Bone Remodeling, Biomaterials And Technological Applications: Revisiting Basic Concepts


Presently, several different graft materials are employed in regenerative or corrective bone surgery. However current misconceptions about these biomaterials, their use and risks may compromise their correct application and development. To unveil these misconceptions, this work briefly reviewed concepts about bone remodeling, grafts classification and manufacturing processes, with a special focus on calcium phosphate materials as an example of a current employed biomaterial. Thus a search on the last decade was performed in Medline, LILACS, Scielo and other scientific electronic libraries using as keywords biomaterials, bone remodeling, regeneration, biocompatible materials, hydroxyapatite and therapeutic risks. Our search showed not only an accelerated biotechnological development that brought significant advances to biomaterials use on bone remodeling treatments but also several therapeutic risks that should not be ignored. The biomaterials specificity and limitations to clinical application point to the current need for developing safer products with better interactions with the biological microenvironments.

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P. Salgado, P. Sathler, H. Castro, G. Alves, A. Oliveira, R. Oliveira, M. Maia, C. Rodrigues, P. Coelh, A. Fuly, L. Cabral and J. Granjeiro, "Bone Remodeling, Biomaterials And Technological Applications: Revisiting Basic Concepts," Journal of Biomaterials and Nanobiotechnology, Vol. 2 No. 3, 2011, pp. 318-328. doi: 10.4236/jbnb.2011.23039.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. M. Hazes and A. D. Woolf, “The bone and joint decade 2000-2010”. The Journal of rheumatology, Vol. 27, No. 1, 2000, pp. 1-3.
[2] D. Williams, “Definitions in biomaterials; proceedings of a consensus conference of the European Society For Biomaterials”. 1986, Elsevier, 1987, pp. 1-72.
[3] M. Geethaa, A. K. Singhb, R. Asokamania, A. K. Gogiac, “Ti based biomaterials, the ultimate choice for orthopaedic implants – A review.” Progress in Materials Science. Vol. 54, No. 3, 2009, pp. 397-425.
[4] A. Sculean, D. Nikolidakis and F. Schwarz, “Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials - biological foundation and preclinical evidence: a systematic review,” Journal of clinical periodontology, Vol. 35, No. 8 Suppl, 2008, 106-116.
[5] Y. Lin, G. O. Gallucci, D. Buser, D. Bosshardt, U. C. Belser and P. C. Yelick, “Bioengineered periodontal tissue formed on titanium dental implants,” Journal of dental research, Vol. 90, No. 2, 2011, pp. 251-256.
[6] G. Serino, W. Rao, G. Iezzi and A. Piattelli, “Polylactide and polyglycolide sponge used in human extraction sockets: bone formation following 3 months after its application,” Clinical oral implants research, Vol. 19, No. 1 2008, pp. 26-31.
[7] H. Browaeys, P. Bouvry and B. H. De, “A literature review on biomaterials in sinus augmentation procedures,” Clinical Implant Dentistry and Related Research, Vol. 9, No. 3, 2007, pp.166-177.
[8] M. Esposito, M. G. Grusovin, P. Coulthard and H. V, Worthington, “The efficacy of various bone augmentation procedures for dental implants: a Cochrane systematic review of randomized controlled clinical trials”. The International Journal of Oral & Maxillofacial Implants, Vol.21, No. 5, 2006, pp. 696-710.
[9] P. S. Tiwana, G. M. Kushner and R. H. Haug, “Maxillary sinus augmentation,” Dental clinics of North America, Vol. 50, No. 3, 2006, pp. 409-24, vii.
[10] M. A. Reynolds, M. E. Ichelmann-Reidy, G. L. Branch-Mays and J. C. Gunsolley, “The efficacy of bone replacement grafts in the treatment of periodontal osseous defects. A systematic review,” Annals of periodontology, Vol. 8, No. 1, 2003, pp. 227-265.
[11] D. E. Albert, “The important role of material and chemical characterisation in device evaluation,” Medical Device Technology, Vol. 15, No. 5, 2004, pp.15-18.
[12] P. E. Murray, G. C. Garcia and G. F. Garcia, “How is the biocompatibilty of dental biomaterials evaluated?” Medicina oral, patologia oral y cirugia bucal, Vol. 12, No, 3, 2007, pp. E258-E266.
