Department of Anatomic Pathology

Faculty of Medicine
Brawijaya University
Regeneration and Healing
Definition :
Regeneration
Healing
Control of Normal Cell Proliferation and Tissue Growth
Cell cycle
Tissue Proliferative Activity
Growth Factor
Extracellular Matrix (ECM) and Cell-Matrix Interactions
Repair by Healing, Scar Formation, and Fibrosis
Healing :
Scar Formation
Cutaneous Wound Healing
Primary Union
Secondary Union
Wound Strength
Local and Systemic Factors That Influence Wound Healing
Regeneration
1. Definition :
Growth of cells and tissues to replace lost structures

2. Occurs if the ECM framework is not damaged / intact

( framework provide for cell migration and maintain the
correct cell polarity for re-assembly of multilayer
structures )

3. Regenerated cells :
- Original cells
- Stem cells

Note :
Stem cells :
- Embryonic stem cells
- Adult stem cells
* Hematopoietic stem cells / HSCs
* Tissue stem cells
- Asymmetric replication
Healing
1. Definition :
A tissue response
* to a wound (commonly in the skin),
* to inflammatory processes in internal organs, or
* to cell necrosis in organs incapable of
regeneration

2. Occurs if the ECM framework is damaged

3. Healing consists regeneration and scar formation

 may restore original structures but involves
collagen deposition and scar formation.
Figure 3-1 Tissue response to injury. Repair after injury can occur by regeneration, which restores normal
tissue, or by healing, which leads to scar formation and fibrosis.
Control of Normal Cell Proliferation and Tissue
Growth
* Repair : Regeneration / growth of cells / tissue
* In adult tissues, the size of cell populations is determined by
the rates of cell proliferation, differentiation, and death by
apoptosis.
* Cell Cycle :
TISSUE-PROLIFERATIVE ACTIVITY
The cells of the body :
1. Labile (Continuously dividing) tissue
Cell proliferate throughout life : surface epithelia, oral cavity,
vagina, cervix, the secretory ducts of the glands,
epithel gastrointestinal tract, uterus, urinary, bone marrow,
and hematopoietic tissue.
 mature cells are derived from stem cells
2. Stable (Quiescent) tissue
Normally have a low level of replication (G0  G1 cell cycle) :
parenchymal cells of liver, kidneys, pankreas, mesenchymal
cells such as fibroblast, smooth muscles, vascular
endothelial cells and resting lymphocytes and other
leukocytes.
3. Permanent (Non dividing) tissue
Contain cell that have left the cell cycle and cannot undergo
mitotic division in postnatal life : neurons, skeletal and
cardiac muscle cell
Growth Factor
Epidermal Growth Factor (EGF) and
Transforming Growth Factor-α (TGF-α)
-EGF : * Mitogenic for a variety of epithelial cells,
hepatocytes, and fibroblasts.
* Produced by keratinocytes, macrophages, and
other inflammatory cells in wound healing

Hepatocyte Growth Factor (HGF)

* Mitogenic effects in hepatocytes, cells of the biliary
epithelium in the liver, and epithelial cells of the lungs,
mammary gland, skin, and others
* Produced by fibroblasts, endothelial cells, and liver non-
parenchymal cells.
Vascular Endothelial Growth Factor (VEGF)
Platelet-Derived Growth Factor (PDGF)
* Produced by activated platelets, activated macrophages,
endothelial cells, smooth muscle cells, and many tumor cells.
* Causes migration and proliferation of fibroblasts, smooth
muscle cells, and monocytes

Fibroblast Growth Factor (FGF)

* Have a large number of functions :
New blood vessel formation (angiogenesis), wound repair,
skeletal muscle development, development of bone marrow
stroma
Extracellular Matrix (ECM) and Cell-Matrix
Interactions
The ECM is secreted locally and assembles into a
network in the spaces surrounding cells.
The ECM serves many functions:
* matrix proteins sequester water that provides
turgor to soft tissues
* minerals give rigidity to skeletal tissues.
* reservoir for growth factors controlling cell
proliferation.
* provides a substratum for cells to adhere,
migrate and proliferate
*directly modulating cell form and function
Macromolecules which are constitute the
ECM:
(1)fibrous structural proteins, such as the collagens and
elastins
(2)adhesive glycoproteins
(3)proteoglycans and hyaluronic acid

