



@article {3266,
	title = {Injectable alginate hydrogels for cell delivery in tissue engineering},
	journal = {Acta Biomaterialia},
	volume = {10},
	year = {2014},
	note = {Export Date: 21 November 2014},
	month = {2014},
	pages = {1646 - 1662},
	abstract = {Alginate hydrogels are extremely versatile and adaptable biomaterials, with great potential for use in biomedical applications. Their extracellular matrix-like features have been key factors for their choice as vehicles for cell delivery strategies aimed at tissue regeneration. A variety of strategies to decorate them with biofunctional moieties and to modulate their biophysical properties have been developed recently, which further allow their tailoring to the desired application. Additionally, their potential use as injectable materials offers several advantages over preformed scaffold-based approaches, namely: Easy incorporation of therapeutic agents, such as cells, under mild conditions; minimally invasive local delivery; and high contourability, which is essential for filling in irregular defects. Alginate hydrogels have already been explored as cell delivery systems to enhance regeneration in different tissues and organs. Here, the in vitro and in vivo potential of injectable alginate hydrogels to deliver cells in a targeted fashion is reviewed. In each example, the selected crosslinking approach, the cell type, the target tissue and the main findings of the study are highlighted. {\textcopyright} 2013 Acta Materialia Inc.},
	keywords = {Alginate, Cell delivery, Injectable, Regeneration, Tissue engineering},
	url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84896403229\&partnerID=40\&md5=fd56573baeefa91edfc45ba61cf0573a},
	author = {Bidarra, S.J. and Barrias, C.C. and Granja, P.L.}
}
@article {2838,
	title = {Functionalization of biomaterials with small osteoinductive moieties},
	journal = {Acta Biomaterialia},
	volume = {9},
	year = {2013},
	note = {Export Date: 12 December 2013Source: Scopus},
	month = {2013///},
	pages = {8773 - 8789},
	url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84885024380\&partnerID=40\&md5=a9ee12bc1c5789cd64861fd8201fc645},
	author = {Maia, F.R. and Bidarra, S.J. and Granja, P.L. and Barrias, C.C.}
}
@article {2235,
	title = {Molecularly designed alginate hydrogels susceptible to local proteolysis as three-dimensional cellular microenvironments},
	journal = {Acta BiomaterialiaActa Biomater.},
	volume = {7},
	year = {2011},
	note = {Cited By (since 1996): 9Export Date: 21 November 2012Source: Scopusdoi: 10.1016/j.actbio.2010.12.029PubMed ID: 21193068Language of Original Document: EnglishCorrespondence Address: Barrias, C. C.; INEB, Instituto de Engenharia Biom{\'e}dica, Divis{\~a}o de Biomateriais, Universidade Do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; email: ccbarrias@ineb.up.ptChemicals/CAS: alginic acid, 28961-37-7, 29894-36-8, 9005-32-7, 9005-38-3; gelatin, 9000-70-8; gelatinase A, 146480-35-5; Alginates; Glucuronic Acid, 576-37-4; Hexuronic Acids; Hydrogels; Matrix Metalloproteinases, 3.4.24.-; Peptides; alginic acid, 9005-32-7References: Lukashev, M.E., Werb, Z., ECM signalling: Orchestrating cell behaviour and misbehaviour (1998) Trends in Cell Biology, 8 (11), pp. 437-441. , DOI 10.1016/S0962-8924(98)01362-2, PII S0962892498013622;Bosman, F.T., Stamenkovic, I., Functional structure and composition of the extracellular matrix (2003) Journal of Pathology, 200 (4), pp. 423-428. , DOI 10.1002/path.1437; 
