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Institute for Biomechanics, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, GermanyInstitute for Biomechanics Paracelsus Medical University Salzburg, Salzburg, Austria
Institute for Biomechanics, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, GermanyInstitute for Biomechanics Paracelsus Medical University Salzburg, Salzburg, Austria
Institute for Biomechanics Paracelsus Medical University Salzburg, Salzburg, AustriaDepartment of Trauma Surgery, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany
Mechanical signals control the fracture repair process and are determined by configuration of the fracture fixation construct, size of the fracture gap and amount of load bearing.
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Mechanical stimulation of the repair process is obtained by flexible fracture fixation and load bearing or muscle activities.
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Additional external stimulation might be applicable in situations of rigid fracture fixation or limited loading capacity.
Abstract
The biomechanical environment plays a dominant role in the process of fracture repair. Mechanical signals control biological activities at the fracture site, regulate the formation and proliferation of different cell types, and are responsible for the formation of connective tissues and the consolidation of the fractured bone. The mechanobiology at the fracture site can be easily manipulated by the design and configuration of the fracture fixation construct and by the loading of the extremity (weight-bearing prescription). Depending on the choice of fracture fixation, the healing response can be directed towards direct healing or towards indirect healing through callus formation. This manuscript summarizes the evidence from experimental studies and clinical observations on the effect of mechanical manipulation on the healing response. Parameters like fracture gap size, interfragmentary movement, interfragmentary strain, and axial and shear deformation will be explored with respect to their respective effects on fracture repair. Also, the role of externally applied movement on the potential enhancement on the fracture repair process will be explored. Factors like fracture gap size, type and amplitude of the mechanical deformation as well as the loading history and its timing will be discussed.
]. In particular, the regeneration process has an amazing potential to create new bone tissue and rebuild the original state after a fracture or a bone defect [
]. Formation of new bone after a fracture is a complex interaction of cellular and molecular processes by which connective tissue, cartilage and bone are formed [
] and recovers its functional competences (Fig. 1). The most fundamental aims of the healing process are recovery of load bearing capacity and restoration of bone strength. As both aims represent mechanical features, it is not surprising that the processes of tissue differentiation and formation are primarily regulated by mechanobiological feedback signals [
]. The mechanical stimulus is experienced by the cells in the healing zone leading to congregation of mesenchymal cells in the early healing phase, formation of callus tissue in the repair phase and the reconstitution of the original bone in the final remodelling phase of healing [
]. This manuscript describes how mechanical signals contribute to the bone healing process and how the mechanical stimulus can be employed to manipulate the healing response by ideally promoting and accelerating the fracture repair process.
Fig. 1Process of fracture healing after fracture of the femoral shaft in a 39-year-old patient (a). Anatomical reduction and flexible fixation with locked plating (b). Four weeks after fracture, advanced periosteal and endosteal callus formation was observed (c) which progressed by week fourteen (d). Almost complete remodelling of the periosteal callus was observed four years after trauma (e). Residuals of intramedullary callus after metal removal six years after trauma (f).
It has been well described that bone homoeostasis is maintained by modelling and remodelling of bone tissue through a well-orchestrated interaction of bone forming osteoblasts and bone resorbing osteoclasts. The regulation of these activities is accompanied by suppression, expression or synthesis of a large variety of cellular and molecular factors, such as hormones and growth factors [
]. Based on the assumption of “Form follows Function”, bone has the ability to adapt its form (mass and structure) to its functional demands. Osteocytes, which form a dense communication network within bone tissue, are thought to be responsible for sensing the mechanical signals and for regulating the survival and activity of osteoblasts and osteoclasts [
]. Mechanical signals that are induced in bone tissue during loading include stress, strain, fluid flow and streaming potentials of which shear stress by interstitial fluid flow in the lacunar-canalicular network appears to be the most relevant signal for mechanotransduction in intact bone [
]. It has also been demonstrated that mechanically induced deformation increases oxygen transport, thereby improving the nutrition supply to cells involved in fracture repair [
The process of mechanotransduction is not limited to the process of bone remodelling but also regulates the process of bone healing after fracture. The mechanical deformation of the fracture at the organ level results in a mechanical response on a tissue, cellular and molecular level. On the tissue level, formation and differentiation is known to be controlled by the mechanical environment leading to “causal histogenesis”. Compressive strain promotes the formation of cartilaginous tissue, and tensile strains induce the formation of fibrous connective tissue with collagenous fibers [
[A new theory on the influence of mechanical stimuli on the differentiation of supporting tissue. The tenth contribution to the functional anatomy and causal morphology of the supporting structure].
