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Journal of Molecular and Clinical Medicine  2018, Vol. 1 Issue (2): 107-114    DOI: 10.31083/j.jmcm.2018.02.012
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Low Intensity Pulsed Ultrasound for Accelerating Distraction Osteogenesis: A Systematic Review of Experimental Animal Studies
Jiriys George Ginini1, 2, *(), Dekel Shilo2, Omri Emodi1, 2, Adi Rachmiel1, 2
1 Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 31096, Israel
2 Department of Oral & Maxillofacial Surgery Rambam Health Care Campus, Haifa, 31096, P.O.B 9602, Israel
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Abstract  

The purpose of this report is to review systematically all studies performed regarding the influence of low intensity pulsed ultrasound (LIPUS) on bone regeneration in animals during distraction osteogenesis (DO). Based on the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) checklist structure, a systematic search using PubMed and EMBASE electronic databases was undertaken utilizing the key words "distraction osteogenesis" and "low intensity ultrasound". Human trials, review articles, case reports and non-English language publications were excluded. Data items were extracted from each eligible study, regarding the study design, risk of bias, results and whether or not LIPUS accelerated bone regeneration. The search identified 40 relevant articles, 15 of which were included for full review. Included studies were characterized by a high risk of bias and considerable variations in study design was observed. However, most studies which reported LIPUS in an intensity of 30-40 mW/cm$^2$ accelerated bone formation via endochondral ossification, thus shortening the consolidation period when applied during distraction and early consolidation periods. According to the current review, application of LIPUS during DO shows promise in accelerating bone formation and density during DO, that bears no adverse effects, thus shortening the consolidation period. Optimal timing of LIPUS application is during the distraction and early consolidation phases. The preferred intensity should be between 30-40 mW/cm$^2$. Histological analysis indicates influence via endochondral ossification. Thus, the effect of LIPUS on chondrocytes should be further investigated in order to decipher the exact molecular and cellular influence of LIPUS on enhancement of bone formation. These findings should be used in future clinical protocols and raise potential directions for future research regarding the molecular mechanisms underlying the influence of LIPUS on bone formation.

Key words:  Distraction osteogenesis      LIPUS      Review     
Submitted:  21 January 2018      Revised:  07 February 2018      Accepted:  09 February 2018      Published:  20 April 2018     
*Corresponding Author(s):  Jiriys George Ginini     E-mail:  jiriysginini@technion.ac.il

Cite this article: 

Jiriys George Ginini, Dekel Shilo, Omri Emodi, Adi Rachmiel. Low Intensity Pulsed Ultrasound for Accelerating Distraction Osteogenesis: A Systematic Review of Experimental Animal Studies. Journal of Molecular and Clinical Medicine, 2018, 1(2): 107-114.

URL: 

https://jmcm.imrpress.com/EN/10.31083/j.jmcm.2018.02.012     OR     https://jmcm.imrpress.com/EN/Y2018/V1/I2/107

