You are on page 1of 28

WOUND HEALING, TISSUE REPAIR, AND FIBROSIS

DR. RIBKA THEODORA DR. REYHAN FARANDI DR. GOESTI YUDISTIRA DR. NUR NATHANIA DRG. DINA NOVIANTI

Wound Healing

Wound : a break in the epithelial integrity of the skin + disruption of the structure & function of underlying normal tissue

Healed Wound :

Connective tissues have been repaired + re-epithelialized Returned to its normal anatomical structure and function

Type :

  • 1. Acute wounds :

    • - Occur within the past 3-4 w

  • 2. Chronic wounds :

    • - Persist trough 4-6 w

    • - Chronic wounds = non healing wounds, recalcitrant, delayed healing

Wound Assessment

Paper-made ruler, transparent gridlines

Wound Assessment Paper-made ruler, transparent gridlines
Wound Assessment Paper-made ruler, transparent gridlines

healing:

Inflammatory Phase (day 1-3)

Purpose: attain homeostasis, remove devitalized tissue and prevent invasive infection

  • 1. Attainment of homeostasis

Fibrillar collagen and tissue factor act to activate the clotting cascade prevent hemorrhage

Platelets degranulates and releases polymerization into a gelatin

..

Fibrin

  • 2. Removal of devitalized tissue & prevent infection

Recruitment of inflammatory cells (neutrophils)attracted by TGF-β & lipopolysaccharide followed by monocytes macrophagesphagocytosis Lymphocyte enters at day 5-7

healing: Inflammatory Phase (day 1-3) Purpose: attain homeostasis, remove devitalized tissue and prevent invasive infection 1.

Proliferative Phase: day

4-21

Purpose: to achieve wound closure by granulation, angiogenesis, and epithelization

1. Tissue proliferation

Macrophages as a conductor of cell interaction and mediators VEGF, FGF, TGF-α& β

Fibroblast FGF-2 regeneration of endothelial cells

Endothelial cells IGF proliferation of keratinocytes and fibroblast

Keratinocytes TGF-α& β 1,2,3 keratinocytosis (centripetal)

Granulation tissue is largely composed of fibroblasts, macrophages, and endothelial cells.

Proliferative Phase: day 4-21 Purpose: to achieve wound closure by granulation, angiogenesis, and epithelization 1. Tissue
  • 2. Angiogenesis Macrophage VEGF, FGF, angiopoietin 1, thrombospondin Upregulated by hypoxia inducible factor

Formation of blood vessels and subsequent granulation tissue to provide the newly formed tissue matrix important for survival

  • 3. Matrix formation (dermis-skeletal structures) Fibroblast collagen III increases

2. Angiogenesis • Macrophage  VEGF, FGF, angiopoietin 1, thrombospondin • Upregulated by hypoxia inducible factor
2. Angiogenesis • Macrophage  VEGF, FGF, angiopoietin 1, thrombospondin • Upregulated by hypoxia inducible factor

Remodelling Phase: day 21-1 year

Purpose: obtaining matrix equilibrium, reorganizing the collagen matrix into a well-organizing one to provide a softer and flatter scar

  • 1. Wound contraction

Myofibroblast scar contraction via specific integrin-mediated cell-matrix interactions with the dermal environmenttighten wound edges

  • 2. Collagen remodeling

Over the next few weeks to months col III will be replaced by col type I (1:4), which are more in regular alignment.

  • 3. Matrix remodeling

Matrix metalloproteinases degrade ECM along with resorption of fluid flatter scar

Remodelling Phase: day 21-1 year Purpose: obtaining matrix equilibrium , reorganizing the collagen matrix into a

The role of macrophages in wound healing

  • 1. Efferocytosis: removal of apoptosis cells (neutrophils) by phagocytosis. Failure in removal of inflammatory cells non-healing wounds

  • 2. Source of growth factor: VEGF (promotion of angiogenesis), FGF (fibroblast proliferation), and ECM synthesis

The roles of neutrophils in wound healing

Effective decontamination destroying normal tissue.

Produce free oxygen radicals superoxide and hydrogen peroxide delaying repair process and modifying healing outcome

The roles of neutrophils in wound healing Effective decontamination  destroying normal tissue. Produce free oxygen

Serine proteases

Include cathepsin-G, elastase, and protease-3 have the same proteolytic activities cleave a variety of extracellular matrix proteins (elastin, fibronectin, laminin, vitronectin, collagen IV.

Unfortunately, they could potentially interfere with re-epithelization. (Gramerin, an elastase inhibitor accelerates re-epithelization. Elastase levels have been observed in chronic wounds)

MMP vs TIMP

Matrix metalloproteinase: degrade protein molecule on the wound bed. Secreted by neutrophils.

Among 23 types, there are 4 types that play important roles in wound healing: MMP-1 (kolagenase-1), MMP-2, MMP-8 (kolagenase neutrophil), MMP-9

Inflammatory phase:

MMP degrades damage ECM at wound edge wound cells to synthesize new ECM to cover raw surface area

Proliferative phase:

MMP degrades capillaries membrane neovascularization, also collagen new epithelial and endothel could move across matrix.

Maturation phase:

Plasmin was activated and subsequently activates prokolagenase to kolagenase. Decrease over synthesized matrix. TIMP: inhibit MMP activities to allow normal healing process, low TIMP chronic wound.

