Tissue Repair

Tissue repair - Ovrview

Definition - Restoration of tissue architecture & function after
an injury
- Sometimes called healing.
Occurs by 1 - Regeneration
2 - Connective tissue deposition ( scaring).
Regeneration
Definition- Proliferation of cells resulting in complete
restitution of lost or damaged tissue component
Occurs by - Proliferation of residual uninjured cells or
- Maturation of stem cells
True regeneration
- Does not occur in mammals
- It usually applies to processes such as liver growth
after partial resection or necrosis .
 Connective tissue deposition (scaring ).
Occurs
- If tissues are incapable of complete restitution, or
- In severe damage of the supporting structures
The fibrous scar is not normal but
- It provides enough structural stability that the injured
tissue is usually able to function.
The relative contribution of regeneration & scarring in
tissue repair depends on
- The type of the injured tissue &
- The extent of the injury.
In inflammation of tissue spaces
- The exudate is often digested and resorbed
- If fibrosis develops it is called organization
Mechanism of tissue repair:
- Regeneration - following mild injury,
- Scar formation - more severe injury
with damage to the connective tissue
 Cell and Tissue Regeneration
The cell cycle & tissue types
Based on the intrinsic proliferative capacity tissues are divided
into three groups.
1 - Labile tissues.
2 - Stable tissues
3 - Permanent tissues
Labile tissues
Cells are continuously being lost & replaced by
- Maturation from tissue stem cells and
- By proliferation of mature cells.
They can readily regenerate
- As long as the pool of stem cells is preserved
Include
- Hematopoietic cells of the bone marrow &
- Majority of surface epithelia
Squamous - skin, oral cavity , esophagus cervix
Cuboidal – excretory glands – bile ducts
Columnar – Endometrium & GIT mucosa

Stable tissues.

