Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation
Vascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in anim...
- Autores:
-
Arce Guerrero, Sandra
Fernández, Tulio
Olave, Gilberto
Valencia, Carlos H.
Quinn, Julián
- Tipo de recurso:
- Article of journal
- Fecha de publicación:
- 2014
- Institución:
- Universidad Autónoma de Occidente
- Repositorio:
- RED: Repositorio Educativo Digital UAO
- Idioma:
- eng
- OAI Identifier:
- oai:red.uao.edu.co:10614/12172
- Acceso en línea:
- http://red.uao.edu.co//handle/10614/12172
https://doi.org/10.1089/ten.tea.2013.0696
- Palabra clave:
- Fosfato de calcio
Injertos óseos
Calcium phosphate
Bone-grafting
- Rights
- openAccess
- License
- Derechos Reservados - Mary Ann Liebert, Inc., 2014
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Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| title |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| spellingShingle |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation Fosfato de calcio Injertos óseos Calcium phosphate Bone-grafting |
| title_short |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| title_full |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| title_fullStr |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| title_full_unstemmed |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| title_sort |
Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation |
| dc.creator.fl_str_mv |
Arce Guerrero, Sandra Fernández, Tulio Olave, Gilberto Valencia, Carlos H. Quinn, Julián |
| dc.contributor.author.none.fl_str_mv |
Arce Guerrero, Sandra Fernández, Tulio Olave, Gilberto Valencia, Carlos H. Quinn, Julián |
| dc.subject.armarc.spa.fl_str_mv |
Fosfato de calcio Injertos óseos |
| topic |
Fosfato de calcio Injertos óseos Calcium phosphate Bone-grafting |
| dc.subject.armarc.eng.fl_str_mv |
Calcium phosphate Bone-grafting |
| description |
Vascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in animal models. In this work, we observed that CaP-based biomaterials implanted into rat calvarial defects showed remarkably accelerated formation and mineralization of new woven bone in defects in the initial stages, at a rate of ∼60 μm/day (0.8 mg/day), which was considerably higher than normal bone growth rates (several μm/day, 0.1 mg/day) in implant-free controls of the same age. Surprisingly, we also observed histological evidence of primary osteon formation, indicated by blood vessels in early-region fibrous tissue, which was encapsulated by lamellar osteocyte structures. These were later fully replaced by compact bone, indicating complete regeneration of calvarial bone. Thus, the CaP biomaterial used here is not only osteoinductive, but vasculogenic, and it may have contributed to the bone regeneration, despite an absence of osteons in normal rat calvaria. Further investigation will involve how this strategy can regulate formation of vascularized cortical bone such as by control of degradation rate, and use of models of long, dense bones, to more closely approximate repair of human cortical bone |
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2014 |
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2014-03 |
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2020-03-25T19:59:35Z |
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2020-03-25T19:59:35Z |
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Artículo de revista |
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1937-3341 |
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https://doi.org/10.1089/ten.tea.2013.0696 |
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Universidad Autónoma de Occidente |
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Repositorio Educativo Digital |
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1937-3341 Universidad Autónoma de Occidente Repositorio Educativo Digital |
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http://red.uao.edu.co//handle/10614/12172 https://doi.org/10.1089/ten.tea.2013.0696 |
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eng |
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eng |
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Tissue Engineering Part A. Volumen 20, número 13-14, (marzo 2014); páginas 1948-1960 |
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1960 |
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13-14 |
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1948 |
