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
