HEALING

DR ANTENEH.B(MD,PATHOLOGIST)
DEFINITION:
 Healing-bodies replacement of destroyed
tissue by living tissue

Two processes:
-Regeneration-by similar tissue
-Repair (scar)-by connective tissue (fibrosis)
Tissue damage Inflammation

Removal of dead tissue and injurious

agents

Replacement by

Specialized tissue Fibrous

tissue
(Regeneration)
(Scarring)
 Healing by regeneration or repair is
determined partly by:
 the type of cell or
 destruction or intactness of stromal frame
work of the organ.
Types of cells
Based on their proliferative capacity there are
three types of cells
A, labile cells-have continuous turnover
 Excellent replicative capacity
 e.g. skin, surface epithelium of the
gastrointestinal treat, surface epithelium of
the genitourinary tract ,lymphoid and
hematopoietic cells and the cuboidal
epithelia of the ducts draining exocrine
organs
 B, stable cells-lower level of replication and
few stem cells.
 undergo division following injury
 e.g. smooth muscle cells, fibroblasts,
osteoblasts, endothelial cells ,
hepatocytes, endocrine glands and renal
tubular epithelium

 C,Permanent cells-non dividing cells

 e.g. neurons, striated muscle cells, cells of
lens and cardiac muscle cells
 Regeneration-renewal of lost tissue in which
the lost cells are replaced by identical ones.

 Regeneration involves two processes:

1. Proliferation of surviving cells to replace
lost tissue
2. Migration of surviving cells into vacant
space.
 The capacity of a tissue for regeneration
depends on:
1. Proliferative ability
2. the degree of damage to stromal
framework
3. type and severity of damage

 NB: labile and stable cells proliferate

provided that framework intact.
 Mechanisms of Tissue Regeneration
 We will consider liver regeneration as a

model of tissue regeneration, because it has

been studied extensively and illustrates the
mechanisms that underlie this process

 Liver regeneration
 Human liver shows remarkable capacity to
regenerate, as demonstrated by its growth
after partial hepatectomy , performed for
tumor resection or for living-donor hepatic
transplantation
 Liver regeneration occurs by two major
mechanisms: proliferation of remaining
hepatocytes and repopulation from progenitor
cells
1,Proliferation of remaining hepatocytes
 Resection of up to 90% of the liver can be

corrected by residual hepatocyte proliferation

triggered by cytokines and polypeptide growth
factors
 In the priming phase, cytokines, such as IL-6

(from Kupffer cells), make remaining

hepatocytes competent to receive and
respond to growth factor signals.
 In the second phase, growth factors, such as
hepatocyte growth factor (HGF) and TGF-α, act
on primed hepatocytes to stimulate cell
metabolism and entry into the cell cycle.

 The wave of hepatocyte replication is followed

by replication of non-parenchymal cells (Kupffer
cells, endothelial cells, and stellate cells).

 In the termination phase, hepatocytes return to

quiescence; The nature of the stop signals is
poorly understood; anti-proliferative cytokines
of the TGF-β family are likely involved
2,Liver regeneration from progenitor cells
 When hepatocyte proliferative capacity is

impaired (chronic liver injury or inflammation),

liver progenitor cells contribute to repopulation

 These progenitor cells reside in specialized

niches called canals of Hering, where bile
canaliculi connect with larger bile ducts

 The signals that drive proliferation of

progenitor cells and their differentiation into
mature hepatocytes are topics of active
investigation
 Repair (healing by connective tissue)
 Orderly process in which lost tissue is

replaced by scar (fibrosis).

 Tissues with permanent cells and extensive

stromal injury heal by scar.
 Steps in tissue Repair (healing by connective
tissue)
 Inflammation
 Angiogenesis
 Granulation tissue formation
 Scar formation
 Connective tissue remodeling
 1,Inflammation
 At this phase, inflammatory exudate

containing polymorphs is seen in the area of

tissue Injury with in 24 hrs.

 In addition, there is platelet aggregation and

fibrin deposition.

 There is an associated macrophage

infiltration
 Macrophages (mostly M2 type) play a central
role in repair by
 Clearing offending agents and dead tissue

 Providing growth factors for cellular

proliferation and

 Secreting cytokines that stimulate

fibroblast proliferation and connective
tissue synthesis and deposition
2, Angiogenesis
 Is the formation of new blood vessels

 Involves the branching and extension of

adjacent pre-existing vessels, but it can also
occur by recruitment of endothelial
progenitor cells (EPCs) from the bone marrow
A, Angiogenesis from Preexisting Vessels.
 The major steps are listed below.