[13] D. Williams, “Revisiting the definition of biocompatibility,” Medical device technology, Vol. 14, No. 8, 2003, pp. 10-3.
[14] M. B. Nasab and M. R. Hassan, “Metallic Biomaterials of Knee and Hip - A Review,” Trends in Biomaterials & Artificial Organs, Vol. 24, No. 1, 2010, pp. 69-82.
[15] M. Navarro, A. Michiardi, O. Castano and J. A. Planell. “Biomaterials in orthopaedics,” Journal of the Royal Society, Interface, Vol. 5, No. 27, 2008, pp. 1137-1158.
[16] M. A. Merkx, J. C. Maltha and P. J. Stoelinga, “Assessment of the value of anorganic bone additives in sinus floor augmentation: a review of clinical reports,” International journal of oral and maxillofacial surgery, Vol. 32, No, 1, 2003, pp.1-6.
[17] M. Hallman and A. Thor, “Bone substitutes and growth factors as an alternative/complement to autogenous bone for grafting in implant dentistry” Periodontology 2000, Vol.47, 2008, pp. 172-192.
[18] D. Logeart-Avramoglou, F. Anagnostou, R. Bizios and H. Petite, “Engineering bone: challenges and obstacles,” Journal of cellular and molecular medicine, Vol. 9, No. 1, 2005, pp. 72-84.
[19] M. Rumpler, A. Woesz, J. W. Dunlop, J. T. Van Dongen and P. Fratzl, “The effect of geometry on three-dimensional tissue growth,” Journal of the Royal Society, Interface, Vol. 5, No. 27, 2008, pp. 1173-1180.
[20] F. Forriol and F. Shapiro, “Bone development: interaction of molecular components and biophysical forces,” Clinical orthopaedics and related research, No. 432, 2005, pp.14-33.
[21] F. Shapiro, “Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts,” European cells & materials, Vol. 15, 2008, pp. 53-76.
[22] I. Fernández-Tresguerres-Hernández-Gil, M. A. Obera-Gracia, M. Del-Canto-Pingarron and L. Blanco-Jerez, “Physiological bases of bone regeneration I. Histology and physiology of bone tissue,” Medicina oral, patologia oral y cirugia bucal, Vol. 11, No. 1, 2006, pp. E47-E51.
[23] R. Murugan and S. Ramakrishna. Development of nanocomposites for bone grafting. Composites Science and Technology, Vol. 65, No. 15-16, 2005, pp. 2385-2406.
[24] K. A. Hing, “Bone repair in the twenty-first century: biology, chemistry or engineering?” Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Vol. 362, No. 1825, 2004, pp. 2821-2850.
[25] G. A. Rodan and T. J. Martin, “Therapeutic approaches to bone diseases,” Science, Vol. 289, No, 5484, 2000, pp. 1508-1514.
[26] J. Street, M. Bao, L. deGuzman, S. Bunting, J. F. V. Peale, N. Ferrara, H. Steinmetz, J. Hoeffel, J. L. Cleland, A. Daugherty, N. van Bruggen, H. P. Redmond, R. A. Carano and E. H. Filvaroff, “Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover,” Proceedings of the National Academy of Sciences of the USA, Vol. 99, No. 15, 2002, pp. 9656-9661.
[27] E. Neovius and T. Engstrand, “Craniofacial reconstruction with bone and biomaterials: review over the last 11 years,” Journal of plastic, reconstructive & aesthetic surgery, Vol. 63, No. 10, 2010, pp. 1615-23.
[28] B. Baroli, “From natural bone grafts to tissue engineering therapeutics: Brainstorming on pharmaceutical formulative requirements and challenges”. Journal of pharmaceutical sciences, Vol. 98, No. 4, 2009, pp. 1317-1375.
[29] T. Martin, J. H. Gooi and N. A. Sims, “Molecular mechanisms in coupling of bone formation to resorption,” Critical reviews in eukaryotic gene expression, Vol. 19, No, 1, 2009, pp. 73-88.
[30] B. Clarke, “Normal bone anatomy and physiology,” Clinical Journal of the American Society of Nephrology, Vol. 3, No. Suppl 3, 2008, pp. S131-S139.
