| | (ii) An update on fracture healing and non-unionAbstract The basic science underlying the process of bone healing has been a topic of intense research activity over the past 50 years. Increasing understanding of events on a molecular level has allowed a greater understanding of factors that might contribute to failure of these mechanisms. From this it has been possible to introduce new treatment methods as adjuncts to traditional methods, both for fresh fractures and for established non-unions. Knowledge of these topics is essential to the day to day practice of the majority of orthopaedic consultants and as such is a favourite topic of examiners in both basic surgical and specialist orthopaedic examinations. The first half of this article summarizes current understanding of the biology of bone healing, highlighting recent advances. The second part is an overview of the aetiology and management of non-union. Introduction  Skeletal fracture occurs when bone absorbs sufficient energy under mechanical loading to fail, resulting in cortical discontinuity. A highly complex sequence of events is then set in motion, resulting finally in restoration of continuity and strength. This process is unique in the body, in that the tissue ultimately heals without scarring; at the end of the healing process the resulting bone both microscopically and macroscopically completely resembles that present prior to injury. This is likely to relate to the fact that in many ways the mechanisms of bone repair are similar to those observed during embryonic bone formation and this is therefore truly a regenerative process.1 It is increasingly understood that bone healing is influenced by both the condition of the host tissues (biology) and the forces and motion (mechanics) at the fracture site. This is the case both immediately following injury and during recovery. It is therefore important that such factors are considered carefully throughout the treatment of injured patients. It is most useful to think of these factors in three broad categories: •Systemic biological environment – host systemic state/conditions influencing bone healing •Local biological environment – local soft tissue/cellular influence on fracture healing •Mechanical environment – the forces and deformation to which the healing tissues are subjected It is possible to influence all of these factors to a greater or lesser degree; during operative fracture management, for example, the chosen stabilization technique will have a profound effect upon both the fracture mechanics and local biology, dependent on whether the zone of injury is violated surgically. In patients with systemic medical conditions it may be possible to influence the impact of these by optimizing pharmacological interventions or withholding medications for a period where this is deemed safe. Despite these efforts, failure or delay in fracture healing still occurs relatively frequently. In the treatment of such cases a full understanding of the mechanisms involved is even more important. The subject matter is vast and far from fully understood; the present article is therefore intended as a knowledge update regarding normal fracture healing and the management of non-unions. It is neither an exhaustive nor a systematic review of current literature. Bone healing The process of bone healing is extremely complex and as such has traditionally been broken down into an arbitrary series of events. In reality it appears that these occur at different rates at different locations and as such may, at times, occur simultaneously. Therefore, whilst it is increasingly understood that fracture healing does not necessarily occur in a strict chronological order, the observed histological phases still help us to understand the events occurring at a cellular level, as we will describe initially. We will subsequently, briefly, consider the role of cytokines and cellular messengers in this process, itself a vast and complex topic, a full description of which is outside the remit of this manuscript. A basic understanding of these factors is, however, increasingly important given that therapeutic applications of these molecules are becoming increasingly common. Finally, we will examine the effect that the mechanical environment exerts upon the process of fracture healing which helps to tie the different healing mechanisms together. Histological descriptors of bone healing Phases of bone healing In 1930, Ham, of the University of Toronto, published a description of bone histology during the early phases of healing after studying fractured rabbit fibulae and ribs.2 An initial phase of bone necrosis occurring at the fracture site was observed, followed by a period of vigorous cellular proliferation within the ‘osteogenic layer’ of the periosteum. This external mass of cells was subsequently seen to undergo further proliferation, with the cells beneath this “growing zone” differentiating into cells that were observed to actively lay down matrix and produce cartilage. The phases of bone healing were subsequently, and more fully, described by McKibben in 1979 as an immediate reaction (phase of inflammation), followed by the development of osteogenic repair tissue then remodelling.3 This description has been modified many times by various authors and different descriptions can be found in the contemporary literature, though all essentially describe the same process. In its simplest form one can consider that bone heals with the same three basic steps as any tissue; inflammation, cellular proliferation and differentiation and finally remodelling. This is complicated however by the highly specialized, calcified nature of bone and the fact that its regenerative capacity is far greater than that found in other tissues. An example of a modern description of the phases of bone healing is found in Figure 1. Haematoma formation: following a fracture, bleeding occurs from the periosteum, the endosteum, the surrounding soft tissue and, occasionally, major blood vessels adjacent to the fracture site. Microvascular disruption leads to regional hypoperfusion and an initial fall in oxygen tension and nutrient delivery. This deprives the osteocytes of nutrition, leading to local bone necrosis at the fracture site as far as the collateral circulation permits. Damaged periosteum and muscle also contribute to this necrotic tissue. The exposure of vascular endothelium and intravascular cells triggers the coagulation cascade leading