Biomarkers as Independent Predictors of Bone Regeneration around Biomaterials: A Systematic Review of Literature
Sultan Albeshri, Abdulaziz Alblaihess, Abdurahman A Niazy, Sundar Ramalingam, Chalini Sundar, Hamdan S Alghamdi
Biomarkers, Biomaterials, Bone regeneration, Systematic review
Citation Information :
Albeshri S, Alblaihess A, Niazy AA, Ramalingam S, Sundar C, Alghamdi HS. Biomarkers as Independent Predictors of Bone Regeneration around Biomaterials: A Systematic Review of Literature. J Contemp Dent Pract 2018; 19 (5):605-618.
Background: Biomarkers are detected during bone formation and resorption associated with the dynamics of bone metabolism and are gaining importance as preferential indicators of bone healing in comparison with conventional methodologies. Current literature suggests that the usage of bone turnover markers for monitoring bone regeneration in association with biomaterials is limited.
Aim: To systematically review literature and evaluate whether bone-biomarkers can independently predict bone regeneration following implantation of various bone biomaterials.
Materials and methods: An electronic search was conducted in PubMed (MEDLINE) database from 1980 to January 2017. The articles for systematic review were selected based on formulated inclusion and exclusion criteria
Results: Upon database searching, 443 articles were retrieved and thoroughly reviewed based on the inclusion and exclusion criteria. In all, 41 studies were finally included for evaluation out of which 4 were clinical studies and the remaining 37 studies utilized animal models. On further evaluation, 12 studies reported the presence of biomarkers in association with cellular response during bone regeneration around biomaterials. Moreover, biomarkers related to enzyme activity and matrix protein derivatives were enhanced during bone-matrix deposition as reported in 14 studies. Inorganic skeletal matrix biomarkers indicative of bone mineralization showed positive expression in eight studies.
Conclusion: Several biomarkers appear to be useful for the assessment of bone regeneration around biomaterials. Although biomarkers are capable of independently predicting bone regeneration, lack of substantial evidence in the literature limits their true clinical utility.
Clinical significance: Noninvasive and inexpensive methods of isolating and characterization of biomarkers from cellular and extracellular skeletal matrix during bone regeneration have proven value in evaluating success of bone biomaterials.
Karring T, Nyman S, Gottlow J, Laurell L. Development of the biological concept of guided tissue regeneration – animal and human studies. Periodontol 2000 1993 Feb;1(1):26-35.
Retzepi M, Donos N. Guided Bone Regeneration: biological principle and therapeutic applications. Clin Oral Implants Res 2010 Jun;21(6):567-576.
Zimmermann G, Henle P, Kusswetter M, Moghaddam A, Wentzensen A, Richter W, Weiss S. TGF-beta1 as a marker of delayed fracture healing. Bone 2005 May;36(5):779-785.
Wang FS, Yang KD, Kuo YR, Wang CJ, Sheen-Chen SM, Huang HC, Chen YJ. Temporal and spatial expression of bone morphogenetic proteins in extracorporeal shock wave-promoted healing of segmental defect. Bone 2003 Apr;32(4):387-396.
Sculean A, Nikolidakis D, Schwarz F. Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials – biological foundation and preclinical evidence: a systematic review. J Clin Periodontol 2008 Sep;35 (8 Suppl):106-116.
Blanco J, Alonso A, Sanz M. Long-term results and survival rate of implants treated with guided bone regeneration: a 5-year case series prospective study. Clin Oral Implants Res 2005 Jun;16(3):294-301.
Farina R, Bressan E, Taut A, Cucchi A, Trombelli L. Plasma rich in growth factors in human extraction sockets: a radiographic and histomorphometric study on early bone deposition. Clin Oral Implants Res 2013 Dec;24(12):1360-1368.
Bishop JA, Palanca AA, Bellino MJ, Lowenberg DW. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012 May;20(5):273-282.
Ram VS, Parthiban, Sudhakar U, Mithradas N, Prabhakar R. Bonebiomarkers in periodontal disease: a review article. J Clin Diagn Res 2015 Jan;9(1):ZE07-ZE10.
Kunimatsu K, Mataki S, Tanaka H, Mine N, Kiyoki M, Hosoda K, Kato Y, Kato I. A cross-sectional study on osteocalcin levels in gingival crevicular fluid from periodontal patients. J Periodontol 1993 Sep;64(9):865-869.
Leeming DJ, Alexandersen P, Karsdal MA, Qvist P, Schaller S, Tanko LB. An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice. Eur J Clin Pharmacol 2006 Oct;62(10):781-792.
Farina R, Trombelli L. Wound healing of extraction sockets. Endodontic Topics 2011 Sep;25(1):16-43.
Cox G, Einhorn TA, Tzioupis C, Giannoudis PV. Boneturnover markers in fracture healing. Bone Joint J Surg Br 2010 Mar;92(3):329-334.
