Bone Reports 6 (2017) 87–100

Contents lists available at ScienceDirect

Bone Reports

journal homepage: www.elsevier.com/locate/bonr

Bone fracture healing in mechanobiological modeling: A review of

principles and methods

Mohammad S. Ghiasi a,c, Jason Chen a, Ashkan Vaziri c, Edward K. Rodriguez b,1, Ara Nazarian a,b,⁎,1
a
Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
b
Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
c
Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA, USA

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

Article history: Bone fracture is a very common body injury. The healing process is physiologically complex, involving both bio-
Received 9 November 2016 logical and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis,
Received in revised form 15 February 2017 and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade,
Accepted 15 March 2017
bone healing simulation and modeling has been employed to understand its details and mechanisms, to investi-
Available online 16 March 2017
gate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and
Keywords:
the most recent work in bone healing simulations with an emphasis on both biological and mechanical proper-
Bone fracture healing ties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key
Biological modeling growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing
Mechanobiological modeling simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general
Mechanical stimuli mechanisms), biological modeling (considering only the biological factors and processes), and
Growth factors mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we eval-
Callus uate different components and clinical applications of bone healing simulation such as mechanical stimuli,
Hematoma
phases of bone healing, and angiogenesis.
Angiogenesis
© 2017 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
Finite element
Mathematical modeling (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Computational modeling

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
2. Biology of Bone Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
3. Hematoma phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4. Angiogenesis and vascularity network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
5. Growth factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
5.1. TGF-β . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
5.2. BMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.3. PDGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.4. PTH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.5. FGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.6. VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
6. Mechanical strain and pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
7. Conceptual models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
8. Mathematical models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
9. Biological modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
10. Mechanobiological modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
11. Mechanical stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

⁎ Corresponding author at: Center for Advanced Orthopaedic Studies, 330 Brookline Avenue, RN115, Boston, MA 02215, United States.
E-mail address: [email protected] (A. Nazarian).
1
These two authors have contributed equally as senior authors.

http://dx.doi.org/10.1016/j.bonr.2017.03.002
2352-1872/© 2017 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
88 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100

12. Steps of healing included in simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

13. Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
14. Clinical application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
15. Summary and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

1. Introduction hematoma is formed at the fracture site, which acts as a temporary scaf-
fold for stem cell differentiation into fibrous tissue, cartilage, and bone.
Bone fracture is one of the more common injuries, and is associated In the inflammatory phase, several biological factors including TNF-
with treatment costs exceeding billions of dollars, societal productivity Alpha, transforming growth factor-beta (TFG-β) superfamily, bone
loss, and individual disability (Pivonka and Dunstan, 2012; Bonafede morphogenetic proteins (BMP), IL-1β, IL-6, IL-17F, and IL-23 are re-
et al., 2013). As access to motorized transportation has increased leased. In addition to these cytokinetic factors, mechanical loads such
throughout the developing world, there has been a dramatic increase as strain or hydrostatic pressure also play a vital role in bone fracture
in trauma and life-threatening long bone fractures (Web-based Injury healing (Pivonka and Dunstan, 2012; Einhorn and Gerstenfeld, 2015;
Statistics Query and Reporting System (WISQARS); Cottrell and Claes et al., 2012; McKibbin, 1978).
O'Connor, 2010). Fracture healing is an intricate coordination of various The aforementioned biological factors and the mechanical envi-
cellular and mechanosensitive processes. Approximately five to 10% of ronment regulate the activities of mesenchymal stem cells (MSC),
fractured bones end in nonunion and/or incomplete healing (Einhorn, which are some of the most important contributors to the bone
1995; Praemer et al., 1992). Understanding the biomechanical aspects formation (Nagel and Kelly, 2010), in addition to the activities of
of the healing process in detail is a crucial for orthopedic surgeons to chondrocytes, osteoblasts, fibroblasts, and endothelial cells
properly create the optimal healing environment for an injured bone (Prendergast et al., 1997; McKibbin, 1978; Pauwels, 1959). Howev-
(Pivonka and Dunstan, 2012; Einhorn and Gerstenfeld, 2015). er, the interaction between cellular activities and the mechanical
There are two general approaches to studying the bone healing pro- environment remains undefined (Pivonka and Dunstan, 2012;
cess: 1) experimental methods and 2) computational modeling. Both of Einhorn and Gerstenfeld, 2015).
these methods have benefits and limitations. Experimental methods With progressive healing, cartilaginous callus (soft callus) is formed
work with real scenarios and generally provide results attributable to clin- through the activities of skeletal and endothelial cells, which bridge the
ical applications. However, experimental methods require state of the art gap between the bone fragments (Pivonka and Dunstan, 2012; Einhorn
equipment, high accuracy, controlled conditions, high cost, and are often and Gerstenfeld, 2015; Claes et al., 2012). Soft callus then progresses to
confounded by other factors such as unknown subject backgrounds, co- hard callus. There are two typical mechanisms of bone formation:
morbidities, and genetic variation (Lacroix et al., 2002; Moran et al., intramembranous ossification and endochondral ossification. In
2016). On the other hand, computational modeling and simulation of intramembranous ossification, MSCs differentiate to osteoblasts, creat-
the bone healing process have been utilized to overcome the limitations ing bone tissue directly in an anabolic process (typical of flat bones
associated with experimental methods (Lacroix and Prendergast, 2002). such as skull and clavicle). In endochondral ossification, MSCs differen-
Nevertheless, computational modeling approaches have their own limita- tiate into chondrocytes, which create cartilage tissue. The synthesized
tions in clinical applications. Thus, these models need to be further devel- cartilage extracellular matrix (ECM) mineralizes through chondrocyte
oped and validated in order to achieve clinically relevant results (Pivonka apoptosis. Subsequently, the osteoblast cells penetrate this dead struc-
and Dunstan, 2012; Carlier et al., 2015a). These models help us better un- ture and lay down the bone tissue (Einhorn and Gerstenfeld, 2015;
derstand the mechanism of bone healing by emphasizing the known cor- McKibbin, 1978; Oryan et al., 2015). Long bones typically grow and
relation between the mechanical environment and the bone healing heal by this process.
process (Claes and Heigele, 1999; Prendergast et al., 1997). They can There are two forms of bone healing: primary and secondary. Prima-
even help us predict how mechanical environments and drug treatment ry bone healing occurs when the bony fragments are tightly fixed to-
strategies affect the biological processes and cellular activities of bone gether under compression from implantation. There is no callus
healing (Geris et al., 2010a; Carlier et al., 2014). Modeling can also provide formation, and two bone fragments are connected together and healed
valuable insight for the design, optimization, and final outcome predic- directly by osteoclasts and osteoblasts activities (Claes et al., 2012;
tions in future treatment strategies. Nevertheless, computational model- Marsell and Einhorn, 2011). Secondary bone healing, the most common
ing approaches have their own limitations in clinical applications. Thus, form of bone healing, occurs when there is a small amount of motion in
these models need to be further developed and validated in order to the fracture site. The interfragmentary motion causes soft callus forma-
achieve clinically relevant results (Pivonka and Dunstan, 2012; Isaksson, tion, and leads to secondary bone formation through both
2012). intramembranous and endochondral ossifications (Claes et al., 2012;
This review aims to summarize the present understanding of the Gerstenfeld et al., 2006). This form of bone healing begins with the an-
biomechanical processes affecting healing and nonunion. We first abolic phase, and overlaps with the catabolic phase when callus volume
review the bone healing biology, factors, and processes previously is reduced. Following these processes, the bone remodeling phase be-
addressed in modeling approaches. Some of the well-known gins by coordinated osteoblast and osteoclast activities over a span of
mechanobiological regulation theories are then reviewed, and specific several months. Callus tissues are reabsorbed and lamellar bone is
mechanical factors which influence biological processes and cellular formed (Schindeler et al., 2008; Little et al., 2007). Fig. 1 illustrates a
activities of bone healing are outlined. Finally, we focus on the clinical example of this healing and remodeling process in a comminut-
mechanobiological model's potential contributions to different real- ed spiral humerus shaft fracture over a two-year time period.
world clinical and research applications, followed by prospective re- Fig. 1 illustrates a typical humeral shaft fracture that is clinically rec-
search directions. ognized as not requiring surgery for its successful healing. Humeral
extra-articular fractures, even very distal ones, can be treated success-
2. Biology of Bone Healing fully without surgical fixation simply with a brace and the bone's ability
to self-heal through callus formation when mechanically stable. The
Fracture healing starts with an initial anabolic phase, where local tis- array of instrumentation and techniques at an orthopedic surgeon's dis-
sue volume increases through inflammation. Following bone fracture, a posal provides the means to create the most ideal and stable healing
 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100 89