These cells
- Are quiescent( In G0)
- Proliferation is normally minimal .
- Divide in response to injury or loss of tissue mass.
Constitute
- Parenchyma of solid organs
liver, kidney, & pancreas.
- Endothelial cells
- Fibroblasts & Smooth muscle cells
With the exception of liver, stable tissues have
- A limited capacity to regenerate after injury.
Permanent tissues.
Cells are - Terminally differentiated
- Nonproliferative
Include - The majority of neurons
- Cardiac muscle cells
- Skeletal muscle - but satellite cells provide some
regenerative capacity
In permanent tissues
- The injury is irreversible
- Repair is dominated by scar formation
 Cell cycle checkpoints, are at
- G1/S transition &
- At G2/M transition
Both are tightly regulated by a balance of
- Growth promoting & growth-suppressing proteins, &
- By sensors of DNA damage.
If activated, these DNA-damage sensors
- Transmit signals that arrest cell cycle and,
- Initiate apoptosis if the damage cannot be repaired,.
Defects in the G1/S checkpoint are more important in
cancer
- Lead to dysregulated growth
- Impair DNA repair - A “mutator” phenotype - cancer
G1 restriction point refers to the stage in G1 where the cell is committed to advance further
in to the cell cycle without requiring any more of growth signals that initiated cell division.
- Cells from labile tissues cycle continuously
- Stable cells are quiescent but can enter the cell cycle
- Permanent cells have lost their proliferative capacity and left the cell cycle
 Signals & Control Mechanisms
Cell proliferation is driven by signals
- Provided by GFs & the EC matrix.
Many different GFs have been described
- Some act on multiple cell types
- Others are cell-selective
Growth factors are produced by cells near the site of damage.
- Macrophages – Are the most important sources
- Epithelial & stromal cells - Also produce some of the GFs.
GFs activate signaling pathways & induce production of
proteins that are involved in
- Driving cells through the cell cycle &
- Release blocks on the cell cycle .
Cells also use integrins to bind to ECM proteins, &
- Signals from the integrins also stimulate cell proliferation
In adults, the most important stem cells for regeneration are
- Tissue stem cells
Which live in specialized niches, &
- Injury can trigger signals in these niches that activate
stem cells to proliferate & differentiate
 Mechanisms of Tissue Regeneration
In labile tissues
Injured cells are rapidly replaced by
- Proliferation of residual cells &
- Differentiation of tissue stem cells provided the
underlying BM is intact.
- GFs involved - Are not defined.
Loss of blood cells
Is corrected by proliferation of hematopoietic stem cells
in the bone marrow & other tissues
- Driven by GFs called CSFs
The lifespan of blood cells
RBCs - Around 120 days.
Platelets - About 9 to 12 days.
WBC - 13 to 20 days
 Parenchymal organs with stable cell
populations
Except in the liver
- Regeneration is usually a limited process.
Pancreas, adrenal, thyroid, & lung
- Have some regenerative capacity.
Surgical removal of a kidney
- Elicits in the remaining kidney both hypertrophy &
hyperplasia of proximal duct cells.
Mechanisms underlying this response are not understood, but
likely involve
- Local production of GFs &
- Interactions of cells with ECM.
 Liver Regeneration
Occurs by two major mechanisms:
- Proliferation of remaining hepatocytes and
- Repopulation from progenitor cells.
Which mechanism plays the dominant role depends on
- The nature of the injury.
Extensive destruction with collapse of the reticulin framework
- Leads to scar formation
Resection of up to 90% of the liver can be corrected by
- Proliferation of residual cells
 Proliferation of hepatocytes following
partial hepatectomy.
Proliferation is triggered by the combined action of
- Cytokines & Polypeptide GFs.
The process occurs in distinct stages .
Priming ( 1st) phase
Cytokines such as IL-6, (from Kupffer cells) make liver cells
- Ready to receive & respond to GF signals.
The proliferation ( 2nd ) phase
GFs ( HGF & TGF-α,) produced by many cell types stimulate
- Primed cell metabolism &
- Entry into the cell cycle
Hepatocytes are quiescent cells, thus
- It takes them several hours to enter the cell cycle,
( G0 to G1 ), & reach the S phase of DNA replication.
 - Almost all hepatocytes replicate
- Followed by replication of nonparenchymal cells
