Bony injury is responsible for a large amount of the work load of orthopaedic surgeons. Consequently, understanding how bone heals and regenerates is vital in order to ensure the best management of different types of injury.

• Fracture healing is a specialised form of tissue healing in which there is reconstruction of the original tissue rather than healing with scar formation. This process is influenced by the local biological and mechanical environment, along with both local and systemic factors.
• Fracture healing can be classified as either primary or secondary healing.

• Fracture stability determines what type of healing will occur.
• Mechanical stability governs the mechanical strain.

• If the strain is below 2%, primary bone healing occurs
• If the strain is between 2 and 10%, secondary bone healing occurs.

Modes of bone healing

• Primary bone healing (strain is <2%). Intramembranous healing occurs with absolute stability constructs via Haversian remodeling.
• Secondary bone healing (strain is between 2 and 10%)occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating, intramedullary nailing, etc. via enchondral healing.
• Combination bone healing may occur as a mixture of primary and secondary bone healing depending on the stability throughout the construct.

Table 1. Types of fracture healing based on method of stabilisation

Primary healing

• With primary bone healing there is no movement across the fracture ends under physiological load.
• There is absolute stability with compression that provides a very low strain environment.
• Features include no callus, cutting cones cross the fracture site, direct laying down of new osteones and intramembraneous ossification. It mimics normal bone remodeling.
• For primary bone healing to occur no significant gap at the fracture site (50 micrometres) should be present.

Primary bone formation

• Primary bone formation means that neither connective tissue nor fibrocartilage was present prior to new bone being laid down. There are two types of primary bone healing:
• Gap healing
• Contact healing
• Both types involve a cutting cone that simultaneously resorbs woven bone and replaces it with lamellar bone.

The cutting cone

• Resorption cavities are formed by groups of osteoclasts that have formed a “cutting cone.” This cutting cone advances longitudinally through the new bone in the gap, leaving a resorption cavity.
• The osteoclasts are followed by a thin-walled capillary loop that runs in the centre of the resorption cavity. These vessels are accompanied by mesenchymal cells and osteoblast precursors.
• Newly formed osteoblasts line the resorption cavity and begin producing osteoid.
• Eventually the resorption cavity will fill entirely with connective layers of new bone and become an osteon.
• The synchronised action of both bone-resorption and bone-forming cells results in a regenerating osteon that is capable of advancing in a longitudinal direction parallel to the long axis of bone.

Table 2. Biochemical steps of fracture healing

Inflammatory phase (immediate)

• Haematoma formation at the fracture site. Bone is fractured along with a damaged soft tissue envelope that includes periosteum and surrounding muscles with various blood vessels crossing the fracture line ruptured.
• There is an accumulation of haematoma within the medullary canal, between fracture ends and beneath any elevated periosteum. This blood rapidly coagulates to form a clot at the fracture site. Osteocytes deprived of their nutrition die back as far as the junction of collateral channels. The immediate ends of a fracture die. Severely damaged periosteum and marrow as well as other surrounding soft tissues may contribute to necrotic material in this region. The presence of necrotic material elicits an intense acute inflammatory response.
• The haematoma provides a source of haematopoietic cells that secret growth factors and cytokines to promote healing. The key inflammatory cytokines are PDGF, TNF-a, TGF-b, IL-6, IL-1. This leads to vascular ingrowth and cell proliferation, with a migration of acute inflammatory cells (polymorphonuclear leukocytes, macrophages and lymphocytes) to the region. The clotting cascade and the complement system are both activated, which results in the activation of cytokines and signalling molecules that are chemotactic to the inflammatory cells and angiogenic to blood vessels. Bone morphogenic proteins (BMPs) are also released from the damaged bone and are osteoinductive, mitogenic and angiogenic.
• Following the formation of the primary haematoma, a fibrin-rich granulation tissue forms as fibroblasts proliferate. Within this tissue, endochondral formation occurs in between the fracture ends and external to periosteal sites.
• Exudate and necrotic tissue are removed by macrophage phagocytosis. Pluripotent mesenchymal stem cells, osteoblasts and fibroblasts proliferate to produce a new matrix.
• This phase peaks at 48 hours and almost disappears by a week post-fracture. As the acute response subsides, the second phase begins and gradually becomes the predominant pattern.

