Regeneration, Repair and Healing

In human beings regeneration occurs only as a compensatory growth e.g

Regeneration of liver
Removal of one kidney causes enlargement of the other.
The other regenerative activity taking place is the continuous replenishment of blood cells,
epithelial cells of GIT and epidermal cells of skin

Repair
Repair refers to replacement of destroyed tissue by living tissue
This replacement or repair of a damaged tissue may be done in two ways:

Healing
Healing is defined as the process whereby lost tissue is replaced by fibrous tissue or scar.
This involves regeneration as well as scar formation e.g
1)Skin healing :
When only epidermis is damaged – heals by regeneration
When dermis is also damaged – Heals by scar formation
2)Myocardial infarction:
Surrounding cells do not have capacity to
regenerate
Healing by scar formation
3)Pericarditis :
Inflamed pericardium heals by fibrosis
Adhesions occurs between two layers of pericardium and constrict
Constriction of heart takes place- known as
Constrictive pericarditis
4) Gastric ulcer:
Heals by fibrosis , causing stricture and deformities e.g pyloric stricture and hour glass deformity
5) Cirrhosis of liver:
Necrosed hepatocytes are replaced by fibrosis

Organisation : During healing lost tissue is

replaced by granulation tissue and finally by
fibrous tissue to form scar. This is termed as
organisation
Factors for healing
1)Proliferative activity of the tissue and stem cells
2)Growth factors
3) Mechanism of cell growth
4) Cell cycle
5) Cell-matrix interaction

Proliferative activity of the tissue and stem cell

Depending on proliferative ability tissues are divided into 3 types:
Labile tissue : continuously dividing cells
Stable tissue : divide at slow rate
Permanent tissue : non-dividing cells

Labile Tissue
The cells continuously proliferate throughout life
They continuously replace the cells which are regularly lost or destroyed e.g
Surface epithelial cells of skin, GIT, urinary bladder etc.
Bone marrow cells
Stem cells
Stem Cells
These cells have unlimited capacity to proliferate and differentiate into various types of cells
Characteristics of stem cells:
Unlimited self-renewal and proliferation capacity
Asymmetric replication:
One of the daughter cell retains self- renewing
(stem cell) character while the other can differentiate
Types of stem cells
Embryonic stem cells:
These are pluripotent cells which give rise to all the different tissues of the body
Adult stem cells:
They have the capacity to differentiate into different adult stem cells
Sites of adult stem cells: 1) Bone marrow 2)Base of colonic crypts 3) Hair follicles 4) Limbus of
cornea
Stable Tissue
Also called quiescent tissue
They divide at slow rate normally
They divide at fast rate when stimulated by
injury
Example: Hepatocytes ( regeneration of liver), renal tubular cells, fibroblasts, smooth muscle
cells and leukcytes
Permanent Tissue
They are non-dividing in postnatal life e.g
1. Neurons: Neurons of the brain cannot be replaced
Neurons can be formed from stem cells
2. Skeletal muscles:
Skeletal muscles cannot divide but can be regenerate from stem cells
3. Cardiac muscle:
Injury to cardiac muscle is replaced by fibrosis e.g Myocardial infarction

Growth Factors
The major growth factors involved in the process of healing are:
Epidermal growth factor- EGF
Transforming growth factor alpha – TGF-a
Platelet derived growth factor- PDGF
Fibroblast growth factor- FGF
Transforming growth factor beta- TGF-b
Vascular endothelial growth factor- VEGF
Cytokines

Mechanism of cell growth

The growth factors function by binding to specific receptors.
There are four types of cell receptors:
1. Ion channel receptors
2. Receptors with intrinsic kinase activity
3. G protein coupled receptors
4. Receptors without intrinsic enzymatic activity
The cells now go through the cell cycle leading to cell division and proliferation

Cell Cycle
Cell cycle is the period between successive cell division during which the cell passes through
four phases ;
M phase – it is the mitotic phase
1 phase – cells pursue normal functioning
S phase – nuclear DNA synthesis takes place
G2 phase- a short gap period, which is followed by the next cell cycle starting with M phase
G0 phase- this is called as quiescent phase, cells do not divide after M phase
Cell-matrix interaction
The connective tissue that surround the cells
form the extracellular matrix – ECM
ECM is made up of:
Fibrous structural proteins e.g collagen, elastin
Adhesive glycoproteins and integrins
Proteoglycans and hyaluronic acid
ECM occurs in two forms:
1.Interstitial matrix
2.Basement membrane
Functions of ECM in repair and healing
Required for tissue repair and growth- basement membrane needed as scaffolding
Storage of growth factor- Fibroblast growth factor is stored in basement membrane
Maintains cell differentiation
Controls cell growth and differentiation
Cell anchorage

Wound contraction
Starts after 2-3 days and completes by about 14th day of injury
Wound contraction occurs due to granulation tissue formation
Granulation tissue is composed of proliferating small blood vessels and fibroblasts
Fibroblasts contract resulting in wound contraction
Although wound contraction is useful, some complications arises e.g
1.Strictures : stomach , intestine, fallopian tube
2. Contracture : burns causing impaired mobility

Granulation Tissue
Granulation tissue consists of proliferating small blood vessels and fibroblasts
Granuloma is a collection of epithelioid cells and histiocytes e.g tuberculosis
Organisation : Replacement of necrotic tissue, inflammatory exudate , thrombus or blood clot
by granulation tissue is called organisation
Organisation occurs in inflammation, pneumonia, wound healing, thrombus and infarct