[31] M. Degidi, L. Artese, C. Rubini, V. Perrotti, G. Iezzi and A. Piattelli, “Microvessel density and vascular endothelial growth factor expression in sinus augmentation using Bio-Oss,” Oral Diseases, Vol. 12, No. 5, 2006, pp. 469- 475.
[32] L. J. Raggatt and N. C. Partridge, “Cellular and molecular mechanisms of bone remodeling,” The Journal of biological chemistry, Vol. 285, No. 33, 2010, pp. 25103- 25108.
[33] K. S. Jones, “Effects of biomaterial-induced inflammation on fibrosis and rejection,” Seminars in immunology, Vol. 20, No. 2, 2008, pp. 130-136.
[34] D. F. Larosa, A. H. Rahman and L. A. Turka, “The innate immune system in allograft rejection and tolerance,” Journal of immunology, Vol. 178, No. 12, 2007, pp. 7503-7509.
[35] A. Shekaran and A. J. García, “Extracellular matrix-mimetic adhesive biomaterials for bone repair,” Journal of biomedical materials research. Part A, Vol. 96, No. 1, 2011, pp. 261-272.
[36] R. C. de Oliveira, E. Carneiro, T. M. Cestari, R. Taga and J. M. Granjeiro, “Dynamics of subcutaneous tissue response to the implantation of tetracycline-treated or untreated membrane of demineralized bovine cortical bone in rats,” Journal of Biomaterials Applications, Vol. 21, No. 2, 2006, pp. 167-78.
[37] R. C. de Oliveira, R. Menezes, T. M. Cestari, E. M. Taga, R. Taga, M. A. Buzalaf and J. M. Granjeiro, “Tissue response to a membrane of demineralized bovine cortical bone implanted in the subcutaneous tissue of rats,” Brazilian Dental Journal, Vol. 15, No, 1, 2004, pp.3-8.
[38] K. El Helow and S. El Askary Ael, “Regenerative barriers in immediate implant placement: a literature review,” Implant Dentistry, Vol. 17, No, 3, 2008, pp. 360-71.
[39] M. V. Thomas and D. A. Puleo, “Infection, Inflammation, and Bone Regeneration: a Paradoxical Relationship,” Journal of dental research, 2011, “in press”.
[40] A. Blinc, M. Bozic, R. Vengust and M. Stegnar, “Methyl-methacrylate bone cement surface does not promote platelet aggregation or plasma coagulation in vitro,” Thrombosis Research, Vol. 114, No. 3, 2004, pp. 179-184.
[41] M. T. Clarke, J. S. Green, W. M. Harper and P. J. Gregg, “Cement as a risk factor for deep-vein thrombosis. Comparison of cemented TKR, uncemented TKR and cemented THR,” Journal of Bone and Joint Surgery (British Volume), Vol. 80, No, 4, 1998, pp. 611-613.
[42] A. J. Donaldson, H. E. Thomson, N. J. Harper and N. W. Kenny, “Bone cement implantation syndrome,“ British Journal of Anaesthesia, Vol. 102, No. 1, 2009, pp. 12-22.
[43] H. Aita, N. Tsukimura, M. Yamada, N. Hori, K. Kubo, N. Sato, H. Maeda, K. Kimoto and T. Ogawa, “N-acetyl cysteine prevents polymethyl methacrylate bone cement extract-induced cell death and functional suppression of rat primary osteoblasts,” Journal of biomedical materials research. Part A, Vol. 92, No 1, 2010, pp. 285-296.
[44] P. H. Nilsson, A. E. Engberg, J. B?ck, L. Fax?lv, T. L. Lindahl, B. Nilsson and K. N. Ekdahl, “The creation of an antithrombotic surface by apyrase immobilization,” Biomaterials, Vol. 31, No. 16, 2010, pp. 4484-4491.
[45] A. P. McGuigan and M. V. Sefton, “The influence of biomaterials on endothelial cell thrombogenicity,” Biomaterials, Vol. 28, No. 16, 2007, pp. 2547-2571.