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20 |
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Arce Guerrero, S.; Fernández, T.; Olave, G.; Valencia, C. y Quinn, J. (2014)Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation. Tissue Engineering Part A. 20(13-14), (marzo); p.p. 1948-1960 |
| dc.relation.ispartofjournal.eng.fl_str_mv |
Tissue Engineering Part A |
| dc.relation.references.none.fl_str_mv |
Burg K.J.L., Porter S., and Kellam J.F. Biomaterial developments for bone tissue engineering. Biomaterials 21, 2347, 2000 Chen Q.Z., Zhu C.H., and Thouas G.A. Progress and challenges in biomaterials for tissue engineering. Prog Biomater 1, 2, 2012 effre C.P., Ochoa J., Margolis D.S., and Szivek J.A. Evaluation of the osteogenic performance of calcium phosphate-chitosan bone fillers. J Invest Surg 23, 134, 2010 Thormann U., Ray S., Sommer U., Elkhassawna T., Rehling T., Hundgeburth M., et al.. Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats. Biomaterials 34, 8589, 2013 Chai Y.C., Carlier A., Bolander J., Roberts S.J., Geris L., Schrooten J., et al.. Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies. Acta Biomater 8, 3876, 2012 Laschke M.W., Harder Y., Amon M., Martin I., Farhadi J., Ring A., et al.. Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng 12, 2093, 2006 Ignjatovic N.L., Ajdukovic Z.R., Savic V.P., and Uskokovic D.P. Size effect of calcium phosphate coated with poly-DL-lactide- co-glycolide on healing processes in bone reconstruction. J Biomed Mater Res B Appl Biomater 94, 108, 2010. Lange T., Schilling A.F., Peters F., Mujas J., Wicklein D., and Amling M. Size dependent induction of proinflammatory cytokines and cytotoxicity of particulate beta-tricalciumphosphate in vitro. Biomaterials 32, 4067, 2011 Yuan H., van Blitterswijk C.A., de Groot K., and de Bruijn J.D. A comparison of bone formation in biphasic calcium phosphate (BCP) and hydroxyapatite (HA) implanted in muscle and bone of dogs at different time periods. J Biomed Mater Res Part A 78A, 139, 2006 Schmitz J.P., Schwartz Z., Hollinger J.O., and Boyan B.D. Characterization of rat calvarial nonunion defects. Acta Anat (Basel) 138, 185, 1990. Kochi G., Sato S., Fukuyama T., Morita C., Honda K., Arai Y., et al.. Analysis on the guided bone augmentation in the rat calvarium using a microfocus computerized tomography analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107, e42, 2009. Develioglu H., Unver Saraydin S., and Kartal U. The bone-healing effect of a xenograft in a rat calvarial defect model. Dent Mater J 28, 396, 2009 Jones L., Thomsen J.S., Mosekilde L., Bosch C., and Melsen B. Biomechanical evaluation of rat skull defects, 1, 3, and 6 months after implantation with osteopromotive substances. J Craniomaxillofac Surg 35, 350, 2007 Egan K.P., Brennan T.A., and Pignolo R.J. Bone histomorphometry using free and commonly available software. Histopathology 61, 1168, 2012 Spicer P.P., Kretlow J.D., Young S., Jansen J.A., Kasper F.K., and Mikos A.G. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc 7, 1918, 2012 Hansson L.I., Menander-Sellman K., Stenstrom A., and Thorngren K.G. Rate of normal longitudinal bone growth in the rat. Calcif Tissue Res 10, 238, 1972 Raman A. Appositional growth rate in rat bones using the tetracycline labelling method. Acta Orthop Scand 40, 193, 1969. Pincus J.B., and Kramer B. Comparative study of the concentration of various anions and cations in cerebrospinal fluid and serum. J Biol Chem 66, 23, 1925 Pannarale L., Morini S., D'Ubaldo E., Gaudio E., and Marinozzi G. SEM corrosion-casts study of the microcirculation of the flat bones in the rat. Anat Rec 247, 462, 1997 Zanetti A.S., Sabliov C., Gimble J.M., and Hayes D.J. Human adipose-derived fstem cells and three-dimensional scaffold constructs: a review of the biomaterials and models currently used for bone regeneration. J Biomed Mater Res Part B Appl Biomater 101B, 187, 2013 Chen M., Song K., Rao N., Huang M., Huang Z., and Cao Y. Roles of exogenously regulated bFGF expression in angiogenesis and bone regeneration in rat calvarial defects. Int J Mol Med 27, 545, 2011 Wernike E., Montjovent M.O., Liu Y., Wismeijer D., Hunziker E.B., Siebenrock K.A., et al.. VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo. Eur Cells Mater 19, 30, 2010 Roldan J.C., Detsch R., Schaefer S., Chang E., Kelantan M., Waiss W., et al.. Bone formation and degradation of a highly porous biphasic calcium phosphate ceramic in presence of BMP-7, VEGF and mesenchymal stem cells in an ectopic mouse model. J Craniomaxillofac Surg 38, 423, 2010 Naito Y., Nagata T., Tachibana S., Okimoto M., Ohara N., Hakamatsuka Y., et al.. Locally applied TCP inhibits tumor growth via possible activation of macrophages. J Biomed Mater Res Part A 92A, 542, 2010 |