Lutolf, M.P., Hubbell, J.A., Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering (2005) Nature Biotechnology, 23 (1), pp. 47-55. , DOI 10.1038/nbt1055; 
Lutolf, M.P., Gilbert, P.M., Blau, H.M., Designing materials to direct stem-cell fate (2009) Nature, 462 (7272), pp. 433-441; 
Tibbitt, M.W., Anseth, K.S., Hydrogels as extracellular matrix mimics for 3D cell culture (2009) Biotechnol Bioeng, 103 (4), pp. 655-663; 
Augst, A.D., Kong, H.J., Mooney, D.J., Alginate hydrogels as biomaterials (2006) Macromolecular Bioscience, 6 (8), pp. 623-633. , DOI 10.1002/mabi.200600069; 
Evangelista, M.B., Hsiong, S.X., Fernandes, R., Sampaio, P., Kong, H.-J., Barrias, C.C., Salema, R., Granja, P.L., Upregulation of bone cell differentiation through immobilization within a synthetic extracellular matrix (2007) Biomaterials, 28 (25), pp. 3644-3655. , DOI 10.1016/j.biomaterials.2007.04.028, PII S014296120700347X; 
Grellier, M., Granja, P.L., Fricain, J.C., Bidarra, S.J., Renard, M., Bareille, R., The effect of the co-immobilization of human osteoprogenitors and endothelial cells within alginate microspheres on mineralization in a bone defect (2009) Biomaterials, 30 (19), pp. 3271-3278; 
Bidarra, S.J., Barrias, C.C., Barbosa, M.A., Soares, R., Granja, P.L., Immobilization of human mesenchymal stem cells within RGD-grafted alginate microspheres and assessment of their angiogenic potential (2010) Biomacromolecules, 11 (8), pp. 1956-1964; 
West, J.L., Hubbell, J.A., Polymeric biomaterials with degradation sites for proteases involved in cell migration (1999) Macromolecules, 32 (1), pp. 241-244; 
Page-Mccaw, A., Ewald, A.J., Werb, Z., Matrix metalloproteinases and the regulation of tissue remodelling (2007) Nat Rev Mol Cell Biol, 8 (3), pp. 221-233; 
Murphy, G., Nagase, H., Progress in matrix metalloproteinase research (2008) Mol Aspects Med, 29 (5), pp. 290-308; 
Chau, Y., Luo, Y., Cheung, A.C.Y., Nagai, Y., Zhang, S., Kobler, J.B., Incorporation of a matrix metalloproteinase-sensitive substrate into self-assembling peptides - A model for biofunctional scaffolds (2008) Biomaterials, 29 (11), pp. 1713-1719; 
Chau, Y., Tan, F.E., Langer, R., Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX (2004) Bioconjugate Chemistry, 15 (4), pp. 931-941. , DOI 10.1021/bc0499174; 
Turk, B.E., Huang, L.L., Piro, E.T., Cantley, L.C., Determination of protease cleavage site motifs using mixture-based oriented peptide libraries (2001) Nature Biotechnology, 19 (7), pp. 661-667. , DOI 10.1038/90273; 
Kong, H.J., Smith, M.K., Mooney, D.J., Designing alginate hydrogels to maintain viability of immobilized cells (2003) Biomaterials, 24 (22), pp. 4023-4029. , DOI 10.1016/S0142-9612(03)00295-3; 
Rowley, J.A., Madlambayan, G., Mooney, D.J., Alginate hydrogels as synthetic extracellular matrix materials (1999) Biomaterials, 20 (1), pp. 45-53. , DOI 10.1016/S0142-9612(98)00107-0, PII S0142961298001070; 
Lorenzen, A., Kennedy, S.W., A fluorescence-based protein assay for use with a microplate reader (1993) Analytical Biochemistry, 214 (1), pp. 346-348. , DOI 10.1006/abio.1993.1504; 
Kuo, C.K., Ma, P.X., Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties (2001) Biomaterials, 22 (6), pp. 511-521. , DOI 10.1016/S0142-9612(00)00201-5, PII S0142961200002015; 
Oliveira, S.M., Barrias, C.C., Almeida, I.F., Costa, P.C., Pena Ferreira, M.R., Bahia, M.F., Injectability of a bone filler system based on hydroxyapatite microspheres and a vehicle with in situ gel-forming ability (2008) J Biomed Mater Res B Appl Biomater, 87 (1), pp. 49-58; 
