FRACTURE HEALING AND FACTORS AFFECTING FRACTURE HEALING

History

Bones have fractured since the beginning of humanity and treated as long as recorded history.

• In 17 th century Albrecht Haller, observed invading capillaries buds in fracture callus and taught that blood vessels are responsible for callus formation.

• John Hunter ,described the morphologic sequence of fracture healing.

• In 1873 , Kolliker observed the role of multinucleated giant cells, osteoclast to be responsible for bone resorption.

• In 1917, Bier reported the stimulation factor for new bone formation was present in organized clot of the fracture hematoma.

• In 1939, Gluksman suggested pressure and shearing stresses are possible for fracture healing.

• In 1961, Tonna and Cronkie demonstrated the role of local mesenchymal cells in a fracture repair.

Definition• A fracture is defined as a break in the structural

continuity of bone.

• Following fracture –there is a complex and dynamic affair with succession of changes commonly involving in restoration of the part by mesenchymal tissue i.e, bone.

• Following fracture no scar formed instead a bone has formed a new at the original fracture site. So appropriate nomenclature would be bone regeneration.

• Fracture in man heal and unite by 2 main ways.

1) Primary healing/ Osteonal healing/Direct healing

Bone formation occurs directly without any callus formation. This occurs in stable,aligned,closely apposed fractures. Occur in cancellous/cortical bone.

Direct bone healing

• Absolute stability, achieved only by inter-fragmentary compression, diminishes the strain at the fracture site to such an extent that allows for direct healing without visible callus

• Under absolute stability, the necrosis of fragment ends induces internal remodeling of bone which eventually crosses and repairs the fracture.

• Primary healing indicates that it occurs without the intermediary formation and replacement of fracture callus

Direct bone healing

This type of healing is noticed in • Rigidly stabilised fractures• Impacted epiphyseal, metaphyseal and

vertebral body fractures, • Osteotomies through metaphyseal bone • Arthrodesis sites treated with rigid

stabilisation

Direct bone healing

• In first few days there is minimal activity near fracture.

• Hematoma reabsorbed• Swelling subsides and surgical wound heals• After 3 to 4 weeks the Haversian system starts

to remodel the bone internally

Direct bone healing• Schenk and Willenegger described 2 types of primary bone

healing– Gap healing– Contact healing

• They found that following rigid fixation not all cortical bone ends are in close contact; there are gaps of varying sizes and the mechanism, structure and rate of bone formation at the fracture site depends on the size of the gaps

Direct bone healing

Contact healingLamellar bone forms directly across the

fracture, parallel to long axis of bone by direct extension of osteons.

CONTACT HEALING• A cluster of osteoclasts cuts across the fracture ,

osteoblasts following the osteoclasts deposit new bone and blood vessels follow the osteoblasts.

• These “cutter heads” or “cutting cones” form new haversian systems or primary osteons in their wake producing an interdigitation of newly formed osteons bridging the fracture

Gap healing• Gaps between bone fragments are invaded by

blood vessels which appear within the first 8 days. • Accompanied by osteoblasts which deposit

osteoid, giving rise to lamellae oriented 90° to the long axis of the bone

• From 4th week onwards haversian remodelling begins with cutting cones traversing the new bone in the fracture gap depositing lamellar bone and forming axially oriented osteons.

Direct vs Indirect healing• In the present day, healing by callus formation is

preferred to primary bone healing as rigid plating results in transient porosis of bone under the plate due to loss of periosteal blood supply, which may take years to remodel, thereby reducing the strength of repair.

• Primary healing is however still desired in

articular fractures, in forearm fractures and in metaphyseal fractures

Secondary healing

• It is usual type consisting of formation of callus either of cartilagenous or fibrous. This callus is later converted into lamellar bone.

• When fracture is not rigidly fixed and movements occur, in such case callus is replaced by secondary bone healing.

• Radiologically characterized by callus formation, temporary widening of fracture and slow disappearance of radiolucent fracture line due to fibro cartilage mineralization.

Sequence of events in fracture healing

• Bone healing proceeds in successive stages.

• Each stage depends on diffrt kinds of differentiated cells to make new capillaries, local connective tissue and bone and cartilage matrices( made by osteoblast and chondroblast)

• Osteoinduction is the first step in bone healing.

• It causes mesenchymal cells to differeciate into various cells which then produce messenger substance which further stimulate the mesenchymal cells to differentiate. The cycle continuous till healing.

