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Tissue Repair

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Outline of Lecture

 Wound  Healing And Tissue Repair   

 LEARNING OBJECTIVES

Review the normal physiology and concepts of cell proliferation, cell growth, cell “cycle”, and cell differentiation

Understand the basic factors of tissue regeneration

Understand the relationships between cells and their ExtraCellular Matrix (ECM)

Understand the roles of the major players of healing—angiogenesis, growth factors (GFs), and fibrosis

Differentiate 1st & 2nd intention healing

Know factors affecting wound healing

RERPAIR   BY  REGENERATION

 REPAIR   BY  HEALING , FIBROSIS , SCAR  FORMATION

REGENERATION

Replacement of lost structures by cells of same tissue

Is dependent on the type of normal turnover the original tissue has

HEALING

Needs a wound, inflammatory process, or necrosis

Many disease appearances anatomically are the result of “healing” such as atherosclerosis

Often ends with a scar

Fibrosis, as one of the 3 possible outcomes of inflammation, follows “healing”

Requires a connective tissue “scaffold”

Fibrosis occurs in proportion to the damage of the ECM

REQUIRMENTS

 1 . CELLS

2 . GROWTH FACTORS , CYTOKINES

3 . EXTRA CELLULAR MATRIX

CELL TYPES

Labile: eg., marrow, GI

Quiescent: liver, kidney

NON-mitotic: neuron, striated muscle

STEM CELLS

1 . EMBRYONIC

2 . ADULT

 Growth Factors (GFs)

Polypeptides

Cytokines

LOCOMOTION

CONTRACTILITY

DIFFERENTIATION

ANGIOGENESIS

Growth Factors (GFs)

Epidermal

Transforming (alpha, beta)

Hepatocyte

Vascular Endothelial

Platelet Derived

Fibroblast

Keratinocyte

Cytokines (TNF, IL-1, Interferons)

ExtraCellular Matrix (ECM)

Collagen(s) I-XVIII

Elastin

Fibrillin

CAMs (Cell Adhesion Molecules)

Immunoglobulins, cadherins, integrins, selectins

Proteoglycans

Hyaluronic Acid

ECM

Maintain cell differentiation

 

“Scaffolding”

 

Establish microenvironment

 

Storage of GF’s

Repair by Healing

Healing is a fibro-proliferative responses that “patches” rather than restores tissue and involves the following processes

 

Induction of an inflammatory response to remove dead and damaged tissue

Proliferation of parenchymal and connective tissue cells

Angiogenesis (blood vessel formation) and formation of Acquisition of wound strength

Synthesis granulation tissue

of ECM proteins and collagen deposition

Tissue remodeling

Wound contraction

 

It usually leads to scar formation and does not lead to complete restitution of the injured tissue

Angiogenesis = growth of new blood vessels

Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow after tissue injury

Healthy angiogenesis is tightly controlled by a serious of “on” and “off switches (Angiogenic growth factors versus angiogenesis inhibitors)

In many serious diseases the body loses control over angiogenesis and angiogenesis-related diseases occur when new blood vessels grow excessively or insufficiently

VEGF and Angiopoietins are the most important angiogenic factors

Anti-VEGF Fab-fragment treatment is used in tumor therapy as well as wet macular degeneration

Anti-VEGF Fab-fragment treatment is used in tumor therapy as well as wet macular degeneration

Role of extracellular matrix in wound healing and scar formation

Extracellular matrix (ECM) is formed by specific secreted macromolecules that form a network on which cells grow and migrate along

ECM is secreted locally and forms a significant proportion of the tissue volume

ECM sequesters

water that provides turgor to soft tissues

and minerals that provides rigidity to skeletal muscles

ECM proteins assemble into two general organizations

Interstitial matrix (present between cells)

Basement membrane [BM] (produced by epithelial and mesenchymal cells and is closely associated with the cell surface)

Three groups of macromolecules constitute the ECM

Fibrous structural proteins

Collagen

Fibrillins

Adhesive glycoproteins

Cadherin

Integrins

Immunoglobulin family

Selectins

Proteoglycans and Hyaluronic Acid

 Fibrous structural proteins

Collagens

Collagens are the most abundant proteins

27 different types

Type I,II, III, V and XI are the most abundant (interstitial or fibrillar collagens)

Provide tensile strength of tissue

Fibrillar collagen requires hydroxylation of proline and lysine in procollagen which is dependent on Vitamin C

Type IV is the main component of BM and forms sheets)

Elastins and Fibrillins

Provide tissue with the ability to recoil

Elastins are found in large vessels, uterus, skin and ligaments

Fibrillins form a scaffolding for the deposition of elastins

Marfan syndrome is an inherited autosomal dominant defect in fibrillin synthesis. Without the structural support provided by fibrillin, many tissues are weakened, which can have severe consequences, for example, ruptures in the walls of major arteries.