Kavimandan, N.J., Losi, E., Wilson, J.J., Brodbelt, J.S., Peppas, N.A., Synthesis and characterization of insulin-transferrin conjugates (2006) Bioconjugate Chemistry, 17 (6), pp. 1376-1384. , DOI 10.1021/bc050344k; 
Lee, K.Y., Rowley, J.A., Eiselt, P., Moy, E.M., Bouhadir, K.H., Mooney, D.J., Controlling mechanical and swelling properties of alginate hydrogels independently by cross-linker type and cross-linking density (2000) Macromolecules, 33 (11), pp. 4291-4294; 
Dent, A., Aslam, M., The functional chemistry of proteins and protein coupling (1998) Bioconjugation: Protein Coupling Techniques for the Biomedical Sciences, pp. 50-100; 
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Drury, J.L., Boontheeku, T., Mooney, D.J., Cellular cross-linking of peptide modified hydrogels (2005) Journal of Biomechanical Engineering, 127 (2), pp. 220-228. , DOI 10.1115/1.1865194; 
Boontheekul, T., Kong, H.-J., Mooney, D.J., Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution (2005) Biomaterials, 26 (15), pp. 2455-2465. , DOI 10.1016/j.biomaterials.2004.06.044, PII S0142961204006064; 
Ries, C., Egea, V., Karow, M., Kolb, H., Jochum, M., Neth, P., MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: Differential regulation by inflammatory cytokines (2007) Blood, 109 (9), pp. 4055-4063. , http://bloodjournal.hematologylibrary.org/cgi/reprint/109/9/4055, DOI 10.1182/blood-2006-10-051060; 
Seiki, M., The cell surface: The stage for matrix metalloproteinase regulation of migration (2002) Current Opinion in Cell Biology, 14 (5), pp. 624-632. , DOI 10.1016/S0955-0674(02)00363-0; 
Will, H., Atkinson, S.J., Butler, G.S., Smith, B., Murphy, G., The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3 (1996) Journal of Biological Chemistry, 271 (29), pp. 17119-17123. , DOI 10.1074/jbc.271.29.17119; 
Itoh, Y., Seiki, M., MT1-MMP: A potent modifier of pericellular microenvironment (2006) Journal of Cellular Physiology, 206 (1), pp. 1-8. , DOI 10.1002/jcp.20431; 
Barbolina, M.V., Adley, B.P., Ariztia, E.V., Liu, Y., Stack, M.S., Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression (2007) Journal of Biological Chemistry, 282 (7), pp. 4924-4931. , http://www.jbc.org/cgi/reprint/282/7/4924, DOI 10.1074/jbc.M608428200
},
	month = {2011///},
	pages = {1674 - 1682},
	abstract = {The development of sophisticated three-dimensional (3-D) cell culture microenvironments that recreate some of the complexity of the natural extracellular matrix (ECM) remains a challenging task. Here, the modification of alginate through partial crosslinking with a matrix metalloproteinase (MMP) cleavable peptide (proline-valine-glycine-leucine-isoleucine-glycine, PVGLIG) is described, and its use in the preparation of injectable, in situ crosslinkable hydrogel-like matrices is proposed. PVGLIG-grafted alginates were synthesized by carbodiimide chemistry and characterized. Their biological performance was evaluated by comparing the response of 3-D cultured mesenchymal stem cells (MSCs) to alginate hydrogels containing only cell-adhesion peptides (RGD-alginate) or both peptides (PVGLIG/RGD-alginate). After 1 week, cells remained essentially round within RGD-alginate, while they exhibited an elongated morphology within PVGLIG/RGD-alginate hydrogels, forming cellular networks. This suggests that cells were able to structurally reorganize the matrix, through enzymatic hydrolysis of PVGLIG residues, overcoming biophysical hydrogel resistance. As shown by gelatine-zymography, MSC presented higher