to haematoma formation at the fracture site. This haematoma is rich in platelets and macrophages that are stimulated to release a series of cytokines, stimulating the next phase of healing. Important cytokines involved in this stage of fracture healing include platelet derived growth factor (PDGF), the transforming growth factor beta group of proteins (PDGF-β), interleukin-1, interleukin-6 (IL-1 & IL-6) and prostaglandin E2 (PG-E2). Even at this early stage this haematoma has been shown to have independent osteogenic capacity. Experimental transplantation of rat fracture haematoma into muscle has been shown to stimulate new bone formation by endochondral ossification,4 and further studies have demonstrated the presence of cells capable of differentiation into various forms of connective tissue.5 These cells are thought to originate predominantly from the periosteum and the bone marrow but have also been isolated from surrounding soft tissues and the systemic circulation. Young first described these “osteoprogenitor cells” in 1962.6 Now known as mesenchymal stem cells they are multi-potent and capable of differentiation into osteogenic, chondrogenic, fibrogenic and lipogenic cells, dependent upon the biological and mechanical stimulus they receive. These cell types are increasingly recognized to play a pivotal role in bone healing.7 The inflammatory response: shortly after injury a local inflammatory reaction is initiated in response to the release of inflammatory mediators from the fracture haematoma. In many respects, the inflammatory response at a fracture site is identical to that which occurs in response to injury in other tissues. There is increased blood flow, increased vascular permeability and inflammatory cell migration (predominantly macrophages), resulting in further cytokine release and activation of the compliment cascade. Osteoclasts are activated and begin resorption of bone debris at the fracture site. Finally, fibroblasts migrate into the fracture site and these begin transforming the haematoma into granulation tissue, laying down a fibrin meshwork. A network of new capillaries invades the granulation tissue, stimulated by various cytokines, including a number of the fibroblast growth factors. Newly established blood flow provides a further source of mesenchymal stem cells and signalling molecules. Proliferation and differentiation: what occurs subsequently at the fracture site is largely dictated by the mechanical environment. In almost every situation there will be a degree of motion, leading to the natural process of fracture healing, termed secondary bone healing. The pattern of healing as described here is therefore observed in the vast majority of situations and all fractures that are treated non-operatively. In certain very specific situations this motion is absent and the mechanical stimulus to normal healing does not occur. This can only occur in fractures treated by internal fixation in such a way that absolute stability of the fracture site is generated. This is discussed more fully in the following section on the effect of mechanics on bone healing; here we shall concern ourselves with secondary bone healing. This phase of bone healing is characterized by the differentiation of primitive mesenchymal stem cells, which have migrated into the fracture site, into cells with osteogenic potential. Thereby tissue is formed in the fracture site known as callus which, as it calcifies, becomes increasingly stiff. Calcified callus eventually bridges the fracture, immobilizing it in every plane and restoring limb function. This phase of fracture healing has classically been sub-divided into the formation of soft callus, which is subsequently calcified to form hard callus. It is increasingly recognized, however, that both soft and hard callus are formed simultaneously by intramembranous and enchondral ossification. Intramembranous ossification occurs predominantly at the periphery of the callus mass with soft callus forming centrally. The soft callus is converted to bone through the process of endochondral ossification and the process continues until new bone bridges the fracture site. It is the gradual increase in callus volume, along with progressive tissue calcification during enchondral ossification, that with time increases fracture stiffness and stability.8 Endochondral ossification (soft callus): in areas of endochondral ossification, mesenchymal stem cells initially differentiate along a chondrogenic cell lineage pathway. Histological evidence of cartilage formation has been observed by the second week after injury in animal models of non-stabilized fractures, the expression of col2a indicating that type II collagen is being synthesized.9 By the third week, though col2a expression continues at a much lower level, calcified tissue is visible in the fracture site and there is increasing expression of osteocalcin. Chondrocytes within the tissue undergo an atypical apoptosis and the chondroid matrix is gradually replaced with a new extracellular matrix consisting of type I cartilage (osteoid).10 Calcium hydroxyapatite crystals are deposited within this matrix and bone slowly replaces the ‘soft’ cartilage callus. Thus a chondroid cartilaginous matrix is initially generated, which gradually replaces fracture haematoma; this is subsequently replaced by osteoid-type matrix, which is progressively calcified. As mineralization proceeds, the bone ends gradually become enveloped in callus and the fracture unites. Intramembranous ossification (hard callus): in areas of intramembranous ossification the expression of cartilaginous proteins is not observed,9 osteocalcin expression is seen earlier and periosteal osteoblasts synthesize type I collagen, leading to the direct generation of calcified tissue. Peripheral ‘hard callus’ is formed, which in secondary bone healing cannot bridge the fracture site in the early phases due to ongoing fracture motion that is incompatible with its material properties. This is a similar process to that which occurs during the calcification of tissue in enchondral ossification. Mineralization of fracture callus is initiated by the cells synthesizing a matrix with a high concentration of type I collagen fibrils. Remodelling: at the end of the 18th century it was observed that the trabecular pattern within bone closely represents the calculated lines of principle stress within it. This formed the basis of Wolff's law, which states that changes in