Fig. 1. Clinical example of humerus fracture healing.

environment. Fractures along the diaphysis, like the one illustrated in 4. Angiogenesis and vascularity network
Fig. 1, can heal through callus formation via endochondral ossification,
as the callus is unlikely to interfere with mechanical function. On the Angiogenesis and redevelopment of the vascular network supplies
other hand, an intra-articular fracture is more likely to require open re- cells, nutrition, oxygen, growth factors and other components required
duction and internal fixation in order to promote primary bone healing for fracture healing. Angiogenesis precedes osteogenesis and plays a
or Haversian remodeling. A callus does not form because it would inter- vital role in both intramembranous and endochondral ossification
fere with joint function. Primary healing can be achieved surgically by (Einhorn, 1998; Geris et al., 2008). During endochondral ossification
creating an environment of absolute stability with compression screw in particular, the cartilaginous matrix is penetrated by a vascular net-
and plate fixation, in the humerus, this can easily be achieved with an work before transforming into osseous tissue (Einhorn, 1998). Several
external brace as Fig. 1 illustrates. In a weight bearing bone such as studies have demonstrated that deficient angiogenesis leads to healing
the femur, a relatively stable condition can usually be achieved with impairment (Carlier et al., 2015b; Kanczler and Oreffo, 2008; Saran et
an intramedullary nail. This allows not only callus formation, but also al., 2014; Tomlinson and Silva, 2013). Moreover, angiogenesis is a key
weight bearing during the healing process. factor for bone remodeling, because it provides the appropriate condi-
tions for osteoblastic and osteoclastic activities (Kanczler and Oreffo,
2008; Saran et al., 2014; Claes et al., 2002). The endothelial cell plays a
3. Hematoma phase critical role in cell migration and transformation, secretion of growth
factors, cell signaling, and other biological processes (Carlier et al.,
Immediately after bone fracture, a hematoma is formed from the 2015b; Hankenson et al., 2015; Mayr-wohlfart et al., 2002).
bleeding at the fracture site, and the healing process is initiated. The he-
matoma fills the fracture gap in the initial step of bone healing, acts as 5. Growth factors
temporary scaffolding for cellular activity, and provides an appropriate
environment for the subsequent biologic cascade of events ultimately Several biological growth factors influence the process of bone
resulting in healing (Chung et al., 2006; Axelrad and Einhorn, 2009; healing by regulating cellular proliferation, migration, differentiation
Echeverri et al., 2015). The hematoma first transitions to granulation tis- and other cellular processes. Table 1, presented by Saran et al. (with per-
sue (Kolar et al., 2011). A majority of mechanobiological models consid- mission of reuse from the publisher), indicates the osteogenic or angio-
ered this phase as the starting point of healing, while mostly neglecting genic function of the aforementioned growth factors in the bone healing
the hematoma phase and its effects on bone healing (Pivonka and process (Saran et al., 2014).
Dunstan, 2012; Isaksson, 2012; Pivonka and Komarova, 2010). While
the biological aspects and cellular effects of the hematoma phase in 5.1. TGF-β
bone healing remain unclear, the hematoma phase is critical in initiating
the healing process. Its removal leads to delayed healing or nonunion Transforming Growth Factor Beta (TFG-β) is a protein superfamily of
(Kolar et al., 2010). Many primary cellular activities and biological pro- growth factors regulating cellular activities including proliferation, dif-
cesses, which include migration and differentiation of MSC, angiogene- ferentiation, and tissue migration (Einhorn and Gerstenfeld, 2015).
sis, and inflammatory and immune system activities, start at the After bone fracture and formation of hematoma, the expression of
hematoma phase (Ozaki et al., 2000). The immune cell spectrum of TFG-β increases at the fracture site and continues to be expressed
the hematoma component also changes quickly in a matter of few throughout the remodeling phase (Patil et al., 2011; Poniatowski et al.,
days (Kolar et al., 2010). Consequently, hematomas and successfully 2015). TFG-β plays a key role in the differentiation and formation of
healed fractures provide the appropriate environment for launching both cartilage and bone tissue by enabling the cellular activities of
several cellular and biological activities critical to successfully healed MSCs, fibroblasts, chondrocytes, osteoblasts and also inhibiting osteo-
fractures (Claes et al., 2012; Kolar et al., 2010; Schmidt-Bleek et al., clastic activity (Patil et al., 2011; Narine et al., 2006). Furthermore,
2014). TFG-β has a function in maintaining homeostasis of cartilage and
90 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100

