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CC BY 4.0 · Eur J Dent 2023; 17(02): 283-295
DOI: 10.1055/s-0042-1757466
Review Article

Temporal Pattern of micro-CT Angiography Vascular Parameters and VEGF mRNA Expression in Fracture Healing: a Radiograph and Molecular Comparison

Aga Satria Nurrachman 
1   Department of Oral and Maxillofacial Radiology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
,
Azhari Azhari
2   Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Padjadjaran University, Bandung, West Java, Indonesia
,
Lusi Epsilawati 
2   Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Padjadjaran University, Bandung, West Java, Indonesia
,
Farina Pramanik 
2   Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Padjadjaran University, Bandung, West Java, Indonesia
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Abstract

Angiogenesis plays an important role in fracture healing with vascular endothelial growth factor (VEGF) as the main protein involved. Micro-computed tomography (CT) angiography may be used to analyze this revascularization with several parameters such as number of branches, total volume, and diameter. This systematic review is aimed to assess available studies on the temporal pattern of vascular imaging on micro-CT angiographs, especially in terms of the number of branches, total volume, and diameter as well as the temporal pattern of VEGF mRNA expression as the molecular comparison during bone fracture healing. This review was conducted according to the PRISMA guidelines. Electronic database searches were performed using PubMed, ProQuest, ScienceDirect, EBSCOhost, Taylor & Francis Online, and hand searching. The search strategy and keywords were adjusted to each database using the Boolean operators and other available limit functions to identify most relevant articles based on our inclusion and exclusion criteria. Screening and filtration were done in several stages by removing the duplicates and analyzing each title, abstract, and full-text in all included entries. Data extraction was done for syntheses to summarize the temporal pattern of each parameter. A total of 28 articles were eligible and met all criteria, 11 articles were synthesized in its angiograph's analysis, 16 articles were synthesized in its VEGF mRNA expression analysis, and 1 article had both parameters analyzed. The overall temporal pattern of both three micro-CT angiographic parameters and VEGF mRNA expression was in line qualitatively. The number of branches, total volume, and diameter of the blood vessels in micro-CT angiography showed an exponential rise at week 2 and decline at week 3 of fracture healing, with the VEGF mRNA expression concurrently showing a consistent pattern in the phase.

Keywords

fracture healing - micro-CT angiography - VEGF mRNA expression - temporal pattern

Note

The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.