]. At the cellular level, the proliferation and differentiation of specific cell types and extracellular matrix production is either promoted or suppressed. At the molecular level, specific pathways involving growth factors, cytokines and morphogens are activated depending on the type and magnitude of the mechanical signal [
]. Multiple experimental studies have provided some understanding about the effects of mechanical signals on their biological responses on each individual level in particular on the molecular and cellular level [
]. However, due to the morphological and material heterogeneity of the tissues involved in fracture healing, the biological response to a physical signal is often difficult to predict and not necessarily unambiguous [
The mechanical environment at the site of the fracture has been shown to have a dominant influence on the healing response. It has been generally accepted that rigid fixation of a fracture requires perfect bone adaptation and leads to intramembranous bone formation and direct healing (Fig. 2). In contrast, flexible fixation induces an endochondral healing pathway characterized by intermittent formation of cartilage and the development of periosteal and endosteal callus (Fig. 3) [
]. Interfragmentary strain has been identified as the most characteristic measure of fracture stability, and Perren and Cordey have formulated a strain theory that postulates for bone formation to occur, the interfragmentary strain needs to be smaller than the failure strain of the bone tissue [
]. Accordingly, Perren postulated that for interfragmentary strains that exceed 2%, no direct formation of bone can occur, yet fibrocartilage or granulation tissue can form [
]. Strains below 2% that allow direct healing can only be achieved by aggressive open reduction and rigid internal fixation and has been advocated by the early pioneers of osteosynthesis [
]. Their philosophy was based on the misleading concept that callus is to be considered a pathological structure “…that can be readily avoided by osteosynthesis and interfragmentary compression” [
Fig. 2Comminuted pilon tibiale fracture after dashboard injury in a 47-year-old professional sports car test driver (a). Anatomical fragment adaptation with lag screw fixation and locked neutralization plating leads to intramembranous bone formation and direct fracture healing (b). One year after surgery restitutio ad integrum allowed for complete metal removal (c).
Fig. 3Combined tibial shaft spiral fracture (a) and proximal fibula fracture (b) in a 59-year-old patient after ski accident. Sagittal CT scan demonstrates an articular fracture line with connection to the upper ankle joint (c). One year after surgery complete fracture consolidation including periosteal and endosteal callus formation following reamed intramedullary locked nailing of the tibial shaft (d).
The much more biological form of fracture healing occurs under flexible fixation which can be achieved by external fixation, locked plating or intramedullary nailing without interfragmentary compression [
]. However, for flexible fixation to result in a successful healing response, an appropriate amount of interfragmentary strain needs to be present to stimulate the healing process. In contrast to direct bone formation, the healing processes through a secondary healing response are characterized by the formation of a periosteal fracture callus. If the fixation is exceptionally rigid or too flexible, bone formation is perturbed and delayed healing or non-union can occur (Fig. 4) [
]. The most dominant factors that influence the amount of interfragmentary strain at the fracture site are the stiffness of the osteosynthesis construct, the size of the interfragmentary gap and the amount of loading [
Fig. 4Nonunion due to varus axis deviation following cephalomedullary nailing with auxiliary cerclage wiring in a 77-year-old patient. Shear forces resulted in impaired bone healing and bowing of the nail as an expression for overloading of the osteosynthesis.
The stiffness of the fixation construct is mainly determined by the design and the material (stainless steel vs. titanium alloy) of the osteosynthesis implant and also by the osteosynthesis configuration [
] chosen by the surgeon (e.g. implant placement or screw configuration). Numerous biomechanical studies measure and compare the stiffness of osteosynthesis implants, typically assuming that a stiffer implant results in a more favourable healing outcome [
]. However, more recent studies have demonstrated that dynamic fracture fixation of diaphyseal fractures resulting in larger axial strains leads to improved healing response compared to stiff fracture fixation. Dynamic fixation was either achieved by modification of the locking screws or by modification of the locking plates. The use of far cortical locking screws [
Dynamization at the near cortex in locking plate osteosynthesis by means of dynamic locking screws: an experimental study of transverse tibial osteotomies in sheep.