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Derechos Reservados - Mary Ann Liebert, Inc., 2014 |
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Arce Guerrero, Sandravirtual::433-1Fernández, Tulio0d020835900be754ed4111c74a93be5bOlave, Gilbertod49150e22c94d5dc2db94d4a62d48a63Valencia, Carlos H.2be1f8278424777434a4baf6a0a6832fQuinn, Julián74e12a164e354a65e93806037eb6c39d2020-03-25T19:59:35Z2020-03-25T19:59:35Z2014-031937-3341http://red.uao.edu.co//handle/10614/12172https://doi.org/10.1089/ten.tea.2013.0696Universidad Autónoma de OccidenteRepositorio Educativo DigitalVascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in animal models. In this work, we observed that CaP-based biomaterials implanted into rat calvarial defects showed remarkably accelerated formation and mineralization of new woven bone in defects in the initial stages, at a rate of ∼60 μm/day (0.8 mg/day), which was considerably higher than normal bone growth rates (several μm/day, 0.1 mg/day) in implant-free controls of the same age. Surprisingly, we also observed histological evidence of primary osteon formation, indicated by blood vessels in early-region fibrous tissue, which was encapsulated by lamellar osteocyte structures. These were later fully replaced by compact bone, indicating complete regeneration of calvarial bone. Thus, the CaP biomaterial used here is not only osteoinductive, but vasculogenic, and it may have contributed to the bone regeneration, despite an absence of osteons in normal rat calvaria. Further investigation will involve how this strategy can regulate formation of vascularized cortical bone such as by control of degradation rate, and use of models of long, dense bones, to more closely approximate repair of human cortical boneapplication/pdf14 páginasengMary Ann Liebert, IncTissue Engineering Part A. Volumen 20, número 13-14, (marzo 2014); páginas 1948-1960196013-14194820Arce Guerrero, S.; Fernández, T.; Olave, G.; Valencia, C. y Quinn, J. (2014)Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation. Tissue Engineering Part A. 20(13-14), (marzo); p.p. 1948-1960Tissue Engineering Part ABurg K.J.L., Porter S., and Kellam J.F. Biomaterial developments for bone tissue engineering. Biomaterials 21, 2347, 2000Chen Q.Z., Zhu C.H., and Thouas G.A. Progress and challenges in biomaterials for tissue engineering. Prog Biomater 1, 2, 2012effre C.P., Ochoa J., Margolis D.S., and Szivek J.A. Evaluation of the osteogenic performance of calcium phosphate-chitosan bone fillers. J Invest Surg 23, 134, 2010Thormann U., Ray S., Sommer U., Elkhassawna T., Rehling T., Hundgeburth M., et al.. Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats. Biomaterials 34, 8589, 2013Chai Y.C., Carlier A., Bolander J., Roberts S.J., Geris L., Schrooten J., et al.. Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies. Acta Biomater 8, 3876, 2012Laschke M.W., Harder Y., Amon M., Martin I., Farhadi J., Ring A., et al.. Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng 12, 2093, 2006Ignjatovic N.L., Ajdukovic Z.R., Savic V.P., and Uskokovic D.P. Size effect of calcium phosphate coated with poly-DL-lactide- co-glycolide on healing processes in bone reconstruction. J Biomed Mater Res B Appl Biomater 94, 108, 2010.Lange T., Schilling A.F., Peters F., Mujas J., Wicklein D., and Amling M. Size dependent induction of proinflammatory cytokines and cytotoxicity of particulate beta-tricalciumphosphate in vitro. Biomaterials 32, 4067, 2011Yuan H., van Blitterswijk C.A., de Groot K., and de Bruijn J.D. A comparison of bone formation in biphasic calcium phosphate (BCP) and hydroxyapatite (HA) implanted in muscle and bone of dogs at different time periods. J Biomed Mater Res Part A 78A, 139, 2006Schmitz J.P., Schwartz Z., Hollinger J.O., and Boyan B.D. Characterization of rat calvarial nonunion defects. Acta Anat (Basel) 138, 185, 1990.Kochi G., Sato S., Fukuyama T., Morita C., Honda K., Arai Y., et al.. Analysis on the guided bone augmentation in the rat calvarium using a microfocus computerized tomography analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107, e42, 2009.Develioglu H., Unver Saraydin S., and Kartal U. The bone-healing effect of a xenograft in a rat calvarial defect model. Dent Mater J 28, 396, 2009Jones L., Thomsen J.S., Mosekilde L., Bosch C., and Melsen B. Biomechanical evaluation of rat skull defects, 1, 3, and 6 months after implantation with osteopromotive substances. J Craniomaxillofac Surg 35, 350, 2007Egan K.P., Brennan T.A., and Pignolo R.J. Bone histomorphometry using free and commonly available software. Histopathology 61, 1168, 2012Spicer P.P., Kretlow J.D., Young S., Jansen J.A., Kasper F.K., and Mikos A.G. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc 7, 1918, 2012Hansson L.I., Menander-Sellman K., Stenstrom A., and Thorngren K.G. Rate of normal longitudinal bone growth in the rat. Calcif Tissue Res 10, 238, 1972Raman A. Appositional growth rate in rat bones using the tetracycline labelling method. Acta Orthop Scand 40, 193, 1969.Pincus J.B., and Kramer B. Comparative study of the concentration of various anions and cations in cerebrospinal fluid and serum. J Biol Chem 66, 23, 1925Pannarale L., Morini S., D'Ubaldo E., Gaudio E., and Marinozzi G. SEM corrosion-casts study of the microcirculation of the flat bones in the rat. Anat Rec 247, 462, 1997Zanetti A.S., Sabliov C., Gimble J.M., and Hayes D.J. Human adipose-derived fstem cells and three-dimensional scaffold constructs: a review of the biomaterials and models currently used for bone regeneration. J Biomed Mater Res Part B Appl Biomater 101B, 187, 2013Chen M., Song K., Rao N., Huang M., Huang Z., and Cao Y. Roles of exogenously regulated bFGF expression in angiogenesis and bone regeneration in rat calvarial defects. Int J Mol Med 27, 545, 2011Wernike E., Montjovent M.O., Liu Y., Wismeijer D., Hunziker E.B., Siebenrock K.A., et al.. VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo. Eur Cells Mater 19, 30, 2010Roldan J.C., Detsch R., Schaefer S., Chang E., Kelantan M., Waiss W., et al.. Bone formation and degradation of a highly porous biphasic calcium phosphate ceramic in presence of BMP-7, VEGF and mesenchymal stem cells in an ectopic mouse model. J Craniomaxillofac Surg 38, 423, 2010Naito Y., Nagata T., Tachibana S., Okimoto M., Ohara N., Hakamatsuka Y., et al.. Locally applied TCP inhibits tumor growth via possible activation of macrophages. J Biomed Mater Res Part A 92A, 542, 2010Derechos Reservados - Mary Ann Liebert, Inc., 2014https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)http://purl.org/coar/access_right/c_abf2Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formationArtículo de revistahttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTREFinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/version/c_970fb48d4fbd8a85Fosfato de calcioInjertos óseosCalcium phosphateBone-graftingPublicationd07563aa-20d1-4a12-ba37-4d6839137e5avirtual::433-1d07563aa-20d1-4a12-ba37-4d6839137e5avirtual::433-1https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001112392virtual::433-1CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://red.uao.edu.co/bitstreams/ea86b6c8-a9cb-4370-9730-839c4d794e78/download4460e5956bc1d1639be9ae6146a50347MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81665https://red.uao.edu.co/bitstreams/f8804b16-dd03-49a4-9b37-4d7fee8ee7cd/download20b5ba22b1117f71589c7318baa2c560MD53ORIGINALEffects of Calcium Phosphate_Chitosan.pdfEffects of Calcium Phosphate_Chitosan.pdfTexto completo del artículoapplication/pdf2504097https://red.uao.edu.co/bitstreams/9a008d68-1281-44c0-accf-2c4e3638668b/downloadccb88dd11fa1f8c6fad414e3d4302d54MD54TEXTEffects of Calcium Phosphate_Chitosan.pdf.txtEffects of Calcium Phosphate_Chitosan.pdf.txtExtracted texttext/plain56970https://red.uao.edu.co/bitstreams/dbcea68e-2ebd-4cf5-acd7-cd4433164c88/downloadc6bdee1d2eae967a33696ca5eeb9d49fMD55THUMBNAILEffects of Calcium Phosphate_Chitosan.pdf.jpgEffects of Calcium Phosphate_Chitosan.pdf.jpgGenerated Thumbnailimage/jpeg13529https://red.uao.edu.co/bitstreams/162987d3-2b3a-4f33-8205-ee29b022b2d3/download49fc35299fc16935570afb8dfbe4eb1eMD5610614/12172oai:red.uao.edu.co:10614/121722024-02-27 15:06:25.771https://creativecommons.org/licenses/by-nc-nd/4.0/Derechos Reservados - Mary Ann Liebert, Inc., 2014open.accesshttps://red.uao.edu.coRepositorio Digital Universidad Autonoma de Occidenterepositorio@uao.edu.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 |