Resolved inflammation

Apoptotic Efferocytosis Proteases So how do these processes turn off? These events are programmed  gradual
Apoptotic
Efferocytosis
Proteases
So how do these processes turn off?
These events are programmed 
gradual self-destruction of cellular
apoptosis.
Afterwards, the proteases activity is
being countered by circulating
proteases inhibitor.
neutrophils &
inhibitor
fibroblast
apoptotic neutrophils are
eventually engulfed by
macrophages
a1-antitrypsin, a1-
antichymotrypsin, and
secretory leukocyte
protease inhibitor
(SLPI)
Resolved inflammation
relatively acellular scar. Less erythematous, less itch flatter scar

Lower apoptotic rates/ failure in apoptotic cell removal persistent inflammation.

BARRIERS OF WOUND HEALING

PROCESS NECROTIC BACTERIAL EXUDATE TISSUE LOAD WOUND HEALING
PROCESS
NECROTIC
BACTERIAL
EXUDATE
TISSUE
LOAD
WOUND
HEALING

IMPAIRED WOUND HEALING

Factors influencing wound healing:

Local factors

Infection: colonization and infection bacterial bio-burden

Foreign bodies: energy is consumed to remove debris and prolong process of healing

Hypoxia/Ischemia: no ATP will lead to endothelial cells apoptosis & necrosis

Venous Insufficiency: metabolic waste being pooled in situ progressive blocking of blood flow

Local toxin: from bacterial/ metabolic

Radiation damage: due to heat penetration radiation affects cell proliferation

Systemic Factors

Malnutrition:

o Glucose, the main fuel for collage synthesis o Arginine and methionine for matrix deposition, cell proliferation, and angiogenesis o Glutamine enhances the actions of PMN cells o Mg, Mn, Cu, Ca, and Fe co-factors in collagen production o Vit C collagen modification o Glycine, arginine, methionine control inflammation o Zn influences re-epithelization and collagen desposition o L-arginine influences endothelial and metabolic function as well as NO synthesis o Albumin oncotic pressure to prevent edema

Diabetes Mellitus: sorbitol key byproduct of ineffective and inefficient glucose metabolism accumulates toxic (impairs O2 delivery and nutrients)angiopathy.

Systemic Corticosteroids: impairs immune system

Alcoholism

Cancer/malignancy: poor nutrition/receive chemotherapy, cytotoxic.

Uremia

Jaundice

Obesity: increase cell-cell distance decreased O2 perfusion. Difficulties in keeping his/her personal hygiene of body fold & distant part

Geriatric age: decreasing tissue regenerative ability

Smoking: vasoconstriction agents: nicotine, hydrogen cyanide, CO2 increase platelet aggregation, decrease collagen deposition

Metabolic/ endocrine disease: hypothyroid: low hydroxyproline collagen instability

Tissue Repair

The repair or reconstitution of a deficit in an organ or tissue, commonly the

skin. As an organism's global response to injury to re-establish homeostasis of tissue/organ

Every organisms and organ systems respond to injuries differently.

Obviously, most processes involve both, but usually one predominates and may be the source of undesirable side effects that we would like to prevent or modify. For cutaneous wounds, scar formation usually predominates.

Occur in two ways : Regeneration and Reparation (Scar Formation)

Tissue types

Permanent

nonproliferative in postnatal life neurons, cardiomyocytes, skeletal

Stable

regeneration as response to injury parenchyma – liver, pancreas, renal tubules mesenchymal cells, endothelium

Continously

continuous regeneration from stem cells (self-renewal) hematopoietic cells in bone marrow surface epithelia – skin, oral cavity, vagina, cervix duct epithelia – salivary glands, pancreas, biliary tract mucosas – GIT, uterus, fallopian tubes, urinary bladder

Tissue Types

Tissue Types

Occur in two ways :

Scar Formation

Substitution of cellular matrix a patch to re-establish continuity physically and physiologically

Occur in two ways : Scar Formation Substitution of cellular matrix  a patch  to

(replacement by connective tissue (fibrosis))

and

Tissue Regeneration

Re-creation of pre-existing tissue

(by parenchymal cells of the same type)

Abnormal response to injury & abnormal wound healing

Inadequate regeneration

CNS injuries following traumatic injury or tumor ablation

Induce neural regeneration implanted

neural stem/progenitor cells Bone nonunions & corneal ulcers

Inadequate scar formation

Diabetic foot ulcers , sacral decubiti, venous statis ulcers

Abnormality in restoring cutaneous integrity and collagen cross-linking

Vit C deficiency

Excessive regeneration

Hyperkeratosis in cutaneous psoriasis,

granuloma formation in healing wounds Loss of growth control & possible transformation to overt cancer

Excessive scar formation

Skin : hypertrophic scarring or keloid

formation. Pulmonary : fibrosis or cirrhosis.

Keloid vs Hypertrophic Scar

Keloid vs Hypertrophic Scar The ideal scar should be Similar to a fine line scar •

The ideal scar should be Similar to a fine line scar

Pigmentation related to the neighboring healthy tissue,

Without any irregularities in texture or contractures distorting the adjacent skin

Fibrosis

Fibrois the formation of excess fibrous connective tissue in an organ or tissue.

If injury is severe. regeneration can't happen. So, fibrosis (tissue scar)

  • 1. New vessel formation

replaces the injured tissue. Four components to this process :

  • 2. Fibroblast proliferation

  • 3. Synthesis of collagen (scar formation)

  • 4. Remodelling scar

The prolonged secretion of inflammatory cytokines has been shown to induce fibrosis in numerous in vitro and animal models. (Grabb and Smith)

Thank You