Fracture healing is a series of events that is triggered from the moment of trauma that caused the fracture to the time of bone remodeling.

Blood supply (bone blood flow) is the most important factor in Fracture healing.

See Also: Factors affecting Fracture Healing

Fracture Healing Stages

StageTimeEvents
Stage I – InflammationUp to 1 week– Hematoma from ruptured blood vessels forms fibrin clot. Damaged tissue and degranulated platelets release signaling molecules, growth factors and cytokines.
– Migration of inflammatory cells into the hematoma occurs, responding to local growth factors and cytokines (IL-1, IL-6, TGF-β super-family including BMPs, PDGF, FGF, IGF).
– Proliferation, differentiation and matrix synthesis as hematoma is replaced by granulation tissue. Capillary in-growth (angiogenesis) and recruitment of fibroblasts, mesenchymal cells and osteoprogenitor cells. The periosteum plays an important role in this process.
– Cell types involved include PMNs, macrophages and then fibroblasts.
– At necrotic bone ends, bone resorption is mediated by osteoclasts and removal of tissue debris by macrophages.
Stage II – Soft Callus1 week- 1month– Increased cellularity, with proliferation, differentiation and soft callus neovascularization.
– Callus is a combination of fibrous tissue, cartilage and woven bone.
– Intramembranous (bony/periosteal) callus = primary callus response: type I collagen (osteoid) laid down from periosteal osteoblasts in the cambium layer as periosteal bony callus or woven bone. This is hard callus but it does not bridge the fracture.
– Endochondral (fibrocartilaginous/bridging) callus = bridging external callus: multipotential cells differentiate to form chondroblasts and fibroblasts within the granulating callus, which produce the type II cartilaginous and fibrous elements of the matrix (chondroid). Chondroblasts then calcify the chondroid matrix they have produced, creating calcified fibrocartilage or soft callus.
– Medullary callus: this is a later process and can slowly unite the fracture if external callus fails.
Stage III – Hard Callus1-4 months– Calcified soft callus is resorbed by chondroclasts and invaded by new blood vessels. These bring with them osteoblast precursors that produce the bony (type I) elements of the matrix (osteoid) and then mineralize it to form woven bone.
– Soft calcified chondroid callus becomes hard mineralized osteoid callus.
– Bony bridging continues peripherally as subperiosteal new bone formation. At this point the fracture is united, solid and pain-free to movement.
Stage IV – RemodelingSeveral Years– Once the fracture has united, the hard callus is remodeled from woven bone to hard, dense lamellar bone by a process of osteoclastic resorption followed by osteoblastic bone formation. The medullary canal reforms at the end of this process.
– This is the same mechanism as for direct cortical, osteonal or primary bone healing, seen following fracture fixation with absolute stability.
– Bone assumes a configuration and shape based on stresses acting upon it (Wolff’s law). Electric fields may play a role in Wolff’s law, with osteoclastic activity being predominant on the electropositive tension side of bone and osteoblastic activity on the electronegative compression side.

Blood Flow in Fractures

Bone blood flow is the major determinant of how well a fracture heals, because it delivers nutrients to the injury site.

  • Initial response is a decrease in bone blood flow after vascular disruption at the fracture site.
  • Within hours to days, bone blood flow increases (as part of the regional acceleratory phenomenon), peaks at approximately 2 weeks, and returns to normal in 3 to 5 months.

Unreamed intramedullary nails preserve endosteal blood supply, while reaming devascularizes the inner 50% to 80% of the cortex and delays revascularization of endosteal blood supply.

See Also: Bone Metabolism

Fracture Healing Types

Types of fracture healing include Primary and Secondary fracture healing.

See Also: Types of Bone Formation

Primary Fracture Healing

Primary Fracture Healing (Direct cortical, Osteonal or Haversian) only occurs when there has been anatomical reduction and interfragmentary compression, leading to absolute stability (no motion between fracture surfaces under functional load).

  • The process is very intolerant of strain (movement) at the fracture site. In the first few days, there is minimal activity in areas of direct contact (contact healing).
  • New blood vessels grow into any small gaps that exist (gap healing), and mesenchymal cells differentiate into osteoblasts, laying down lamellar bone in small gaps and woven bone in large gaps.
  • Subsequently, osteoclasts form cutting cones that tunnel across the fracture site wherever there is contact between the bone ends or a minute gap.
  • This leaves a path for blood vessels and osteoblasts to follow in their wake, laying down lamellar bone in the form of new osteons.
  • This process of newly formed osteons bridging the gap may take many months and may be difficult to see on an X-ray.
  • This is the same process as the remodelling phase (stage IV) of secondary bone healing.