Table 1
Growth Factors involved in osteogenesis and angiogenesis by Saran et al. (2014) (with permission of reuse from the publisher).

Growth Osteogenic or angiogenic Function Influence of/over other growth factor

Factors effect

VEGF Both Chemoattractant for osteoblasts, MSC and Endothelial Cells Central mediator for other growth factors
TGF-β Both Chemoattractant for MSC, differentiation of osteoblasts FGF, VEGF
PDGF Both Chemoattractant and mitogenic stimulation for osteoblasts VEGF
FGF Angiogenic Stimulated osteoblast migration, mitogenic factor for Endothelial Cells, MSC and VEGF
osteoblasts
BMP-2, 4, 7 Osteogenic, indirectly Differentiation of osteoblast-like cells; Chemoattractant for neighboring EC VEGF-A
angiogenic

bone, ECM synthesis, angiogenesis, intracellular signaling, and interac- FGFs, including FGF1 to FGF22 and FGFR1 to FGFR4, involved in bone
tions with other growth factors (Patil et al., 2011; Davidson et al., 2007). healing (Kawaguchi et al., 2010; Riazuddin et al., 2011; Du et al., 2012;
Toydemir et al., 2006). Experimental studies have shown that the ap-
5.2. BMP propriate dosage of FGF can enhance bone healing and serve as a poten-
tial clinical application (Einhorn and Gerstenfeld, 2015; Kawaguchi et
Bone Morphogenetic Proteins (BMPs), act as signals for cellular mi- al., 2010; Du et al., 2012).
gration, differentiation, division, and matrix synthesis, (Einhorn and
Gerstenfeld, 2015; Garrison et al., 2010). Their presence is vital for 5.6. VEGF
bone healing, and have been used clinically since the commercial intro-
duction of BMP-2 and BMP-7 to enhance the timing and quality of bone Vascular Endothelial Growth Factor (VEGF) is a signaling protein
fracture healing (Einhorn and Gerstenfeld, 2015). The combination of that stimulates angiogenesis (Nauth et al., 2010). VEGF also directly in-
BMP treatments with other procedures such as bone grafts and surgery fluences bone formation and stimulates osteoblast differentiation and
are commonly used to improve the outcome of bony fusions (Garrison proliferation (Keramaris et al., 2008). Moreover, combinations of VEGF
et al., 2010; Nauth et al., 2010), and have been used off label for the with BMP growth factors and gene therapy techniques have been sug-
management of recalcitrant nonunions (Axelrad and Einhorn, 2009; gested to enhance bone fracture healing (Peng et al., 2002; Senel et al.,
Garrison et al., 2010). However, complications such as hematomas, en- 2013).
hanced inflammatory responses, swelling, and longer periods of hospi-
talization have been reported with their use (Garrison et al., 2010; 6. Mechanical strain and pressure
Nauth et al., 2010; Shields et al., 2006).
Mechanical factors such as strain, pressure, stability, and fluid veloc-
5.3. PDGF ity are important parameters that act as stimuli for tissue formation dur-
ing bone healing. However, the transduction from mechanical factors to
Platelet-Derived Growth Factor (PDGF) functions in bone formation cellular stimuli has not yet been fully understood (Isaksson, 2012; Epari
by regulating cell migration, growth, and division in order to promote et al., 2010; Isaksson et al., 2006a).
angiogenesis (Nauth et al., 2010; Hollinger et al., 2008). A combined Prendergast et al. investigated the correlation between strain and
PDGF and β-tricalcium phosphate scaffold has been analyzed as a po- relative fluid/solid velocity as mechanical stimuli for the survival and
tential treatment for bone fracture healing in preclinical and clinical differentiation of cells. They developed a biphasic finite element (FE)
stages (Nauth et al., 2010; DiGiovanni et al., 2013). PDGF treatments model and simulated a bone healing experiment previously conducted
are also an area of interest for periodontal defect repairs, especially in by Saballe (1993), which aimed to deduce the required mechanical en-
the context of diabetes and smoking (Nauth et al., 2010; DiGiovanni et vironment for musculoskeletal tissue regeneration. They presented a
al., 2013). hypothesis in which three types of mechanical stimuli (strain and rela-
tive fluid/solid velocity) drive the formation of fibrous tissue (high
5.4. PTH strain and velocity), cartilage tissue (moderate strain and velocity),
and bone tissue (low strain and velocity) (Prendergast et al., 1997).
Parathyroid hormone (PTH) is an 84 amino acid peptide naturally Carter et al. studied MSC differentiation as a function of mechanical
produced and secreted by parathyroid glands, which adjusts the sys- stimulus. They utilized FE modeling to calculate mechanical stimulus
temic metabolism of calcium, phosphate, and vitamin D. Although con- during bone healing and its association with the formation of different
tinuous exposure of this hormone is associated with osteoclastic tissue types. They found that hydrostatic stress and tensile strain were
activities, periodic exposure stimulates osteoblastic function and im- the mechanical stimuli for tissue regeneration, and assigned different
proves bone density. The increase in bone density can help enhance ranges of stress and strain for formation of bone, cartilage, fibrocartilage
bone fracture healing in osteoporosis treatments (Einhorn and and fibrous tissue (Carter et al., 1998).
Gerstenfeld, 2015; Little et al., 2007; Nauth et al., 2010; Bukata et al., Claes et al. presented a hypothesis on the relationship between me-
2009; Alkhiary et al., 2005). PTH analogs are commercially available chanical strain, hydrostatic pressure, and cell differentiation in bone
(Forteo uses the noncommercial name teriparatide) and have been healing. They utilized FE modeling and histological data to outline dif-
used to manage severe osteoporosis (Brixen et al., 2004; Daddona et ferent regions of mechanical stimuli corresponding to different types
al., 2011; Hodsman et al., 2005) and are now progressively used off- of differentiation and tissue formation. Intramembranous ossification
label to manage recalcitrant nonunion as well (Cipriano et al., 2009). (for strains less than ± 5% and hydrostatic pressures less than
± 0.15 MPa) and endochondral bone formation (for strains less than
5.5. FGF ±15% and compressive pressure larger than −0.15 MPa) were predict-
ed by their hypothesis. With larger mechanical stimuli, connective and
Fibroblast Growth Factors (FGF) play a vital role in angiogenesis, fibrous tissues formed (Claes and Heigele, 1999). Fig. 2 illustrates the
MSC mitosis, chondrogenesis, and osteoblast activity during fracture mechanobiological regulations presented by Prendergast et al. (1997),
healing (Nauth et al., 2010; Nakajima et al., 2001). There are several Carter et al. (1998) and Claes and Heigele (1999).
 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100 91

