Tissue Repair

Tissue Repair, Renewal : Regeneration Healing Fibrosis

•      The ability to repair the damage caused by toxic insults and inflammation – is critical for the survival .

•      Repair refers to the restoration of tissue architecture and function after an injury.

Two types of Repair

1. Regeneration – Restitution of lost tissue

2. Healing – Collagen deposition and scar formation 

Proliferative Capacities of Tissues

1.  Continuously Dividing Tissues  (Labile cells ) - continuously being lost and replaced –

A.   Hematopoietic cells in the bone marrow

B.  Surface epithelia  eg.

a)  Stratified squamous of surfaces of the skin, oral cavity, vagina, and cervix.

b)  Cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract).

c)  Columnar epithelium of the gastrointestinal tract, uterus, and fallopian tubes.

d)  Transitional epithelium of the urinary tract.

2. Stable Tissues :  Quiescent (in the G₀ stage of the cell cycle) and have only minimal replicative activity in their normal state.

•      Cells are capable of proliferating in response to injury or loss of tissue mass.

•      Example- Parenchyma of most solid tissues, such as liver, kidney, and pancreas. Endothelial cells, fibroblasts, and smooth muscle cells.

3. Permanent Tissues - terminally differentiated and non proliferative in postnatal life .

Example - Majority of neurons and cardiac muscle cells.

•      Skeletal muscle is usually classified as a permanent tissue, but satellite cells attached to the endomysial sheath provide some regenerative capacity for this tissue.

•      In permanent tissues, repair is typically dominated by scar formation.

The Cell Cycle

Stem Cells : Stem cells are characterized by two important properties:

1. Self-renewal capacity

2. Asymmetric replication - some progeny enter a differentiation pathway, while others remain undifferentiated, retaining their self-renewal capacity.

Embryonic stem cells

Adult stem cells

Repair by connective tissue deposition

Consists of four sequential processes:

1.  Formation of new blood vessels (angiogenesis).

2.  Migration and proliferation of fibroblasts.

3.  Deposition of ECM (scar formation).

4.  Maturation and reorganization of the fibrous tissue (remodeling) .

Angiogenesis

Migration of Fibroblasts and ECM Deposition (Scar Formation)

•      Scar formation builds on the granulation tissue framework of new vessels and loose ECM that develop early at the repair site.

•      It occurs in two steps:

(1) migration and proliferation of fibroblasts into the site of injury

(2) deposition of ECM by these cells.

The recruitment and stimulation of fibroblasts is driven by many growth factors, including PDGF, FGF-2 and TGF-β.

ECM and Tissue Remodeling

After its synthesis and deposition, scar ECM continues to be modified and remodeled.

The outcome of the repair process is, in part, a balance between ECM synthesis and degradation.

The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), which are dependent on zinc ions for their activity.

 Eg - interstitial collagenases, gelatinases , stromelysins

MMPs are produced by - fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells.

Their synthesis and secretion are regulated by growth factors, cytokines, and other agents.

Healing

Healing occurs by 2 ways :

1.  Healing by 1^st  intention .

2.  Healing by 2^nd intention .

Healing by 1^st intention :

It is the healing of a clean, uninfected surgical incision approximated by surgical sutures.

This is referred to as primary union, or healing by first intention. A small scar is formed, but there is minimal wound contraction.

The narrow incisional space first fills with fibrin-clotted blood, which is rapidly invaded by granulation tissue and covered by new epithelium.

Healing by First Intention

Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot.

Within 24 to 48 hours - epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane components as they progress.

By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space. Collagen fibers are now evident at the incision margins, but these are vertically oriented and do not bridge the incision.

By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. Collagen fibrils become more abundant and begin to bridge the incision.

 During the second week, there is continued collagen accumulation and fibroblast proliferation. The leukocyte infiltrate, edema, and increased vascularity are substantially diminished.

By the end of the first month, the scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an essentially normal epidermis.

Healing by Second Intention

When cell or tissue loss is more extensive, such as in large wounds, abscess formation, and ulceration, the repair process is more complex.

In second-intention healing, also known as healing by secondary union the inflammatory reaction is more intense, there is abundant development of granulation tissue, and the wound contracts by the action of myofibroblasts. This is followed by accumulation of ECM and formation of a large scar.

Wound Strength

•      Carefully sutured wounds have approximately 70% of the strength.

•      When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks.

•       The recovery of tensile strength – 1. Collagen synthesis ( 2 months )

      2. From structural modifications of collagen (e.g., cross-linking and increased fiber size)

•      Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point.

Factors influencing wound healing

Local factors   

1.  Infection – Persistent tissue injury and inflammation

2.  Mechanical factors –Early motion of the wound

3.  Foreign bodies – Fragments of steel, glass, bone etc.

4.  Size ,Location , Type of wound – Face – heals fast

5. Hematoma , Denervation , Necrotic tissue , Protection (Dressing ) etc.

Systemic Factors

1. Nutrition-protein deficiency, vitamin C deficiency, Zn, Fe etc .

2. Metabolic status – DM – Microangiopathy

3. Circulatory Status – Arteriosclerosis , Vericose vein etc.

4. Hormones – glucocorticoids – antiinflammatory effects .

5. Age , Temperature, Uremia, Malignancy , Genetic diseases etc .

Keloid Formation