammation

> 2 weeks, often months or years

Granulocytes disappear, mononuclear cells (lymphocytes, monocytes,

macrophages) persist

Necrotic tissue

Contaminated with pathogens

• Bacterial lipopolysaccharide inhibit Keratinocyte migration

Contain foreign material cannot be phagocytized

• Fibroblasts produce collagen granuloma



Proliferative phase

Re-epithelialization

Migration & Proliferation of epidermal keratinocytes

Neoepithelium to stratified epidermis

Restoration of an intact basement membrane zone

Repopulation of specialized cells

• Merkel’s cells which direct sensory function

• Melanocytes that foster pigmentation

• Langerhans cells that regulate immune functions


Keratinocyte migration

Within 24 h

Also occurs from the remaining skin appendages, including the hair follicle

“leap frog” theory -- epidermal cells migrate two or three cell lengths from

their initial position and slide over epidermal cells previously implanted in

the wound

Migrating keratinocytes produce matrix metalloproteinases (MMPs):

disrupts and allows for continued migration


Restoration of the basement

membrane zone

Within 7–9 days

The BMZ of the skin consists of many extracellular matrix proteins, with

collagens and laminins being the major components


Reconstitution of the dermis

Granulation tissue begins to form within 3–4 days of injury

Provisional extracellular matrix or fibronectin rich fibrin clot --

• Providing scaffolding and contact guidance for cells to migrate

• Angiogenesis

• Fibroplasia

Formation of granulation tissue


Mechanism of wound contraction

In direct proportion to depth

Full-thickness wounds -- peaks at 2 weeks, up to a 40% decrease in wound

size

Partial-thickness wounds -- parts of the adnexa remain and allow

epithelialization, contract less than full-thickness wounds

Myofibroblasts

By day 7, fibroblasts begin to change into myofibroblasts

Contraction resulting in “skin tension lines”


Wound angiogenesis

During wound healing, endothelial cells released cytokines, low oxygen

tension, lactic acid, and biogenic amines stimulate angiogenesis


Angiogenic growth factors



Remodeling phase

Deposition of matrix materials

Occurs through the whole process of wound repair

Total amount of collagen increases

• maximum 2 and 3 weeks

Tensile strength (functional assessment of collagen) increases to 40%, and

continue to increase for up to 1 year

• Never greater than 80% of its pre injury strength

Type III collagen is the major collagen in granulation tissue

• > 1 yr, the dermis returns to the preinjury phenotype (type I collagen)


Extracellular matrix

In part comprised of glycosaminoglycans and

proteoglycans

Dermal compliance, flexibility, and integrity

Strength, support, and density to tissue



Hyaluronic acid is nonsulfated glycosaminoglycan

• peak within the first 4–5 days

• Stimulus for fibroblast proliferation and migration, absorb large amounts of

water space for the migration of fibroblasts



Sulfated glycosaminoglycans are proteoglycans

• Stable and resilient matrix that inhibits cell migration and proliferation

• Chondroitin-4-sulfate and dermatan sulfate eventually replace

hyaluronic acid as the major glycosaminoglycan on days 5–7



Non-weight-bearing skin

• Progressive decrease of glycosaminoglycan content from fetal

development to maturity

Weight-bearing skin, such as the plantar aspect of the foot

• Minimal change in glycosaminoglycan

Chondroitin sulfate, are proportionally altered in pathologic skin states,

such as Dupuytren’s contracture or hypertrophic scarring


Collagen

80% of dry weight of the dermis

providing structure, strength, and stiffness to dermal tissue

In normal adults

• type I collagen -- 80% type III collagen -- 10%

Type III type I collagen during wound healing process


Biosynthesis of collagen


Elastic fibers

Elastin

• Provides elasticity and extensibility to the dermis

• Assists in recovery from deformation

Comprising only 2% of the total protein in the dermis

With aging, the amount of elastin increases


Proteinases and tissue remodeling

The most important protein are MMPs

Partly controlled by a family of tissue inhibitors of

metalloproteinases (TIMP1, TIMP2, TIMP3, TIMP4)