Supplementary Material



Publication History

Article published online:
30 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Haagsma JA, Graetz N, Bolliger I. et al. The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013. Inj Prev 2016; 22 (01) 3-18
    CrossrefPubMedSearch in Google Scholar
  • 2 The National Institute of Health Research and Development Ministry of Health of the Republic of Indonesia. Main Results of Basic Health Research 2018; 2018. Accessed September 22, 2022, at: http://labdata.litbang.kemkes.go.id/ccount/click.php?id=19
  • 3 Khallaf M, Shahine MS. Epidemiological features of patients with craniomaxillofacial fractures: a single centre study. Open J Mod Neurosurg 2019; 09: 132-144
    CrossrefSearch in Google Scholar
  • 4 Carvalho TBO, Cancian LRL, Marques CG, Piatto VB, Maniglia JV, Molina FD. Six years of facial trauma care: an epidemiological analysis of 355 cases. Rev Bras Otorrinolaringol (Engl Ed) 2010; 76 (05) 565-574
    Search in Google Scholar
  • 5 Namirah N. Prevalensi Fraktur Maksilofasial pada Kasus Kecelakaan Lalu Lintas di RSUD Andi Makkasau Kota Pare-Pare Tahun 2013. Hasanuddin University Repository. 2014 . Accessed September 22, 2022 at: https://core.ac.uk/display/25496471
    PubMedSearch in Google Scholar
  • 6 Kairupan C, Monoarfa A, Ngantung J. Angka Kejadian Penderita Fraktur Tulang Fasial di SMF Bedah BLU RSUD RSU Prof. R.D. Kandou Periode Januari 2012 - Desember 2012. J e-CliniC 2014; 2 (02) 1-4
    Search in Google Scholar
  • 7 Christi M. Prevalensi Kasus Fraktur Maksilofasial dengan Fraktur Basis Kranii di RSUP H. Adam Malik Tahun 2014–2016. Repos Institusi USU. 2017. Accessed August 23, 2022 at: https://repositori.usu.ac.id/handle/123456789/1619
  • 8 Ghodke MH, Bhoyar SC, Shah SV. Prevalence of mandibular fractures reported at C.S.M.S.S Dental College, aurangabad from february 2008 to september 2009. J Int Soc Prev Community Dent 2013; 3 (02) 51-58
    CrossrefPubMedSearch in Google Scholar
  • 9 Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone 2016; 91: 30-38
    CrossrefPubMedSearch in Google Scholar
  • 10 Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: a review of principles and methods. Bone Rep 2017; 6: 87-100
    CrossrefPubMedSearch in Google Scholar
  • 11 Filipowska J, Tomaszewski KA, Niedźwiedzki Ł, Walocha JA, Niedźwiedzki T. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis 2017; 20 (03) 291-302
    CrossrefPubMedSearch in Google Scholar
  • 12 Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development 2016; 143 (15) 2706-2715
    CrossrefPubMedSearch in Google Scholar
  • 13 Zhao C, Popel AS. Computational model of MicroRNA control of HIF-VEGF pathway: insights into the pathophysiology of ischemic vascular disease and cancer. PLOS Comput Biol 2015; 11 (11) e1004612
    CrossrefPubMedSearch in Google Scholar
  • 14 Urao N, Okonkwo UA, Fang MM, Zhuang ZW, Koh TJ, DiPietro LA. MicroCT angiography detects vascular formation and regression in skin wound healing. Microvasc Res 2016; 106: 57-66
    CrossrefPubMedSearch in Google Scholar
  • 15 Macdonald W, Shefelbine SJ. Characterising neovascularisation in fracture healing with laser Doppler and micro-CT scanning. Med Biol Eng Comput 2013; 51 (10) 1157-1165
    CrossrefPubMedSearch in Google Scholar
  • 16 Udagawa A, Sato S, Hasuike A, Kishida M, Arai Y, Ito K. Micro-CT observation of angiogenesis in bone regeneration. Clin Oral Implants Res 2013; 24 (07) 787-792
    CrossrefPubMedSearch in Google Scholar
  • 17 Zagorchev L, Oses P, Zhuang ZW. et al. Micro computed tomography for vascular exploration. J Angiogenes Res 2010; 2 (01) 7
    CrossrefPubMedSearch in Google Scholar
  • 18 Nebuloni L, Kuhn GA, Vogel J, Müller R. A novel in vivo vascular imaging approach for hierarchical quantification of vasculature using contrast enhanced micro-computed tomography. PLoS One 2014; 9 (01) e86562
    CrossrefPubMedSearch in Google Scholar
  • 19 Baird E, Taylor G. X-ray micro computed-tomography. Curr Biol 2017; 27 (08) R289-R291
    CrossrefPubMedSearch in Google Scholar
  • 20 Keklikoglou K, Faulwetter S, Chatzinikolaou E. et al. Micro-computed tomography for natural history specimens: a handbook of best practice protocols. Eur J Taxon 2019; (522) 1-55
    CrossrefSearch in Google Scholar
