Definition/Introduction
A fracture is a breach in the structural continuity of the bone cortex, with a degree of injury to the surrounding soft tissues. Following the fracture, secondary healing begins, which consists of four steps:
Hematoma formation
Fibrocartilaginous callus formation
Bony callus formation
Bone remodeling
Failed or delayed healing can affect up to 10% of all fractures and can be due to various factors like comminution, infection, tumor, and disrupted vascular supply. During this article, we will work through each of these steps in order and detail before then touching on primary healing, factors affecting fracture healing, and methods of stimulation of fracture healing.[1][2]
Issues of Concern
The mechanism of fracture healing is an intricate and fluent process. This process can be broken down into four stages. However, these stages have considerable overlap.
Hematoma Formation (Days 1 to 5)
This stage begins immediately following the fracture. The blood vessels supplying the bone and periosteum are ruptured during the fracture, causing a hematoma to form around the fracture site. The hematoma clots and forms the temporary frame for subsequent healing. The injury to bone results in the secretion of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), bone morphogenetic proteins (BMPs), and interleukins (IL-1, IL-6, IL-11, IL-23). These cytokines act to stimulate essential cellular biology at the site, attracting macrophages, monocytes, and lymphocytes. These cells act together to remove damaged, necrotic tissue and secrete cytokines like vascular endothelial growth factor (VEGF) to stimulate healing at the site.
Fibrocartilaginous Callus Formation (Days 5 to 11)
The release of VEGF leads to angiogenesis at the site, and within the hematoma, fibrin-rich granulation tissue begins to develop. Further mesenchymal stem cells are recruited to the area and begin to differentiate (driven by BMPs) to fibroblasts, chondroblasts, and osteoblasts. As a result, chondrogenesis begins to occur, laying down a collagen-rich fibrocartilaginous network spanning the fracture ends, with a surrounding hyaline cartilage sleeve. At the same time, adjacent to the periosteal layers, a layer of woven bone is laid down by the osteoprogenitor cells.
Bony Callus Formation (Days 11 to 28)
The cartilaginous callus begins to undergo endochondral ossification. RANK-L is expressed, stimulating further differentiation of chondroblasts, chondroclasts, osteoblasts, and osteoclasts. As a result, the cartilaginous callus is resorbed and begins to calcify. Subperiosteally, woven bone continues to be laid down. The newly formed blood vessels continue to proliferate, allowing further migration of mesenchymal stem cells. At the end of this phase, a hard, calcified callus of immature bone forms.
Bone Remodelling (Day 18 onwards, lasting months to years)
With the continued migration of osteoblasts and osteoclasts, the hard callus undergoes repeated remodeling - termed 'coupled remodeling.' This 'coupled remodeling' is a balance of resorption by osteoclasts and new bone formation by osteoblasts. The center of the callus is ultimately replaced by compact bone, while the callus edges become replaced by lamellar bone. Substantial remodeling of the vasculature occurs alongside these changes. The process of bone remodeling lasts for many months, ultimately resulting in the regeneration of the normal bone structure.[3][4][5][6]
An important point to expand on is endochondral ossification, which is the name given for the process of conversion of cartilage to bone. As described above, this occurs during the formation of bony callus, in which the newly formed collagen-rich cartilaginous callus gets replaced by immature bone. This process is also the key to the formation of long bones in the fetus, in which the bony skeleton replaces the hyaline cartilage model. The second type of ossification also occurs in the fetus; this is intramembranous ossification; this is the process by which mesenchymal tissue (primitive connective tissue) is converted directly to the bone, which no cartilage intermediate. This process takes place in the flat bones of the skull.[7]
Clinical Significance
Primary bone healing is the reestablishment of the cortex without the formation of a callus. It occurs if a fracture is adequately "fixed" through reduction, immobilization, and rehabilitation. Secondary bone healing, as described above, occurs through the formation of a callus and subsequent remodeling.
By reducing and fixating, the clinician moves the two ends of the fracture into close apposition, which results in the minimal formation of granulation tissue and callus. 'Cutting cones' of osteoclasts cross the fracture site to the resorbed damaged bone, and 'forming zones' of osteoblasts lay down new bone.[5][8]
Reduction and fixation of fractures can be either open or closed. If treated as closed, this happens without the need to make an incision into the skin. Open refers to the need or choice to open the skin with a surgical incision. If a fracture pattern appears stable, then the most appropriate method is closed. Options for this would be to use a cast (e.g., plaster of Paris), a brace, or a splint. Open reduction tends to be the choice with unstable fractures and commonly occurs alongside internal fixation - hence the term ORIF. Internal fixation involves the use of surgical implants to hold the two ends of the fracture closely opposed. Commonly used methods of internal fixation include plating, screws, wires, and intramedullary nails. A final method of external fixation is also an option, and this involves the placing of pins through the skin, which are then held in place by an external 'scaffold.' This method tends to be used in complex fractures and can serve as a temporary option before internal fixation.[9]
Multiple factors affect fracture healing, which can broadly categorize into local and systemic categories.
Local Factors
Fracture characteristics - excessive movement, misalignment, extensive damage, and soft tissues caught within fracture ends can lead to delayed or non-union
Infection - can lead to poor healing and delayed or non-union.
Blood supply - reduced blood supply to the fracture site can lead to delayed or non-union.
Systemic Factors (the presence of any of these factors predisposes to poor healing)
Fractures have significant mortality and morbidity; therefore, an interprofessional approach is essential for good outcomes.[10][11][12]
There are multiple methods that the interprofessional team can utilize to promote/stimulate fracture healing, including:
Dietary supplements - calcium, protein, vitamins C and D
Bone stimulators - which can be electrical, electromagnetic, and ultrasound. The current effectiveness of these methods is still equivocal, and this area requires further research.
Bone graft - this involves the use of bone to help provide a scaffold to the newly forming bone. This graft can be from the patient's body (autograft) or a deceased donor (allograft).
[13][14]