The balance between MMPs and TIMPs is critical to

the wound repair process and remodeling


FACTORS AFFECTING WOUND

HEALING

Systemic factors

Malnutrition, protein deprivation, and deficiencies of vitamin A and vitamin

C

Vitamin C -- cofactor for the collagen crosslinking

Vitamin A -- potentiates epithelial repair and collagen synthesis by enhancing

inflammatory reactions

Zinc deficiency reduces the rate of epithelialization

Corticosteroids, penicillamine, nicotine, NSAIDs, and antineoplastic agents

penicillin decreases collagen cross-linking

Chronic debilitating illness, endocrine disorders, systemic vascular

disorders, and connective tissue disease

Advancing age 長庚皮膚科 R2 劉人鳳

Systemic steroids in the first 3 days postwounding

blocks initial inflammation

prolongation of healing time

loss of skin turgor

suppress the mitotic activity of fibroblasts

Ameliorated with administration of local and systemic vitamin A, and a

single injection of TGFβ


Local factors

Poor surgical techniques (excessive tension or excess devitalized tissue)

Vascular disorders (arteriosclerosis or venous insufficiency), tissue ischemia

Infectious processes

Certain topically applied medications, extravasation of antineoplastic

drugs

Hemostatic agents such as aluminum chloride or ferric subsulfate

Foreign body reactions

Adverse wound microenvironment (dry vs occlusive dressings)

Pressure, neuropathy, and chronic radiation injury


OPTIMIZING OUTCOMES

Surgical techniques

Aseptic surgical techniques

Use of buried deep sutures – lessen risk for hematoma and subsequent

infection

Proper hemostasis and elimination of necrotic tissue

Apposition of wound edges, not closed too tightly – prevent ischemia and

necrosis


Topical skin adhesives

Novel, noninvasive alternative

Degrade with skin cells

Hemostatic, occlusive dressing, antimicrobial barrier

Similar rates of infection and scarring

Higher rates of wound dehiscence

2 classes: butyl and octylcyanoacrylates

• Dermabond® (Johnson and Johnson, New Brunswick, NJ) advanced has

the greatest strength and is the most flexible


Occlusive dressings

Healed up to 40% faster than those left exposed to air

Film dressings: face and other cosmetically important areas

Hydrocolloid dressings: exudative wounds

Foam dressings: wound associated pain

To be left in place until the exudate leaks from the dressing (early removal

can strip away newly formed epithelium)


Emerging dressings/topicals

Honey

decreases oxidative stress

Increase proinflammatory cytokines TNF-α, IL-1β, IL-6

reduce healing time in superficial and partial thickness burn wounds

But NOT for chronic leg ulcers

Protein kinase C

keratinocyte and fibroblast migration and differentiation, matrix deposition

Topical bacteriophage-based preparation

Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli


Emerging dressings/topicals

Human amniotic membrane allograft

many growth factors

facilitate angiogenesis, dampen inflammation, prevent infection, and promote healing

Thymosin beta-4

released by macrophages and platelets

interacts with actin and promotes angiogenesis, cell mobilization, migration, and tissue regeneration, decreasing myofibroblasts

Connexin 43

downregulates cell migration at wound edges


Investigational tissue and cell therapy

Activated allogeneic white blood cells, monocytes, macrophages,

neutrophils, and lymphocytes from healthy donors (topical or injected)

Living, growth-arrested keratinocytes and fibroblasts (spray)

release of growth factors

Bone marrow derived mesenchymal stem cells

heal chronic wounds

Human processed lipoaspirate -- contains stem cells and is easily harvested


Future growth factors

Topical fibroblast growth factor 1

Chemotaxis, proliferation of fibroblasts and keratinocytes, increase the

expression of TGF-β

5-amino acid deleted recombinant human hepatocyte growth factor

chronic wounds

promoting re-epithelialization, angiogenesis, and granulation tissue

formation


Partial-thickness versus

full-thickness wounds


Partial-thickness versus

full-thickness wounds

Early fetal skin wounds

regeneration can take place after dermal injury

higher concentrations of type III collagen and glycosaminoglycans

decreased inflammatory response and amounts of TGF-β1 長庚皮膚科 R2 劉人鳳

Summary

Wound healing is a complex process

Understanding of its underlying mechanisms is vital for practitioners

Older patients

slower healing

less tensile strength, secondary to reduced amounts of collagen

less scarring


Thank You For Your Attention

chapter 7 wound healing of the... · during wound healing, endothelial cells released cytokines,...

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