( Kupffer cells, endothelial cells, & stellate cells ).
Termination (final) phase
Hepatocytes return to quiescence
Nature of the stop signals is poorly understood;
- Antiproliferative cytokines of the TGF-β family are
likely to be involved.
Liver regeneration from progenitor cells.
Where the proliferative capacity of hepatocytes is impaired,
such as after
- Chronic liver injury or inflammation,
- Progenitor cells in the liver contribute to repopulation.
Liver regeneration by proliferation of hepatocytes following partial hepatectomy
The process occurs in stages including priming followed by GF induced proliferation
 Repair by Connective Tissue Deposition
If repair cannot be accomplished by regeneration alone, it occurs
- By scar formation- replacement with connective tissue or
- By a combination of regeneration & scar formation.
Scaring may happen
- If injury is severe or chronic or
Damage to - Parenchymal cells,
- Epithelia &
- Connective tissue framework
- If non-dividing cells are injured.
In contrast to regeneration,
- Scar formation “patches” rather than restores the tissue.
 Steps in Scar Formation
Consists of sequential processes that follow tissue injury & the
inflammatory response : including
- Angiogenesis
- Granulation tissue formation &
- Remodeling
Angiogenesis
It involves sprouting of new vessels from existing ones,
Critical in - Healing at sites of injury
Supply nutrients & oxygen needed
- Development of collateral at sites of ischemia
- Allow tumors to increase in size .
Newly formed vessels are leaky because of
- Incomplete inter-endothelial junctions &
- VEGF - Drives angiogenesis ; increases permeability
Consists of the following steps :
- Vasodilation in response to NO
- Increased permeability induced by VEGF
- Separation of pericytes from the abluminal surface &
- Breakdown of the BM to allow formation of a vessel sprout
- Migration of endothelial cells toward the area of injury
- Proliferation of endothelial cells just behind the leading
front (“tip”) of migrating cells
- Remodeling into capillary tubes
- Recruitment of periendothelial cells to form the mature vessel
- Pericytes for small capillaries
- Smooth muscle cells for larger vessels
- Suppression of endothelial proliferation & migration &
deposition of the BM.
The process of angiogenesis involves
- Several signaling pathways
- Cell-cell interactions
- ECM proteins , & Tissue enzymes .
Growth factors.
VEGFs , mainly VEGF-A
- Stimulates both migration & proliferation of endothelial cells,
thus initiating the process of capillary sprouting .
- It promotes vasodilation by stimulating the production of NO
- Contributes to the formation of the vascular lumen.`
FGFs, mainly FGF-2
- Stimulates the proliferation of endothelial cells.
- Promotes the migration of macrophages & fibroblasts , &
- Stimulates epithelial cell migration to cover the wounds.
Angiopoietins 1 & 2 (Ang 1 & Ang 2)
Play a role in angiogenesis & maturation of new vessels.
Stabilize the newly formed vessels by
- The recruitment of pericytes & smooth muscle cells &
- The deposition of connective tissue.
PDGF & TGF-β
Also participate in the stabilization process:
- PDGF recruits smooth muscle cells
- TGF-β suppresses endothelial proliferation & migration,
& enhances the production of ECM proteins
 Notch signaling.
Through “cross-talk” with VEGF,
- Regulates the sprouting & branching of new vessels & thus
ensures proper spacing to effectively supply the healing tissue.
ECM proteins
Participate in the process of angiogenesis,
- Largely through interactions with integrin receptors in
endothelial cells and
- By providing the scaffold for vessel growth.
Enzymes in the ECM,
Notably the matrix metalloproteinases (MMPs),
- Degrade the ECM to permit remodeling & extension of
the vascular tube.
 Formation of granulation tissue.
Migration & proliferation of fibroblasts & deposition of loose
connective tissue, together with vessels & leukocytes,
- Form granulation tissue.
Histology shows
- Proliferation of fibroblasts
- New thin-walled, capillaries
- Loose ECM, &
- Mixed inflammatory cells, mainly macrophages
Granulation tissue progressively invades the site of injury.
A, Granulation tissue- Numerous blood vessels, edema, & a loose
ECM containing occasional inflammatory cells. Collagen is stained
blue by the trichrome stain; minimal mature collagen can be seen