Fig. 2. Different mechanobiological regulations presented: A) Prendergast et al. (1997) B) Carter et al. (1998) C) Claes and Heigele (1999) (with permission of reuse from the publisher).

In the mechanobiological regulations presented by Carter et al. and appropriate mechanical environment for bone formation in the
Cleas et al., bone forms in a relatively low strain - low stress environ- healing process differs from that of normal bone formation. In the
ments, in which bone typically functions. Cartilage, which is known first few weeks of healing, the fracture site is usually fixed complete-
for tolerating compression and absorbing shock, forms in a low strain ly, while in the non-injured state, bone that is inactive for a long du-
- high compression zone. Connective tissues and fibrocartilage, that ration will be resorbed by osteoclast activities (Pivonka and Dunstan,
are able to sustain large deformations, form in high strain regions. 2012; Prendergast et al., 1997; McKibbin, 1978; Banijamali et al.,
Therefore, in these mechanobiological regulations, the mechanical 2015). In spite of mechanobiological regulations, Comiskey et al.
zone that is consistent with the type of tissue formation is analogous found a positive correlation between callus stiffening rate and strain,
to the same mechanical environment where the tissue performs its nor- based on their meta-analysis data from multiple studies. They also
mal activities. reported that healing rate is linear at low strain and nonlinear (expo-
On the other hand, the mechanobiological regulations presented in nential) at high strain (Comiskey et al., 2010). One possible reason
Prendergast et al. are based on shear deformation of MSCs. Both fluid ve- for this inconsistency is that Comiskey et al. only considered the ini-
locity and shear strain lead to shear deformation of MSCs, which is a tial interfragmentary gap for strain, while mechanobiological regula-
well-known stimulus for MSC activities. Using Digital Image Correlation tions involve temporal and spatial strain. Thus, these inconsistencies
(DIC) (Fig. 3), Morgan et al. reported a significant correlation between emphasize the importance of studying initial bone fracture healing
octahedral shear strain and tissue type differentiation, especially in mechanisms.
the early steps of bone healing; however, the lowest correlation was be- Distraction osteogenesis is the controlled, gradual increase of dis-
tween volumetric strain and tissue differentiation (Morgan et al., 2010). tance between bone fragments in order to form new bone. It is used
In contrast from Claes et al. and Carter et al., Prendergast et al. consid- to treat some clinical diseases and orthopedic disorders. Unlike typical
ered the shear components of strain to be more compatible with the ex- bone healing, the fracture site is under dilatation rather than compres-
perimental data. sion, and stress relaxation is involved in tissues growth (Brunner et al.,
Based on Prendergast et al.’s regulations, bone formation occurs 1994; Morgan et al., 2006). Therefore, distraction osteogenesis requires
when both mechanical stimuli are minimal. Therefore, the mechanobiological regulations for healing, tissue growth and stress

Fig. 3. Strain measurement by DIC method: A) before loading, B) after loading, and C) displacement vector. Morgan et al. (2010) (with permission of reuse from the publisher).
92 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100

