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Matrix Formation and

Granulation Tissue

Dr . Prihartini Widiyanti, drg, M.Kes


October 13th , 2015

SEQUENCE OF HOST REACTION

Injury
Bloodmaterial interactions
Provisional matrix formation
Acute inflammation
Granulation tissue
Foreign body reaction
Fibrosis/fibrous capsule development

Based on the depth and wide of wound, wound has been


classified into :

1. Superficial wound
2. Partial thickness wound
3. Full thickness wound
4. Wound related with muscles, tendon and
bone.
Based on the healing time :
1. Acute wound ( > 12 weeks)
2. Chronic wound ( < 12 weeks) unhealed
wound because endogen factor and exogen factor.

1.

3.

2.

4.

DEFINITIONS:

REGENERATION: Growth of cells to replace lost tissues (normal


process)
HEALING: A reparative tissue response to a wound, inflammation
or necrosis, often leads to fibrosis (follows damage)
GRANULATION TISSUE: new connective tissue and tiny blood
vessels that form on the surfaces of a wound during the healing
process /the perfused, fibrous connective tissue that replaces a fibrin
clot in healing wounds. Granulation tissue typically grows from the
base of a wound and is able to fill wounds of almost any size it heals.

Repair

Regeneration of injured cells by cells of same


type as with regeneration of skin/oral mucosa
(requires basement membrane)
Replacement by fibrous tissue (fibroplasia,
scar formation)
Both require cell growth, differentiation, and
cell-matrix interaction

Generally, the integrity of skin and damaged


tissue is restored by:
(1) resolution (process by which damaged cells
recover and re-establish their normal function),
(2) regeneration (cell duplication),
(3) scar formation (replacement of damaged
cells with fibrous scar tissue).

Phases of healing
1.
2.
3.
4.

Hemostasis
Inflammation ( 0-3 days after injury)
Proliferation ( 3-21 days )
Maturation ( 21 days 1,5 years)

There are three basic components of ECM:


(1) fibrous structural proteins such as collagens and elastins, which
confer tensile strength and recoil;
(2) water-hydrated gels such as proteoglycans and hyaluronan, which
permit resilience and lubrication;
(3) adhesive glycoproteins that connect the matrix elements to one
another and to cells
The ECM serves several important functions:
1. Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity
2. Control of cell proliferation by binding and displaying growth factors and by signaling through cellular
receptors of the integrin family. The type of ECM proteins can affect the degree of differentiation of the cells
in the tissue, again acting largely through cell surface integrins.
3. Scaffolding for tissue renewal. Because maintenance of normal tissue structure requires a basement
membrane or stromal scaffold, the integrity of the basement membrane or the stroma of parenchymal cells
is critical for the organized regeneration of tissues. Thus, although labile and stable cells are capable of
regeneration, disruption of the ECM results in a failure of the tissues to regenerate and repair by scar
formation
4. Establishment of tissue microenvironments. Basement membrane acts as a boundary between epithelium
and underlying connective tissue and also forms part of the filtration apparatus in the kidney.
An intact ECM is required for tissue regeneration, and if the ECM is damaged, repair can be accomplished
only by scar formation.
Fibrosis is depended on the degree of ECM destruction

Extracellular matrix

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Hemostasis
4 major events :
1. The initial phase of the process is vascular constriction. This
limits the flow of blood to the area of injury.
2. Next, platelets become activated by thrombin and aggregate at
the site of injury, forming a temporary, loose platelet plug.
3. To insure stability of the initially loose platelet plug, a fibrin mesh
(also called the clot) forms and entraps the plug.
4. Finally, the clot must be dissolved in order for normal blood flow
to resume following tissue repair. The dissolution of the clot occurs
through the action of plasmin (important enzyme present in blood
that degrades many blood plasma proteins, including fibrin clots.
The degradation of fibrin is termed fibrinolysis.)