activity of MMP-2 when cultured within alginate functionalized with MMP-sensitive peptide, suggesting that the cell{\textquoteright}s proteolytic phenotype was modulated by the matrix composition. Additionally, PVGLIG/RGD-alginate hydrogels were clearly degraded in cell culture. Taken together, the results demonstrate that the co-incorporation of MMP-labile peptides in cell-adhesive RGD-alginate hydrogels improved their performance as ECM analogues, providing a more dynamic and physiological 3-D cellular microenvironment. {\textcopyright} 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.},
	keywords = {3-D Cell culture, Alginate, Alginates, alginic acid, Amino Acid Sequence, article, cell adhesion, cell composition, Cell Count, Cell culture, Cell Culture Techniques, Cell Shape, cell structure, cell survival, cell viability, Cells, Cultured, controlled study, Enzyme Activation, enzyme activity, extracellular matrix, Extracellular matrix (ECM), gelatin, gelatinase A, Glucuronic Acid, Hexuronic Acids, human, human cell, Humans, hydrogel, Hydrogels, hydrolysis, matrix metalloproteinase, Matrix Metalloproteinases, Matrix metalloproteinases (MMPs), Mesenchymal stem cell, Mesenchymal Stem Cells, Molecular Sequence Data, morphology, peptide derivative, Peptides, phenotype, priority journal, prolylvalylglycylleucylisoleucylglycine, Protease-sensitive, protein cleavage, protein degradation, Protein Processing, Post-Translational, Subcellular Fractions, tumor microenvironment, unclassified drug, zymography},
	isbn = {17427061 (ISSN)},
	url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-79952189303\&partnerID=40\&md5=191596b948bd4cc2569264a992052b88},
	author = {Fonseca, K.B. and Bidarra, S.J. and Oliveira, M.J. and Granja, P.L. and Barrias, C.C.}
}
@article {2264,
	title = {Immobilization of human mesenchymal stem cells within RGD-grafted alginate microspheres and assessment of their angiogenic potential},
	journal = {BiomacromoleculesBiomacromolecules},
	volume = {11},
	year = {2010},
	note = {Cited By (since 1996): 18Export Date: 21 November 2012Source: ScopusCODEN: BOMAFdoi: 10.1021/bm100264aPubMed ID: 20690708Language of Original Document: EnglishCorrespondence Address: Granja, P. L.; INEB-Instituto de Engenharia Biom{\'e}dica, Rua do Campo Alegre No. 823, 4150-180 Porto, Portugal; email: pgranja@ineb.up.ptMolecular Sequence Numbers: GENBANK: BC021289, NM_000088, NM_002046;Chemicals/CAS: alginic acid, 28961-37-7, 29894-36-8, 9005-32-7, 9005-38-3; alkaline phosphatase, 9001-78-9; arginylglycylaspartic acid, 99896-85-2; Alginates; Alkaline Phosphatase, 3.1.3.1; Collagen Type I; DNA Primers; Oligopeptides; arginyl-glycyl-aspartic acid, 99896-85-2References: Temenoff, J.S., Mikos, A.G., Injectable biodegradable materials for orthopedic tissue engineering (2000) Biomaterials, 21, pp. 2405-2412;Barralet, J.E., Wang, L., Lawson, M., Triffitt, J.T., Cooper, P.R., Shelton, R.M., Comparison of bone marrow cell growth on 2D and 3D alginate hydrogels (2005) J. Mater. Sci.: Mater. Med., 16, pp. 515-519; 
Ma, H.L., Hung, S.C., Lin, S.Y., Chen, Y.L., Lo, W.H., Chondrogenesis of human mesenchymal stem cells encapsulated in alginate beads (2003) J. Biomed. Mater. Res., 64, pp. 273-281; 
Augst, A.D., Kong, H.J., Mooney, D.J., Alginate hydrogels as biomaterials (2006) Macromol. Biosci., 6, pp. 623-633; 
Smidsrod, O., Skjak-Braek, G., Alginate as immobilization matrix for cells (1990) Trends Biotechnol., 8, pp. 71-78; 
