Fracture Healing (Bone Regeneration)

Fracture-healing is a specialized type of wound healing response in which the regeneration of bone leads to a restoration of skeletal integrity.

• Fracture healing is a complex process that requires the recruitment of appropriate cells (fibroblasts, macrophages, chondroblasts, osteoblasts, osteoclasts) and the subsequent expression of the appropriate genes (genes that control matrix production and organization, growth factors, transcription factors) at the right time and in the right anatomical location. 
• A fracture initiates a sequence of inflammation, repair, and remodeling that can restore the injured bone to its original state within a few months if each stage of this complex interdependent cascade proceeds undisturbed. 
• Clinical union occurs when progressively increasing stiffness and strength provided by the mineralization process make the fracture site stable and pain-free. 
• Radiographic union is present when plain radiographs show bone trabeculae or cortical bone crossing the fracture site. 
• Radioisotope studies have shown increased activity in fracture sites long after painless function has been restored and radiographic union is present, indicating that the remodeling process continues for years.

There Are 4 Methods Of Fracture Healing:

1. Secondary healing
2. Primary healing
3. Distraction osteogenesis
4. Transformation osteogenesis

Healing By Callus

• This is the ‘natural’ form of healing in tubular bones; in the absence of rigid fixation, it proceeds in five stages:

1. Tissue Destruction And Haematoma Formation – Vessels are torn and a haematoma forms around and within the fracture. 

• Bone at the fracture surfaces, deprived of a blood supply, dies back for a millimetre or two.

2. Inflammation And Cellular Proliferation– Within 8 hours of the fracture there is an acute inflammatory reaction with migration of inflammatory cells and the initiation of proliferation and differentiation of mesenchymal stem cells from the periosteum, the breached medullary canal and the surrounding muscle. 

• The fragment ends are surrounded by cellular tissue, which creates a scaffold across the fracture site. A vast array of inflammatory mediators (cytokines and various growth factors) is involved. 
• The clotted haematoma is slowly absorbed and fine new capillaries grow into the area.

3. Callus Formation– The differentiating stem cells provide chrondrogenic and osteogenic cell populations; given the right conditions – and this is usually the local biological and biomechanical environment – they will start forming bone and, in some cases, also cartilage. 

• The cell population now also includes osteoclasts (probably derived from the new blood vessels), which begin to mop up dead bone. 
• The thick cellular mass, with its islands of immature bone and cartilage, forms the callus or splint on the periosteal and endosteal surfaces. 
• As the immature fibre bone (or ‘woven’ bone) becomes more densely mineralized, movement at the fracture site decreases progressively and at about 4 weeks after injury the fracture ‘unites’.

4. Consolidation– With continuing osteoclastic and osteoblastic activity the woven bone is transformed into lamellar bone. 

• The system is now rigid enough to allow osteoclasts to burrow through the debris at the fracture line, and close behind them. 
• Osteoblasts fill in the remaining gaps between the fragments with new bone. 
• This is a slow process and it may be several months before the bone is strong enough to carry normal loads.
• Each of these stages overlaps the end of the stage preceding it so that fracture healing is a continuous process.

5. Remodelling– The fracture has been bridged by a cuff of solid bone. 

• Over a period of months, or even years, this crude ‘weld’ is reshaped by a continuous process of alternating bone resorption and formation. 
• Thicker lamellae are laid down where the stresses are high, unwanted buttresses are carved away and the medullary cavity is reformed. 
• Eventually, and especially in children, the bone reassumes something like its normal shape.

Healing By Direct Union

• If the fracture site is absolutely immobile – for example, an impacted fracture in cancellous bone, or a fracture rigidly immobilized by a metal plate – there is no stimulus for callus. 
• Instead, osteoblastic new bone formation occurs directly between the fragments. 
• Gaps between the fracture surfaces are invaded by new capillaries and osteoprogenitor cells growing in from the edges, and new bone is laid down on the exposed surface (gap healing). 
• Where the crevices are very narrow (less than 200 μm), osteogenesis produces lamellar bone; wider gaps are filled first by woven bone, which is then remodelled to lamellar bone. 
• By 3–4 weeks the fracture is solid enough to allow penetration and bridging of the area by bone remodelling units, i.e. osteoclastic ‘cutting cones’ followed by osteoblasts.
• Where the exposed fracture surfaces are in intimate contact and held rigidly from the outset, internal bridging may occasionally occur without any intermediate stages (contact healing).

Primary Bone Healing involves a direct attempt by the cortex to re-establish itself after interruption without the formation of a fracture callus.

• Just like in skin, primary healing only works when the edges are touching exactly. And since touching edges are not common, primary healing is the less commonly seen type of healing.
• In fact, this method is employed only after rigid surgical fixation, or in case with a partial crack in the bone, a so-callled "unicortical" fracture, where the remaining bone holds everything rigid.
• The basic science, in brief: Primary bone healing is lead by the formation of a so-called cutting cone (consisting of osteoclasts at the front of the cone to remove bone and trailing osteoblasts to lay down new bone) across the gaps to form a secondary osteon. 

Secondary Bone Healing involves the classical stages of injury, hemorrhage inflammation, primary soft callus formation, callus mineralization, and callus remodeling.  

• This method of bone healing closely resembles endochondral ossification (which involves a cartilage template being replaced by bone).

 During the complex fracture repair process, Four Basic Types Of New Bone Formation Occur:  

1. Osteochondral ossification, 
2. Intramembranous ossification, 
3. Oppositional new bone formation, and 
4. Osteonal migration (creeping substitution). 

• The type, amount, and location of bone formed can be influenced by fracture type, gap condition, fixation rigidity, loading, and biological environment.