Injury 52S2 (2021) S78–S83

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Injury
journal homepage: www.elsevier.com/locate/injury

The role of mechanical stimulation in the enhancement of bone

healingR
Peter Augat a,b,∗, Marianne Hollensteiner a,b, Christian von Rüden b,c
a
Institute for Biomechanics, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany
b
Institute for Biomechanics Paracelsus Medical University Salzburg, Salzburg, Austria
c
Department of Trauma Surgery, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The biomechanical environment plays a dominant role in the process of fracture repair. Mechanical sig-
Accepted 1 October 2020 nals 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 frac-
Keywords: tured bone. The mechanobiology at the fracture site can be easily manipulated by the design and configu-
Bone ration of the fracture fixation construct and by the loading of the extremity (weight-bearing prescription).
Fracture Depending on the choice of fracture fixation, the healing response can be directed towards direct heal-
Fracture healing ing or towards indirect healing through callus formation. This manuscript summarizes the evidence from
Fracture repair experimental studies and clinical observations on the effect of mechanical manipulation on the healing
Interfragmentary movement
response. Parameters like fracture gap size, interfragmentary movement, interfragmentary strain, and ax-
Strain, Biomechanics, Stimulation
ial 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.
© 2021 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction mechanobiological feedback signals [5]. The mechanical stimulus

Bone as a living skeletal tissue is capable of adaptation and re-
generation [1]; it responds to changing physical demands and trig-
gers a complex repair process after injury [2]. In particular, the re-
generation process has an amazing potential to create new bone
tissue and rebuild the original state after a fracture or a bone de-
fect [3]. Formation of new bone after a fracture is a complex in-
teraction of cellular and molecular processes by which connec-
tive tissue, cartilage and bone are formed [4]. Constant remod-
elling of these tissues reconstitutes the bone’s anatomy and struc-
ture [5] and recovers its functional competences (Fig. 1). The most
fundamental aims of the healing process are recovery of load bear-
ing capacity and restoration of bone strength. As both aims rep-
resent mechanical features, it is not surprising that the processes
of tissue differentiation and formation are primarily regulated by
R
This paper is part of a supplement supported by the Osteosynthesis and Trauma
Care Foundation (OTCF) through a research grant from Stryker.
∗
Corresponding author at: Institute for Biomechanics Berufsgenossenschaftliche
Unfallklinik Murnau Professor-Küntscher-Str. 8, 82418 Murnau, Germany.
E-mail address: biomechanik@bgu-murnau.de (P. Augat).
is experienced by the cells in the healing zone leading to con-
gregation of mesenchymal cells in the early healing phase, forma-
tion of callus tissue in the repair phase and the reconstitution of
the original bone in the final remodelling phase of healing [6].
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.
Mechanobiology of fracture repair
It has been well described that bone homoeostasis is main-
tained 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 accom-
panied by suppression, expression or synthesis of a large variety
of cellular and molecular factors, such as hormones and growth
factors [6]. As early as 1892, Julius Wolff postulated that mechan-
ical signals are the key regulators of the remodelling process [7].
Based on the assumption of “Form follows Function”, bone has the
ability to adapt its form (mass and structure) to its functional de-

https://doi.org/10.1016/j.injury.2020.10.009
0020-1383/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
P. Augat, M. Hollensteiner and C. von Rüden Injury 52S2 (2021) S78–S83

Fig. 1. Process 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).

