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Physical stimulations and their osteogenesis-inducing mechanisms
[74]
stem cells was controlled by the electric field intensity . osteoclast cell counts. Korstjens et al. [85] found that
Banks et al. [75] were also verified this viewpoint, and low intensity pulsed ultrasound (1.5 MHz, 30 mW/
2
found that the bone mesenchymal stem cells became cm ) treated at 20 min/day for 3 or 6 days significantly
significantly elongated and were perpendicular to the increased the bone collar volume and calcified cartilage.
electric field vector. Creecy et al. [76] exposed bone It was worth noting that ultrasound stimulation
mesenchymal stem cells to either 10 or 40 mA alternating displayed pronounced biological effects on cells which
electric current for 6 h/day, and they found that the cultured on 3D printed bone scaffolds [62,86,87] . Zhou
stimulations significantly increased the gene expressions et al. investigated the effects of low intensity pulsed
of osteopontin, osteocalcin and runt-related transcription ultrasound on human bone marrow mesenchymal stem
factor 2, thereby promoting the differentiation of cells seeded on hydroxyapatite scaffolds, and they found
bone mesenchymal stem cells to osteoblasts. Wang et that the ultrasound stimulation combined with scaffolds
al. [77] reported that direct current electric stimulation significantly improved the alkaline phosphatase activity
[86]
promoted bone mesenchymal stem cells migration. The and calcium deposition .
optimal intensity and duration were 200 mV/mm and 4 The mechanical stresses with various peak stress
h, respectively, and they up-regulated the osteocalcin, amplitude, frequency and duration have different
alkaline phosphatase and runt-related transcription factor influences on cell behaviors. Bone cells could distinguish
2 expressions which benefited to bone mesenchymal different stress magnitude and adjust the bio-chemical
stem cells proliferation and differentiation. In addition, response accordingly. Tang et al. [88] investigated the
some scholars investigated the cell responses to bioeffects of cyclic stretching (500 , 1000 and 1500 )
electrical stimulation which combined with 3D printed on osteoblasts. The results indicated that the stretching
bone scaffolds [78,79] . Grunert et al. studied the effects of at 500 increased osteoblast collagen synthesis, while
electric stimulation on osteoblasts which cultured on 3D the stretching at 1000 and 1500 inhibited collagen
printed calcium phosphate/collagen composite scaffolds. production, indicating that the response of osteoblasts
The results indicated that the stimulation promoted the was dependent on the stretching magnitude. Jagodzinski
[78]
[89]
proliferation and differentiation of osteoblasts . et al. proved the mechanical strain with an elongation
of 2% and 8% increased the alkaline phosphatase
3.3 Mechanical Stimulation on Bone Cells levels and osteocalcin secretion of mesenchymal stem
The mechanical stimulation is mainly including the cells after loading 4 days, and the increased rate of
ultrasonic stimulation and mechanical stress stimulation. 8% stretching group was higher than 2% stretching
The ultrasound is a high frequency mechanical wave group. Kearney et al. [90] found that the 2.5%, 0.17 Hz
which can be transmitted into biological tissues to cyclic tensile mechanical strain obviously reduced
produce biochemical reactions [80] . Mechanical stresses mesenchymal stem cells proliferation after 2 and
are mainly divided into compressive stress, tensile 3days, and increased the expression of transcription
stress and fluid shear stress. The effects of mechanical factor Cbfa1, osteocalcin, collagen type I and bone
stimulation on bone cells mainly depend on loading morphogenetic protein-2 which related to osteogenic
[91]
mode, intensity, frequency and duration. The low differentiation (Figure 3A). Sanchez et al. reported the
2
intensity pulsed ultrasound (< 100 mW/cm ) could cyclic compression stress (1 MPa at 1 Hz) significantly
modulate the proliferation and differentiation of increased the genes expression of cyclooxygenase 2,
osteoblasts and osteoclast through regulating bone- interleukin-6, receptor activator of nuclear factor κB
related gene expressions, and the regulatory effects were ligand, etc. which involved in bone remodeling and
[83]
related with intensity [21,81,82] . Yang et al. examined the bone formation. Li et al. [92] investigated the bioeffects
effect of ultrasonic stimulation with different intensities of different oscillating frequencies, peak shear stress
2
2
2
(62.5 mW/cm , 125 mW/cm and 250 mW/cm ) on amplitudes, and total flow durations on osteocyte
the osteoblasts differentiation and osteoclastogenesis. activity. The results indicated that the three dynamic
2
The results indicated that the 125 mW/cm ultrasound fluid flow parameters could regulate the osteocyte
at obviously enhanced the mineralization, collagen activity, and faster oscillating frequencies, higher peak
synthesis and alkaline phosphatase activity of shear stress amplitudes and longer loading durations
osteoblasts. Moreover, low intensity pulsed ultrasound were beneficial to bone formation. Liu et al. [93] proved
2
at 62.5 and 125 mW/cm significantly inhibited the that fluid shear stress at 1.6 and 1.9 Pa significantly
formation and differentiation of osteoclasts. Sun et induced the cell elongation and reorientation parallel
al. [84] reported that low intensity pulsed ultrasound (1 to the direction of fluid flow, indicating that the fluid
2
MHz, 68 mW/cm ) obvious increased the osteoblast cell shear stress could influence the cell growth direction. Li
2
counts and alkaline phosphatase level after ultrasonic et al. [94] found that the fluid shear stress at 12 dyn/cm
stimulation for 7 days, and significantly reduced the could reorganize the cytoskeleton in MC3T3-E1 pre-
6 International Journal of Bioprinting (2018)–Volume 4, Issue 2