relaxation (Morgan et al., 2006; Isaksson et al., 2007; Reina-Romo et al., Little and his colleagues described the healing process as a set of an-
2010; Rodriguez et al., 1994). Moreover, residual stress has been report- abolic (bone forming) and catabolic (bone resorbing) responses. They
ed as an important factor involved in soft and hard tissue growths outlined the two responses as a net response leading to either bone
(Cowin, 2004; Yamada and Tadano, 2013). Both mathematical formula- healing, incomplete healing, or nonunion. All mechanical, biological,
tion and experimental studies have indicated that there is a positive cor- and pharmacological stimuli activate cellular responses for either ana-
relation between tissue growth and residual stress. Hence, tissue bolic or catabolic functions. Their model investigated the effects of
growth can produce residual stress and vice versa (Rodriguez et al., changes in the magnitude or time of anabolic and catabolic responses
1994; Yamada and Tadano, 2013; Holzapfel, 2000). on bone healing, and also included factors such as BMP, PTH, and Nitro-
Bone healing is not only dependent on the magnitude and type of gen-containing bisphosphonates (N-BPs) (Schindeler et al., 2008; Little
loading, but also the rate and frequency of cyclic loading. These pa- et al., 2007).
rameters can influence the quality of healing because of the visco- Elliott et al. considered the whole fracture to be a “bone-healing
elastic properties of connective tissue (Epari et al., 2010; Goodship organ,” which works as a functional unit and responds to biological
et al., 1998; Kenwright and Goodship, 1989; Augat et al., 2001; and mechanical stimuli. They combined Wolff's law (i.e. normal
Wolf et al., 1981). Experimental studies have shown there is a rela- bone response to mechanical environment) (Wolff, 1892), Perren's
tively positive correlation between compression rate and bone strain theory (i.e. broken bone response to mechanical environment)
healing (Goodship et al., 1998; Hente et al., 2004). However, the re- (Perren, 1978), and Frost's “mechanostat” model (i.e. bone homeo-
ports on distraction and tension rate have been inconsistent. While stasis response to mechanical environment) (Frost, 1987) to create
some studies have shown that healing quality does not depend on their own model of bone homeostasis, healing, and nonunion (BHN
distraction rate (Augat et al., 2001; Hente et al., 2004), others have conceptual model). Using BHN, the behavior of “bone healing
data which indicate the opposite (Isaksson et al., 2007; Aarnes et organ” was determined with respect to the mechanical strain ap-
al., 2002; Ilizarov, 1989). One possible explanation for this inconsis- plied to the organ (Fig. 5). In BHN, the bone is in homeostatsis
tency, might be that the tissues and cells involved in bone healing are when under tolerable strain (much less than 2%). For strains greater
more sensitive to compression rather than tension. Also, endochon- than 2% and less than 100%, a fracture occurs and is considered to be
dral ossification and chondrogenesis occur only in compression, the beginning of the “bone-healing organ.” Finally, for strains above
based on mechanobiological regulation (Claes and Heigele, 1999; 100%, the “bone-healing organ” stops and fails to heal, leading to
Carter et al., 1998). Therefore, the rate of compressive loading nonunion (Elliott et al., 2016).
might be more important for the bone healing process. The conceptual models do not look at the bone healing process
through the conventional four-phase process perspective. For instance,
the model proposed by Little et al. divided the whole process in catabol-
7. Conceptual models ic and anabolic phases. The conceptual model in Elliot et al. presented
the whole process only based on strain. Although these models are sim-
Conceptual models are qualitative tools that help us better under- ple, they are straightforward and can be employed as a guide to formu-
stand the concept of bone fracture healing. Therefore, they are very use- late the healing process. For instance, the different parameters could be
ful for hypothesis formulation, experimental design, and detailed formulated into the mathematical model depending on their temporal
mathematical modeling development. Conceptual modeling simplifies catabolic and anabolic roles. In addition, interfragmentary strain can
the complex process of bone fracture healing into a simple and under- be utilized to account for healing rate in mathematical formulation.
standable theory (Pivonka and Dunstan, 2012; Pivonka and Komarova, Therefore, conceptual models are useful in formulating the temporal as-
2010). pect of healing, but are unable to incorporate spatial evolution. Howev-
Fracture healing is commonly described as a 4-phase concept: 1) er, the approximations for the temporal aspect of healing are sometimes
inflammation phase, 2) soft callus formation (cartilage form), 3) not accurate. This occurs because some biological parameters can pos-
hard callus formation (woven bone), and 4) bone remodeling (Fig. sess both anabolic and catabolic roles which depend on spatial condi-
4). The first step is the inflammatory phase where several cells and tions. In addition, strain is not the only mechanical stimulus that
materials prepare the fracture area for healing. The second step is affects the healing process. Furthermore, in the conceptual model of
the formation of soft callus (cartilage) around the fracture area. The Elliott et al., strain in the normal activity zone is less than the strain in
third step is the conversion of soft callus to hard callus (cartilage to the healing zone. Based on experimental data, in order to have a suc-
woven bone), and the final phase 4) is the remodeling of bone, cessful healing, the fracture site must be well-fixed. Consequently,
where woven bone changes to lamellar bone (Pivonka and interfragmentary strain in healing might be less than that of regular ac-
Dunstan, 2012; Einhorn and Gerstenfeld, 2015; Claes et al., 2012; tivities (Pivonka and Dunstan, 2012; Prendergast et al., 1997; McKibbin,
Pivonka and Komarova, 2010). 1978).

Fig. 4. Schematic of the 4-phase conceptual model for bone fracture healing by Pivonka and Dunstan (2012) (with permission of reuse from the publisher).
 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100 93

Fig. 5. Schematic of BHN conceptual model by Elliott et al. (2016).

8. Mathematical models 9. Biological modeling

Conceptual models give a general qualitative understanding of the In biological modeling, cellular activity, and matrix synthesis are
bone fracture healing process. However, to quantitatively describe the regulated by biological and biochemistry factors such as growth fac-
bone healing process, design of growth factor delivery, optimization of tors, chemotaxis, or haptotaxis. Temporal and spatial systems of
bone healing, and investigate different kinds of treatments or causes of nonlinear partial differential equations (PDE) describe the change
nonunion, sophisticated mathematical modeling is required (Pivonka in concentration and density of cells, ECMs, and growth factors
and Dunstan, 2012; Claes et al., 2012; Pivonka and Komarova, 2010; (Geris et al., 2008; BailÓN-Plaza and Van Der Meulen, 2001). For in-
Geris et al., 2008). Biological approaches in mathematical models consider stance, in a study by BailÓN-Plaza and Van Der Meulen (2001), cell
only the effects of growth factors, cell density, chemotaxis, haptotaxis, or density was determined using the haptotactic and haptokinetic mi-
other factors affecting cellular activities and matrix synthesis in bone gration speed, cell proliferation rate, and cell differentiation rate as
healing (Geris et al., 2008; BailÓN-Plaza and Van Der Meulen, 2001). In a function of growth factor concentration. In this study, Bailon-
contrast, mechanobiological approaches consider the effects of mechani- Plaza et al. considered only the haptotaxis effects on cell migration.
cal loading on the cellular activities and biology of healing bone (Lacroix Geris et al. (2008) extended this formulation by adding the chemo-
and Prendergast, 2002; Isaksson et al., 2006a). Some mechanobiological tactic effects on cellular activities and migration (Fig. 6-A). The che-
approaches aim to combine both models together and consider the effects motaxis effects, in addition to the haptotaxis effects, enhanced bone
resulting from biological factors and mechanical loading on healing healing in simulation as well as the distribution of bone density dur-
(Bailón-Plaza and van der Meulen, 2003; Geris et al., 2010b). ing bone healing.