Repair phase (starts within 2 weeks)

• The haematoma is organised and serves as a fibrin scaffold. There is a change of environment from slightly acidic (acidic tide), to neutral and then slight alkaline (alkaline tide). Osteoblasts need an alkaline environment to lay down bone.
• Pluripotential mesenchymal cells are directly involved in the repair of fractures and form collagen, cartilage and bone. Small variations in their microenvironment determine which behaviour predominates. The manner in which mechanical factors influence fracture healing is explained by Perren’s strain theory (see below). A fracture gap strain of 200% promotes fibroblast proliferation, with fibrous tissue forming in the fracture gap. Less than 15% strain and chondrocytes proliferate laying down collagen matrix and soft callus in the fracture gap. With 2–5% strain osteoblasts start to lay down osteoid that is then mineralised to form hard callus (woven bone).
• Endosteal cells also participate. Surviving osteocytes do not take part in the repair process, because they are destroyed during resorption.
• The majority of cells involved directly in fracture healing enter the fracture site along with granulation tissue, which invades the region with the ingress of capillary buds. Under normal circumstances, the periosteal vessels contribute the majority of capillary buds early in bone healing, with the nutrient medullary artery becoming more important later in the process.
• The cells invade the haematoma and begin to produce callus, which is made up of fibrous tissue, cartilage and young, immature fibre bone. This quickly envelopes the bone ends and leads to a gradual increase in stability of the fracture fragments. The mechanisms that control the behaviour of each individual cell at this stage of the repair process derive from the microenvironment in which the cell finds itself. Compression or the absence of tension discourages the formation of fibrous tissue. Variations in oxygen tension lead to the formation of either bone or cartilage. Cartilage is formed in areas of low oxygen tensions. An environment with a high oxygen tension is beneficial for osteogenic progenitor cell differentiation. Bridging callus (if bone ends are not in continuity) is formed; soft callus initially, later replaced by hard callus (woven bone) via a process of enchondral ossification.
• Early in the repair process, cartilage formation predominates, and glycosaminoglycans (mucopolysaccharides) are found in high concentrations. Later, bone formation is more obvious.
• Hard callus is formed at the periphery by intramembranous bone formation and soft callus is formed in the central region by endochondral ossification. Initially the matrix consists of types I, III and V collagen, glucosaminoglycans and proteoglycans. Some of this collagen is converted to type II and type IX collagen and then type I collagen dominates during osteogenesis, mineralisation and remodeling.

Remodeling phase

• The last phase, which lasts many months, involves stress orientation of disorganised woven bone into hard, dense lamellar bone via cutting cones and is governed by Wollf’s law.
• Osteoclastic resorption of trabeculae occurs, and new struts of bone are laid down that correspond to lines of force. The control mechanism is believed to be electrical.
• The cellular module that controls remodeling is the resorption unit, consisting of osteoclasts, which first resorb bone, followed by osteoblasts, which lay down new Haversian systems. The end result of remodeling is a bone that, if it has not returned to its original form, has been altered so that it may best perform the function demanded of it.

• 16:12:05Bone adapts its external shape and internal structure (and remodels) in response to the mechanical forces it is required to support.
• Wolff's law is explainable in terms of alterations in the electrical currents generated by crystalline structures within the bone, which have a direct effect on cellular behaviour.
• When a bone is subjected to stress, electropositivity occurs on the convex surface and electronegativity on the concave, a current produced by a piezoelectric effect. Studies suggest that regions of electropositivity are associated with osteoclastic activity and regions of electronegativity with osteoblastic activity.
• Other theories of the origin of the mechanical signal that drives the adaptation process include: (1) bone microdamage; or (2) strain in the mineralised bone tissue.

• States that fracture healing is dependent upon the mechanical stability of the fracture site.
• Strain is the deformation of a material (e.g. granulation tissue within a gap) when a given force is applied. It is the change in length (Δ l) in comparison to original length (l) after a given load is applied. Thus, it has no dimensions and is usually expressed as a percentage.
• Perren’s strain theory suggests that the mechanical environment governs the type of tissue that is laid down in fracture healing.
• The amount of deformation that a tissue can tolerate and still function varies greatly. Granulation tissue has a strain tolerance of 100%, fibrous tissue 17% and fibrocartilage up to 10%. Intact bone has a normal strain tolerance of 2% (before it fractures).
• Each of these tissues is stiffer than the previous one. Secondary fracture healing progresses from granulation to fibrous and fibrocartilage tissue until bone is formed and as the tissue type progresses, the fracture site becomes stiffer, thus reducing the strain for a given stress and allowing the process to progress. Bony bridging between the distal and proximal callus can only occur when local strain (i.e. deformation) is less than the forming woven bone can tolerate.
• Thus hard callus will not bridge a fracture gap when the movement between the fracture ends is too great. Nature deals with this problem by expanding the volume of soft callus. This results in a decrease in the local tissue strain to a level that allows bony bridging.
• However, if the fracture gap is considerably narrowed (usually operatively) but there is continued inter-fragmentary movement, there is a resultant high-strain environment with a risk of non-union. This is also seen if the fracture is overloaded with inter-fragmentary movement (for instance with early weight bearing) later in the healing process after the fracture gap has been narrowed by callous.