[46] Y. X. Wang, J. L. Robertson, W. B. J. Spillman and R. O. Claus, “Effects of the chemical structure and the surface properties of polymeric biomaterials on their biocompatibility,” Pharmaceutical research, Vol. 21, No. 8, 2004, 1362-1373.
[47] B. F. Lai, A. L. Creagh, J. Janzen, C. A. Haynes, D. E. Brooks and J. N. Kizhakkedathu, “The induction of thrombus generation on nanostructured neutral polymer brush surfaces,” Biomaterials, Vol. 31, No. 26, 2010, pp. 6710-6718.
[48] J. Hong, E. K. Nilsson, H. Reynolds, R. Larsson and B. Nilsson, “A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin,” Biomaterials, Vol. 20, No. 7, 1999, pp. 603-11.
[49] D. Ricklin, G. Hajishengallis, K. Yang and J. D. Lambris, “Complement: a key system for immune surveillance and homeostasis,” Nature immunology, Vol. 11, No. 9, 2010 pp. 785-797.
[50] E. Cenni, D. Granchi, M. Vancini and A. Pizzoferrato, “Platelet release of transforming growth factor-beta and beta-thromboglobulin after in vitro contact with acrylic bone cements,” Biomaterials, Vol. 23, No. 6, 2002, pp. 1479-1484.
[51] E. A. Vogler and C. A. Siedlecki, “Contact activation of blood-plasma coagulation,” Biomaterials, Vol. 30, No. 10, 2009, pp. 1857-1869.
[52] D. M. Smith, G. M. Cooper, M. P. Mooney, K. G. Marra and J. E. Losee, “Bone morphogenetic protein 2 therapy for craniofacial surgery,” The Journal of craniofacial surgery, Vol. 19, No. 5, 2008, pp. 1244-1259.
[53] M. O. Klein, P. W. K?mmerer, T. Scholz, M. Moergel, C. M. Kirchmaier and B. Al-Nawas, “Modulation of platelet activation and initial cytokine release by alloplastic bone substitute materials,” Clinical oral implants research, Vol. 21, No. 3, 2010, pp. 336-345.
[54] C. T. J. Vangsness, I. A. Garcia, C. R. Mills, M. A. Kainer, M. R. Roberts and T. M. Moore. “Allograft transplantation in the knee: tissue regulation, procurement, processing, and sterilization,” The American journal of sports medicine, Vol. 31, No. 3, 2003, pp. 474-481.
[55] L. K. Cannada, “Viable bone and circulatory factors required for survival of bone grafts,” The Orthopedic clinics of North America, Vol. 41, No. 1, 2010, pp. 5-13.
[56] C. N. Cornell and J. M. Lane, “Current understanding of osteoconduction in bone regeneration,” Clinical Orthopaedics and Related Research, No. 355 Suppl, 1998, pp. S267-S273.
[57] R. Z. LeGeros, “Properties of osteoconductive biomaterials: calcium phosphates,” Clinical orthopaedics and related research, No 395, 2002, pp. 81-98.
[58] M. L. Taga, J. M. Granjeiro, T. M. Cestari and R. Taga, “Healing of critical-size cranial defects in guinea pigs using a bovine bone-derived resorbable membrane,” The International journal of oral & maxillofacial implants, Vol. 23, No. 3, 2008, pp. 427-36.
[59] M. Retzepi and N. Donos, “Guided Bone Regeneration: biological principle and therapeutic applications,” Clinical oral implants research, Vol. 21, No. 6, 2010, pp. 567-576.
[60] R. V. Shevchenko, S. L. James, S. E. James, “A review of tissue-engineered skin bioconstructs available for skin reconstruction,” Journal of the Royal Society, Interface, Vol. 7, No.43, 2010, pp. 229-258.
[61] H. Chim and A. K. Gosain, “Biomaterials in craniofacial surgery: experimental studies and clinical application”. Journal of Craniofacial Surgery, Vol. 20, No. 1, 2009, pp. 29-33.
[62] E. Puricelli, A. Corsetti, D. Ponzoni, G. L. Martins, M. G. Leite and L. A. Santos, “Characterization of bone repair in rat femur after treatment with calcium phosphate cement and autogenous bone graft,” Head & face medicine, Vol. 6, 2010, pp.10.