Fig. 6. Schematic of mathematical modeling: A) developed by Geris et al. (2008) and B) developed by Carlier et al. (2012) (B-1: scale map and B-2: model) (with permission of reuse from
the publishers).
94 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100

The abovementioned models simulated bone healing at the tissue Similar to biological modeling, bone healing has been investigated
level; however, Carlier et al. (2014, 2012) simulated bone healing in tis- through discrete lattice-based mechanobiological modeling (Byrne et
sue at the cellular and intra-cellular levels (Fig. 6-B) (Peiffer et al., 2011). al., 2011; Checa and Prendergast, 2009; Khayyeri et al., 2009). Instead
Incorporating cellular and intra-cellular level simulation provided the of solving PDEs, mechanobiological modeling simulates cell migration,
opportunity to investigate cell movement and vascular sprouting direc- vascular network redevelopment, and other cellular activities. These
tion in a discrete space (i.e. lattice-based space). In an agent-based are tracked in a lattice based model, and regulated by mechanical and
model, Buenzli et al. (2012) tracked osteoclast activities such as migra- biological factors. As an additional benefit, stochastic movement of
tion, proliferation, bone resorption, and apoptosis in a lattice-based dis- cells can be inserted in the model, and activities of each cell can be
crete space. Simulation at the cellular level could individually track and tracked (Checa and Prendergast, 2009).
control each cell or capillary. Therefore, this methodology will be suit- Fuzzy logic mechanobiological modeling is another methodology to
able if the pattern of cellular activities or an angiogenesis map is the simulate bone healing. Fuzzy logic methodology is a set of if-then rules
goal (Carlier et al., 2012; Buenzli et al., 2012). (i.e. if a premise is true, then there is a consequent) to formulate condi-
Although biological models simulate a spatial and temporal evolu- tional statements based on “degrees of truth” instead of usual “true or
tion in bone healing biology, they neglect the mechanical parameters false”. In fuzzy logic modeling of bone healing, the mechanobiological
which undeniably affect the bone healing process. Thus, they are not regulations are simulated by fuzzy rules and the mechanical stimulus
able to explain mechanical bone healing issues including fixation, calculations can be performed by FE analysis (Shefelbine et al., 2005;
interfragmentary stability or rate of loading effects on union or non- Simon et al., 2003; Ament and Hofer, 2000). Fuzzy rules provide a rather
union. Nonetheless, biological models provide detailed mathematical qualitative expression of mechanobiological regulation and preclude
equations for biological processes and factors, which can be combined the need to solve sets of several nonlinear PDEs Wehner et al. (2012,
with mechanical parameters to be employed in mechanobiological 2010).
modeling. Also, these models might better formulate some healing pro-
cesses such as cell migration or growth factor effects, since they depend
more on biological parameters rather than the mechanical environment 11. Mechanical stimulus
(Pivonka and Dunstan, 2012).
There are some well-known mechanobiological formulations, such
as those introduced by Prendergast et al. (1997), 3 et al. (Carter et al.,
10. Mechanobiological modeling 1998), and Claes and Heigele (1999), which employ different mechani-
cal stimuli such as shear strain (or other strain), hydrostatic pressure,
Due to the computational complexity of modeling mechanical and and fluid velocity. In stress-strain tensor algebra, there are two
biological components simultaneously in fracture healing, progress in deviatoric and volumetric components. Octahedral shear strain, derived
its implementation has been successful only in recent years. A primary from the deviatoric part, contributes to shape distortion and hydrostatic
limitation, when considering both the mechanical and biological as- pressure, derived from the volumetric part, contributes to the volume
pects, is that is it necessary to solve a series of PDEs and formulate a change (Shames, 1997). Because bone and other tissues involved in
FE implementation within an iterative procedure (Isaksson, 2012; bone healing are biphasic, some studies introduced fluid velocity in-
Anderson et al., 2014; Betts and Müller, 2014). stead of hydrostatic pressure as the mechanical stimulus (Prendergast
To the best of our knowledge, Lacroix et al. (2002) and Lacroix and et al., 1997). Based on the mechanics of biphasic materials, fluid velocity
Prendergast (2002) were the first group to develop a mechanobiological is proportional to the hydrostatic pressure gradient (Dorfmann and
model of bone healing. Typically, the process of mechanobiological Ogden, 2015). Fluid velocity is also a time dependent parameter. Thus,
modeling starts from the initial phase (granulation tissue) at the frac- the effects of time dependent factors such as loading rate on bone
ture site. Mechanical parameters such as stress, strain, pressure, and healing can be investigated using fluid velocity instead of hydrostatic
fluid velocity are then calculated utilizing a FE analysis. Subsequently, pressure (Lacroix and Prendergast, 2002; Prendergast et al., 1997;
the calculated mechanical parameters regulate the biological processes, Epari et al., 2010).
which include cellular activity and tissue formation, by solving the PDEs Implementation of different mechanical stimuli in bone healing sim-
corresponding to the biological processes of interest. As a general ex- ulations can lead to different results. Isaksson et al. (2006a, 2006b) re-
pression, higher values of mechanical loading and deformation lead to ported that simultaneously utilizing both deviatoric strain and fluid
the formation of fibrous tissue, and lower values lead to bone formation. velocity led to a better and more compatible result with experimental
By allowing new tissue formation and updating the tissue type, material data. Ribeiro et al. (2014) also found that combining interfragmentary
properties and geometry are revised in each iteration and are used for strain and the second invariant of deviatoric gap strain tensor as me-
calculations of the mechanical parameters in the next iteration (Fig. 7) chanical stimuli with inflammatory factors as chemical stimuli,
(Pivonka and Dunstan, 2012; Isaksson, 2012; Irandoust and Muftu, achieved the callus shape most compatible with histological data. In ad-
2015; Irandoust and Muftu, 2014). dition, when axial, shear, or torsion loading are applied to the bone dur-
ing healing, a different set of mechanical stimuli should be utilized to
predict bone healing that is consistent with experimental data. Hence,
the selected mechanical stimuli in mechanobiological modeling depend
on the mechanical environment during the bone healing process
(Isaksson et al., 2006b; Epari et al., 2006).
Experimental studies have shown that healing rate is not always lin-
ear during the whole process (Comiskey et al., 2010). Therefore, the
consideration of different patterns for tissue formation, MSCs differenti-
ation or growth factor secretion rates can improve bone healing simula-
tion. For instance, Alierta et al. investigated the different patterns of
tissue formation in each healing zone as a result of mechanobiological
regulations. In the zone corresponding to chondrogenesis, healing (i.e.
tissue formation) has an exponential relationship with the time, and
in the zone corresponding to bone formation, healing has a linear rela-
Fig. 7. Schematic of a general mechano-bioregulatory model. tionship with the time (Fig. 8) (Alierta et al., 2014, 2015.
 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100 95