Proteoglycans and hyaluronic acid 

 

Proteoglycans  (mucoproteins) are formed of glucosaminoglycans (GAGs) covalently attached to core proteins and are highly negatively charged

Biophysical functions due to ability to fill space, bind and organize water molecules and repel negatively charges molecules

They are ideal lubricating fluids in the joint due to high viscosity and low compressibility

 

Biochemical functions are mediated by specific binding of GAGs to other macromolecules

e.g Antithrombin III (AT III) binds tightly to heparin and heparin sulfates and inactivates factor II, IXa and XIa thus controlling  blood coagulation

Cutaneous wound healing

is generally divided into three overlapping phases

 

Inflammation

 

Granulation tissue formation and re-epithelialization

 

Wound contraction, extracellular matrix deposition and remodeling

Skin wounds are classically described to heal by either
primary or secondary intention

and the distinction is made by the nature and extent of the wound

Healing by first intention: wounds with clean opposing edges (surgical incision)

Healing by second intention: wounds with separated edges (trauma that requires abundance of granulation tissue for wound closure)

Granulation tissue consists of newly formed blood vessels, macrophages, fibroblasts and loose ECM framework

As collagen accumulation increases, the granulation tissue scaffolding is converted into a mature scar composed of mature spindle-shaped fibroblasts, dense collagen and elastic fibers.

The mature scar does not contain vessels

Complications of wound healing

Deficient scar formation

Wound dehiscence

Ulceration

Excessive formation of scar tissue

Keloid (excessive collagen deposition)

Exuberant granulation (proliferation of fibroblasts that inhibits re-epithelialization)

Desmoid (aggressive fibromatosis, semi-malignant)

Contraction

Factors that influence wound healing

Systemic factors

Malnutrition

Protein deficiency

Vitamin C deficiency (inhibition of collagen synthesis)

Metabolic status

e.g Diabetes mellitus

Consequence of microangiopathy

Cortison treatment

inhibits inflammation and collagen synthesis

Circulatory status

Inadequate blood supply due to ateriosclerosis

Varicose veins (retarded venous drainage)

Factors that influence wound healing (continue)

Local Factors

Infection (single most important reason for delayed wound healing)

Foreign bodies

suture material, bone and wood splinters ….

 

Mechanical factors

Early movement

Pressure

 

Mechanisms of fibrosis

Cell proliferation

Cell – cell  interactions

Cell matrix interactions

ECM deposition

A balance between TH-2 and TH-1 cytokines is necessary to promote healing but inhibit excessive fibrotic tissue remodeling

Fibrotic tissue remodeling can result in
loss of organ function

Fibrotic changes can occur in various vascular diseases including

Cardiac diseases

Peripheral vascular diseases

 

They can affect  main organ systems like

Skin

Lung

Liver

Kidney

ANGIOGENESIS
(NEOVASCULARIZATION)

From endothelial precursor cells

From PRE-existing vessels

Stimulated/Regulated by GF’s, especially VEGF

Also regulated by ECM proteins

aka, “GRANULATION”, “GRANULATION TISSUE”, “ORGANIZATION”, “ORGANIZING INFLAMMATION”

WOUND HEALING

1st INTENTION

 

Edges lined up

2nd INTENTION

 

Edges NOT lined up

Ergo….

More granulation

More epithelialization

MORE FIBROSIS

FIBROSIS/SCARRING

DEPOSITION OF COLLAGEN by FIBROBLASTS

With time (weeks, months, years?) the collagen becomes more dense, ergo, the tissue becomes “STRONGER”

Wound RETARDING factors
(LOCAL)

DECREASED Blood supply

Denervation

Local Infection

FB

Hematoma

Mechanical stress

Necrotic tissue

Wound RETARDING factors (SYSTEMIC)

DECREASED Blood supply

Age

Anemia

Malignancy

Malnutrition

Obesity

Infection

Organ failure

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