mands. 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 [8]. 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 rel-
evant signal for mechanotransduction in intact bone [9]. It has
also been demonstrated that mechanically induced deformation in-
creases oxygen transport, thereby improving the nutrition supply
to cells involved in fracture repair [10].
The process of mechanotransduction is not limited to the pro-
cess 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, cel-
lular and molecular level. On the tissue level, formation and dif-
ferentiation is known to be controlled by the mechanical environ-
ment 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 [11].
At the cellular level, the proliferation and differentiation of specific
Fig. 2. Comminuted pilon tibiale fracture after dashboard injury in a 47-year-old
cell types and extracellular matrix production is either promoted professional sports car test driver (a). Anatomical fragment adaptation with lag
or suppressed. At the molecular level, specific pathways involving screw fixation and locked neutralization plating leads to intramembranous bone for-
growth factors, cytokines and morphogens are activated depend- mation and direct fracture healing (b). One year after surgery restitutio ad integrum
ing on the type and magnitude of the mechanical signal [4]. Multi- allowed for complete metal removal (c).
ple 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 formation and direct healing (Fig. 2). In contrast, flexible fixation
level [12]. However, due to the morphological and material hetero- induces an endochondral healing pathway characterized by inter-
geneity of the tissues involved in fracture healing, the biological mittent formation of cartilage and the development of periosteal
response to a physical signal is often difficult to predict and not and endosteal callus (Fig. 3) [3]. Interfragmentary strain has been
necessarily unambiguous [4]. identified as the most characteristic measure of fracture stability,
and Perren and Cordey have formulated a strain theory that pos-
Effect of mechanical signals on fracture healing tulates for bone formation to occur, the interfragmentary strain
needs to be smaller than the failure strain of the bone tissue [13].
The mechanical environment at the site of the fracture has been Accordingly, Perren postulated that for interfragmentary strains
shown to have a dominant influence on the healing response. It that exceed 2%, no direct formation of bone can occur, yet fibro-
has been generally accepted that rigid fixation of a fracture re- cartilage or granulation tissue can form [14]. Strains below 2% that
quires perfect bone adaptation and leads to intramembranous bone allow direct healing can only be achieved by aggressive open re-