 Vasodilation in response to nitric oxide, and

VEGF-induced increased permeability of the

preexisting vessel
 Proteolytic degradation of the basement

membrane of the parent vessel by matrix

metalloproteinases (MMPs) and disruption of
cell-to-cell contact between endothelial cells
by plasminogen activator
 Migration of endothelial cells toward the

angiogenic stimulus
 Proliferation of endothelial cells, just behind
the leading front of migrating cells

 Maturation of endothelial cells, which

includes inhibition of growth and remodeling
into capillary tubes

 Recruitment of periendothelial cells

(pericytes and vascular smooth muscle cells)
to form the mature vessel
B, Angiogenesis from Endothelial Precursor
Cells (EPCs).
 EPCs can be recruited from the bone marrow

into tissues to initiate angiogenesis

 The nature of the homing mechanism is

uncertain.
 3,Granulation tissue formation
 Forms through the migration and proliferation of

fibroblasts and deposition of loose connective

tissue, combined with the new vessels and
interspersed mononuclear leukocytes.

 The term derives from its pink, soft, granular

appearance on the surface of wounds.

 Its characteristic histologic feature is the

presence of new small blood vessels
(angiogenesis) and the proliferation of
fibroblasts
 Fibroblasts actively synthesize and secrete
extra-cellular matrix components, including
fibronectin, proteoglycans, and collagen
types I and III

 The synthesis of collagen by fibroblasts

begins within 24 hours of the injury although
its deposition in the tissue is not apparent
until 4 days.

 By day 5, collagen type III is the predominant

matrix protein being produced
 but by day 7 to 8, type I collagen is
prominent, and it eventually becomes the
major collagen of mature scar tissue.

 This type I collagen is responsible for

providing the tensile strength of the matrix in
a scar
 Migration of fibroblasts to the site of injury &
their subsequent proliferation are triggered
by multiple growth factors, including TGF-β,
PDGF, EGF, FGF & the cytokines IL-1 & TNF

 TGF-β is most important: it stimulates

fibroblast migration and proliferation,
increased synthesis of collagen and
fibronectin.
4,Scar formation
 The leukocytic infiltrate, edema, and

increased vascularity largely disappear

during the second week.

 Accomplished by the increased accumulation

of collagen within the wound area and
regression of vascular channels.
 Ultimately, the original granulation tissue
scaffolding is converted into a pale, avascular
scar, composed of spindle-shaped fibroblasts,
dense collagen, fragments of elastic tissue,
and other ECM components

 Collagen accumulates at a steady rate, usually

reaching a maximum 2 to 3 months after the
injury.

 The tensile strength of the wound continues to

increase many months after the collagen
content has reached a maximum
5,Remodeling of Connective Tissue
 The outcome of the repair process is

influenced by a balance between synthesis

and degradation of ECM proteins.

 After its deposition, the connective tissue in

the scar continues to be modified and
remodeled.
 The degradation of collagens and other ECM
components is accomplished by a family of
matrix metalloproteinases (MMPs), so called
because they are dependent on metal ions
(e.g., zinc) for their activity
 Wound contraction
 Wound contraction is a mechanical
reduction in the size of the defect.

 The wound is reduced approximately by

70-80% of its original size.

 Contraction results in much faster healing

 It
is said to be due to contraction by
myofibroblasts
 Healing of Skin Wounds
 Healing of a wound demonstrates both

epithelial regeneration (healing of the

epidermis) and repair by scarring (healing of
the dermis).

 There are two patterns of skin wound healing

depending on the amount of tissue damage
1. Healing by first intention (Primary union)
2. Healing by second intention
1. Healing by first intention (Primary union)
 Is the healing of a clean surgical incision

 The wound edges are approximated by surgical

sutures, and healing occurs with a minimal loss of
tissue

 The incisional space is narrow and immediately

fills with clotted blood, containing fibrin and blood
cells

 Dehydration of the surface clot forms the well-

known scab that covers the wound and seals it
from the environment
 Within 24 hours, neutrophils arrive at the
incision margin, releasing proteolytic
enzymes that begin to clear the debris.

 Within 24 to 48 hours, epithelial cells from

both edges have migrated and proliferated
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

 By day 5, neovascularization reaches its peak

with ongoing migration of fibroblasts, which
are producing ECM proteins.

