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Shuai C, et al.

improve permeability of cell membrane, thereby stimulation could activate various signaling pathways
contributing the extracellular ions to pass through cell when the stimulation acted on bone cells, and trans-
[33]
membrane to enhance cell activity . (2) Improving cell duce the extracellular mechanical signals into the
membrane permeability: Phospholipid molecules on cell corresponding biochemical signals, such as Wnt
membrane possess diamagnetic anisotropy, they could be receptors, integrins, insulin-like growth factor, G pro-
[35]
suffered magnetic field force, then rotated and orientated teins and calcium ion channel , etc. (Figure 1), thereby
along the direction of the magnetic fields which caused inducing a series of gene expression to promote bone
the expansion of ion channels on cell membrane [36,37] . cell proliferation, differentiation, apoptosis [54,55] . (2)
Therefore, numerous ions could pass through the Mechanical stimulation could activate the calcium
cell membrane, and thus increasing conductivity and ion channel on cell membrane which could induce the
inducing much powerful current which produced a extracellular calcium ion flow into the cell to increase
series of bioeffects to promote bone formation [38] . (3) the intracellular calcium concentration, thereby con-
Regulating calcium ions concentration: Calcium ions ducing to bone healing [56,57] . (3) The pressure wave
were the basic substance of all cells, which could affect produced by the ultrasound could enhance the fluid flow
the activity of intracellular enzymes, participate in cell in the fracture area to increase the supply of nutrients
signal transduction, regulate cell metabolism and cell and the removal of metabolites, and thus contributing
activity, etc. [39,40] Magnetic fields could activate calcium to the proliferation and differentiation of osteoblasts
ion-dependent protein kinase by altering calcium ions and fibroblasts [58] . (4) Bone tissues possess abundant
level, further regulate nuclear factors including cyclin interconnected microchannels, mechanical stress could
which played a regulatory role in osteoblasts [41,42] . produce strain gradients and cause ionic current flow
(4) Activating the cyclic adenosine monophosphate along the microchannels, which played an important role
[59]
system: Magnetic stimulation could activate the cyclic in the process of mechanotransduction .
adenosine monophosphate system, and then activate 3. The Effects of Physical Stimulations on
various enzyme systems which could induce bone cells
to produce special physiological functions, thereby Bone Cells
accelerating bone growth . The effectiveness of physical stimulations in bone
[43]
2.2 Electric Stimulation repair has been investigated in vitro and in vivo. It was
proved that physical stimulations could promote bone
The osteogenesis-inducing mechanisms of electric mesenchymal stem cells differentiate to osteoblasts,
stimulation were explained as follows: (1) Inducing accelerate osteoblasts proliferation and differentiation,
inverse piezoelectric effect: When an electric field was and inhibit osteoclasts formation, thereby contributing to
applied to bone defect sites, the stress and strain could bone repair and regeneration.
be generated between the anode and cathode of the
defect sites which could produce electric signals, thereby 3.1 Magnetic Stimulation on Bone Cells
regulating bone cell behaviors [34] . (2) Up-regulating The studies of magnetic stimulation used to stimulate
calcium level: Electric field could facilitate the calcium bone cells were mainly focused on the static magnetic
[44]
salt to move to the cathode , and elevate intracellular field and pulse electromagnetic field. In general, static
calcium level by promoting extracellular calcium ion magnetic field could promote osteoblasts proliferation
influx into cells, thereby accelerating cells proliferation and differentiation as well as inhibited osteoclasts
and bone tissue calcification and mineralization [14,45–49] . formation, thereby promoting the process of bone
(3) Regulating growth factors: Electrical stimulation repair [60] . Moreover, the strong static magnetic field
could regulate the expression of growth factors, such as (> 1 T) could regulate the orientation of bone cells
insulin-like growth factors I and II, transforming growth and matrix proteins. Yamamoto et al. [61] investigated
factors, fibroblast growth factors, bone morphogenetic the effects of 0.16 T static magnetic field continuously
proteins, etc., thereby promoting bone formation [50–52] . (4) exposed 20 days on the rat calvaria cell and found that
Changing local microenvironment: Electrical stimulation static magnetic field significantly increased activity of
could improve local blood circulation and cause bio- alkaline phosphatase and osteocalcin content. Zhang et
chemical changes in the microcirculation around the al. [62,63] investigated the bioeffects of 16 T static magnetic
bones and chondrocytes, such as elevated pH, thereby field on osteoblasts and osteoclasts. They found that
[53]
promoting ossification . static magnetic field enhanced osteoblast differentiation
2.3 Mechanical Stimulation determined by the formed nodules area and the calcium
deposition, and inhibited osteoclast formation evaluated
The osteogenesis-inducing mechanisms of mechanical by tartrate-resistant acid phosphatase, integrin β3,
stimulation were explained as follows: (1) Mechanical matrix metalloproteinase 9, receptor activator of nuclear

International Journal of Bioprinting (2018)–Volume 4, Issue 2 3