  • 21 Boerckel JD, Mason DE, McDermott AM, Alsberg E. Microcomputed tomography: approaches and applications in bioengineering. Stem Cell Res Ther 2014; 5 (06) 144
    CrossrefPubMedSearch in Google Scholar
  • 22 Blery P, Pilet P, Bossche AV. et al. Vascular imaging with contrast agent in hard and soft tissues using microcomputed-tomography. J Microsc 2016; 262 (01) 40-49
    CrossrefPubMedSearch in Google Scholar
  • 23 Zhao F, Zhou Z, Yan Y. et al. Effect of fixation on neovascularization during bone healing. Med Eng Phys 2014; 36 (11) 1436-1442
    CrossrefPubMedSearch in Google Scholar
  • 24 Hooijmans CR, Rovers MM, de Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14 (01) 43
    CrossrefPubMedSearch in Google Scholar
  • 25 Chen P, Gu WL, Gong M-ZZ, Wang J, Li DQ. GIT1 gene deletion delays chondrocyte differentiation and healing of tibial plateau fracture through suppressing proliferation and apoptosis of chondrocyte. BMC Musculoskelet Disord 2017; 18 (01) 320
    CrossrefPubMedSearch in Google Scholar
  • 26 Cheung WH, Sun MH, Zheng YP. et al. Stimulated angiogenesis for fracture healing augmented by low-magnitude, high-frequency vibration in a rat model-evaluation of pulsed-wave doppler, 3-D power Doppler ultrasonography and micro-CT microangiography. Ultrasound Med Biol 2012; 38 (12) 2120-2129
    CrossrefPubMedSearch in Google Scholar
  • 27 Cottrell JA, Keane O, Lin SS, O'Connor JP. BMP-2 modulates expression of other growth factors in a rat fracture healing model. J Appl Biomed 2014; 12 (03) 127-135
    CrossrefSearch in Google Scholar
  • 28 Ding WG, Zhang ZM, Zhang YH, Jiang SD, Jiang LS, Dai LY. Changes of substance P during fracture healing in ovariectomized mice. Regul Pept 2010; 159 (1-3): 28-34
    CrossrefPubMedSearch in Google Scholar
  • 29 Ding WG, Jiang SD, Zhang YH, Jiang LS, Dai LY. Bone loss and impaired fracture healing in spinal cord injured mice. Osteoporos Int 2011; 22 (02) 507-515
    CrossrefPubMedSearch in Google Scholar
  • 30 Gilbert SR, Camara J, Camara R. et al. Contaminated open fracture and crush injury: a murine model. Bone Res 2015; 3: 14050
    CrossrefPubMedSearch in Google Scholar
  • 31 He YX, Liu Z, Pan XH. et al. Deletion of estrogen receptor beta accelerates early stage of bone healing in a mouse osteotomy model. Osteoporos Int 2012; 23 (01) 377-389
    CrossrefPubMedSearch in Google Scholar
  • 32 He Y-X, Zhang G, Pan X-H. et al. Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: A drill-hole defect model. Bone 2011; 48 (06) 1388-1400
    CrossrefPubMedSearch in Google Scholar
  • 33 Hurley MM, Adams DJ, Wang L. et al. Accelerated fracture healing in transgenic mice overexpressing an anabolic isoform of fibroblast growth factor 2. J Cell Biochem 2016; 117 (03) 599-611
    CrossrefPubMedSearch in Google Scholar
  • 34 Kidd LJ, Stephens AS, Kuliwaba JS, Fazzalari NL, Wu ACK, Forwood MR. Temporal pattern of gene expression and histology of stress fracture healing. Bone 2010; 46 (02) 369-378
    CrossrefPubMedSearch in Google Scholar
  • 35 Li L, Tang P, Zhou Z. et al. GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF-κB/Notch signalling to promote angiogenesis. Cell Prolif 2019; 52 (06) e12689
    CrossrefPubMedSearch in Google Scholar
  • 36 Li R, Nauth A, Li C, Qamirani E, Atesok K, Schemitsch EH. Expression of VEGF gene isoforms in a rat segmental bone defect model treated with EPCs. J Orthop Trauma 2012; 26 (12) 689-692
    CrossrefPubMedSearch in Google Scholar
  • 37 Li X, Sun DC, Li Y, Wu XY. Neurotrophin-3 improves fracture healing in rats. Eur Rev Med Pharmacol Sci 2018; 22 (08) 2439-2446
    CrossrefPubMedSearch in Google Scholar
  • 38 Liu X, McKenzie JA, Maschhoff CW, Gardner MJ, Silva MJ. Exogenous hedgehog antagonist delays but does not prevent fracture healing in young mice. Bone 2017; 103: 241-251
    CrossrefPubMedSearch in Google Scholar
  • 39 Martinez MD, Schmid GJ, McKenzie JA, Ornitz DM, Silva MJ. Healing of non-displaced fractures produced by fatigue loading of the mouse ulna. Bone 2010; 46 (06) 1604-1612
    CrossrefPubMedSearch in Google Scholar
  • 40 Matsumoto T, Goto D, Sato S. Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent. Lab Invest 2013; 93 (09) 1054-1063
    CrossrefPubMedSearch in Google Scholar