] has shown to induce favourable axial interfragmentary strains which lead to faster and stronger fracture healing. Also, the modification of the locking plate itself by inducing a biphasic plate stiffness [
The size of the interfragmentary gap depends on the efficiency of the bone reduction process during operative surgery. There is large variability of the quality of reduction depending on fracture location, type of fracture and type of osteosynthesis. In humeral shaft fractures, gap sizes have been reported to be typically between 0.5 mm and 2 mm [
]. Small gap sizes of around 1 mm appear to be less sensitive to different interfragmentary strain levels than larger gap sizes (> 2 mm), and have shown to tolerate interfragmentary strains as large as 30%. In contrast, large gaps tolerate less interfragmentary strain for a timely healing response and show delayed healing for strains of 30% compared to strains of 7% [
]. However, it is not only the amount of interfragmentary movement but also the type of deformation (axial, torsion, shear) that influences the repair process. Pre-clinical and clinical studies have unmistakably demonstrated that axial compressive interfragmentary strain promotes fracture healing by stimulating periosteal callus production and maturation [
Finally, the amount of loading determines the interfragmentary strain at the site of fracture. Loading of the fracture site occurs during joint movement and weight bearing. It has been generally accepted that early loading after fracture needs to be limited. This then results in the prescription of reduced weight bearing and the frequent use of temporary casts for immobilization even after surgical fixation of the fracture. Pre-clinical experiments, which have shown beneficial effects of early weight bearing, have led to a rethinking of the concept of unloading the fracture [
]. Recent clinical findings suggest that early weight-bearing after open reduction and internal fixation induces the necessary stimulatory strain at the fracture site without compromising the stability of fracture fixation or increasing the frequency of post-operative complications [
Early Weightbearing and Range of Motion Versus Non-Weightbearing and Immobilization After Open Reduction and Internal Fixation of Unstable Ankle Fractures: a Randomized Controlled Trial.
Stress or load at the fracture sites originates from weight bearing activities or from muscle contraction. For a perfectly reduced fracture, loading compresses the fracture but there is no initial movement at the fracture site. If the fracture is incompletely reduced or the trauma created a comminuted fracture situation, loading results in movement of the fracture gap. But even well reduced fracture gaps may eventually widen through stress-induced bone resorption at the fragment ends and will permit fracture gap movement in the course of the healing process. The initial interfragmentary gap (IFM Gap) is reduced by a certain amount of interfragmentary movement (IFM) and results in the interfragmentary strain ε (Fig. 5). The amount of interfragmentary movement which can occur during weight bearing has been determined by using instrumented external fixator frames in patients with tibial shaft fractures [
]. Even in a reduced weight bearing situation, axial compression in the tibial shaft amounted to a range of 0.5 mm to 1.5 mm with fracture gaps of around 1 mm, and during walking the amount of shear movement was about 0.3 mm. Most interestingly, the same amount of movement as measured during weight-bearing was obtained by unloaded muscle contraction causing dorsi flexion and plantar flexion of the foot. As all patients in this investigation had fully healed, their interfragmentary strains between 30% and 100% in the very early healing phase produced some stimulatory effects and did not obstruct the repair process.
Fig. 5The interfragmentary gap (IFgap) in a long bone fracture which is compressed during loading by a certain amount of interfragmentary movement (IFM) experiences a interfragmentary strain (ε) within the fracture gap.
Obviously, it is much more challenging to obtain measurements of interfragmentary movement after internal fixation with plates or nails. Biomechanical assessment of fracture fixation construct stiffness measured under physiologic loading conditions can shed some light on the interfragmentary movements to be expected during full or partial weight-bearing after internal fracture fixation. In general, intramedullary implants provide much larger axial stability compared to extramedullary implants and consequently result in smaller interfragmentary compressional movement. For distal tibia fractures, it has been shown that an extramedullary locking plate (axial stiffness about 450 N/mm) allows up to 1 mm of axial compression compared to only 0.2 mm compression for interlocked nails (axial stiffness about 700 N/mm) under partial weight-bearing [
Biomechanical comparison of locked plate osteosynthesis, reamed and unreamed nailing in conventional interlocking technique, and unreamed angle stable nailing in distal tibia fractures.
Journal of Trauma and Acute Care Surgery.2012; 73: 933-938
]. In contrast, the resulting shear or torsion under physiologic torsional loading has been observed to be similar for intramedullary and extramedullary fixation [
Biomechanical comparison of locked plate osteosynthesis, reamed and unreamed nailing in conventional interlocking technique, and unreamed angle stable nailing in distal tibia fractures.
Journal of Trauma and Acute Care Surgery.2012; 73: 933-938
]. These findings would suggest that for distal tibia fractures, intramedullary nailing would provide more stability and would enable earlier weight-bearing while extramedullary plating would provide more stimulatory axial gap movement [
Based on frequent observations of the stimulatory effect of axial mechanical signals on the repair process of fractures, it has been attempted to use externally applied mechanical signals to boost the repair process. The challenge for these externally applied signals is to find the adequate type, magnitude, frequency and timing of the loading events. The use of externally applied stimulation of fracture repair has first been advocated by the research group of John Kenwright and Allen Goodship at the University of Oxford. They found externally applied intermittent axial cyclical loading that promoted fracture healing in sheep tibiae and resulted in the acceleration of callus formation and the increase of fracture stability [
]. Based on their encouraging findings in the animal experiment, they have treated a consecutive series of patients with fractures of their tibia by application of daily micromovement and found an earlier return to weight-bearing and less frequent healing delays compared to patients who received no supplementary stimulation [
]. They attributed the positive effect specifically to the application of the axial stimulation in the early healing phase during which patients tend to unload their limbs and lack an adequate mechanical stimulus. Also, the stimulation was performed in a rather rigid frame configuration which might have suppressed callus formation in the absence of a suitable stimulus through external stimulation or more aggressive weight-bearing.