79
P. Augat, M. Hollensteiner and C. von Rüden
Fig. 3. Combined 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).
duction and rigid internal fixation and has been advocated by the
early pioneers of osteosynthesis [15]. Their philosophy was based
on the misleading concept that callus is to be considered a patho-
logical structure “…that can be readily avoided by osteosynthesis
and interfragmentary compression” [16].
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 com-
pression [15,17]. However, for flexible fixation to result in a suc-
cessful healing response, an appropriate amount of interfragmen-
tary 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) [18,19]. The most dominant factors
that influence the amount of interfragmentary strain at the frac-
ture site are the stiffness of the osteosynthesis construct, the size
of the interfragmentary gap and the amount of loading [20].
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 configu-
ration [21] chosen by the surgeon (e.g. implant placement or screw
configuration). Numerous biomechanical studies measure and com-
pare the stiffness of osteosynthesis implants, typically assuming
that a stiffer implant results in a more favourable healing out-
come [22]. 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 modi-
fication of the locking screws or by modification of the locking
plates. The use of far cortical locking screws [23,24] or dynamic
locking screws [25] has shown to induce favourable axial interfrag-
mentary strains which lead to faster and stronger fracture heal-
ing. Also, the modification of the locking plate itself by inducing a
biphasic plate stiffness [26] or enabling limited deformation of the
plate around the screws [27,28] has resulted in superior fracture
healing.
80
Injury 52S2 (2021) S78–S83
Fig. 4. Nonunion due to varus axis deviation following cephalomedullary nailing
with auxiliary cerclage wiring in a 77-year-old patient. Shear forces resulted in im-
paired bone healing and bowing of the nail as an expression for overloading of the
osteosynthesis.
The size of the interfragmentary gap depends on the effi-
ciency 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 typ-
ically between 0.5 mm and 2 mm [29] but can be up to 4 mm
in individual patients [30]. Small gap sizes of around 1 mm ap-
pear to be less sensitive to different interfragmentary strain levels
than larger gap sizes (> 2 mm), and have shown to tolerate inter-
fragmentary strains as large as 30%. In contrast, large gaps toler-
ate less interfragmentary strain for a timely healing response and
show delayed healing for strains of 30% compared to strains of
7% [18]. 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 interfrag-
mentary strain promotes fracture healing by stimulating periosteal
callus production and maturation [31-37]. In contrast, shear move-
ment has shown to inhibit vascularization of the callus and the
fracture gap from early on [38] and results in a lengthened healing
period and a decrease in mechanical stability [32].
Finally, the amount of loading determines the interfragmen-
tary strain at the site of fracture. Loading of the fracture site oc-
curs during joint movement and weight bearing. It has been gen-
erally 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 af-
ter 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 [39,40]. Re-
cent clinical findings suggest that early weight-bearing after open
P. Augat, M. Hollensteiner and C. von Rüden
Fig. 5. The interfragmentary gap (IFgap ) in a long bone fracture which is com-
pressed during loading by a certain amount of interfragmentary movement (IFM)
experiences a interfragmentary strain (ε) within the fracture gap.
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 com-
plications [41,42]. Immediate weight bearing and early mobiliza-
tion may in fact improve functional outcome and lead to earlier
return to work [43].
Interfragmentary movement
Stress or load at the fracture sites originates from weight bear-
ing 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 re-
duced or the trauma created a comminuted fracture situation,
loading results in movement of the fracture gap. But even well re-
duced 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 inter-
fragmentary gap (IFM Gap) is reduced by a certain amount of in-
terfragmentary movement (IFM) and results in the interfragmen-
tary 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 tib-
ial shaft fractures [37]. Even in a reduced weight bearing situa-
tion, 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 dur-
ing 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 contrac-
tion causing dorsi flexion and plantar flexion of the foot. As all
patients in this investigation had fully healed, their interfragmen-
tary strains between 30% and 100% in the very early healing phase
produced some stimulatory effects and did not obstruct the repair
process.
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
81
Injury 52S2 (2021) S78–S83
during full or partial weight-bearing after internal fracture fixation.
In general, intramedullary implants provide much larger axial sta-
bility compared to extramedullary implants and consequently re-
sult in smaller interfragmentary compressional movement. For dis-
tal tibia fractures, it has been shown that an extramedullary lock-
ing plate (axial stiffness about 450 N/mm) allows up to 1 mm of
axial compression compared to only 0.2 mm compression for inter-
locked nails (axial stiffness about 700 N/mm) under partial weight-
bearing [44]. In contrast, the resulting shear or torsion under phys-
iologic torsional loading has been observed to be similar for in-
tramedullary and extramedullary fixation [44,45]. These findings
would suggest that for distal tibia fractures, intramedullary nail-
ing would provide more stability and would enable earlier weight-
bearing while extramedullary plating would provide more stimula-
tory axial gap movement [46].
External mechanical stimulation
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 sig-
nals 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 stabil-
ity [47,48]. Based on their encouraging findings in the animal ex-
periment, 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 stim-
ulation [49,50]. 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 ad-
equate 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 ex-
ternal 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 [51,52]. Even if the addi-
tional mechanical stimulation is capable of promoting callus for-
mation, this is not necessarily associated with increased mechani-
cal stability or with increased loa-bearing capacity of the fracture.
It has been frequently observed that larger flexibility at the frac-
ture site results in an enhanced callus proliferation [52,53] but
that the larger callus volume is not necessarily associated with
improved mechanical stability [54-56]. 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 mea-
sure [54].
In conjunction with the amount of loading, the loading his-
tory 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
[57]. However, if these externally induced strains are applied in
the late healing phase they may rather inhibit healing [57]. On the
other hand, variation of stimulation frequencies from 1 Hz to 10 Hz
did neither enhance callus formation nor improve mechanical sta-
bility of the fracture compared to flexible fixation without external
stimulation [51]. However, the response to loading scenarios might
be different if bone regeneration during distraction osteogenesis is
P. Augat, M. Hollensteiner and C. von Rüden
considered. In a study in which different loading frequencies and
loading rates were employed for the stimulation of bone regener-
ation during bone segment transport, a lower distraction rate has
slowed bone regeneration, whereas increased distraction frequency
has accelerated bone regeneration [58].
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 composi-
tion, 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 [59]. In general, it appears that it is more effec-
tive to stimulate healing earlier rather than later during the repair
process [60-62]. 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 [55,63,64]. It might be
more beneficial to stimulate during the soft callus formation phase
when the tissue already contains some chondrogenic cells [12,65]
and bone precursor cells which can respond to mechanical stimu-
lus [66]. The faster maturation during the soft callus phase may
then result in increased mineralization and remodelling of hard
callus, leading to improved biomechanical properties [66].
Conclusion
In conclusion, targeted adjustment of the mechanical environ-
ment in fracture repair can enhance the healing response, acceler-
ate 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 frac-
ture 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 interfragmen-
tary 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 stimu-
late 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 Osteosyn-
thesis 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 in-
terest.
Acknowledgement
The authors of this manuscript express their thanks to the Os-
teosynthesis 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.
82
Injury 52S2 (2021) S78–S83
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