bone structure will occur in response to the mechanical demands placed upon it – “form follows function”. This remarkable feature of bone can only occur because it is constantly being broken down and replaced – this is termed remodelling. Remodelling occurs throughout the skeleton and is a normal physiological function. Bone responds to the mechanical stresses to which it is subjected, increasing bone density in areas of increased mechanical stress. This occurs via the closely coupled action of osteoblasts and osteoclasts in bone remodelling units. These are observed to move through bony tissue, leading to organized breakdown and synthesis. Detection of micro-strain within the bone at a cellular level appears to stimulate this response. Strain above a certain threshold results in net local bone deposition, whereas lower strain results in net resorption. Several different control mechanisms have been proposed to dictate this response. Osteocytes are thought to be able to sense mechanical stress within the bone via electrochemical signals generated by fluid shift within their interconnecting systems of canaliculae. It has also been postulated that certain cell types directly sense their mechanical environment via cell membrane mechanoreceptors and direct connections between the cell nucleus and the local cytoskeleton. This topic is extremely complex and the subject of intense ongoing research – a more complete explanation can be found elsewhere.11 These same mechanisms that are responsible for bone remodelling also come into effect following a fracture. Once union has occurred the collagen fibres within the newly formed bone are observed to have a random orientation, in contrast to those observed in normal lamellar bone; this is known as woven bone. The haphazardly arranged collagen fibres become mineralized, the orientation of the calcified component of the newly formed bone is therefore also disorganized. This profoundly affects the mechanical properties of the bone, with reduced strength and stiffness. The bone is also much more isotropic than normal lamellar bone and therefore less able to withstand forces to which it may be subjected. The fracture repair process therefore continues, with remodelling slowly replacing woven bone with lamellar bone over a period of months, restoring its highly ordered micro-architecture and with this, the normal mechanical characteristics. The resultant tissue is indistinguishable from bone found elsewhere. Cellular signalling molecules As early as 1920 Bier suggested the presence of a “wound hormone” that might be responsible for initiating the cellular changes that lead to tissue healing. The signalling pathways that govern skeletal repair remain a topic of intense research and are extremely complex in nature: it is increasingly recognized that there is considerable overlap with the mechanisms that control embryologic skeletogenesis.12 Cellular signalling molecules that are involved in bone healing can be divided into four broad categories; those influencing the initial inflammatory response, those influencing cellular growth and differentiation, those promoting angiogenesis and the inhibitory molecules, these are summarized in Table 1.13, 14 Inflammatory mediators are critical in the initial stages of fracture healing. They are particularly important in promoting chemotaxis of further inflammatory cells into the zone of injury and initiating the formation of matrix and new blood vessels. Growth and differentiation factors are critical in the subsequent steps of bone healing and their function is extremely complex. There has been particular interest in the bone morphogenetic proteins (BMP), a group of molecules with critical functions in the development of many body tissues, including the skeleton, and a key role in fracture healing and remodelling.15 These are members of the transforming growth factor β (TGF-β) family and more than 40 different types have been identified, including BMPs 2–14 and the growth and differentiation factors (GDF). They appear to be particularly important in directing mesenchymal stem cells along specific cell lineages and many are capable of inducing osteogenic activity in relevant, fully differentiated cells. Their expression has been demonstrated in fracture callus at early stages of healing, continuing at lower levels until mature lamellar bone is present, at which point levels return to baseline.16 To maintain the high levels of cellular activity within a fracture site it is critical that the blood supply to the region is restored in the initial phases and then enhanced. Whilst the presence of various angiogenic factors has been demonstrated at different stages of bone healing, it is perhaps their function in skeletal repair that is least understood.17 Though their importance in fracture healing is becoming apparent, further work is required to specifically delineate this. Similarly, the role of inhibitory molecules in fracture healing is being increasingly recognized. These act as a form of auto-regulation to prevent excessive activation of other components, acting at every stage. It is possible that abnormal forms, or over-expression of such molecules, in certain patients may result in delayed or non-union. Influencing this inhibitory function may therefore hold promise for future therapeutic interventions.18 The role of the mechanical environment Although the role of the mechanical environment in fracture healing has already been alluded to, it is a topic deserving of specific attention. A clear understanding is critical to those managing bony injuries, as it is over this that the orthopaedic surgeon will ultimately have most control. It is generally recognized that excessive motion at a fracture site not only produces pain but delays or prevents fracture union, with archaeological evidence of splints and plaster casts being used to reduce fracture motion for thousands of years. It is increasingly understood that cells are able to sense their mechanical environment, as discussed above, and that this can profoundly affect their growth and differentiation. Tissue within a fracture site will almost always be subject to some micro-strain generated by relative inter-fragmentary motion. This situation is known as relative stability. These conditions stimulate natural ‘secondary bone healing’, with an initial zone of inflammation, the formation of fracture callus, then woven bone, which is subsequently remodelled to normal