Inflammation
0- 3 days after injury
5 cardinal of inflammation :
a. rubor /redness
b.tumor / swelling
b. calor/ heat
c. dolor / pain
e. functiolaesa

Inflammation signs
Rubor arteriol are supplied blood, dilatation,
more blood sirculate to local microsirculation.
Empty capillarie then would be full of blood
(hyperemia / congestion) cause localized red/
acute inflammation
Calor inflammation area could be hotter
compared with the surrounding area because
blood number which sirculate in that area are
more than normal area.

Inflammation signs

Dolor / pain. Local pH alteration / certain


concentration of ions, release of chemistry substances
could stimulate some nerves. Oedema tissue cause the
increase of local pressure and yield pain.
Tumor. This is caused by delivery of liquid and cells
from blood sirculation to interstitial tissue. The mixed
of liquid and cell is namely exudate.
Functiolaesa / function alteration. The four signs
before could yield the declination of part of body
function.

Proliferation
Proliferation : period during which new cells
fill and seal a wound
occurs from 2 days to 3 weeks after the
inflammatory phase.
Characterized
by
the
appearance
of
granulation tissue (combination of new blood
vessels, fibroblasts, and epithelial cells ), bright
pink to red because of the extensive projections
of capillaries in the area.

What is granulation ?
The term granulation tissue was used by ancient surgeons for
the red, granular tissue filling the non healing wounds.
Granulation tissue occurs in all wounds during healing and
may occur in chronic inflammation as well
It consists of fibroblasts surrounded by abundant extracellular
matrix (the extracellular part of multicellular structure (e.g.,
organisms, tissues, biofilms) that typically provides structural and
biochemical support to the surrounding cells), newly formed blood
vessels, and scattered macrophages (its function in both nonspecific defense (innate immunity) as well as help initiate specific
defense mechanisms (adaptive immunity) and some other
inflammatory cells (neutrophil, macrophage, monocyte, eosinophil,
basophil).

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GRANULATION
Granulation tissue grows from the
wound margin toward the center.
It is fragile and easily disrupted by
physical or chemical means.
As more and more fibroblasts
produce collagen (a tough and
inelastic protein substance), the
adhesive strength of the wound
increases.
light red or dark pink in color, being
perfused (permeated) with new
capillary loops or "buds"; soft to the
touch; moist; and bumpy (granular)
in appearance

Granulation tissue is composed of tissue matrix supporting a variety of cell types, most
of which can be associated with one of the following functions:
1. extracellular matrix (cell adhesion, cell-to-cell communication and differentiation are
common functions of the ECM)
The extracellular matrix of granulation tissue is created and modified by fibroblasts.
Initially, it consists of a network of type-III collagen, a weaker form of the structural
protein that can be produced rapidly. This is later replaced by the stronger, longstranded type-I collagen, as evidenced in scar tissue.
2. immune system (The main immune cells active in the tissue are macrophages and
neutrophils, although other leukocytes are also present. These work to phagocytize old
or damaged tissue, and protect the healing tissue from pathogenic infection. This is
necessary both to aid the healing process and to protect against invading pathogens, as
the wound often does not have an effective skin barrier to act as a first line of defense).
3. Vascularisation (It is necessary for a network of blood vessels to be established as soon as
possible to provide the growing tissue with nutrients, to take away cellular wastes, and
transport new leukocytes to the area. Fibroblasts, the main cells that deposit granulation
tissue, depend on oxygen to proliferate and lay down the new extracellular matrix).

GRANULATION TISSUE
The healing response ( 1 day after implantation) is initiated by :
1. action of monocytes and macrophages
(1) replenishing resident macrophages and dendritic cells under normal states,
and
(2) in response to inflammation signals, monocytes can move quickly (approx.
812 hours) to sites of infection in the tissues and divide/differentiate into
macrophages and dendritic cells to elicit an immune response.
Dendritic cells (DCs) are antigen-presenting cells, (also known as accessory
cells) of the mammalian immune system. Their main function is to process
antigen material and present it on the cell surface to the T cells of the immune
system. They act as messengers between the innate and the
adaptive immune systems.
Dendritic cells are present in those tissues that are in contact with the external
environment, such as the skin (where there is a specialized dendritic cell type
called the Langerhans cell) and the inner lining of the nose, lungs, stomach and
intestines.
2. proliferation of fibroblasts and vascular endothelial cells at the
implant site,
3. leading to the formation of granulation tissue
4. the standard of healing inflammation.