  • 41 McCabe NP, Androjna C, Hill E, Globus RK, Midura RJ. Simulated microgravity alters the expression of key genes involved in fracture healing. Acta Astronaut 2013; 92 (01) 65-72
    CrossrefSearch in Google Scholar
  • 42 Minkwitz S, Faßbender M, Kronbach Z, Wildemann B. Longitudinal analysis of osteogenic and angiogenic signaling factors in healing models mimicking atrophic and hypertrophic non-unions in rats. PLoS One 2015; 10 (04) e0124217
    CrossrefPubMedSearch in Google Scholar
  • 43 Qiao J, Zhou M, Li Z. et al. Comparison of remote ischemic preconditioning and intermittent hypoxia training in fracture healing. Mol Med Rep 2019; 19 (03) 1867-1874
    CrossrefPubMedSearch in Google Scholar
  • 44 Reumann MK, Nair T, Strachna O, Boskey AL, Mayer-Kuckuk P. Production of VEGF receptor 1 and 2 mRNA and protein during endochondral bone repair is differential and healing phase specific. J Appl Physiol 2010; 109 (06) 1930-1938
    CrossrefPubMedSearch in Google Scholar
  • 45 Suen PK, He YX, Chow DHK. et al. Sclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats. J Orthop Res 2014; 32 (08) 997-1005
    CrossrefPubMedSearch in Google Scholar
  • 46 Sun MH, Leung KS, Zheng YP. et al. Three-dimensional high frequency power Doppler ultrasonography for the assessment of microvasculature during fracture healing in a rat model. J Orthop Res 2012; 30 (01) 137-143
    CrossrefPubMedSearch in Google Scholar
  • 47 Wang D, Gilbert JR, Cray Jr JJ. et al. Accelerated calvarial healing in mice lacking Toll-like receptor 4. PLoS One 2012; 7 (10) e46945
    CrossrefPubMedSearch in Google Scholar
  • 48 Wilson SS, Wong A, Toupadakis CA, Yellowley CE. Expression of angiopoietin-like protein 4 at the fracture site: regulation by hypoxia and osteoblastic differentiation. J Orthop Res 2015; 33 (09) 1364-1373
    CrossrefPubMedSearch in Google Scholar
  • 49 Yin G, Sheu T-J, Menon P. et al. Impaired angiogenesis during fracture healing in GPCR kinase 2 interacting protein-1 (GIT1) knock out mice. PLoS One 2014; 9 (02) e89127
    CrossrefPubMedSearch in Google Scholar
  • 50 Yuasa M, Mignemi NA, Barnett JV. et al. The temporal and spatial development of vascularity in a healing displaced fracture. Bone 2014; 67: 208-221
    CrossrefPubMedSearch in Google Scholar
  • 51 Sengupta P. The laboratory rat: relating its age with human's. Int J Prev Med 2013; 4 (06) 624-630
    PubMedSearch in Google Scholar
  • 52 Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci 2016; 152 (152) 244-248
    CrossrefPubMedSearch in Google Scholar
  • 53 Johnson M. Laboratory mice and rats. Mater Methods 2012; 2
    CrossrefSearch in Google Scholar
  • 54 Willinghamm MD, Brodt MD, Lee KL, Stephens AL, Ye J, Silva MJ. Age-related changes in bone structure and strength in female and male BALB/c mice. Calcif Tissue Int 2010; 86 (06) 470-483
    CrossrefPubMedSearch in Google Scholar
  • 55 Haffner-Luntzer M, Kovtun A, Rapp AE, Ignatius A. Mouse models in bone fracture healing research. Curr Mol Biol Rep 2016; 2 (02) 101-111
    CrossrefSearch in Google Scholar
  • 56 Wehrle E, Tourolle Né Betts DC, Kuhn GA, Scheuren AC, Hofmann S, Müller R. Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models. Sci Rep 2019; 9 (01) 17445
    CrossrefPubMedSearch in Google Scholar
  • 57 O'Neill KR, Stutz CM, Mignemi NA. et al. Micro-computed tomography assessment of the progression of fracture healing in mice. Bone 2012; 50 (06) 1357-1367
    CrossrefPubMedSearch in Google Scholar
  • 58 Lienau J, Schmidt-Bleek K, Peters A. et al. Differential regulation of blood vessel formation between standard and delayed bone healing. J Orthop Res 2009; 27 (09) 1133-1140
    CrossrefPubMedSearch in Google Scholar
  • 59 Sarahrudi K, Thomas A, Braunsteiner T, Wolf H, Vécsei V, Aharinejad S. VEGF serum concentrations in patients with long bone fractures: a comparison between impaired and normal fracture healing. J Orthop Res 2009; 27 (10) 1293-1297
    CrossrefPubMedSearch in Google Scholar
  • 60 Geiger F, Bertram H, Berger I. et al. Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. J Bone Miner Res 2005; 20 (11) 2028-2035
    CrossrefPubMedSearch in Google Scholar
  • 61 Garcia P, Pieruschka A, Klein M. et al. Temporal and spatial vascularization patterns of unions and non-unions – role of VEGF and BMP's. Paper presented at: ORS 2011 Annual Meeting. Vol 27.; 2011