• The inductor factors are bone morphogenic protein(BMP). Growth factors,and hyaluronidase.

• In osteoconduction , a scaffold of collagenous network has developed, upon which the reparative cells produce callus and bone.

• It fascilitates bone deposition in an orderly fashion and helps the callus to bridge the gap b/w fragments.

• Allograft have powerful osteoinductive and as well as osteoconductive properties.

• The natural course of fracture heaing includes:-1. Stabilization of the fractured bone fragments

by periosteal and endosteal callus formation and by fibrocartilage differentiation.

2. Restoration of continuity and bone union by ossification.

3. Substitution of avascular and necrotic areas by haversian remodelling.

4. Malalignment may be corrected , to a certen extent,by remodelling at fracture site.

5. Functional adaptation.

INDIRECT HEALING/Secondary healing

• Five stages.– Tissue destruction and stage of hematoma formation

Hematoma forms from torn vessels.– Inflammation and cellular proliferation/granulation tissue

Inflammatory cells absorb hematoma, angiogenesis.– Callus formation/repair

Stem cells differentiate under influence of growth factors and form cartilage, woven bone Callus.

– ConsolidationWoven bone converted to lamellar bone.

– RemodelingCrude weld of solid bone is reshaped according to physiological forces over years.

• These stages overlap and are determined only arbitrarily

Radiological picture of stages of fracture healing

Indirect healingHealing by callus is the

natural method of healing and has distinct

advantages• Ensures mechanical

strength while bones heal• With increased stress,

callus grows stronger• No porosis of bone

occurs as is seen with remodeling during direct healing.

Stage of hematoma formation(7days)

• Begins immediately following injury and followed rapidly by repair.

• Following # the local marrow, periosteum and adjacent soft tissue and living bone itself get damaged. As a result there will be accumulation of blood within the modularly cavity, fracture ends and beneath the periosteum and surrounding soft tissue.

The hematoma provide 3 important factors:--

1. The # hematoma immobilizes fracture and swelling hydrostatically splints the # and thus provides small amount of mechanical stability of # site.

2. The # hematoma provides a fibrin scaffold that fascilitate migration of repair cells.

3. Hematoma brings osteoblast and the chondrocyte precursors to # site in large numbers that begin to differentiate into osteoblasts and chondrocytes to begin producing matrix.

The loss of hematoma will impair fracture healing.

Stage of granulation tissue• Granulation tissue invades and replaces initial

hematoma and then differentiate into connective tissue and fibro cartilage.

• Injured tissue and platelets releases vasoactive mediators such as serotonin and histamine cause blood vessels to dilate and exude plasma , leading to acute edema.

• Macrophages and osteoclasts come into the site to remove damaged and necrotic tissue.

• The precursor cells from deep surface of periosteum close to the # in sensitized and stimulated local mediator mechanism begin to produce new cells that differentiate and organize to provide new vessels, fibroblast, intercellular matrix and supporting cells.

• Collectively they form granulation tissue which

grows forward , outside and inside the bone to bridge the fracture.

• The granulation tissue may be viewed as one among the mediator that leads to the reparative stage.

Stage of callus (1-4 months)• Process of osteogenesis

continues and fracture callus bridges the fracture site and subsequent transition to mature bone take place.

• Bone produced through intramembranous/ endochondral ossification or both.

• There is proliferative response in blood vessels of the periosteal tissue and marrow.

• Nest of cartilage cells or their precursors lay new osteoid tissue.

• Mineralization sets in because of ordered sequence of cell activities.

• Cells synthesize a matrix with a high concentration of type-1 collagen fibrills, and then create conditions that promote deposition of cluster of calcium hydroxy apatite crystals in collagen fibrils.

• Later osteoblsts ,release ‘ prepackaged ‘ calcium phosphate complex into the matrix.

• As mineralisation proceeds , bone ends gradually become enveloped in a fusiform mass of callus, also called woven bone- immature bone of fracture callus.

• The callus is the first sign of union visible on x-rays, usually 3 wks after fracture.

• External bridging callus/periosteal callus: existing on the other surface of the bone.

• Modularly callus: present in modularly canal• Cartilaginous/ soft fibrous callus: formed in

central region of fracture because of low oxygen tension. Consists of primary cartilage.

• Hard callus : formed at periphery of fracture due to increased oxygen concentration .

• It is formed by membranous bone formation, gradually replaces cartilage.