lamellar bone. The only situation where this does not occur is in fractures that have been reduced anatomically and fixed in compression, either using a lag screw or dynamic compression plating techniques. This very specific situation, in which no inter-fragmentary motion occurs and the cells within the fracture site are effectively subject to zero strain, is termed absolute stability.19 Only under these circumstances does the lack of mechanical stimulus inhibit the formation of callus, the fracture healing slowly by direct bone healing, a process more akin to remodelling.19 This is termed ‘primary bone healing’. Understanding of the effect of mechanical stability and inter-fragmentary motion on fracture healing is currently evolving; it is far from fully understood and some of the available evidence is contradictory.20 Various studies using cells in culture have demonstrated that cellular development is greatly influenced by local mechanics, with growth more favourable when tissues are subjected to their physiological mechanical environment. Fibroblasts appear to respond to tension, chondroblasts to shear and osteoblasts to combinations of compression and distraction.20 It seems logical that cells are primed to grow in response to the mechanical environment in which they develop, with fibroblasts being found in connective tissues such as ligaments and tendons, chondrocytes in cartilage and osteoblasts in bone. Similarly, it has been shown that multi-potent mesenchymal cell stem cells will differentiate along a fibroblastic, chondrocytic or osteoblastic lineage based upon the load magnitude and type applied in a similar fashion, so long as appropriate growth factors and local chemical stimulation is present.20 Thus it appears that mesenchymal tissues are capable of developing in accordance with their local mechanical environment into tissues best suited to resist the forces to which they are subjected. Though experimental attempts to determine the ideal mechanical environment to promote fracture healing have been made, this evidence remains elusive. Several studies using animal models have demonstrated that cyclical axial displacement might enhance fracture healing, particularly in the early phase; however the ideal rate and load are unclear and some studies refute this.21, 22 Similarly, shear forces have been shown to impede callus formation and union, though again some studies contradict this.23, 24 Various studies suggest that whilst axial micromotion might stimulate fracture healing early in the clinical course, at around 8 weeks the opposite becomes true. It is noted that increasing callus stiffness is likely to decrease motion in most cases where healing is occurring at this stage.20 It has also been demonstrated that very low strain rates promote intramembranous ossification, with enchondral ossification occurring when the strain rate is increased. When these strain rates are increased further differentiation along soft tissue lineage leads to delayed or non-union.25 In summary, whilst it is understood that the mechanical environment can profoundly influence the way a fracture heals, the ideal healing environment is unclear and appears to vary in different clinical situations. Uni-axial micromotion appears to stimulate bone healing to a point, with off-axis motion inhibiting this. The potential effect of bending or torsional loading is even less clear. Torsion is likely to create rotational shear. Bending will lead to large differential compressive and tensile loads across the cross section of the fracture. Both these situations are likely to be unfavourable. Perren's strain theory of fracture healing Perren first described a “unified theory” for the relationship between bone healing and fracture site mechanics more than 30 years ago. This “strain theory of fracture healing” provides perhaps the most elegant and easily understood description of the link between fracture mechanics and bone healing. The principles of this theory hold true today and in many ways modern evidence supports them, though some aspects have more recently been called into question.20 The theory effectively explains the evolution of the apparently complex mechanism of fracture healing – why, when its tissues are clearly capable of doing so, does a bone not simply heal by direct formation of hard calcified tissue, which would seem a more efficient way of achieving stability and thus rapid return to function? In answering this, one must consider the fact that stiff tissues such as bone are also relatively brittle. As the entire fracture site is not able to transform into bone simultaneously, for fractures to heal by direct bone formation a transitional phase would have to occur in which small areas of bridging callus are present. These would not have the tensile strength to withstand the forces to which they are subjected and would therefore fail. Similarly, different cell types are able to withstand different amounts of mechanical strain without destruction and it follows that “a tissue cannot be produced under strain conditions which exceed the elongation at rupture of the given tissue element”.26 During fracture healing, the initial situation is complete instability – the tissues within the fracture site are subject to large strains. A stepwise progression in tissue differentiation then occurs, with granulation tissue being replaced by fibrous tissue then cartilage-like tissue and finally calcified bone. Each of these tissues is increasingly stiff, resulting in reducing strain across the fracture site. The changing mechanical environment results in conditions which favour differentiation of the tissue along cell lines compatible with the next stage of healing. Thus, tissue is formed which is able to withstand the forces to which it is subjected. Ultimately, ossification can only occur once displacement at the fracture gap is reduced to a critical level by the formation of progressively stiffer tissue within it. It has been demonstrated that these conditions vary within different areas of the fracture callus; there is relatively increased motion in the inter-fragmentary gap compared to the external callus. The external callus ossifies quicker and when this eventually bridges the fracture, reducing motion at the fracture site to a critical level, ossification of inter-fragmentary tissue occurs.27 The susceptibility of a region to ossification is therefore at least partially determined by whether or not the appearance