 The epidermis recovers its normal thickness as

differentiation of surface cells yields a mature
epidermal architecture with surface
keratinization.
 During the second week, there is continued
collagen accumulation and fibroblast
proliferation

 But leukocyte infiltrate, edema, and vascularity

are diminished

 By 4 weeks, scar is well formed with few

inflammatory cells.

 Although the epidermis is essentially normal,

dermal appendages destroyed in the line of the
incision are permanently lost
 2. Healing by second intention (secondary
union)
 Occurs when there is more extensive loss of

cells and tissue, such as occurs in infarction,

inflammatory ulceration, abscess formation,
and surface wounds that create large defects

 the reparative process is more complicated.

 The common denominator in all these situations
is a large tissue defect that must be filled.

 Regeneration of parenchymal cells cannot

completely reconstitute the original architecture.

 Abundant granulation tissue grows in from the

margin to complete the repair

 A greater volume of granulation tissue generally

results in a greater mass of scar tissue
 Secondary healing differs from primary
healing in several respects:
1. Inevitably, large tissue defects initially have
more fibrin and more necrotic debris and
exudate that must be removed. Consequently,
the inflammatory reaction is more intense.

2. Much larger amounts of granulation tissue

are formed.
3. Perhaps the feature that most clearly
differentiates primary from secondary healing
is the phenomenon of wound contraction,
which occurs in large surface wounds.

4. Healing by second intention takes much

longer than when it occurs by first intention
 Wound Strength
 Carefully sutured wounds have approximately

70% of the strength of normal skin, largely

because of the placement of sutures.

 The recovery of tensile strength results from the

excess of collagen synthesis over collagen
degradation during the first 2 months of
healing.

 Wound strength reaches approximately 70% to

80% of normal by 3 months but usually does
not substantially improve beyond that point.
FACTORS AFFECTING WOUND HEALING

 Local factors

 Systemic factors
Local factors:
 Type, size and location of the wound

 Vascular supply

 Infection excessive granulation tissue

formation (proud flesh) large deforming scar

 Movement

 Foreign bodies such as unnecessary sutures

or fragments of steel, glass or bone impede
healing
Systemic factors
 Circulatory status
 Systemic infection
 Metabolic status

e.g.-poorly controlled DM delayed wound

healing
 Nutritional deficiencies

-Protein deficiency
-Vitamin deficiency
 Glucocorticoids (steroids)
 Complications in cutaneous wound
healing
1,Deficient Scar Formation
 Inadequate formation of granulation tissue or

an inability to form a suitable extracellular

matrix leads to deficient scar formation and
its complications.
A) Wound dehiscence and incisional hernias
 Dehiscence (bursting of a wound) is most

concern after abdominal surgery.

 If insufficient extracellular matrix is

deposited or there is inadequate cross-linking
of the matrix, weak scars result.

 It occurs in 0.5% to 5% of abdominal

operations.
 Inappropriate suture material and poor
surgical techniques are important factors.

 Wound infection, increased mechanical stress

on the wound from vomiting, coughing, or
ileus is a factor in most cases of abdominal
dehiscence.
 An incisional hernia, usually of the abdominal
wall, refers to a defect caused by poor wound
healing following surgery into which the
intestines protrude
B) Ulceration
 Wounds ulcerate because of an inadequate

intrinsic blood supply or insufficient

vascularization during healing.

 For example
 Leg wounds in persons with varicose veins
or severe atherosclerosis typically
ulcerate.
2,Excessive scar formation
 failure in 'maturation arrest' or block in the

healing process
 Eg .keloid-exuberant scar that tends to
progress and recur after excision

 Grows beyond the boundaries of the

original wound

 Frequent after burns

 Common on neck &ear lobes.

 Hypertrophic scar-structurally similar to
keloid

 but never gets worse after 6 months

 Does not Grows beyond the boundaries of

the original wound

 Does not recur after excision

[Link] Contraction (contracture)
 A decrease in the size of a wound depends

on the presence of myofibroblasts,

development of cell-cell contacts and
sustained cell contraction.

 An exaggeration of these processes is termed

contracture (cicatrisation)

 and results in severe deformity of the wound

and surrounding tissues.
 The palms, the soles, and the anterior aspect
of the thorax are the ones prone to
contractures.

 Contractures are commonly seen after

serious burns and can compromise the
movement of joints