[63] D. C. Olsson, N. L. Pippi, G. K. Tognoli and A. G. Raiser, “Bone marrow progenitor cells enriched scaffold biological behavior in bone repair.” Ciência Rural, Vol. 38, No. 8, 2008, pp. 2403-2412.
[64] D. W. Lee, K. T. Koo, Y. J. Seol, Y. M. Lee, Y. Ku, I. C. Rhyu, C. P. Chung and T. I. Kim, “Bone regeneration effects of human allogenous bone substitutes: a preliminary study,” Journal of periodontal & implant science, Vol. 40. No. 3, 2010, pp. 132-138.
[65] T. J. Blokhuis and T. Lindner, “Allograft and bone morphogenetic proteins: an overview,” Injury, Vol. 39, No. Suppl 2, 2008, pp. S33-S36.
[66] K. Kaveh, R. Ibrahim, M. Z. A. Bakar and T. A. Ibrahim, “Bone Grafting and Bone Graft Substitutes,” Journal of Animal and Veterinary Advances, Vol. 9, No. 6, 2010, pp.1055-1067.
[67] L. V. Marins, T. M. Cestari, A. D. Sottovia, J. M. Granjeiro and R. Taga, “Radiographic and histological study of perennial bone deffect repair in rat calvaria after treatment with blocks of porous bovine organic graft material,” Journal of applied oral science, Vol. 12, No. 1, 2004, pp. 62-69.
[68] R. T. Kao, S. Murakami and O. R. Beirne, “The use of biologic mediators and tissue engineering in dentistry,” Periodontology 2000, Vol. 50, 2009, pp. 127-153.
[69] M. T. Fulmer, I. C. Ison, C. R. Hankermayer, B. R. Constantz, J. Ross, “Measurements of the solubilities and dissolution rates of several hydroxyapatites,” Biomaterials, Vol. 23, No. 3, 2002, pp.751-755.
[70] V. Karageorgiou and D. Kaplan, “Porosity of 3D biomaterial scaffolds and osteogenesis”. Biomaterials, Vol. 26, No. 27, 2005, pp. 5474-5491.
[71] Z. Artzi, M. Weinreb, N. Givol, M. D. Rohrer, C. E. Nemcovsky, H. S. Prasad and H. Tal, “Biomaterial resorption rate and healing site morphology of inorganic bovine bone and beta-tricalcium phosphate in the canine: a 24-month longitudinal histologic study and morphometric analysis,” The International Journal of Oral & Maxillofacial Implants, Vol. 19, No. 3, 2004, pp. 357-68.
[72] Y. Yang, D. Dennison and J. L. Ong, ”Protein adsorption and osteoblast precursor cell attachment to hydroxyapatite of different crystallinities,” The International journal of oral & maxillofacial implants, Vol. 20, No. 2, 2005, pp. 187-192.
[73] G. Bezzi, G. Celotti, E. Landi, T. M. G. La Torretta, I. Sopyan and A. Tampieri, “A novel sol-gel technique for hydroxyapatite preparation”. Materials Chemistry and Physics, Vol. 78, No.3, 2003, pp.816-824.
[74] S. Sharma, V. Sikri, K. M. Sharma and V. M. Sharma, “Regeneration of tooth pulp and dentin: trends and advances,” Annals of Neurosciences, Vol 17, No. 1, 2010, pp. 31-43.
[75] T. M. Chu, D. G. Orton, S. J. Hollister, S. E. Feinberg and J. W. Halloran, “Mechanical and in vivo performance of hydroxyapatite implants with controlled architectures,” Biomaterials, Vol. 23, No. 5, 2002, pp. 1283-1293.
[76] M. Mastrogiacomo, S. Scaglione, R. Martinetti, L. Dolcini, F. Beltrame, R. Cancedda and R. Quarto, “Role of scaffold internal structure on in vivo bone formation in macroporous calcium phosphate bioceramics,’ Biomaterials Vol. 27, No. 17, 2006, pp. 3230-3237.
[77] H. Schliephake, R. Gruber, M. Dard, R. Wenz, and S. Scholz, “Repair of calvarial defects in rats by prefabricated hydroxyapatite cement implant,” Journal of biomedical materials research. Part A, Vol. 69, No. 3, 2004, pp. 382-390.