of increasingly stiffer differentiated tissues succeeds in forming a sufficiently low strain environment.28 Non-union and delayed union Non-union of a fracture represents a challenging clinical scenario for the orthopaedic trauma surgeon. Diagnosis in itself can be difficult and treatment consumes considerable time and resources. Fracture non-union prolongs morbidity, delays return to function and affects the psychological response to injury.29 The incidence of non-union is highly dependent on both injury and host factors and is extremely site dependent, but overall rates of between 5% and 10% have been reported.30 More recently, advances in the understanding of fracture healing have enabled surgeons to improve the initial management of fractures to reduce the risk of non-union and greatly improve the management of established non-unions. The management of non-union is demanding and requires specialist skills, knowledge and resources. It has been highlighted repeatedly that patients have often undergone multiple procedures prior to referral to a specialist unit in a cycle of futile treatment and failure, further complicating their management. It is increasingly recommended that, particularly in complex cases, early referral to specialist trauma and limb reconstruction services is undertaken. This has the potential to not only simplify the management of the patient but reduce the overall cost of treatment and reduce morbidity and disability suffered by the patient.31 Definitions The definitions of delayed and non-union are inconsistent, subjective and no true consensus exists.32 Various temporal systems have been used, defining a bone as un-united after a certain amount of time has passed, but even these are conflicting. The United States Food and Drug Administration (FDA) defines non-union as a fracture that is at least 9 months old and has not shown any signs of progression to healing for three consecutive months.33 Others have defined a non-union as a fracture that has failed to unite in 6–8 months or twice the time in which one would usually expect such a fracture to heal. To specify a time period that applies to every fracture is not particularly helpful. The time taken for a fracture to unite is dictated not only by the bone involved but also by injury-specific factors. In some situations 9 months wait prior to union is a very reasonable expectation, particularly in high energy diaphyseal injuries, whilst in other injuries one would consider that a fracture is unlikely to spontaneously unite if it has not healed long before this. Furthermore it is not helpful to wait for an arbitrary length of time before considering any fracture to be a non-union and commence treatment. It would therefore seem more sensible to define non-union clinically as “a symptomatic fracture with no apparent potential to heal without intervention”. A delayed union can similarly be defined as “a fracture in which healing has not occurred in the expected time and the outcome remains uncertain” and a pseudarthrosis as “a painless fracture that has failed to unite and has no potential to do so without intervention”. Classification Weber and Czech classified non-unions into two broad categories, based upon the biological vitality of the non-union site, in a paper published in 1976. This system is still widely employed: •Hypertrophic – implies the fracture site is hyper-vascular and retains biological potential. In simplistic terms the problem is likely to be mechanical. This can be further sub-divided based upon X-ray appearance into elephant's foot, horse's hoof or oligotrophic, as regards the degree of bony expansion observed adjacent to the non-union site. An example of a hypertrophic non-union is shown in Figure 2. •Atrophic – implies that the fracture site is hypo-vascular, inert and seemingly incapable of biological activity. In these situations more than optimization of the mechanical environment will be required to attain union. These can be further sub-divided into torsion wedge, comminuted, defect and atrophic, dependent on the fracture pattern and the distribution of avascular tissue. An example is shown in Figure 3. A further sub-group of infected non-unions is generally added to these, an example is shown in Figure 4. Many other classifications of non-union exist, including that of Ilizarov who classified non-unions as stiff or lax based upon their mobility. Aetiology A thorough understanding of the normal process of fracture healing allows the potential to better understand the underlying causes of non-union. Giannoudis et al have described the “diamond concept” of requirements for successful fracture union, in an attempt to simplify this process and aid decision making.34 The traditionally accepted requirement of osteogenic cells, growth factors, and a stable osteoconductive scaffold is modified by adding a fourth component; mechanical stability. If any of these factors are sub-optimal a non-union may occur and frequently multiple factors will be present. In order to understand what has lead to failure of healing at each point of the diamond, it is useful to consider these in both local and systemic terms. A summary of such factors is tabulated in Table 2.35 More recently, Calori et al have proposed a “Non-union Severity Score” in an attempt to quantify the contribution of different factors and guide treatment. Though this remains un-validated it may provide a useful structure for clinical assessment in the future and the basis of further investiagtion.36 Lack of osteogenic cells Osteogenic cells, vital for fracture healing, are recruited locally or delivered to the fracture site via the systemic circulation. Adequate fracture site vascularity along with a local biological environment optimum for cellular survival is therefore imperative. High energy fractures are associated with periosteal stripping and damage to surrounding soft tissue, with resultant disruption of local blood flow. This tenuous blood supply may be further disrupted by operative intervention. Intra-medullary nailing has been shown to disrupt intra-medullary blood supply and plate fixation may further injure periosteal and local capillary blood flow. Open fractures are associated with an increased risk of non-union.37 The reasons behind this are multiple but high energy injuries with disruption of the local soft tissue envelope in the zone of injury will undoubtedly impair the blood supply and biological environment. The additional