B, Trichrome stain of mature scar, showing dense collagen, with

only scattered vascular channels.
 Deposition of Connective Tissue
Occurs in two steps:
(1)- Migration & proliferation of fibroblasts into the site of injury
(2)- Deposition of ECM proteins produced by these cells.
These processes are orchestrated by
- Locally produced cytokines & GFs ( PDGF, FGF-2 , & TGF-β).
Major sources of these factors are
- Inflammatory cells, particularly alternatively activated ( M2 )
macrophages, at the sites of injury & in granulation tissue.
Transforming growth factor-β (TGF-β)
Most important for
- Synthesis & deposition of connective tissue proteins.
Produced by
- Most of the cells in granulation tissue
 Trasforming growth factor -β (TGF-β )
- Stimulates migration & proliferation of fibroblasts
- Increase synthesis of collagen & fibronectin,
- Decrease degradation of extracellular matrix
( Inhibition of MMPs )
- Involved in fibrosis that follows chronic inflammation
( In the Lung, liver, & kidneys )
- Antiinflammatory
Limit & terminate inflammation by inhibiting
lymphocyte proliferation & other leukocytes
As healing progresses,
- Proliferating fibroblasts & new vessels decrease
- Fibroblasts- Become synthetic( increased deposition of ECM ).
Collagen synthesis
- Critical for strength in a healing wound site.
- Begins early (days 3-5) & continues for several weeks
- Net accumulation depends on both
Increased synthesis &
Diminished collagen degradation .
Finally granulation tissue evolves into a scar composed of
- Inactive, spindle-shaped fibroblasts
- Dense collagen
- Fragments of elastic tissue, &
- Other extracellular matrix components.
As the scar matures some fibroblasts acquire
- Features of smooth muscle cells ( myofibroblasts.)
Myofibroblasts
- Contribute to contraction of the scar over time
Remodeling of Connective Tissue
Outcome of the repair is a balance
- Between synthesis & degradation of ECM proteins.
The deposited connective tissue
- Continues to be modified & remodeled.
- The amount increases with maturation & reorganization
eventualy producing the stable fibrous scar.
Degradation of collagens & other ECM components
- Is accomplished by a family of MMPs .
MMPs include
- Interstitial collagenases - Cleave fibrillar collagen
- Gelatinases - Degrade amorphous collagen & fibronectin;
- Stromelysins - Degrade ECM constituents – PGns, laminin,
fibronectin, & amorphous collagen.
MMPs
- Are produced by fibroblasts, macrophages, neutrophils,
synovial cells, & some epithelial cells , &
- Their synthesis & secretion are regulated by GFs, cytokines,
& other agents.
Activity of the MMPs is tightly controlled
- Produced as inactive precursors (zymogens) that must be
first activated; Accomplished by proteases (e.g- plasmin)
likely to be present only at sites of injury.
Activated collagenases
- Can be rapidly inhibited by specific tissue inhibitors of MMPs
(TIMPs) produced by most mesenchymal cells.
- During scar formation, MMPs are activated to remodel the
deposited ECM & then their activity is shut down by TIMPs.
A family of enzymes related to MMPs
- Is called ADAM ( a disintegrin metalloproteinase ).
- ADAMs are anchored to the plasma membrane , cleave &
release EC domains of cell-associated cytokines & GFs ,
such as TNF, TGF-β, & members of the EGF family
The four phases repair by scar
formation in as muscle ,
Hemostasis phase
inflammatory phase- which clears
dead cells & microbes, if any.
Proliferative phase- formation of
vascularized granulation tissue and

Maturation phase
- Deposition of ECM to form the
scar.
 Factors That Influence Tissue Repair
Tissue repair may be altered by
- A variety of influences, frequently reducing the quality or
adequacy of the reparative process
Variables that modify healing may be
- Extrinsic or Intrinsic to the injured tissue &
- Systemic or local:
• Infection - The most important causes of delay in healing;
- Prolongs inflammation & increases local tissue injury.
• Diabetes - Compromises repair & one of the most important
systemic causes of abnormal wound healing.
• Nutritional status
- Protein deficiency, & particularly vitamin C deficiency,
inhibits collagen synthesis & retards healing.
• Glucocorticoids
- Have anti-inflammatory effect
- Inhibit TGF-β production & diminished fibrosis