Table 1  Summary of the study design of included studies.
Animal Bone model Groups Latency Distraction Distraction Consolidation LIPUS LIPUS LIPUS Study
species period rate period period (Days) application intensity duration reference
(Days) (mm/d) (Days) period (mW/cm2) (min/day)
64 rabbits Tibia 1. Control 2. LIPUS 7 1 10 7, 14 or 21 Consolidation 30 20 [10]
18 sheep Metatarsal 1. Control 2. LIPUS 4 1 15 63 Consolidation 30 20 [11,12]
26 rabbits Tibia 1. Control 2. LIPUS 7 1 10 20 Consolidation 30 20 [13]
20 rabbits Tibia 1. Control 2. LIPUS 7 1 10 20 Consolidation 30 20 [14]
21 rabbits Mandible 1. Control 2. Bilateral LIPUS every other day 3. Unilateral LIPUS daily 3 2 5 28 Consolidation 30 20 [15]
34 rats Femur 1. Control 2. LIPUS 7 0.334 21 35 Consolidation 30 20 [16]
34 rabbits Tibia 1. Control 2. LIPUS 1 0.75 14 28 Consolidation 30 20 [17]
75 rabbits Tibia 1. Control 2. LIPUS at latency
3.LIPUS at distraction
4.LIPUS at consolidation
7 1.5 7 14 Latency, distraction or consolidation 30 20 [18]
17 rabbits Tibia 1. Control 2. LIPUS 7 1 18 28 Consolidation 30 20 [19]
18 rabbits Tibia 1. Control 2. 20 min/day LIPUS 3. 40 min/day LIPUS 7 2 6 Not mentioned Distraction 30 20 and 40 [20]
44 rabbits Tibia 1. Control 2. LIPUS 7 1 10 10or 20 Distraction and early consolidation 30 20 [21]
36 rabbits Mandible 1. Control 2. LIPUS 3. Continuous ultrasound 3 3 5 7, 14 or 21 Consolidation 30 20 [22]
7 dogs Mandible 1. Control 2. LIPUS 7 1 20 0, 7,14, 28, 42, 56 or 84 Distraction 40 10x2 [23,24]
24 rabbits Mandible 1. Control 2. LIPUS 3 1 10 0, 14 or 28 Distraction and consolidation 30 20 [25]
15 rabbits Mandible 1. Control 2. LIPUS 3. Laser 7 1 10 13or 43 Distraction 30 20 [26]
Table 2  Summary of assessment methods, main results and accelerated regeneration of included studies
Assessment methods Results
regeneration
Accelerated Study reference
Radiography, DEXA (BMD), Mechanical test, Histology Radiography, BMD and mechanical tests significantly greater in LIPUS. Yes [10]
Radiography, qCT (BMD), Mechanical test, Histology BMD, BMC, stiffness and callus formation were significantly higher in LIPUS. Yes [11,12]
Radiography, DEXA (BMD), Mechanical test, Histology BMD higher in LIPUS but no significant difference. Stiffness and strength not significant. Radiographically significantly larger callus in LIPUS. Histology significant less fibrous tissue in LIPUS No [13]
Radiography, DEXA (BMD), Mechanical test, Histology BMD showed no significant differences. Torsional strength was significantly higher in control. Histologically, LIPUS displayed more cartilage and fibrous tissue formation No [14]
Radiography, Vibratory coherence, Mechanical test, Histology BMD, vibratory, stiffness and histology were significantly higher in LIPUS groups, especially in daily unilateral LIPUS treatment. Yes [15]
Radiography, pCT(BMD), Mechanical test Radiography higher density in LIPUS. Bone volume fraction significantly higher in LIPUS. BMD and BMC slightly higher in LIPUS. LIPUS group stiffer and stronger (not significant) Yes [16]
qCT (BMD), Mechanical test, Histology BMD, BMC, cross-sectional area and strength showed no significant differences. Histology showed no differences in bone volume fraction No [17]
Radiography, DEXA (BMD), Mechanical test, y,CT Lengthening group had significantly greater BMD and mechanical strength. 3D-CT: more accelerated bone formation. Bone regeneration was enhanced more in the LIPUS applied at lengthening group. Yes [18]
Radiography (BMD), qCT, Mechanical test BMD, BMC and Bone scan index were significantly greater in LIPUS at 2 weeks of consolidation, but not at 4 weeks. The maximum torque was smaller in LIPUS. Yes [19]
Radiography, qCT (BMD), Histology BMC of both LIPUS groups was greater than the control group in a dose-dependent manner. BMD showed no significant differences in LIPUS groups. Histology: LIPUS enhanced endochondral formation in a dose-dependent manner. Yes [20]
Radiography, Mechanical test, Histological No differences in bone mineral appositional rates or tissue composition. No difference in structural stiffness. No [21]
qCT, Mechanical test, Histology BMD in the first 2 weeks was higher in Continuous US > LIPUS > Control. BMD in 3rd and 4th weeks LIPUS > Continuous US > Control. Mechanical test was higher in LIPUS > Continuous US > Control group. Histology: more bone volume and fraction in LIPUS > Continuous US > Control Yes [22]
Radiography, mTc-MD bone imaging, DEXA (BMD), CT, Histology Higher 99mTc-MDP uptake in LIPUS group at the early consolidation. Radiography: earlier maturation of bone, higher BMD in LIPUS group. Histology: thicker trabeculae and endochondral bone formation Yes [23,24]
Radiography, pCT, Mechanical test, Histology Mechanical tests, bone microhardness and radiopacity were significantly higher in LIPUS at early consolidation. At week 4 after the distraction - no significant differences. Yes [25]
DEXA (BMD) BMD was significantly higher in LIPUS compared to control at early consolidation. BMD in laser group was significantly increased at late consolidation. Yes [26]
Table 3  Methodological quality and risk of bias of included studies
Randomization Investigators blinding Assessor blinding Attrition bias Reporting bias Risk of bias Study reference
No No No Yes Yes High [10]
No No Yes No Yes High [11,12]
Yes No No Yes Yes High [13]
Yes No Yes Yes Yes High [14]
No No No Yes Yes High [15]
Yes No No Yes Yes High [16]
No No No Yes Yes High [17]
No No No No Yes High [18]
No No No No Yes High [19]
No No Yes Yes Yes High P0]
Yes No No Yes Yes High P1]
No No No Yes Yes High P2]
No No No Yes Yes High [23, 24]
Yes No No Yes Yes High [25]
Yes No No Yes Yes High [26]
Fig. 1.  Flow chart of the systematic search stratergy.

Fig. 2.  Summary of the suggested effects of LIPUS on DO. The physical energy transmitted by the transducer of the LIPUS is converted into biological response, leads to up-regulation of growth factors via endochondral ossification.

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