insult to local vascularity caused by open surgical fixation is increasingly well recognized. Techniques and implants have developed that allow the surgeon to respect the “fracture biology”. The presence of infection will also have a directly and indirectly detrimental effect on osteogenic cells, leading both to cellular injury and reducing the ability of local tissues to support the cellular component of the healing tissue. Cellular biology at a fracture site will also be influenced by the systemic biology of the patient. Any systemic illness may affect fracture healing, as will the administration of many drugs. Examples include diabetes, inflammatory arthritis, smoking and steroids; these are also summarized in Table 2. Lack of signalling molecules Fracture haematoma is normally rich in various growth factors, as previously described. These are secreted by endothelial cells, platelets, macrophages, monocytes, chondrocytes, mesenchymal stem cells and osteoblasts. Loss of fracture haematoma in open fractures or at the time of internal fixation will lead to a disturbance of the ideal environment for callus formation and thereby predispose to non-union. This will also be detrimentally affected by loss of fracture site vascularity, as loss of perfusion will not only lead to death of inflammatory and synthetic cells within the zone of hypoperfusion but also to reduced delivery of further cells to that zone. Lack of stability As has been previously discussed, the mechanical environment at the fracture site will profoundly alter the behaviour of tissue within it.19 Non-union can occur due to excessive or inadequate motion in particular situations. Excessive motion is classically associated with hypertrophic non-union and may occur following conservative management of fractures with inadequate splinting, or after operative treatment where inappropriate fixation methods have been employed. Conversely, excessive stability in situations where fractures have not been adequately reduced may also result in non-union due to the loss of normal mechanical stimulus to secondary bone healing along with a fracture gap too large for primary bone healing to occur. Referral to Perren's strain theory aids understanding of this concept. In fractures with excessive motion, mechanical conditions do not progress beyond those favouring the early soft tissue elements of bone healing. Inadequate motion means that the conditions for the formation of these tissue types critical to the early stages of fracture healing never occur and secondary bone healing is not initiated. Further information on this topic can be found in a review article by Jagodzinski and Krettek.20 Lack of osteoconductive scaffold With good bony apposition, necrotic bone at the fracture site will act as an osteoconductive scaffold for the osteogenic cells. The micro-architecture in the fracture environment appears to be critical in cellular migration and adhesion. Should an excessive area without such a scaffold exist, cells are unable to stimulate sufficient new bone formation to bridge this gap without intervention.35 Such a situation is known as a critical defect, the size of which varies dependent on the bone in question. This can occur due to traumatic or surgical bone loss, comminution, inadequate reduction and resorption of bone at the fracture site due to infection or inadequate vascularity. Very high rates of aseptic non-union have been reported in open tibial fractures associated with significant bone loss.37 Diagnosis Diagnosis of delayed or non-union is the first step in management and is itself often difficult to achieve. Particularly in patients with complex injuries, there may be multiple reasons for ongoing pain or loss of function in an injured limb. For the reasons already discussed, it is not possible to depend entirely on the chronology of fracture union because different fractures heal at different rates, depending on the location in the body, and in different parts of the same bone. Factors governing the time that is expected to elapse prior to union are multi-factorial and should be considered in a similar systematic manner to those contributing to bone union. It is therefore important to adopt a systematic approach to the assessment of such patients. History The importance of an adequate history cannot be overemphasized. Pain at the fracture site is a common complaint in delayed and non-union. In fact this is probably the most important point to elicit from the history, as it is usually the symptom that dictates whether treatment will be necessary. Functional requirements and current impairment of activities are also important in this process. Further questioning relates to a search for potential causes for the non-union and it is often helpful to think in terms of the diamond concept. The mechanism and velocity of the initial injury, initial treatment, co-morbidities, current medications and social history are therefore essential information. Any factors which raise the possibility of occult infection are also important, including open fracture, delayed initial wound healing, prolonged wound discharge, second operations, administration of antibiotics, late inflammation and subsequent discharge from the limb. Initial treatment may have been carried out in a different institution or indeed in a different country, therefore all efforts should be made to obtain all possible original documentation. Often this is not possible and therefore thorough history taking is imperative. Examination This should follow the standard principles of any orthopaedic examination and include the limb segment in question as well as adjacent joints. Particular attention should be paid to mobility of the fracture, warmth, scars, sinuses, range of movement of neighbouring joints, shortening or lengthening of the segment and functional impairment. Investigations The gold standard for confirmation of non-union is open exploration, but this is usually not feasible as a purely diagnostic exercise and should represent the first stage in reconstruction. Investigations are therefore essential both in an attempt to confirm or refute the clinical diagnosis and to look for potential remediable causes of the problem. Zimmermann et al have reviewed the literature regarding the value of laboratory and imaging studies in the evaluation of long-bone non-unions.38 Blood tests: routine blood tests such as a full blood count, urea, creatinine, electrolytes, liver function