Secondary Fracture Healing

In the presence of relative stability (some controlled motion between fracture surfaces under functional load), strain or movement at the fracture site stimulates secondary healing by two discrete processes:

  1. Periosteal bony callus (intramembranous ossification): multipotent cells in the periosteum differentiate into osteoprogenitor cells, which produce bone directly without first forming cartilage. This hard callus forms early on at the periphery of the fracture site, providing there has not been extensive periosteal stripping.
  2. Fibrocartilaginous bridging callus (endochondral ossification): this process occurs simultaneously between the adjacent bone ends and involves the formation of fibrocartilage that becomes calcified and is then replaced by osteoid or woven bone. This process also occurs within the surrounding soft tissues.

These processes are dependent on some movement occurring at the fracture site (strain). Rigid fixation inhibits the differentiation of cells and the formation of callus.

Perren’s Strain Theory Of Fracture Healing

After any form of fixation or immobilization, a fracture that is loaded will undergo some degree of movement or strain. This may be compressive, tensile, bending or torsional.

Strain at a fracture site is decreased with increased fracture gap or greater surface area, such as in metaphyseal fractures (larger bone diameter) and in multifragmentary or segmental fractures (where the overall strain is shared among the individual fragments).

Fracture callus becomes increasingly stiff with time, from a gelatinous granulation tissue, to soft callus and to subsequently hard bony callus.

Each of these tissues is able to tolerate a different amount of strain:

  1. Granulation tissue: up to 100 per cent.
  2. Fibrous connective tissue: up to 17 per cent.
  3. Fibrocartilage: 2–10 per cent.
  4. Lamellar bone: 2 per cent.
  • The degree of interfragmentary strain appears to govern the cellular response and therefore the type of tissue that forms between the fracture fragments.
  • Initially the strain is high, stimulating granulation tissue formation, but as the strain decreases with time cartilage and then bone form.
  • In the presence of absolute stability (compression plating or rigid external fixation), if the fragments are in intimate contact, then the fracture site strain is so low as to inhibit callus formation and allow direct (primary) Haversian remodelling.
  • If fragments are fixed rigidly but a gap is present, then primary bone healing (cutting cones) may not be able to bridge the gap. The lack of strain may inhibit callus formation and secondary healing, predisposing to non-union.
  • In the presence of relative stability (splint immobilization, intramedullary fixation or bridge plating), the more strain-tolerant cartilaginous callus is required to stiffen the fracture site before hard woven bony callus forming and replacing it (secondary healing). A larger strain produces a bigger callus.
  • In the presence of complete instability, callus is unable to form because the strain is too much for it to tolerate. The more strain tolerant fibrous tissue forms, creating a hypertrophic non-union.

Type of Fracture Healing Based on Type of Stabilization

Type of StabilizationType of Fracture Healing
Cast (closed treatment)Periosteal bridging callus and interfragmentary enchondral ossification
Compression platePrimary cortical healing (cuttingcone type or haversian remodeling)
Intramedullary nailEarly: periosteal bridging callus; enchondral ossification.
Late: medullary callus and intramembranous ossification.
External fixatorDependent on extent of rigidity:
– Less rigid: periosteal bridging callus; enchondral ossification.
– More rigid: primary cortical healing; intramembranous ossification.
Inadequate immobilization with adequate blood supplyHypertrophic nonunion (failed enchondral ossification); type II collagen predominates
Inadequate immobilization without adequate blood supplyAtrophic nonunion
Inadequate reduction with displacement at the fracture siteOligotrophic nonunion
Type of Fracture Healing Based on Type of Stabilization

Growth Factors of Bone

GROWTH FACTOR ACTIONNOTES
Bone morphogenetic protein (BMP)– Osteoinductive; stimulates bone formation
– Induces metaplasia of mesenchymal cells into osteoblasts
– Target cells of BMP are the undifferentiated perivascular mesenchymal cells; signal through serine-threonine kinase receptors
– Intracellular molecules called SMADs serve as signaling
mediators for BMPs
Transforming growth factor (TGF)-β– Induces mesenchymal cells to produce type II collagen and proteoglycans
– Induces osteoblasts to synthesize collagen
– Found in fracture hematomas; believed to regulate cartilage and bone formation in fracture callus; signal through serine/threonine kinase receptors Coating porous implants with TGF-β enhances bone ingrowth
Insulin like growth factor (IGF)-2Stimulates type I collagen, cellular proliferation, cartilage matrix synthesis, and bone formationSignal through tyrosine kinase receptors
Platelet-derived growth factor (PDGF)

Attracts inflammatory cells to the fracture site (chemotactic)Released from platelets; signal through tyrosine kinase receptors
Growth Factors of Bone

Endocrine Effects on Fracture Healing

HORMONE EFFECTMECHANISM
Cortisone Decreased callus proliferation
Calcitonin +? Unknown
TH, PTH + Bone remodeling
Growth hormone+Increased callus volume
Endocrine Effects on Fracture Healing