Konopka L, Pietrzak A, Brzezinska-Blaszczyk E. Effect of scaling and root planing on interleukin-1beta, interleukin-8 and MMP-8 levels in gingival crevicular fluid from chronic periodontitis patients. J Periodont Res 2012 Dec;47(6):681-688.
Sexton WM, Lin Y, Kryscio RJ, Dawson DR 3rd, Ebersole JL, Miller CS. Salivary biomarkers of periodontal disease in response to treatment. J Clin Periodontol 2011 May;38(5): 434-441.
Leenaars M, Hooijmans CR, van Veggel N, ter Riet G, Leeflang M, Hooft L, van der Wilt GJ, Tillema A, Ritskes-Hoitinga M. A step-by-step guide to systematically identify all relevant animal studies. Lab Anim 2012 Jan;46(1):24-31.
Higgins, JP.; Green, S. editors. Cochrane handbook for systematic reviews of interventions. West Sussex: John Wiley & Sons; 2011.
Prati AJ, Casati MZ, Ribeiro FV, Cirano FR, Pastore GP, Pimentel SP, Casarin RC. Release of bone markers in immediately loaded and nonloaded dental implants: a randomized clinical trial. J Dent Res 2013 Dec;92(12 Suppl):161S-167S.
Schulze-Spate U, Dietrich T, Kayal RA, Hasturk H, Dobeck J, Skobe Z, Dibart S. Analysis of bone formation after sinus augmentation using beta-tricalcium phosphate. Compend Contin Educ Dent 2012 May;33(5):364-368.
Kabashima H, Nagata K. Presence of interleukin-4-producing cells for human bone regeneration after application of guided tissue regeneration membranes. J Endod 2001 Jul;27(7):444-448.
Lima LL, Goncalves PF, Sallum EA, Casati MZ, Nociti FH Jr. Guided tissue regeneration may modulate gene expression in periodontal intrabony defects: a human study. J Periodontal Res 2008 Aug;43(4):459-464.
Aghaloo T, Cowan CM, Chou YF, Zhang X, Lee H, Miao S, Hong N, Kuroda S, Wu B, Ting K, et al. Nell-1-induced bone regeneration in calvarial defects. Am J Pathol 2006 Sep;169(3):903-915.
Tera Tde M, Nascimento RD, Prado RF, Santamaria MP, Jardini MA. Immunolocalization of markers for bone formation during guided bone regeneration in osteopenic rats. J Appl Oral Sci 2014 Nov-Dec;22(6):541-553.
Kodama N, Nagata M, Tabata Y, Ozeki M, Ninomiya T, Takagi R. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone 2009 Apr;44(4):699-707.
Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, Ke HZ, Liu M, Giannobile WV. Sclerostin antibody stimulates bone regeneration after experimental periodontitis. J Bone Miner Res 2013 Nov;28(11):2347-2356.
Adeyemo WL, Reuther T, Bloch W, Korkmaz Y, Fischer JH, Zöller JE, Kuebler AC. Influence of host periosteum and recipient bed perforation on the healing of onlay mandibular bone graft: an experimental pilot study in the sheep. Oral Maxillofac Surg 2008 May;12(1):19-28.
Moreira DC, Sa CN, Andrade MG, Bório dos Santos Calmon de Bittencourt TC, de Almeida Reis SR, Pithon MM, Sadigursky M. Angiogenesis and osteogenesis at incorporation process of onlay bone graft. J Oral Maxillofac Surg 2013 Dec;71(12):2048-2057.
Tera Tde M, Prado RF, De Marco AC, Santamaria MP, Jardini MA. The RANK/RANKL/OPG interaction in the repair of autogenous bone grafts in female rats with estrogen deficiency. Braz Oral Res 2014 Sep;28(1):1-9.
Osugi M, Katagiri W, Yoshimi R, Inukai T, Hibi H, Ueda M. Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue Eng Part A 2012 Jul;18(13-14):1479-1489.
Colombo JS, Balani D, Sloan AJ, Crean SJ, Okazaki J, Waddington RJ. Delayed osteoblast differentiation and altered inflammatory response around implants placed in incisor sockets of type 2 diabetic rats. Clin Oral Implants Res 2011 Jun;22(6):578-586.
Colombo JS, Satoshi S, Okazaki J, Crean SJ, Sloan AJ, Waddington RJ. In vivo monitoring of the bone healing process around different titanium alloy implant surfaces placed into fresh extraction sockets. J Dent 2012 Apr;40(4):338-346.
Jiang X, Zhao J, Wang S, Sun X, Zhang X, Chen J, Kaplan DL, Zhang Z. Mandibular repair in rats with premineralized silk scaffolds and BMP-2-modified bMSCs. Biomaterials 2009 Sep;30(27):4522-4532.