  • 62 Nakatsu MN, Sainson RCA, Pérez-del-Pulgar S. et al. VEGF(121) and VEGF(165) regulate blood vessel diameter through vascular endothelial growth factor receptor 2 in an in vitro angiogenesis model. Lab Invest 2003; 83 (12) 1873-1885
    CrossrefPubMedSearch in Google Scholar
  • 63 Stiver SI, Tan X, Brown LF, Hedley-Whyte ET, Dvorak HF. VEGF-A angiogenesis induces a stable neovasculature in adult murine brain. J Neuropathol Exp Neurol 2004; 63 (08) 841-855
    CrossrefPubMedSearch in Google Scholar
  • 64 Hankenson KD, Dishowitz M, Gray C, Schenker M. Angiogenesis in bone regeneration. Injury 2011; 42 (06) 556-561
    CrossrefPubMedSearch in Google Scholar
  • 65 Hu K, Olsen BR. Vascular endothelial growth factor control mechanisms in skeletal growth and repair. Dev Dyn 2017; 246 (04) 227-234
    CrossrefPubMedSearch in Google Scholar
  • 66 Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest 2016; 126 (02) 509-526
    CrossrefSearch in Google Scholar
  • 67 Beamer B, Hettrich C, Lane J. Vascular endothelial growth factor: an essential component of angiogenesis and fracture healing. HSS J 2010; 6 (01) 85-94
    CrossrefPubMedSearch in Google Scholar
  • 68 Street J, Winter D, Wang JH, Wakai A, McGuinness A, Redmond HP. Is human fracture hematoma inherently angiogenic?. Clin Orthop Relat Res 2000; (378) 224-237
    CrossrefPubMedSearch in Google Scholar
  • 69 Stegen S, van Gastel N, Carmeliet G. Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration. Bone 2015; 70: 19-27
    CrossrefPubMedSearch in Google Scholar
  • 70 Jackson SJ, Andrews N, Ball D. et al. Does age matter? The impact of rodent age on study outcomes. Lab Anim 2017; 51 (02) 160-169
    CrossrefPubMedSearch in Google Scholar
  • 71 Tinubu J, Scalea TM. Management of fractures in a geriatric surgical patient. Surg Clin North Am 2015; 95 (01) 115-128
    CrossrefPubMedSearch in Google Scholar
  • 72 Shoji H, Takao K, Hattori S, Miyakawa T. Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. Mol Brain 2016; 9 (01) 11
    CrossrefPubMedSearch in Google Scholar
  • 73 Deng Z, Gao X, Sun X, Cui Y, Amra S, Huard J. Gender differences in tibial fractures healing in normal and muscular dystrophic mice. Am J Transl Res 2020; 12 (06) 2640-2651
    PubMedSearch in Google Scholar
  • 74 Charan J, Kantharia ND. How to calculate sample size in animal studies?. J Pharmacol Pharmacother 2013; 4 (04) 303-306
    CrossrefPubMedSearch in Google Scholar
  • 75 Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 2010; 25 (07) 1468-1486
    CrossrefPubMedSearch in Google Scholar
  • 76 Christiansen BA. Effect of micro-computed tomography voxel size and segmentation method on trabecular bone microstructure measures in mice. Bone Rep 2016; 5: 136-140
    CrossrefPubMedSearch in Google Scholar
  • 77 Kozera B, Rapacz M. Reference genes in real-time PCR. J Appl Genet 2013; 54 (04) 391-406
    CrossrefPubMedSearch in Google Scholar
  • 78 Knight A. Systematic reviews of animal experiments demonstrate poor contributions toward human healthcare. Rev Recent Clin Trials 2008; 3 (02) 89-96
    CrossrefPubMedSearch in Google Scholar
  • 79 Donneys A, Tchanque-Fossuo CN, Farberg AS, Deshpande SS, Buchman SR. Bone regeneration in distraction osteogenesis demonstrates significantly increased vascularity in comparison to fracture repair in the mandible. J Craniofac Surg 2012; 23 (01) 328-332
    CrossrefPubMedSearch in Google Scholar
  • 80 Donneys A, Tchanque-Fossuo CN, Farberg AS. et al. Quantitative analysis of vascular response after mandibular fracture repair using microcomputed tomography with vessel perfusion. Plast Reconstr Surg 2011; 127 (04) 1487-1493
    CrossrefPubMedSearch in Google Scholar
  • 81 Sathyendra V, Darowish M. Basic science of bone healing. Hand Clin 2013; 29 (04) 473-481
    CrossrefPubMedSearch in Google Scholar
  • 82 Marsell R, Einhorn TA. The biology of fracture healing. Injury 2011; 42 (06) 551-555
    CrossrefPubMedSearch in Google Scholar
  • 83 Olate S, Vásquez B, Sandoval C, Vasconcellos A, Alister JP, Del Sol M. Histological analysis of bone repair in mandibular body osteotomy using internal fixation system in three different gaps without bone graft in an animal model. BioMed Res Int 2019; 2019: 8043510
    CrossrefPubMedSearch in Google Scholar