Mechanism of granulation tissue formation

It involves two processes namely:
1.Angiogenesis
2.Fibroblastic proliferation ( scar formation)
Angiogenesis
A marked vascular proliferation starts 48 – 72 hours after injury and continues for several days
Two important growth factors needed for angiogenesis are:
1.Vascular endothelial growth factor – VEGF
2.Basic fibroblastic growth factor - BFGF
Fibroblastic proliferation – Scar formation
Fibroblasts form an important component of granulation tissue
They are found within 2-3 days after injury
Fibroblastic migration, proliferation and finally scar formation involves three processes:
1.Emigration and proliferation of fibroblasts
2.Extracellular matrix deposition: Fibroblasts synthesise ECM
3.Remodeling of tissue: this involves replacement of granulation tissue with scar tissue
 Wound healing in the skin
Two types of healing process may be seen in the skin according to the type of wound
1. Healing by first intention or primary union
This occurs in clean incised wound with edges in
apposition
2. Healing by second intention or secondary union
This occurs in wounds with separate edges
The basic mechanism of healing is same for both but the quantity of scarring differs
Healing by first intention
Is also known as primary union
Occurs in clean uninfected surgical incision
Changes taking place in first intention
Initial effect
24 hours
By third day
By fifth day
During second week
End of first month

1. Initial effect
Limited cell death and disruption seen
Narrow incisional space filled with blood clot
Clot dries up and forms scab

2) 24 hours
Within 24 hours the polymorphs appear at the margins of the incision
Epithelial cells from opposing epidermis migrate into the wound
Migrating cells fuse in the middle forming
epithelial layer that covers wound surface

3) By third day
Neutrophils are replaced by macrophages
Granulation tissue starts forming
Laying down of collegen fibers starts in the margins
Epithelial layer formed start thickening

4) By fifth day
Granulation tissue completely fills up wound space
Collagen laying down bridges the incision gap
Epithelial cell proliferation is complete, restoring the normal thickness
5) During second week
Inflammatory cells, edema and increased vascularity disappear
Increased collection of collagen and fibroblasts
This leads to scar formation

6) End of first month

Scar is formed which is covered by epidermis
Permanent loss of skin appendages in the scar area
Strength of scar increases and takes months to reach maximum strength

Healing by secondary intention

Also called as secondary union
Takes place when there is excessive tissue loss
Granulation tissue is the main bulk which repairs the wound
Changes taking place in secondary intention:
Initial effect
Wound contraction
Epithelial cell migration
Granulation tissue formation
Regeneration of epidermis
Scar formation

Factors influencing healing and repair

There are multiple factors delay wound healing.
They are: a) Local factors b)General factors
Local Factors
Blood supply:
Varicose ulcers: There is stagnation of blood and poor supply
Bedsores: Pressure points leads to poor blood supply
Chronic inflammation: Thickening of vessel wall causes poor blood supply
Old age: Atherosclerosis in old age leads to poor blood supply
Movement: Movement causes delayed healing e.g wound in the corner of mouth and fracture
of mandible
Bony adhesions: Adhesion of wound edges to bony surface delays healing
Radiation: Ionising radiation causes destruction of vessels and delayed healing
Local temperature: Hyperthermic environment enhances wound healing

Factors influencing healing and repair- General Factors

1.Infection and inflammation
2.Nutritional deficiencies: deficiency of Vitamin C , protein or zinc delay wound healing.
Vitamin C is needed for collagen synthesis
3.Age : Healing is slower in old age
Diabetes mellitus: Healing delayed due to its effect of hyperglycaemia
Delayed healing in tooth extraction and suture wound in diabetes
5. Hormones: Corticosteroids delay wound healing by inhibiting collagen synthesis

Complications of wound healing

1.Hypertrophic scar
Keloid formation:
Excessive laying down of collagen and ECM result in raised area of scar formation
When these are localised at the site of injury and do not progress , they are called hypertrophic
scar
When these scar spreads beyond injury site and recurs after excision, they are called keloid.
Clinically they are raised, itchy and tender
Hypertrophic and keloid scars do not occur in oral cavity
2) Bursting of wound: e.g bursting of abdominal wound called burst abdomen
3) Wound contraction: e.g severe contraction can cause deformities in stomach and strictures
in intestines
4) Pigmentation : Healing in skin causes hyper or hypopigmented areas e.g lichen planus scar is
blackish in colour
5) Dry socket: Alveolar osteitis
Dry socket is a focal osteomyelitis of the bone around the socket of the extracted tooth .
This is commonly seen in:
Extraction of an impacted bone
Traumatic extraction
Radiotherapy
Women taking oral contraceptives

Pathogenesis of dry socket:

Following dental extraction cavity gets filled with blood clot
In dry socket clot gets destroyed exposing bone.
Destruction of clot occurs by:
Protelytic enzymes of bacteria
Plasminogen released by injured bone and soft tissue
Morphology: Inflammation and sequestrum seen
Clinical picture: severe throbbing pain, foul smell , fever occurs

Healing in different organs

1. Bone: Healing takes place by laying down of woven bone by osteoprogenitor cells and
cartilage by chondroblasts.
The newly formed tissue is called callus.
The bony callus joins the fractured ends.
2. Liver: Liver has the highest capacity to regenerate.
The hepatocytes along with fibrous tissue laid down by stellate cells of liver.
This gives a multinodular appearance called cirrhosis
3) Central nervous system:
Brain has limited regenerating capacity.
Necrosed tissue is replaced by proliferating neuroglia to form glial scar (gliosis)

4) Heart:
Cardiac muscles do not show any regeneration.
Necrosed cells are replaced by fibrosis (scar) called myocardial infarction