Reis-Filho CR, Silva ER, Martins AB, Pessoa FF, Gomes PV, de Araújo MS, Miziara MN, Alves JB. Demineralised human dentine matrix stimulates the expression of VEGF and accelerates the bone repair in tooth sockets of rats. Arch Oral Biol 2012 May;57(5):469-476.
Kunert-Keil C, Scholz F, Gedrange T, Gredes T. Comparative study of biphasic calcium phosphate with beta-tricalcium phosphate in rat cranial defects – a molecular-biological and histological study. Ann Anat 2015 May;199:79-84.
Pedersen TO, Xing Z, Finne-Wistrand A, Hellem S, Mustafa K. Hyperbaric oxygen stimulates vascularization and bone formation in rat calvarial defects. Int J Oral Maxillofac Surg 2013 Jul;42(7):907-914.
Kamakura S, Sasano Y, Homma H, Suzuki O, Kagayama M, Motegi K. Implantation of octacalcium phosphate nucleates isolated bone formation in rat skull defects. Oral Dis 2001 Jul;7(4):259-265.
Pati F, Song TH, Rijal G, Jang J, Kim SW, Cho DW. Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. Biomaterials 2015 Jan;37: 230-241.
Lu K, Xu L, Xia L, Zhang Y, Zhang X, Kaplan DL, Jiang X, Zhang F. An ectopic study of apatite-coated silk fibroin scaffolds seeded with AdBMP-2-modified canine bMSCs. J Biomater Sci Polym Ed 2012 Jul;23(1-4):509-526.
Nomura I, Watanabe K, Matsubara H, Hayashi K, Sugimoto N, Tsuchiya H. Uncultured autogenous adipose-derived regenerative cells promote bone formation during distraction osteogenesis in rats. Clin Orthop Relat Res 2014 Dec;472(12):3798-3806.
Tanaka S, Matsuzaka K, Sato D, Inoue T. Characteristics of newly formed bone during guided bone regeneration: analysis of cbfa-1, osteocalcin, and VEGF expression. J Oral Implantol 2007 Feb;33(6):321-326.
Turri A, Elgali I, Vazirisani F, Johansson A, Emanuelsson L, Dahlin C, Thomsen P, Omar O. Guided bone regeneration is promoted by the molecular events in the membrane compartment. Biomaterials 2016 Apr;84:167-183.
Ratanavaraporn J, Furuya H, Kohara H, Tabata Y. Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration. Biomaterials 2011 Apr;32(11):2797-2811.
Sela J, Gross UM, Kohavi D, Shani J, Dean DD, Boyan BD, Schwartz Z. Primary mineralization at the surfaces of implants. Crit Rev Oral Biol Med 2000 Oct;11(4):423-436.
Du Z, Chen J, Yan F, Doan N, Ivanovski S, Xiao Y. Serum bone formation marker correlation with improved osseointegration in osteoporotic rats treated with simvastatin. Clin Oral Implants Res 2013 Apr;24(4):422-427.
Itala A, Valimaki VV, Kiviranta R, Ylänen HO, Hupa M, Vuorio E, Aro HT. Molecular biologic comparison of new bone formation and resorption on microrough and smooth bioactive glass microspheres. J Biomed Mater Res Part B Appl Biomater 2003 Apr;65(1):163-170.
Samee M, Kasugai S, Kondo H, Ohya K, Shimokawa H, Kuroda S. Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) transfection to human periosteal cells enhances osteoblast differentiation and bone formation. J Pharmacol Sci 2008 Sep;108(1):18-31.
Liu HC, Ling-Ling E, Wang DS, Su F, Wu X, Shi ZP, Lv Y, Wang JZ. Reconstruction of alveolar bone defects using bone morphogenetic protein 2 mediated rabbit dental pulp stem cells seeded on nano-hydroxyapatite/collagen/poly(Llactide). Tissue Eng Part A 2011 Jun;17(19-20):2417-2433.
Marukawa K, Ueki K, Alam S, Shimada M, Nakagawa K, Yamamoto E. Expression of bone morphogenetic protein-2 and proliferating cell nuclear antigen during distraction osteogenesis in the mandible in rabbits. Br J Oral Maxillofac Surg 2006 Apr;44(2):141-145.
Alam S, Ueki K, Nakagawa K, Marukawa K, Hashiba Y, Yamamoto E, Sakulsak N, Iseki S. Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009 Jan;107(1):22-29.
Trejo CG, Lozano D, Manzano M, Doadrio JC, Salinas AJ, Dapía S, Gómez-Barrena E, Vallet-Regí M, García-Honduvilla N, Buján J, et al. The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model. Biomaterials 2010 Nov;31(33):8564-8573.