Fig. 8. exponential and linear patterns of healing in chondrogenesis and bone formation zones of mechanobiological regulations, respectively, presented by Alierta et al. (2014).

Moreover, some threshold should be assigned to the mechanical employed different mechanobiological regulations, material models,
stimulus to determine the type of differentiated tissue. For instance, and experimental data to set their selected thresholds, this reveals sig-
when shear strains are lower than a determined threshold, bone tissue nificant inconsistencies in the modeling process.
will be formed; otherwise, cartilage tissue will be formed instead. The Ribeiro et al. (2014) utilized optimization algorithms to investigate
threshold magnitudes of mechanical stimulus could be determined the effects of different mechanical and chemical stimulus on callus
through experimental data or based on an optimization process in shape and stability. After studying different regions of the callus under
which some aspects of bone healing such as healing rate would desig- each stimulus, they concluded that callus growth can be an optimal re-
nated as the optimized variable (Lacroix et al., 2002; Isaksson et al., sponse to the local mechanical instability and inflammatory reaction.
2006a). Mechanical stimulus thresholds can also depend on the animal Wilson et al. (2015) showed that mechanical stimuli such as deviatoric
or bone size. In a comparison of mechanobiological models in sheep ver- and dilatational strain could also affect the pattern of bone formation
sus rat, Checa et al. (2011) suggested higher thresholds for larger ani- (i.e. start point and direction of bone formation) in initial callus and sub-
mals, while Wehner et al. (2014) implemented higher thresholds for sequent hard callus development. Repp et al. (Vetter et al., 2012; Vetter
smaller animals. Since Wehner et al. (2014) and Checa et al. (2011) et al., 2010; Repp et al., 2015) investigated three scenarios of

Fig. 9. Mechanobiological regulations by Prendergast et al. (1997) without bone resorption (a) and with bone resorption (b).
96 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100

mechanical stimulus regulations including: 1) A time delay between the 14. Clinical application
mechanical stimulation of cells and tissue formation, 2) variable and
bell shaped thresholds instead of step function for mechanical stimulus, The final goal of bone healing simulation and modeling is to be
and 3) an alteration of mechanical stimulus during bone healing. All employed for clinical applications such as assessing diagnosis and treat-
three of these had the largest effect on cartilage formation, as opposed ment strategies. The limitations involve a scope mismatch between
to other tissues. existing models and clinical requirements, limited quantitative experi-
mental data, and lack of human case studies for clinical applications
(Carlier et al., 2015a). A model should be predictive, case sensitive,
12. Steps of healing included in simulation and adjustable for different individuals (Khayyeri et al., 2011;
Khayyeri et al., 2015).
In bone healing simulations, either all or a subgroup of the four bone
healing processes (i.e. inflammation phase, soft callus, hard callus and
remodeling) can be considered. Some studies have focused only on
soft callus or hard callus by utilizing a predefined, fixed callus geometry
in their simulation (Carlier et al., 2014; Bailón-Plaza and van der
Meulen, 2003; Geris et al., 2010b; Checa and Prendergast, 2009). How-
ever, a number of researchers have included callus resorption in the re-
modeling phase of their bone healing simulation (Lacroix and
Prendergast, 2002; Isaksson et al., 2006a; Irandoust and Muftu, 2015;
Shefelbine et al., 2005). Hence, if the level of loading falls under a certain
threshold, there will be bone resorption and eventual callus resorption
at the end of the bone healing simulation (Fig. 9). However, this remod-
eling simulation algorithm covers only geometry and does not include
structure remodeling or directional mechanical properties in bone.
On the other hand, simulations of the initial bone healing phases,
such as inflammation, granulation tissue formation, and callus develop-
ment have not been frequently modeled (Isaksson et al., 2007;
Gómez-Benito et al., 2005a; Ribeiro et al., 2015). This may be partly
due to mechanical factors playing a lessor role in this phase, while bio-
logical and chemical factors are much more significant (Pivonka and
Dunstan, 2012; Claes et al., 2012). Furthermore, the material properties
of the hematoma and granulation tissues have also not been completely
established (Isaksson et al., 2006b). Callus development, as a transient
state from the inflammatory phase to the soft callus formation phase,
has been simulated through a pseudo volume expansion, made possible
by thermal expansion (Gómez-Benito et al., 2005a; Gómez-Benito et al.,
2005b) or application of a swelling pressure (Isaksson et al., 2007).