tests, bone profile and blood sugar are useful as a baseline assessment and to exclude undiagnosed systemic diseases that may be contributory. Tests assessing systemic inflammatory activation including the white cell count, C-reactive protein and plasma viscosity should be performed but it is important to note that normal tests do not absolutely exclude infection and these markers are very non-specific. The possibility of a specific biological marker of delayed and non-union has provoked much research but no candidate has yet proved useful in routine clinical practice. Bone-specific alkaline phosphatase (ALP) has been shown to be elevated for prolonged periods in animal models of delayed union and is one potential prognostic indicator in long-bone fracture healing.39 Similarly, clinical studies have been performed examining the prognostic value of osteocalcin (OC),40 transforming growth factor (TGF) β1,41 and matrix metalloproteases.42 At present results are inconsistent and difficult to interpret. Further studies are required to prove their diagnostic value in the assessment of fracture healing.38 Imaging studies: plain radiographs are readily available and often helpful. It is particularly useful to review all radiology from the original injury and subsequent treatment. The fracture site should be assessed for signs of progressive union as well as bone quality and malalignment. Increasing displacement and angulation at the fracture site imply inadequate fixation and union. The status of any orthopaedic implants should be carefully examined, looking in particular for adequacy of fixation as well as signs of actual or impending implant failure or loosening (Figure 5). Though the presence of bony trabeculae crossing the fracture site on multiple views is defined as radiological union, this is often difficult to assess, particularly where obscured by implants. Whilst having some limitations, plain radiology provides useful information and is likely to remain the mainstay of imaging in these cases due to availability, practicality and cost.38 Other imaging modalities may be useful to define the non-union and identify sources of potential problems, such as avascular bone segments or occult infection. This is a difficult area and early advice from a specialist musculoskeletal radiologist can be very helpful prior to arranging such investigations. Particularly in the presence of metallic implants, some investigations which would otherwise be helpful might prove futile and timely advice can prevent a prolonged wait for the patient. Computed tomography (CT) can define non-union more readily than plain radiology, as it allows construction of multi-planar and three dimensional imaging (Figure 6). Its utility can be increased by the use of newer technologies such as CAD (Computer Aided Diagnosis), 3D micro CT, TACT (Tuned Aperture CT) and MDCT (Multi Detector CT). These techniques have led to higher diagnostic accuracy in animal models of delayed and non-union. Magnetic Resonance Imaging (MRI) can also prove extremely helpful, both in defining non-union and assessing the vascularity of local tissue and the presence and extent of infection. Certain metallic implants however can severely degrade image quality making the techniques useless in many situations. In animal experiments Dual Energy X-ray Absorptiometry (DEXA) shows a higher sensitivity and negative predictive value than plain radiology and enables significantly earlier diagnosis of delayed union. DEXA is already used in the diagnosis of bone mineral density and bone mineral content change in humans. It should be the subject of further clinical studies, to assess its value in cases of delayed fracture healing. In cases of problematic vascularization of the fracture zone, power Doppler ultrasonography may be used in clinical trials to evaluate the viability of tissue and thereby the necessity for debridement and soft tissue reconstruction. Treatment The aim of treatment should be to restore pain-free function to the body part. As has already been discussed, this is a highly complex area and we will discuss only the principles of management here.35 It is again useful to refer back to basic principles and the diamond concept can be a useful aid.34 The patient's general status should be addressed and measures such as improving nutritional status, cessation of smoking and avoidance of non-steroidal anti-inflammatory medication may be beneficial.43 In general, local treatment can be thought of as applying a set of basic conditions to a non-union site: •Restore alignment – “straighten” the limb segment to restore normal mechanics and function. •Obtain appropriate stability – “stabilize” the fracture site to optimize the mechanical environment. The stability obtained must be appropriate to the specific situation, as already discussed. •Enhance fracture site biology – “stimulate” the fracture site – this can be achieved by directly accessing the non-union site to remove non-vital or inert tissue and the application of various biological adjuncts, discussed in the following section. Mechanical stimulation can also be applied using compression plating techniques or dynamically using the Ilizarov method. It may be necessary to replace damaged or deficient soft tissue by the use of local or free soft tissue transfer to restore or enhance the vascularity of the region, particularly in infected cases. •Eradicate infection – “sterilize” the fracture site to remove the deleterious effects of micro-organisms on the biological environment. Tissue samples should be sent for microbiological culture in all non-union cases and the involvement of microbiologists is helpful in determining antimicrobial therapy. It is essential that any non-viable material is removed and this may include any pre-existing implants. These factors should usually be considered and addressed simultaneously; restoring one with neglect or detriment to another will usually result in treatment failure. Treatment should therefore be highly individualized and specific to the patient and the non-union requirements. For example, whilst in some infected cases the removal of implants may be essential, in the absence of mechanical stability the eradication of infection and achievement of bony union will likely be impossible-often the use of external fixation is appropriate. This may be revised to an alternate fixation technique once the infection has been dealt with or represent definitive