Healing and Repair/2014-2015

Healing and Repair/2014-2015Dr.Ban Jumaa

TISSUE REPAIR

· Tissue repair = restoration of tissue architecture and function after an injury

· Occurs in two ways:

· Regeneration : proliferation of cells to replace lost structures

· Replacement by connective tissue (scarring)

· Usually, tissue repair involves both processes

· Involves cell proliferation, and interaction between cells and extracellular matrix

CELLULAR PROLIFERATION

· Lots of cells proliferate during tissue repair:

· injured tissue remnants

· vascular endothelial cells

· fibroblasts

Control of Normal Cell Proliferation and Tissue Growth

In adult tissues the size of cell populations is determined by the rates of cell proliferation, differentiation, and death by apoptosis

Stem cells

· They are source of mature cells

· There is a homeostatic equilibrium between replication and differentiation of stem cells and the death of the mature, fully differentiated cells. Examples are skin and GI tract. Stem cells with the capacity to generate multiple cell lineages (pluripotent stem cells) can be isolated from embryos and are called embryonic stem (ES) cells. Bone marrow stem cells are able to generate fat, cartilage, bone, endothelium, and muscle.

· Stem cells have 2 characteristic properties:

· Self-renewal capacity

· Asymmetric replication

· Some differentiate to a specific cell type

· Some remain undifferentiated: These maintain their self-renewal capacity.

Tissues of the body are divided into three groups according to their proliferative capacity:

1. Continuously dividing (labile) tissues

· cells are continuously proliferating

· can easily regenerate after injury

· contain a pool of stem cells

· examples: bone marrow, skin, GI epithelium

2. Stable tissues

· cells have limited ability to proliferate

· limited ability to regenerate (except liver!)

· normally in G0, but can proliferate if injured

· examples: liver, kidney, pancreas

3. Permanent tissues

· cells can’t proliferate

· can’t regenerate (so injury always leads to scar)

· examples: neurons, cardiac muscle

GROWTH FACTORS

Cell proliferation can be triggered by: Growth factors, hormones, cytokines.

Growth factors are polypeptides produced by leukocytes, parenchymal cells, and connective tissue ,affect cell proliferation by:

1)Expanding cell population

· Stimulating cell division (mitosis)

· Increase cell size (growth)

· Protection from apoptotic death (survival)

2)Other functions

· Stimulate migration, differentiation, angiogenesis, contractility, and fibrogenesis

· Involved in growth control – can stimulate or inhibit

· May act on multiple cell types

Huge list! Usually have “GF” in name:

· EGF: Epidermal Growth Factor

· TGF: Transforming Growth Factor

· PDGF :Platelet Derived Growth Factor

· VEGF: Vascular Endothelial Growth Factor

Signaling Mechanisms of Growth Factor:

· 3 types:

· Autocrine

· Substance acts on cell that secretes it:

· Lymphocyte proliferation, liver regeneration

· Paracrine

· Substance affects cell in the vicinity:

· Recruiting inflammatory cells, wound healing

· Endocrine

· Acts on target cells at a distance:

· Hormones

GF either :

· Affect receptors on cell surface membrane

· Affect receptors inside the cell – intracellular:

· must be hydrophobic to enter

· Vitamin D, steroid and thyroid hormones

THE EXTRACELLULAR MATRIX (ECM)

· ECM is the network that surrounds cells

· Two forms: interstitial matrix and basement membrane

· Does lots of things!

· Sequesters water and minerals

· Gives cells a scaffold(Mechanical support) to adhere to

· Stores growth factors

· ECM regulates proliferation, movement, and differentiation of the cells living in it.

· If ECM is damaged, tissue can’t regenerate! It will form a scar instead.

REGENERATION

· Occurs all the time in labile tissues

· Cells are constantly being lost and replaced

· If demand increases, supply increases easily

· Occurs in limited form in stable tissues

· Remove one kidney: the other one undergoes hypertrophy and hyperplasia

· Remove half of the liver: it will grow back

· Only occurs if residual tissue is intact!