However, if a fracture already experiences a certain amount of interfragmentary strain, for example by partial weight-bearing and flexible fracture fixation, external mechanical stimulation is unable to further promote the healing process [
]. Even if the additional mechanical stimulation is capable of promoting callus formation, this is not necessarily associated with increased mechanical stability or with increased loa-bearing capacity of the fracture. It has been frequently observed that larger flexibility at the fracture site results in an enhanced callus proliferation [
]. The mechanical stability is much more related to the tissue quality within the fracture for which the local bone density has shown to be an excellent measure [
In conjunction with the amount of loading, the loading history has also shown to influence the repair process. Moderate to high strain rates similar to that obtained during brisk walking have shown to promote healing if applied during the early healing phase [
]. On the other hand, variation of stimulation frequencies from 1 Hz to 10 Hz did neither enhance callus formation nor improve mechanical stability of the fracture compared to flexible fixation without external stimulation [
]. However, the response to loading scenarios might be different if bone regeneration during distraction osteogenesis is considered. In a study in which different loading frequencies and loading rates were employed for the stimulation of bone regeneration during bone segment transport, a lower distraction rate has slowed bone regeneration, whereas increased distraction frequency has accelerated bone regeneration [
Besides rate and frequency of external loading, also the timing of external stimulation appears to be critical for the initiation of a healing response. During fracture healing, different healing phases can be observed which differ amongst others in tissue composition, cellular and vascular activities and mechanical integrity. These phases include the inflammation phase, the repair phase with soft callus formation followed by hard callus formation and the final remodelling phase [
]. However, in the very early inflammatory phase the healing response is dominated by revascularization at the fracture site and early motion has been suggested to inhibit new vessels to form and existing capillaries to rupture [
]. The faster maturation during the soft callus phase may then result in increased mineralization and remodelling of hard callus, leading to improved biomechanical properties [
In conclusion, targeted adjustment of the mechanical environment in fracture repair can enhance the healing response, accelerate bone restoration and reduce fracture healing complications. The mechanical environment in long bones which favours secondary healing with periosteal callus formation is based on an accurate reduction of the fracture ends and flexible fixation of the fracture enabling interfragmentary movement. The interfragmentary fracture gap which remains after operative reduction, should ideally be minimal but not larger than 2 to 4 mm in size. Correspondingly, the interfragmentary movement under weight-bearing should be somewhere between 0.2 to 1 mm, equivalent to a interfragmentary strain of less than 30%. The direction of loading should be dominantly along the axis of the bone and shear movement should be avoided by proper fracture fixation. Mechanical activity through weight-bearing or muscular contraction can be utilized to stimulate the repair process most effectively in the early repair phase during which the soft callus is produced and maturated.
OTC_Supplement
This paper is part of a Supplement supported by The Osteosynthesis and Trauma Care Foundation (OTCF).
Declaration of Competing Interest
All authors have significantly contributed to the work and the writing of the manuscript. Peter Augat is member of the Research Committee of the Osteosynthesis and Trauma Care Foundation. None of the authors has to declare any additional conflict of interest.
Acknowledgement
The authors of this manuscript express their thanks to the Osteosynthesis and Trauma Care Foundation for the sponsorship of the publication of this Supplement in Injury, Katarina Ruehlicke for language editing and proof reading of the manuscript and Annika Hunfeld for providing graphical support.
References
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Orr T.E
Skeletal development and bone functional adaptation.
[A new theory on the influence of mechanical stimuli on the differentiation of supporting tissue. The tenth contribution to the functional anatomy and causal morphology of the supporting structure].
Dynamization at the near cortex in locking plate osteosynthesis by means of dynamic locking screws: an experimental study of transverse tibial osteotomies in sheep.
Early Weightbearing and Range of Motion Versus Non-Weightbearing and Immobilization After Open Reduction and Internal Fixation of Unstable Ankle Fractures: a Randomized Controlled Trial.
Biomechanical comparison of locked plate osteosynthesis, reamed and unreamed nailing in conventional interlocking technique, and unreamed angle stable nailing in distal tibia fractures.
Journal of Trauma and Acute Care Surgery.2012; 73: 933-938
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