Jen, A.C., Wake, M.C., Mikos, A.G., Review: Hydrogels for cell immobilization (1996) Biotechnol. Bioeng., 50, pp. 357-364; 
Oliveira, S.M., Barrias, C.C., Almeida, I.F., Costa, P.C., Ferreira, M.R.P., Bahia, M.F., Barbosa R. M, A., Injectability of a bone filler system based on hydroxyapatite microspheres and a vehicle with in situ gel-forming ability (2008) J. Biomed. Mater. Res. B, 87, pp. 49-8; 
Evangelista, M.B., Hsiong, S.X., Fernandes, R., Sampaio, P., Kong, H.-J., Barrias, C.C., Salema, R., Granja, P.L., Upregulation of bone cell differentiation through immobilization within a synthetic extracellular matrix (2007) Biomaterials, 28, pp. 3644-3655; 
Rowley, J.A., Madlambayan, G., Mooney, D.J., Alginate hydrogels as synthetic extracellular matrix materials (1999) Biomaterials, 20, pp. 45-53; 
Kong, H.J., Smith, M.K., Mooney, D.J., Designing alginate hydrogels to maintain viability of immobilized cells (2003) Biomaterials, 24, pp. 4023-4029; 
Grellier, M., Granja, P.L., Fricain, J.-C., Bidarra, S.J., Renard, M., Bareille, R., Bourget, C., Barbosa, M.A., The effect of the co-immobilization of human osteoprogenitors and endothelial cells within alginate microspheres on mineralization in a bone defect (2009) Biomaterials, 30, pp. 3271-3278; 
Caplan, A.I., Adult mesenchymal stem cells for tissue engineering versus regenerative medicine (2007) J. Cell. Physiol., 213, pp. 341-347; 
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Markusen, J.F., Mason, C., Hull, D.A., Town, M.A., Tabor, A.B., Clements, M., Boshoff, C.H., Dunnill, P., Behavior of adult human mesenchymal stem cells entrapped in alginate-GRGDY beads (2006) Tissue Eng., 12, pp. 821-830; 
Duggal, S., Fronsdal, K.B., Szoke, K., Shahdadfar, A., Melvik, J.E., Brinchmann, J.E., Phenotype and gene expression of human mesenchymal stem cells in alginate scaffolds (2009) Tissue Eng., Part A, 15, pp. 1763-1773; 
Kasper, G., Dankert, N., Tuischer, J., Hoeft, M., Gaber, T., Glaeser, J.D., Zander, D., Duda, G.N., Mesenchymal stem cells regulate angiogenesis according to their mechanical environment (2007) Stem Cells, 25, pp. 903-910; 
Gruber, R., Kandler, B., Holzmann, P., Vogele-Kadletz, M., Losert, U., Fischer, M.B., Watzek, G., Bone marrow stromal cells can provide a local environment that favors migration and formation of tubular structures of endothelial cells (2005) Tissue Eng., 11, pp. 896-903; 
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Potapova, I.A., Gaudette, G.R., Brink, P.R., Robinson, R.B., Rosen, M.R., Cohen, I.S., Doronin, S.V., Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro (2007) Stem Cells, 25, pp. 1761-1768; 
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Soares, R., Guo, S., Ga{\textquoteright}rtner, F., Schmitt, F., Russo, J., 17β-Estradiol-mediated vessel assembly and stabilization in tumor angiogenesis requires TGFβ and EGFR crosstalk (2003) Angiogenesis, 6, pp. 271-281; 
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Grellier, M., Ferreira-Tojais, N., Bourget, C., Bareillke, R., Guillemot, F., Am{\'e}d{\'e}e, J., Role of vascular endothelial growth factor in the communication between human osteoprogenitors and endothelial cells (2009) J. Cell. Biochem., 106, pp. 390-398; 
Yu, J., Gu, Y., Du, K.T., Mihardja, S., Sievers, R.E., Lee, R.J., The effect of injected RGD modified alginate on angiogenesis and left ventricular function in a chronic rat infarct model (2009) Biomaterials, 30, pp. 751-756
},
	month = {2010///},
	pages = {1956 - 1964},