13. Angiogenesis

Proper vascular regeneration is a key factor in bone healing (Martin

et al., 1998). Shefelbine et al. (2005) considered angiogenesis for the
first time in healing bone healing simulation by developed with a
fuzzy logic controller. Geris et al. (2008, 2010b, 2010c) proposed PDEs
for endothelial cellular activities, vascular matrix synthesis, and angio-
genesis growth factor such as VEGF. Carlier et al. (2015b) improved
the angiogenesis effects by introducing oxygen to bone healing simula-
tions. Oxygen dependent cellular activities include cell differentiation,
endochondral ossification, cell proliferation, oxygen consumption, pro-
duction of growth factors, and cell death.
Checa and Prendergast (2009) utilized a lattice-based model to de-
velop two sets of mechanobiological regulations for bone healing and
angiogenesis, which involved sprout branching and sprout growth. In
their angiogenesis algorithm (Fig. 10), sprout growth and branching
were regulated by mechanical stimuli and biochemical parameters
such as a growth factor gradient and sprout length. Having separate
mechanobiological regulations for angiogenesis offered the possibility
of studying factors, diseases, and treatments for bone that were influ-
enced by angiogenesis (Checa and Prendergast, 2009; Checa et al.,
2011; Checa and Prendergast, 2010). Although consideration of another
mechanobiological regulation for angiogenesis complicates the simula-
tion, it could provide a map of vascular network evolution during the
healing process. The effects from the mechanical environment on
different aspects of angiogenesis could then also be involved in the Fig. 10. Algorithm of model for angiogenesis of bone fracture healing by Checa et al. (Checa
simulation. and Prendergast, 2009) (with permission of reuse from the publisher).
 M.S. Ghiasi et al. / Bone Reports 6 (2017) 87–100 97

Fig. 11. Study of fixation stability via modeling and experimental study by Wehner et al. (Wehner et al., 2010) (with permission of reuse from the publisher).

Interfragmentary fixation has been investigated by different simula- Parametric studies have been employed to determine the sensitivity
tion research efforts. Gomez-Benito et al. (Gómez-Benito et al., 2005b) and importance of different parameters such as cellular characteristics,
studied the effects of external fixation stiffness on the shape and tissue angiogenesis factors, or material properties in the many aspects of
distribution of calluses. In a human case study, Wehner et al. (Wehner et bone healing, which include sequential healing events, bone formation
al., 2010) studied the effects of fixation stability and interfragmentary quantity, mechanical stability, and healing time (Checa and
movement through both simulation and experimentation on a fractured Prendergast, 2009; Geris et al., 2006; Isaksson et al., 2008a; Isaksson et
tibia. In their experimental study, fixation stability could be adjusted by al., 2008b; Isaksson et al., 2008c; Isaksson et al., 2009). Parametric stud-
altering the length of the fixator. An asymmetric fracture geometry was ies improve simulation quality and experiments by testing which pa-
considered to be compatible with the patients' fracture geometry (Fig. rameters are important and which can be neglected in the simulation
11). In agreement with clinical observations, they reported that lower (Isaksson, 2012).
fixation stiffness led to larger callus and longer healing time (Wehner
et al., 2010; Gómez-Benito et al., 2005b). Modeling can be employed
for implant modifications to achieve optimal design. For instance, 15. Summary and future directions
Wehner et al. (Wehner et al., 2012; Wehner et al., 2014; Wehner et
al., 2011) suggested that a stiffer and thicker nailing implant could In this article, we focused on the bone fracture healing process and
lead to quicker healing. the biological and mechanical factors involved in it. In the past decade,
Determining appropriate interfragmentary gap size is another chal- several well-known investigations have considered both mechanical
lenging clinical issue for optimal bone healing. Interfragmentary gap and biological perspectives to analyze and simulate the bone healing
size can affect the mechanism of bone healing (i.e. intramembranous process. Mechanobiological modeling helps us understand how me-
bone formation versus endochondral bone formation) and healing chanical factors interact with biological processes, and considers both
time (Lacroix and Prendergast, 2002; Claes et al., 2012). In line with of these aspects simultaneously. This has improved the accuracy of
clinical and experimental data, simulations have shown that larger modeling predictions. Recently, due to advances in computational
gap size leads to greater instability of the fracture site, a delay in healing, modeling, the effects of different drugs, implants, healing strategies,
and possible nonunion (Lacroix and Prendergast, 2002; Carlier et al., and injection of growth factors in fracture sites have been studied. How-
2014). Isakson et al. (Isaksson et al., 2007) simulated distraction osteo- ever, there are a number of unknown parameters and mechanisms like
genesis as a means to create controlled increases of gap size, which con- the role of growth factors in healing, the mechanism of cellular activi-
sequently increased bone length. They reported that a decrease in ties, and angiogenesis in bone healing that have yet to be incorporated
distraction rate led to longer healing time. Ultimately all simulation re- into modeling efforts.
sults need to be verified by experiments and clinical observations To the best of our knowledge, there is no comprehensive simulation
(Carlier et al., 2015a). and model for bone fracture healing that encompasses all the phases of
Computational modeling of bone healing can be useful in investigat- healing, from inflammation to remodeling. Due to its nonlinearity and
ing the effects of growth factors or cell treatments. First, a computation- complexity, the initial phase of bone healing has been mostly excluded
al model (i.e. biological or mechanobiological models) is developed and from past simulations or has been only considered linearly. In addition,
validated. Different scenarios of injection, seeding, and production of the bone remodeling phase has its own special theories with different
growth factors or cells are simulated through the validated model simulation methodologies and different external loading regimens. By
(Carlier et al., 2015a; Geris et al., 2010a), which allow the study of differ- considering bone fracture healing as a whole package and simulating
ent aspects such as dosage and density effects (Geris et al., 2008; Checa it from beginning to the end, it can help provide us a better understand-
and Prendergast, 2010; Geris et al., 2006), injection location, mode of ing of the process and contribute to our understanding of each phase.
seeding (i.e. uniform or peripheral seeding) (Checa and Prendergast, Furthermore, the introduction of optimization and artificial intelligence
2010), type of growth factors (i.e. chondrogenic growth factors such algorithms may help improve the accuracy of models and outline novel
as BMP-2/4 or osteogenic growth factor such as TGF-β1) (Geris et al., and optimal treatment strategies.
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