Reduce the transcription of genes encoding many proteins

involved in inflammation, including
- COX-2,
- Phospholipase A2
- Proinflammatory cytokines (e.g., IL-1)
• Mechanical factors
- Increased pressure or torsion may cause wound dehiscence
• Poor perfusion
- Arteriosclerosis or obstructed venous drainage (varicose
veins), also impairs healing.
• Foreign bodies - Impede healing.
• The type & extent of tissue injury
Stable & labile tissues
- Complete restoration ; but extensive injury leads to
incomplete regeneration & loss of function
Permanent tissue
- Result in scarring with at most, attempts at functional
compensation
•- Location of the injury & the character of the tissue
Tissue space = Exudation – Digestion – Resolution
If extensive = Organization – Scaring
 Examples of Tissue Repair and Fibrosis
Healing of Skin Wounds
Healing of skin wounds occur
- By 1st , 2nd or 3rd intention.
- It is based on the size and nature of the wound
Healing by First Intention
Also called primary union
It occurs if
- The wound is clean
- Tissue loss is minimal
Focal disruption of BM continuity
Death of epithelial & connective tissue cells is little
- Wound edges are closely approached
Main mechanism of repair is
- Epithelial regeneration,
 Example - Clean surgical incision approximated by sutures.
Phases of repair
Consists of four connected processes:
- Hemostasis phase ( Clot formation)
- Inflammatory phase,
- Proliferative phase - of epithelial & other cells
- Maturation phase.
Hemostasis phase
Occur immediately after injury
1 - Vasoconstriction – Restrict blood flow
2 – Formation of platelet plug – Seal the break
3 – Coagulation – Fibrin reinforces the platelet plug
The clot - Contains - Fibrin
- Fibronectin
- Complement proteins &
- Entrapped RBC
- Stops the bleeding
- Acts as a scaffold for migrating cells
Scab is formed as dehydration occurs at the external surface
- Prevents dehydration
- Facilitates rapid healing
 Inflammatory phase
Release of VEGF
- Leads to increased permeability & edema.
Within 24 hours neutrophils are seen at the incision margin.
- Release proteolytic enzymes
begin to clear the debris.
- Basal cells of the epidermis show increased mitosis.
By day 3 neutrophils are replaced by macrophages.
Macrophages clear
- Extracellular debris
- Fibrin, & other foreign material
 Proliferative phase
Within 24 to 48 hours
Epithelial cells
- Begin to migrate & proliferate along the dermis,
- Deposit basement membrane as they progress.
Macrophages promote
- Angiogenesis
- Deposition of the ground substance (ECM).
Type III collagin , fibronetin
Granulation tissue - Progressivly invades the incision space.
Epithelial cell proliferation
- Continues, forming a covering approaching the normal
thickness of the epidermis.
By day five
Neovascularization reaches its peak
- As granulation tissue fills the incisional space.
Fibroblasts - Produce ECM proteins, & collagen fibrils become
more abundant & begin to bridge the incision.
Epidermis mature
– Of normal thickness with keratinization.
Proliferatin and migration
- Is driven by chemokines, TNF, PDGF, TGF-β, & FGF.
- Subsequent proliferation is triggered by multiple GFs
( PDGF, EGF, TGF-β, & FGF, & the cytokines IL-1 & TNF )
Macrophages - Are the main source for these factors,
- Other inflammatory cells & platelets may
also produce them.
 Maturation Phase
During the second week,
Collagen deposition & fibroblast proliferation
- Are continued.
Leukocytes, edema, & vascularity
- Are markedly reduced.
By the end of the first month
The scar comprises
- Acellular connective tissue
- No or minimal inflammatory cells
- Normal covering of epidermis.
Dermal appendages
- In the line of the incision are permanently lost.
The tensile strength of the wound
- Increases with time,
 Healing by Second Intention
Also known as healing by secondary union
Here - Tissue loss is more extensive,
- There may be an infection
- Wound edges can not be approximated
Repair involves
- The four stages of wound healing
- A combination of regeneration & scarring
- Abundant ECM proteins, & collagen fibrils deposition
Inflammatory reaction is more intense
Greater volume of necrotic debris , exudate & fibrin
& hence secondary inflammation-mediated , injury.
Granulation tissue
- Abundant to fill in the gaps
- Results in a greater mass of scar tissue .
At first a provisional matrix is formed
- Containing fibrin, plasma fibronectin, & type III collagen
- In about 2 weeks this is replaced by type I collagen.
Ultimately
- The original granulation tissue scaffold is converted into a
pale, avascular scar, with spindle-shaped fibroblasts,
- Dense collagen, fragments of elastic tissue, &
- Other ECM components.
Destroyed dermal appendages in the line of the incision
- Are permanently lost.
The epidermis
- Recovers its normal thickness & architecture.
By the end of the first month
The scar is made up of
- Acellular connective tissue devoid of inflammatory infiltrate,
covered by intact epidermis.
Wound contraction
- Generally occurs in large surface wounds.
- Helps to close the wound by decreasing the gap .
- An important feature in healing by secondary union.
- The initial steps involve the formation of a network of
myofibroblasts , at the edge of the wound
Within 6 weeks
- Large skin defects may be reduced to 5% to 10% of their
original size, largely by wound contraction.
Steps in wound healing by 1st intention (Lt)
& 2nd intention ( Rt). In the latter, note the
large amount of granulation tissue and
wound contraction.
 Healing by the third intention
It is also called delayed primary union
- Some wounds are cleaned & debrided & left to granulate
- Later on approximated or grafted
Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic
patients. The histologic slides show a skin ulcer with a large gap between the edges
of the lesion (B), a thin layer of epidermal reepithelialization and extensive
granulation tissue formation in the dermis (C), and continuing reepithelialization of
the epidermis and wound contraction (D).
 Wound Strength
Sutured wounds - 70% of the strength of normal skin,
- largely because of the placement of sutures.
Sutures removed - 10% of that of unwounded skin
- This increases rapidly over the next 4 weeks.
Recovery of tensile strength
- Results from excess of collagen synthesis over collagen
degradation during the first 2 months of healing , &
- Later , from structural modifications of collagen fibers
Cross-linking
Increased fiber size - Synthesis ceases.
By 3 months
- Wound strength reaches approximately 70 - 80% of normal
- Usually does not substantially improve beyond that point.
 Fibrosis in Parenchymal Organs
The basic mechanisms of fibrosis
- Are the same as those of scar formation in the skin