	abstract = {In this work, human mesenchymal stem cells (hMSC) immobilized in RGD-coupled alginate microspheres, with a binary composition of high and low molecular weight alginate, were investigated. Cells immobilized within RGD-alginate microspheres (during 21 days) showed metabolic activity, with an overall viability higher than 90\%, short cell extensions, and, when induced, they were able to differentiate into the osteogenic lineage. In osteogenic conditions (comparing to basal conditions), immobilized cells presented alkaline phosphatase (ALP) activity and an upregulation of ALP, collagen type I, and Runx 2 expression. Moreover, mineralization was also detected in immobilized cells under osteogenic stimulus. In addition, it was demonstrated for the first time that MSCs immobilized in this 3D matrix were able to enhance the ability of neighboring endothelial cells to form tubelike structures. Overall, these findings represent a step forward in the development of injectable stem cell carriers for bone tissue engineering. {\textcopyright} 2010 American Chemical Society.},
	keywords = {Alginate, Alginates, alginic acid, alkaline phosphatase, Alkaline phosphatase activity, angiogenesis, arginylglycylaspartic acid, article, Basal conditions, Base Sequence, Binary composition, bone development, Bone tissue engineering, Cell culture, cell differentiation, Cell extension, Cell immobilization, cell metabolism, cell structure, cell viability, collagen type 1, Collagen type I, controlled study, DNA Primers, Endothelial Cells, endothelium cell, enzyme activity, human, human cell, Human mesenchymal stem cells, Humans, immobilized cell, Immobilized cells, Low molecular weight, matrix, Mesenchymal stem cell, Mesenchymal Stem Cells, Metabolic activity, Microscopy, Electron, Scanning, microsphere, Microspheres, molecular weight, Neovascularization, Physiologic, nucleotide sequence, Oligopeptides, osteoblast, Osteogenic, Phosphatases, priority journal, protein expression, quantitative analysis, Reverse Transcriptase Polymerase Chain Reaction, stem cell, Stem cells, three dimensional imaging, Tissue engineering, transcription factor RUNX2, umbilical vein, Up-regulation, upregulation},
	isbn = {15257797 (ISSN)},
	url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-77955575798\&partnerID=40\&md5=d2d378c63dc49de9324e8dddb24ff2e9},
	author = {Bidarra, S.J. and Barrias, C.C. and Barbosa, M.A. and Soares, R. and Granja, P.L.}
}
@article {2305,
	title = {The effect of the co-immobilization of human osteoprogenitors and endothelial cells within alginate microspheres on mineralization in a bone defect},
	journal = {BiomaterialsBiomaterials},
	volume = {30},
	year = {2009},
	note = {Cited By (since 1996): 38Export Date: 21 November 2012Source: ScopusCODEN: BIMADdoi: 10.1016/j.biomaterials.2009.02.033PubMed ID: 19299013Language of Original Document: EnglishCorrespondence Address: Grellier, M.; INSERM, U577, Universit{\'e} Victor Segalen Bordeaux 2, UMR-S577, F-33076 Bordeaux Cedex, France; email: maritie.grellier@inserm.frChemicals/CAS: alginic acid, 28961-37-7, 29894-36-8, 9005-32-7, 9005-38-3; alkaline phosphatase, 9001-78-9; arginylglycylaspartic acid, 99896-85-2; osteocalcin, 136461-80-8; Alginates; Glucuronic Acid, 576-37-4; Hexuronic Acids; alginic acid, 9005-32-7References: Oreffo, R.O., Triffitt, J.T., Future potentials for using osteogenic stem cells and biomaterials in orthopedics (1999) Bone, 25 (2 SUPPL), pp. 5S-9S;Lubiatowski, P., Kruczynski, J., Gradys, A., Trzeciak, T., Jaroszewski, J., Articular cartilage repair by means of biodegradable scaffolds (2006) Transplant Proc, 38 (1), pp. 320-322; 