Stage of consolidation

• The woven bone that forms the primary callus is gradually transformed by the activity of the osteoblasts into more mature bone with a typical lamellar structure.

Stage of remodeling• The process occurs along

with usual deposition- resorption phenomenon.

• It is a gradual modification of the fracture region under the influence of mechanical loads until it reaches some threshold of optimal shape, which typically is similar to the shape it had before the fracture.

• Osteoclast has important role in this phase.• It causes resorption of unneeded trabecular

bone,at the same time new trbeculae are being laid down(according to Wolf’s Law) in a functionally more advantageous orientation.

• Angular deformities slowly decreases/disappear as bone is laid down on concave surface and removed from convex surface.

Remodeling does four things(1-4 years)

1. It replaces mineralized cartilage with woven bone to form a kind of primary spongiosa.

2. It replaces the latter and the woven bone with packets of new lamellar bone.

3. Replaces the callus b/w the ends of compacta with a secondary osteons made or lamellar bone.

4. Tends to remove any callus plugging the marrow cavity, restoring the cavity.

Fracture healing in cancellous bone

• The extent of bone and marrow necrosis following cancellous bone fracture is much less than that seen in compact bone fractures, this is because of good circulation.

• Primary healing teke place in the cancellous bone, secondary healing rare and endochondral bone formation exceptional.

FACTORS INFLUENCING/AFFECTING FRACTURE HEALING

• These factors can be subdivided into systemic and local factors.

• Systemic factors present at the time of injury with exception of trauma to the CNS.

• Local factors subdivided according to their nature such as mechanical , chemical ,physical, or environmental. Such classification has little clinical importance.

• Therefore chosen to subdivide the factors depending on whether they were present at the time of injury, whether they are due to injury, whether they depend on the treatment, and whether they are associated with complications.

SYSTEMIC FACTORS

A. AgeB. Activity level including--- 1. General immobilization 2. space flightC. Nutritional statusD. Hormonal factors 1.GH 2.Corticosteroids(microvascular AVN) 3. others- thyroid, estrogen , androgen, calcitonin, PTH,PG

E. Diseases:- anemia, neuropathies,tabesF. Vitamin defcncy: A,D,E,KG. Drugs : NSAIDs, anticoagulants ,CCB, sodium

fluride, tetracycline.H. Nicotine, alcoholI. HyperoxiaJ. Systemic growth factorsK. Environmental temperatureL. CNS trauma

LOCAL FACTORS

A. Factors independent of injury, treatment, or complications

1. Type of bone 2. Abnormal bone -- radiation necrosis --- infection --- tumours and other pathologic

conditions. 3. Denervation

B. Factors depending on injury 1. Degree of local damage a.compound # b. communition of # c. velocity of injury d. low circulation levels of vit.K

2. Extent of disruption of vascular supply to bone, it,s fragments, soft tissue or severity of injury.

3. Type and location of fracture( one /2 bones ie tibia and fibula or tibia alone.

4. Loss of bone 5. soft tissue interposition 6. Local growth factors.

C. Factors depending on treatment___ 1. Extent of surgical trauma( bld supply,

heat) 2. Implant induced altered bld flow 3. Degree and kind of rigidity of

external/internal fixation and influence of timing.

4. Degree, duration and direction of load- induced deformation of bone and soft tissue

5. Extent of contact b/w fragments6. Factors stimulating post traumatic

osteogenesis ----- bone graft, BMPs, electrical

stimulation ,surgical technique ,intermittent venous stasis.

D. Factors associated with complications 1. infection 2. venous stasis 3. metal allergy

Influence of fixation devices in Fracture healing

Regional accelaratory phenomenon( RAP) : It increases the rapidity of the healing

stages, it makes healing occur 2-10 times more quickly.

injury RAP granulation ------------------------------------------ callus -------------------------------------------- remodelling----------------------------------- final healing------------------------------

Inter fragmentary strain interfragmentary strain influences

differentiation of pluripotent or precursor cells invading gap.

Highly specialised osteogenic cells can tolerate greater deformation than osteocytes. Importance of IF strain is when a fracture is fixed by plates.

RODS

• IM rods permits the transmission of load –generated axial forces in an axial direction and promote callus formation.

• Axial loading will lead to high bone stresses at sites of contact.

• This will lead to formation of external callus which later replaced by bone through endochondral ossification.

• Disadvantage----- damage to medullary blood supply.

Plates

• Rigid plate fixation reduces the intermittent bone strainat fracture site to a point where no external callus is formed.