Fibrosis
Is induced by persistent injurious stimuli such as
- Chronic infections and
- Immunologic reactions
It is typically associated with loss of tissue.
It may be responsible
- For organ dysfunction & even organ failure.
TGF-β - The major cytokine involved in fibrosis.
- Mechanisms of its activation here not known but cell
death & production of ROS seem to be important triggers
Myofibroblasts
- Are main source of collagen, in most organs
( Such as lung & kidney )
Stellate cells
- Are the major collagen producers in liver cirrhosis.
Fibrotic disorders are diverse & include
- Liver cirrhosis,
- Systemic sclerosis (scleroderma),
- Fibrosing diseases of the lung ( IPF, pneumoconioses, &
drug - radiation induced, pulmonary fibrosis)
- End-stage kidney disease, and
- Constrictive pericarditis.
 Mechanisms of fibrosis.
Persistent tissue injury leads to
- Chronic inflammation & loss of tissue
architecture.
Cytokines stimulate
- Migration & proliferation of fibroblasts &
myofibroblasts &
- Deposition of collagen & other ECM proteins.
The net result is
- Replacement of normal tissue by fibrosis.
 Abnormalities in Tissue Repair
Complications in tissue repair
Arise from abnormalities of the basic process of healing
- Deficient scar formation
- Excessive formation of the repair components, and
- Formation of contractures.
Chronic Wounds
Wound dehiscence & ulceration
Dehiscence
Result from inadequate granulation tissue or scar formation
- Not common
- Occurs frequently after abdominal surgery &
- Is due to increased abdominal pressure.
Wounds can ulcerate

Because of inadequate vascularization during healing.