Dendritic cells

Granulation tissue process


1. Within one day following implantation of a biomaterial, the healing response
is initiated by reaction of monocytes
(Monocytes are a type of
white blood cells (leukocytes). They are the largest of all leukocytes ) and
macrophages (type of white blood cell that engulf and digest cellular debris,
foreign substances, microbes, and cancer cells in a process called
phagocytosis. They play a critical role in non-specific defense (
innate immunity), and also help initiate specific defense mechanisms (
adaptive immunity) by recruiting other immune cells such as lymphocytes.)
2. Fibroblasts and vascular endothelial cells in the implant site proliferate and
begin to form granulation tissue. Granulation tissue: form pink, soft granular
appearance on the surface of healing wounds, and its characteristic histologic
features include proliferation of new small blood vessels and fibroblasts.

Granulation tissue process


The new small blood vessels formed in a process known as
angiogenesis (neovascularization ) . This process involves:
proliferation, maturation and organization of endothelial cells into
capillary vessels.
3. In the early stage of granulation tissue development, proteoglycan
(involved in binding cations such as sodium, potassium and
calcium and water, and also regulating the movement of molecules
through the matrix. It can affect the activity and stability of proteins
and signalling molecules within the matrix ) predominates but later
collagen (type III) (fibrous scleroprotein in bone, cartilage, dentin,
tendon, bone marrow stroma and other connective tissue )
predominate and form fibrous capsule.

Granulation tissue process


5. Some fibroblasts in developing granulation tissue
may have the feature of smooth muscle cells.
These cells are called myofibroblasts and
responsible for the wound contraction seen
during the development of granulation tissue.

Neutrophil ( mediation of immune response to microorganisms),


macrophage,endothelial cell ( inner layer of vessel for bridging blood
circulation and muscle of vessel) and fibroblast appear.

HEALTHY Granulation Tissue

Repair by connective tissue


granulation tissue
1.Fibroblastic proliferation ( syntesis ECM and Collagen) and
synthesizing of proteoglycans and collagen
2. Macrophages ridding the area of extracellular debris, fibrin and
foreign matter
3. Further healing:
- increased collagen,
- decreased active fibroblasts
-new vessels(thrombosis (coagulation process) and degeneration)
4. At the end -- scar
- inactive fibroblasts,
- dense collagen,
- fragments of elastic tissue,
- extracellular matrix,
- few vessels

PROCESS OF GRANULATION TISSUE


early stages of granulation tissue development,
proteoglycans predominate;
later, collagen especially type I collagen
predominates and forms the fibrous capsule.
Some fibroblasts in developing granulation tissue
may have features of smooth muscle cells. These
cells are called myofibroblasts and are considered to
be responsible for the wound contraction seen
during the development of granulation tissue.

Summary

Wound healing as evolving, changing process


Various mechanisms involved
Various mediators
Orderly movement, proliferation, and
differentiation of cells

Proteoglycans
Proteoglycans are a major component of the
extracellular matrix, the "filler" substance
existing between cells in an organism.
Function :
involved in binding cations (such as sodium,
potassium and calcium) and water,
also regulating the movement of molecules
through the matrix.
affect the activity and stability of proteins and
signalling molecules within the matrix.

Fibronectin
Fibronectin is a high-molecular weight
(~440kDa) glycoprotein of the
extracellular matrix that binds to membranespanning receptor proteins called integrins).
Functions :
Plays a major role in cell adhesion, growth,
migration, and differentiation, and it is
important for processes such as wound healing
and embryonic development.

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