[78] T. Accorsi-Mendonca, M. B. Conz, T. C. Barros, L. A. de Sena, G.A. Soares and J. M. Granjeiro, “Physicochemical characterization of two deproteinized bovine xenografts,” Brazilian Oral Research, Vol. 22, No.1, 2008, pp. 5-10.
[79] M. D. Calasans-Maia, S. R. A. Santos, A. M. Rossi and J. M. Granjeiro, “In vivo behavior of hydroxyapatite evaluated by attenuated total reflection infrared microscopy (ATR-FTIR),”. Key Engineering Materials, Vol. 396-398, 2009, pp. 61-64.
[80] M. B. Conz, J. M. Granjeiro and G. A. Soares, “Physicochemical characterization of six commercial hydroxyapatites for medical-dental applicatons as bone graft,” Journal of Applied Oral Science, Vol. 13, No. 2, 2005, pp. 136-140.
[81] K. B. S. Paiva, T. Accorsi-Mendonca, J. M. Granjeiro, R. Taga and C. M. Bramante, “Physicochemical characterization and histologic analysis of different xenografts in the repair of critical size defect in calvaria of rats,” Bone, Vol. 36, 2005, pp. S186-S187.
[82] S. K. Nandi, S. Roy, P. Mukherjee, B. Kundu, D. K. De and D. Basu, “Orthopaedic applications of bone graft & graft substitutes: a review,” Indian Journal of Medical Research, Vol. 132, 2010, pp. 15-30.
[83] N. Huebsch and D. J. Mooney, “Inspiration and application in the evolution of biomaterials,” Nature, Vol. 462, No. 7272, 2009, pp. 426-432.
[84] H. Shin, K. Zygourakis, M. C. Farach-Carson, M. J. Yaszemski and A. G. Mikos, “Attachment, proliferation, and migration of marrow stromal osteoblasts cultured on biomimetic hydrogels modified with an osteopontin-derived peptide,” Biomaterials, Vol. 25, No. 5, 2004, pp. 895-906.
[85] S. I. Stupp, “Self-Assembly and Biomaterials,” Nano Letters, Vol. 10, 2010, pp. 4783-4786.
[86] N. Tsapis, D. Bennett, B. Jackson, D. A. Weitz and D. A. Edwards, “Trojan particles: large porous carriers of nanoparticles for drug delivery,” Proceedings of the National Academy of Sciences of the USA. Vol. 99, No. 19, 2002, pp. 12001-12005.
[87] S. T. Reddy, A. J. van der Vlies, E. Simeoni, V. Angeli, G. J. Randolph, C. P. O'Neil, L. K. Lee, M. A. Swartz and J. A. Hubbell, “Exploiting lymphatic transport and complement activation in nanoparticle vaccines,” Nature Biotechnology, Vol. 25, No. 10, 2007, 1159-1164.
[88] J. H. Park, G. von Maltzahn, L. Zhang, A. M. Derfus, D. Simberg, T. J. Harris, E. Ruoslahti, S. N. Bhatia and M. J. Sailor, “Systematic surface engineering of magnetic nanoworms for in vivo tumor targeting,” Small, Vol. 5, No. 6 2009, pp. 694-700.
[89] E. A. Silva, E. S. Kim, H. J. Kong and D. J. Mooney, “Material-based deployment enhances the efficacy of endothelial progenitor cells,” Proceedings of the National Academy of Sciences of the USA. Vol. 105, No. 38, 2008, pp. 14347-14352.
[90] D. J. Needleman, M. A. Ojeda-Lopez, U. Raviv, H. P. Miller, L. Wilson and C. R. Safinya, “Higher-order assembly of microtubules by counterions: from hexagonal bundles to living necklaces,” Proceedings of the National Academy of Sciences of the USA. Vol. 101, No. 46, 2004, pp. 16099-16103.
[91] J. L. Tan, J. Tien, D. M. Pirone, D. S. Gray, K. Bhadriraju and C. S. Chen, “Cells lying on a bed of microneedles: an approach to isolate mechanical force,” Proceedings of the National Academy of Sciences of the USA, Vol. 100, No, 4, 2003, pp. 1484-1489.

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