Eg- Leg ulcers in atherosclerotic peripheral vascular disease

Non-healing wounds
Also form in areas devoid of sensation.
- Neuropathic ulcers Seen in diabetic peripheral neuropathy.
 Excessive Scarring
Hypertrophic scars & keloids
A result of excessive formation of the components of repair
Hypertrophic scar
A raised scar
- A result of accumulation of excess collagen
- Generally develop after thermal or traumatic injury that
involves the deep dermis.
Keloid
It is a scar tissue that
- Grows beyond the boundaries of the original wound
- Does not regress
There seems to be an individual predisposition
- Somewhat more common in African Americans.
`
Exuberant granulation
- Formation of excessive amounts of granulation tissue
- Protrudes above the level of the surrounding skin &
blocks re-epithelialization ( Proud flesh). .
- Rarely follow, incisional or traumatic scars
- Recur after excision.
- Must be removed to restore continuity of the epithelium
Contracture
- Contraction in the size of a wound is an important part of
the normal healing process.
- An exaggeration of this process gives rise to contracture &
results in deformities.
Contractures are particularly prone to develop on
- The palms
- The soles, &
- The anterior aspect of the thorax.
Commonly seen after serious burns &
- Can compromise the movement of joints.
Keloid. A, Excess collagen deposition in the skin forming a raised scar
B, Note the thick connective tissue deposition in the dermis.
 Healing of Fractures
Can be separated into overlapping stages
- With particular molecular, biochemical, histologic, features.
Immediately after fracture,
Rupture of blood vessels results in a hematoma
- Which fills the fracture gap &
- Surrounds the area of bone injury.
The clotted blood
- Provides a fibrin mesh, sealing off fracture site &
- Creates a framework for the influx of inflammatory cells &
in growth of fibroblasts & new capillaries.
Degranulated platelets & migrating inflammatory cells
- Release PDGF, TGF-β, FGF, & other factors
- Activate osteoprogenitor cells and
- Stimulate osteoclastic & osteoblastic activity.
 By the end of the first week
The major changes are
- Organization of the hematoma,
- Matrix production in adjacent tissues, and
- Remodeling of the fractured ends of the bone.
The fusiform & predominantly uncalcified tissue
- Is called Soft tissue callus or procallus
Soft tissue callus
- Provides some anchorage between fractured ends but
- Not rigid enough for weight bearing
 After approximately two weeks,
The soft tissue callus
- Is transformed into a bony callus.
The activated osteoprogenitor cells deposit woven bone
- Subperiosteal trabeculae and
- Within the medullary cavity.
Activated mesenchymal cells in the soft tissues & bone
surrounding the fracture line
- In some cases differentiate into chondrocytes that make
fibrocartilage & hyaline cartilage
 By the end of second or third week
Bony callus
- Reaches its maximal girth
- Helps to stabilize the fracture site.
The newly formed cartilage along the fracture line
- Undergoes enchondral ossification, forming a contiguous
network of bone with newly deposited bone trabeculae
The fractured ends are bridged, &
- As it mineralizes, the stiffness & strength of the callus
increases - Controlled weight bearing is tolerated .
.
In the early stages of callus formation,
- Excess fibrous tissue, cartilage, & woven bone is produced.
As the callus matures & is subjected to weight-bearing forces,
- The portions that are not physically stressed are resorbed
In this manner the callus is reduced in size & the shape
- And outline of the fractured bone are reestablished
as lamellar bone.
The healing process is complete
- With restoration of the medullary cavity.
A, Fracture of the fibula . B, Marked callus formation 6 weeks later.
 Abnormalities of fracture healing
Mal-union
- Displaced & comminuted fractures frequently
result in some deformity
Delayed union or nonunion
Inadequate immobilization permits movement of the
callus & prevents its normal formation
Pseudoarthrosis
If a nonunion persists the malformed callus undergoes cystic
degeneration, & become lined by synovial-like cells
Malunion of the left femer
 Definition of non-union = No sign of healing 9 months after a fracture ocured

Humeral shaft non-union Non-union leg bones

 Obstacles to healing
Infection of the fracture site
- Common in open fractures.
Malnutrition & skeletal dysplasia
- Also hinder fracture healing.
Old age
- Fractures often occur in the background of other bone
disorders (e.g., osteoporosis & osteomalacia).
- Surgical immobilization is often needed .
In children & young adults
- Near perfect union is the norm.