SCARRING

· If injury is severe, regeneration can’t happen

· So, fibrosis (a scar) replaces the injured tissue

· Four components to this process:

· new vessel formation (angiogenesis)

· fibroblast proliferation

· synthesis of collagen (scar formation)

· remodeling of scar

· By 24 hours:

· Endothelial cells start proliferating

· Fibroblasts emigrate

· By 3-5 days:

· Granulation tissue is formed which has pink, soft, granular gross appearance and histologically characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), in a loose ECM .

· Weeks later:

· dense fibrosis (scar)

· scar is remodeled over time

SKIN WOUND HEALING

Healing by First Intention:

· This is referred to as primary union or healing by first intention.

· Occurs in small wounds that close easily

· Epithelial regeneration predominates over fibrosis

· Healing is fast, with minimal scarring/infection

Examples:

· Paper cuts

· Clean ,uninfected surgical incision approximated by surgical sutures

· Timeline:

· By 24 hours

· clot forms

· neutrophils come in

· epithelium begins to regenerate

· By 3-7 days

· macrophages come in

· granulation tissue is formed

· new blood vessels

· fibroblasts

· collagen begins to bridge incision

· epithelium increases in thickness

· Weeks later

· granulation tissue gone

· collagen is remodeled

· epidermis full, mature (but without dermal appendages!)

· eventually, scar forms

Healing by Second Intention:

· Also known as healing by secondary union

· When cell or tissue loss is more extensive, such as in large wounds, that have gaps between wound margins abscess formation, large burns , ulcers, and infarction in parenchymal organs.

· The repair process is more complex.

· Fibrosis predominates over epithelial regeneration

· Healing is slower, with more inflammation and granulation tissue formation, and the wound contraction by the action of myofibroblasts which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.

· This is followed by formation of a large scar. Within 6 weeks, large skin defects may be reduced to 5% to 10% of their original size, by contraction.

· Secondary healing differs from primary healing in several respects:

· A larger clot or scab rich in fibrin and fibronectin .

· Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed.

· Much larger amounts of granulation tissue are formed. Larger defects require a greater volume of granulation tissue to fill in the gaps.

· Wound contraction: a greater volume of granulation tissue results in a greater mass of scar.

Wound Strength

· At suture removal: 10%

· Rapid increase over next 4 weeks

· At third month: 70-80%

LOCAL AND SYSTEMIC FACTORS THAT INFLUENCE WOUND HEALING

Systemic factors:

· Nutrition: vitamin C deficiency inhibits collagen synthesis and retards healing.

· Inadequate blood supply: due either to arteriosclerosis and diabetes or to obstructed venous drainage (e.g. in varicose veins), also impairs healing.

· Diabetes mellitus: hyperglycemia, reduced immunity, impairment of the leukocyte movement.

· Steroids: have well-documented anti-inflammatory effects and their administration may result in poor wound strength due to diminished fibrosis.

Local factors:

· Infection is the single most important cause of delay in healing; it prolongs inflammation and increases the local tissue injury.

· Foreign bodies: such as fragments of steel, glass, or even bone impede healing.

· Mechanical factors: early motion, increased local pressure or torsion may cause wounds to pull apart, or dehisce.

· Size, location, and type of wound: larger wounds are slower in healing; wounds in the face are healed faster than in the lower limb because of rich blood supply, healing by first intension is faster than second intension.

Complications in wound healing

1. Dehiscence (rupture )of a wound

Most common after abdominal surgery due to increased abdominal pressure

2. ulceration

· inadequate vascularization

· areas devoid of sensation

3. keloid

The accumulation of excessive amounts of collagen, giving rise to prominent, raised scars. Develops after thermal or traumatic injury. There is a heritable predisposition to keloid formation, and the condition is more common in blacks.

4. Proud flesh

· Excessive formation of granulation tissue

5. Contracture

· commonly seen after serious burns

· can impair the movement of joints

Notes

· Not all injuries result in permanent damage; some are resolved almost completely

· More often, there is some degree of scarring

· Scar is usually good (provides a resilient patch) but occasionally bad (can cause permanent dysfunction).

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