• Dis advantage--- loss of vascular blood supply to bone

• Recent advances in LC-DCP cause minimal vascular damage.

External fixation

• The stiffness of external fixation is less and hence results in a biomechanically less mature union.

VARIABLES THAT INFLUENCE FRACTURE HEALING

• Cruess and Buck Walter have devided the varibles into 4 Groups

1. INJURY VARIABLES2. PATIENT VARIABLES3. TISSUE VARIBLES4. TREATMENT VARIABLES

1. INJURY VARIABLE

A) Open #s---- causes soft tissue destruction and disturbe blood suply prevent haematoma fornation and delayed repair

B) Severity of injury----- severe injury lead to extensive soft tissue damage and bone communition with displacement ,leading to retardation of fracture healing.

C. Intra-articular #s ---- synovial fluid hinders the fracture healing

as it contains collagenases which degrade the matrix of initial # callus. So intra-articular #s require reconstruction of joint, stable fixation of fragments and early mobilisation.

D) Soft tissue interposition---- compromise # healingE) Segmental fracture------ of long bone impairs

the intramedullary blood suply of middle fragment resulting in delayed union/non union.

F) Damage to blood supply---- lead to delay/ prevent # healing.

PATIENT VARIBLES

1. Age:- infants and childrn have rapid rate of healing where as healing declines significantly with age advances.

2. Nutrition :- poor nutritional status decreases synthesis of large volumes of collagens, polyglycans and other matrix macromolecules, hence affect fracture healing and can lead to mortality.

3. Systemic hormones:-- corticosteroids, NSAIDs , anticoagulants inhibit fracture healing. Where as GH, TH,insulin,and anabolic steroids enhance fracture healing.

4. Nicotine :-- cigarette smoking inhibit # healing by inhibiting vascularisation of cancellous bone graft.

TISSUE VARIABLES

1. Form of bone ( cancellous/ cortical): cancellous bone healing rapid because of larger

surface area per unit volume,and rich blood supply.

2. Bone necrosis :-- leads to decreased bone healing.3. Bone diseases :- osteoporosis, osteomalacia,

primary malignant tumors, osteogenesis imperfecta etc all cause pathological # and delay in healing process.

4. Infection :- slow down / prevents healing. Infection will cause necrosis of normal tissue, edema and thrombosis of blood vessels, threby retarding or prevent healing.

TREATMENT VARIABLES

1. Apposition of fracture fragments :- Decreasing the # gap decreases volume of repair tissue needed to heal a fracture. Anatomical reduction causes rapid healing as compared to displaced fragments.

2. Loading and micromotion:-- Loading a # site stimulate bone formation while decreased loading slows fracture healing.

Immediate controlled loading and limb movement, including induced micromotion at long fracture sites, promotes fracture healing but too much movement cause nonunion.

3. Stabilization of fracture :- will prevent repeated disruption of repair tissue and speed up the fracture callus.

4. Rigid fixation :-- Plate like LC-DCP leads to primary union of fracture, stable fixation allows early mobilization of joints and hence prevents stiffness.

5. Bone grafting :-- It is osteo inductive as well as osteoconductive. BMP stimulates healing. Autograft and allograft of cancellous , cortical or cortico-cancellous bone are used to stimulate # healing and replace lost bone.

6. Ultrasound:- low intensity pulsed USG accelerate # healing. It increases the concentration of intracellular calcium in fracture callus chondrocytes.

7 . Demineralized mone marrow :--- The factors in bone marrow stimulate bone formation, by migration of undifferentiated mesenchymal cells to the implanted matrix and differentiation into chodrocytes.

Electrical and electromagnetic stimulation

The fibrous union can be converted into a fibrocartilage which then undergoes enchondral ossification by using cathode electrodes,each delivering an optimal osteogenic current of 20micro.amp

At least 3 electrical and electromagnetic methodes are available.

1. Invasive2. Semi-invasive3. Non-invasive

Invasive method

• A self powered, self contained and totally implantable electrical stimulation is used.

• Union is achieved in more than 85% 0s cases within 12-36 weeks.

Semi-invasive method

• Consists of insertion of cathodes percutaneously into the nonunion site and continous application of small amount of direct current. Early osteogenesis can be detected in 12 weeks.

Non-invasive method

• Weak electric currents are induced by pulsating elctromagnetic fields.

• radiograph made after 4-6 wks interwal shows evidence of healing.

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