Uchida R, Bhawal UK, Kiba H, Arai K, Tanimoto Y, Kuboyama N, Asakura T, Nishiyama N. Effect of plasma-irradiated silk fibroin in bone regeneration. J Biosci Bioeng 2014 Sep;118(3): 333-340.
Yoon SJ, Park KS, Kim MS, Rhee JM, Khang G, Lee HB. Repair of diaphyseal bone defects with calcitriol-loaded PLGA scaffolds and marrow stromal cells. Tissue Eng 2007 May;13(5):1125-1133.
Monjo M, Ramis JM, Ronold HJ, Taxt-Lamolle SF, Ellingsen JE, Lyngstadaas SP. Correlation between molecular signals and bone bonding to titanium implants. Clin Oral Implants Res 2013 Sep;24(9):1035-1043.
Monjo M, Lamolle SF, Lyngstadaas SP, Ronold HJ, Ellingsen JE. In vivo expression of osteogenic markers and bone mineral density at the surface of fluoride-modified titanium implants. Biomaterials 2008 Oct;29(28):3771-3780.
Wohlfahrt JC, Monjo M, Ronold HJ, Aass AM, Ellingsen JE, Lyngstadaas SP. Porous titanium granules promote bone healing and growth in rabbit tibia peri-implant osseous defects. Clin Oral Implants Res 2010 Feb;21(2):165-173.
Zhang W, Wang G, Liu Y, Zhao X, Zou D, Zhu C, Jin Y, Huang Q, Sun J, Liu X, et al. The synergistic effect of hierarchical micro/nano-topography and bioactive ions for enhanced osseointegration. Biomaterials 2013 Apr;34(13):3184-3195.
Rios CN, Skoracki RJ, Mathur AB. GNAS1 and PHD2 short-interfering RNA support bone regeneration in vitro and in an in vivo sheep model. Clin Orthop Relat Res 2012 Sep;470(9):2541-2553.
Barhanpurkar AP, Gupta N, Srivastava RK, Tomar GB, Naik SP, Joshi SR, Pote ST, Mishra GC, Wani MR. IL-3 promotes osteoblast differentiation and bone formation in human mesenchymal stem cells. Biochem Biophys Res Commun 2012 Feb;418(4):669-675.
Tan J, Yang N, Fu X, Cui Y, Guo Q, Ma T, Yin X, Leng H, Song C. Single-dose local simvastatin injection improves implant fixation via increased angiogenesis and bone formation in an ovariectomized rat model. Med Sci Monit 2015 May;21:1428-1439.
Shirakura M, Fujii N, Ohnishi H, Taguchi Y, Ohshima H, Nomura S, Maeda T. Tissue response to titanium implantation in the rat maxilla, with special reference to the effects of surface conditions on bone formation. Clin Oral Implants Res 2003 Dec;14(6):687-696.
Guda T, Labella C, Chan R, Hale R. Quality of bone healing: perspectives and assessment techniques. Wound Repair Regen 2014 May;22(Suppl 1):39-49.
Adell R, Lekholm U, Rockler B, Brånemark PI. A 15-year study of osseointegrated implants in the treatment of the edentulous jaw. Int J Oral Surg 1981 Dec;10(6):387-416.
Zarb GA, Schmitt A. The longitudinal clinical effectiveness of osseointegrated dental implants: the Toronto study. Part III: problems and complications encountered. The J Prosthet Dent 1990 Aug;64(2):185-194.
Coulibaly MO, Sietsema DL, Burgers TA, Mason J, Williams BO, Jones CB. Recent advances in the use of serological bone formation markers to monitor callus development and fracture healing. Crit Rev Eukaryot Gene Expr 2010;20(2):105-127.
Cremers, S.; Garnero, P.; Seibel, MJ. Biochemical markers of bone metabolism. In: Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology. 3rd ed. San Diego (CA): Academic Press; 2008. pp. 1857-1881.
Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone 2007 Feb;40(2):251-264.
Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 2004 Dec;15(6):457-475.
Esteves JC, Marcantonio E Jr, de Souza Faloni AP, Rocha FR, Marcantonio RA, Wilk K, Intini G. Dynamics of bone healing after osteotomy with piezosurgery or conventional drilling – histomorphometrical, immunohistochemical, and molecular analysis. J Transl Med 2013 Sep;11:221.
Dabra S, China K, Kaushik A. Salivary enzymes as diagnostic markers for detection of gingival/periodontal disease and their correlation with the severity of the disease. J Indian Soc Periodontol 2012 Jul;16(3):358-364.
Florez-Moreno GA, Marin-Restrepo LM, Isaza-Guzman DM, Tobon-Arroyave SI. Screening for salivary levels of deoxypyridinoline and bone-specific alkaline phosphatase during orthodontic tooth movement: a pilot study. Eur J Orthod 2013 Jun;35(3):361-368.