management. The Ilizarov technique of distraction osteogenesis has revolutionized the treatment of complex infected non-union.44 Radical debridement of infected bone followed by regeneration of lost bone length achieves the aim of maintaining limb length and eradication of infection with the frame providing mechanical stability and a means of applying mechanical stimulation.45, 46 Treatment adjuncts in the management of skeletal non-union Various techniques are available to aid in the treatment of non-union, the majority aimed at biological stimulation. An overview is presented here but further information can be found in several review articles.47, 48, 49 These products can be classified in terms of their biological effect as: •Osteogenic – capable of independent bone formation due to the presence of an osteogenic cellular component. •Osteoinductive – capable of inducing bone formation when introduced into an appropriate environment due to the presence of biological signalling molecules. •Osteoconductive – capable of supporting the biological processes of bone healing by providing a scaffold for growth. The treatment of critical defects is a complex topic and options include distraction osteogenesis and the use of vascularized bone grafts. This is the subject of a separate review article in this journal. Bone graft Autograft remains the only clinically available source of tissue that is osteogenic and osteoinductive osteoconductive and contains viable precursor cells. Iliac crest bone graft (ICBG) remains the gold standard for the biological treatment of non-unions and is the technique to which other methods are compared.50 Other sources traditionally used include the distal radius and proximal tibia dependent on the amount of graft required and the clinical situation. The main disadvantage of these techniques is donor site morbidity. ICBG in particular is associated with a high incidence of post-operative pain, immobility and prolonged hospital stay. The morbidity of autograft harvest appears to be reduced with the recent introduction of the reamer irrigator aspirator (RIA) system. This uses a suction reaming technique to obtain large volumes of viable autograft from the femoral canal and can be employed using a percutaneous approach.51 The surgical technique has been well described by Giannoudis et al and early results are extremely promising with very low rates of complications or pain.52 Vascularized autograft including free microvascular fibular transfer finds application in specific circumstances and has been shown to be effective, but again is associated with high levels of donor site morbidity and late failure.53 Alternatives to autograft include allograft and xenograft but treatment to eradicate the infective risk and remove immune stimulatory cellular content renders these products less useful. The transfer of certain highly resistant infective agents remains a concern, including certain viruses and prions. Demineralized bone matrix is osteoconductive and may be osteoinductive due to the retention of cellular signalling molecules; it appears to be effective in treating fracture non-unions and reduces the donor site morbidity associated with the harvest of autograft.54 There is increasing interest in the use of cells from the patient's own body to enhance fracture healing. Bone marrow aspirates have been employed and work is currently focused upon isolating and concentrating relevant cells from this source though little evidence of their efficacy is yet available. Synthetic bone substitutes These are predominantly osteoconductive void fillers and include hydroxyapatite, tricalcium phosphate, calcium phosphate, calcium carbonate and calcium sulphate in varying combinations. They show increased potential for use when combined with osteoinductive agents and when mixed with autograft or bone marrow aspirate.55 Bone morphogenetic proteins (BMPs) and other growth factors BMPs, described previously, are finding increasing clinical use in non-union and spinal fusion. They have been found to be at least as effective as ICBG and remove the problem of donor site morbidity and are associated with very low rates of adverse events.56 They are purely osteoinductive and therefore usually need to be used in combination with other techniques. A review of UK BMP-7 usage has concluded that this bone stimulating agent is safe, well established and could be considered a powerful adjunct in the surgeons armamentarium.57, 58 Other potential biological stimulants for local application to non-union sites are currently under investigation. These include fibroblast growth factor-2 (FGF-2), growth and differentiation factor-5 (GDF-5), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β) and platelet derived growth factor (PDGF).59, 60 Molecules such as prostaglandin E receptor antagonists and thrombin related peptide, TP508, have shown promise in animal models. Systemically applicable options including parathyroid hormone, growth hormone and the HMG-CoA reductase inhibitors are currently being investigated but have not as yet realized clinical application.59 Adjuvant therapies External stimulants, including electromagnetic radiation and low intensity pulsed ultrasound, have been widely employed, based mainly on the results of multiple small case series. They are relatively inexpensive, easy to use and carry very low risk of complications. However, the methodology and quality of current evidence on their effectiveness has been called into question. Meta-analysis has concluded that evidence for the use of both techniques is contradictory and no true confirmation of their effectiveness exists.61, 62 Ultrasound in particular holds some promise, though this will need substantiation in well conducted randomized controlled trials. Given the low associated risk it would seem reasonable to use this modality in cases where patients do not feel that surgical intervention is yet indicated. However, delaying definitive proven intervention for many months whilst such treatments are employed in patients suffering serious impairment of function would not seem reasonable. Summary Fracture non-union is a difficult situation to manage for both the patient and the treating surgeon. A systematic method of evaluation and treatment is imperative for management to be successful. It has been said that the best treatment for non-union is to prevent its occurrence in the first instance. 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