• Primary healing– occurs when strain is less than 2%, usually after operative fixation provides absolute stability. Also known as Haversian remodeling, healing occurs via osteoclast and ostoblast cutting cones forming secondary osteons across the fracture. No callus formation occurs.
• Secondary healing– occurs with strain between 2 and 10%, resulting in either endochondral or intramembranous healing in isolation or in combination. This healing mechanism involves the replacement of a cartilage template with new bone and includes responses from the surrounding periosteum and soft tissues, resulting in callus formation.
• Fibrous non-union– occurs when strain is over 10%, leading to cartilage formation that will not progress to ossification due to mechanical instability.
• Whether a fracture heals is dependent on both local and systemic factors.

Local factors that adversely affect healing include:

• Instability or motion at fracture site
• Infection
• Bone loss
• Location of fracture in bone
• Vascular injury or disease
• Overlying periosteum and soft tissue stripping, damage or loss
• Presence of tumour (primary or metastasis)

Systemic factors that adversely affect healing include:

• Malnutrition
• Sepsis
• Diabetes
• Smoking
• Systemic steroid medication
• Anti-inflammatory medication
• (Head injury may speed healing)

Enhancement of fracture healing

Biological methods

• A biological approach to enhancing fracture healing aims to provide the key components that are pivotal to bone repair. Important functions of any material utilised at a fracture site to aid healing include structural osteoconductive, osteoinductive and osteogenic properties. Such materials include bone auto and allograft and synthetic biomaterials which must also be biocompatible and absorbable.
• Osteoconduction properties provide a supportive structure to allow ingrowth of newly formed bone into the implanted material. Synthetic osteoconductive materials that have been investigated most are generally calcium-based ceramics including hydroxyapatite, tricalcium phosphate and bioactive glasses. Although these materials have excellent in vitro osteoconductive properties, their use in large bone defects is rarely successful as bone ingrowth is usually limited to superficial layers. Thus the need for biologically active substances is also required in these circumstances.
• Osteoinduction occurs naturally at the time of fracture with the cascade of events that eventually leads to fracture healing. This can be simulated, especially when implanting synthetic grafts by the addition of various growth factors, with BMPs the most common. Currently the use of BMPs has mainly been studied in the treatment of non-unions and augmentation of fusion sites in elective surgery. Further research is focusing on delivery systems to allow prolonged elution of growth factors at levels similar to those seen in vivo.
• The use of osteogenic materials combines an osteoconductive scaffold with osteogenic cells. These cells are derived from bone marrow stromal fibroblasts which are harvested from the bone marrow stroma and are then isolated and amplified in vitro using techniques that retain the cells’ ability to form new tissues. These cells can then be loaded onto a scaffold to allow implantation into a bone defect. Current work focuses on producing scaffolds that allow adhesion, proliferation and differentiation of these cells while also allowing rapid vascular invasion.¹
• Bone auto and allograft is covered fully in a later section.

Physical methods

• Low intensity pulsed ultrasound – studies suggest this works by stimulating the expression of numerous genes involved in fracture healing, leading to increased soft callus formation and endochondral ossification (via increasing the incorporation of calcium within cartilage and woven bone).¹
• Meta-analysis of randomised clinical studies (examining distal radius, tibial shaft and scaphoid fractures) has shown that this modality can significantly reduce healing time.
• Electromagnetic and electrical stimulation – is thought to mimic the effect of mechanical stress on bone. When a mechanical load is applied to bone, pressure gradients in the interstitial fluid drive fluid through canaliculi, creating electrical potentials. However, the cellular mechanisms of this modality are not fully understood. Application of an external electrical field to fracture healing has limited clinical evidence at present and remains an experimental theory.

Bisphopsphonates and fracture healing

• Bisphosphonates inhibit bone resorption by inhibiting osteoclast function and because fracture healing requires callus remodeling via the synergistic function of osteoblasts and osteoclasts there has been concern that this may affect fracture union.
• A number of clinical studies have suggested delayed healing or non-union in patients taking bisphosphonates. However, a more recent comprehensive meta-analysis of studies examining this suggests that there is no detectible delay to fracture healing via external callus,²and that early administration of bisphosphonates after surgery for fractures did not appear to delay radiological or clinical fracture union.³