1,2 and 3 : assemble into two general organizations:

a. Interstitial matrix
It consists of fibrillar and nonfibrillar collagen, elastin,
fibronectin, proteoglycans, hyaluronate
b. basement membrane (BM)
Produced by epithelial and mesenchymal cells
They consist of a network of amorphous nonfibrillar
collagen (mostly type IV), laminin, heparan sulfate,
proteoglycan, and other glycoproteins.
Repair by Healing, Scar Formation, and
Fibrosis
Healing : involving a number of processes:
Induction of an inflammatory process in response
to the initial injury, with removal of damaged and
dead tissue
Proliferation and migration of parenchymal and
connective tissue cells
Formation of new blood vessels (angiogenesis) and
granulation tissue
Synthesis of ECM proteins and collagen deposition
Tissue remodeling
Wound contraction
Acquisition of wound strength
Scar formation
Growth factors and cytokines released at the site of
injury induce fibroblast proliferation and migration
into the granulation tissue framework of new blood
vessels and loose ECM that initially forms at the
repair site.

Three processes that participate in the formation of

a scar:
(1) emigration and proliferation of fibroblasts in the
site of injury,
(2) deposition of ECM, and
(3) tissue remodeling.
Cutaneous wound healing
Cutaneous wound healing : divided into three phases:
(1) inflammation (early and late);
(2) granulation tissue formation and
reepithelialization;
(3) wound contraction, ECM deposition, and
remodeling
These phases overlap, and their separation is
somewhat arbitrary.
HEALING BY FIRST INTENTION ( primary union )
 WOUNDS WITH OPPOSED EDGES
In a clean, uninfected surgical incision

•Within 24 hours, neutrophils at the margins of the incision,

moving toward the fibrin clot.
•In 24 to 48 hours, epithelial cells move from the wound edges
along the cut margins of the dermis  fuse in the midline
beneath the surface scab  producing a continuous but thin
epithelial layer that closes the wound.
•By day 3, neutrophils replaced by macrophages.
- Granulation tissue invades the incision space.
- Collagen fibers present in the margins of the incision,
at first : vertically oriented and do not bridge the incision.
- Epithelial cell proliferation  thickens the epidermal layer.
By day 5, the incisional space is filled with granulation tissue.
Collagen fibrils : more abundant and begin to bridge the
incision.
The epidermis  normal thickness, surface keratinization.
During the second week : accumulation of collagen,
proliferation of fibroblasts, leukocytic infiltrate, edema,
increased vascularity ↓ blanching, accumulation of collagen ↑
within the incisional scar, regression of vascular channels.
By the end of the first month, the scar is made up of a cellular
connective tissue , inflammatory infiltrate (-), covered by
intact epidermis, the dermal appendages are permanently
lost. Tensile strength of the wound increases thereafter, but it
may take months for the wounded area to obtain its maximal
strength.
HEALING BY SECOND INTENTION
( secondary union )
 WOUNDS WITH SEPARATED EDGES
* In surface wounds that create large defects
* Regeneration of parenchymal cells cannot
completely restore the original architecture
 abundant granulation tissue
Figure 3-21 Steps in wound healing by first intention (left) and second intention (right). Note large
amounts of granulation tissue and wound contraction in healing by second intention.
WOUND STRENGTH
At the end of the first week, wound strength ±10%
 increases rapidly over the next 4 weeks.
This rate of increase then slows at ± the third
month after the original incision reaches a
plateau at about 70% to 80% of the tensile strength
 persist for life.
LOCAL AND SYSTEMIC FACTORS THAT
INFLUENCE WOUND HEALING
Systemic factors :
Nutrition : Protein deficiency, vit C deficiency
 inhibit collagen synthesis
Metabolic status : Diabetes mellitus
(microangiopathy)
Circulatory status : arteriosclerosis / venous
abnormalities (e.g. varicose veins)
 Inadequate blood supply
Hormones : glucocorticoids
 inhibit collagen synthesis.
Local factors :
Infection : persistent tissue injury and inflammation.
Mechanical factors : early motion of wounds 
delay healing, by compressing blood vessels
and separating the edges of the wound.
Foreign bodies : fragments of steel, glass, bone
Location : wounds in richly vascularized areas
e.g.faceheal faster than those in poorly
vascularized ones e.g. foot.
Size : small incisional injuries heal faster and < scar
formation than large excisional wounds
Type of wound : wounds caused by blunt trauma
heal slower
 Thank You
For
Your Attention