Evangelista, M.B., Hsiong, S.X., Fernandes, R., Sampaio, P., Kong, H.J., Barrias, C.C., Upregulation of bone cell differentiation through immobilization within a synthetic extracellular matrix (2007) Biomaterials, 28 (25), pp. 3644-3655; 
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},
	month = {2009///},
	pages = {3271 - 3278},
	abstract = {Bone regeneration seems to be dependant on cell communication between osteogenic and endothelial cells arising from surrounding blood vessels. This study aims to determine whether endothelial cells can regulate the osteogenic potential of osteoprogenitor cells in vitro and in vivo, in a long bone defect, when co-immobilized in alginate microspheres. Alginate is a natural polymer widely used as a biomaterial for cell encapsulation. Human osteoprogenitors (HOP) from bone marrow mesenchymal stem cells were immobilized alone or together with human umbilical vein endothelial cells (HUVEC) inside irradiated, oxidized and RGD-grafted alginate microspheres. Immobilized cells were cultured in dynamic conditions and cell metabolic activity increased during three weeks. The gene expression of alkaline phosphatase and osteocalcin, both specific markers of the osteoblastic phenotype, and mineralization deposits were upregulated in co-immobilized HOPs and HUVECs, comparing to the immobilization of monocultures. VEGF secretion was also increased when HOPs were co-immobilized with HUVECs. Microspheres containing co-cultures were further implanted in a bone defect and bone formation was analysed by μCT and histology at 3 and 6 weeks post-implantation. Mineralization was observed inside and around the implanted microspheres containing the immobilized cells. However, when HOPs were co-immobilized with HUVECs, mineralization significantly increased. These findings demonstrate that co-immobilization of osteogenic and endothelial cells within RGD-grafted alginate microspheres provides a promising strategy for bone tissue engineering. {\textcopyright} 2009 Elsevier Ltd. All rights reserved.},
	keywords = {adult, aged, Alginate, Alginates, alginic acid, alkaline phosphatase, animal tissue, Animals, arginylglycylaspartic acid, article, Bioactivity, Biopolymers, Blood vessel prostheses, Blood Vessels, Bone, Bone and Bones, bone defect, Bone defects, Bone formations, Bone marrow mesenchymal stem cells, bone mineralization, Bone Regeneration, Bone regenerations, bone tissue, Bone tissue engineerings, Calcification, Physiologic, Cell communications, Cell culture, Cell encapsulations, cell function, cell growth, Cell immobilization, Cell membranes, cell metabolism, Cells, Cultured, Co immobilizations, Co-culture, coculture, computer assisted tomography, controlled study, Defects, Dynamic conditions, Endothelial Cells, endothelium cell, gene expression, gene expression regulation, Glucuronic Acid, Grafting (chemical), Hexuronic Acids, histology, human, human cell, Human umbilical vein endothelial cells, Humans, Humulus, immobilized cell, Immobilized cells, in vitro study, in vivo study, In-vitro, In-vivo, irradiation, long bone, Long bones, Mesenchymal stem cell, Metabolic activities, Mice, Mice, Nude, microsphere, Microspheres, Middle Aged, Mineralogy, monoculture, mouse, nonhuman, osteoblast, osteocalcin, Osteogenic, Osteogenic potentials, Osteoprogenitor cells, Osteoprogenitors, Oxidation, Peptides, phenotype, Post implantations, priority journal, Self assembly, Sodium compounds, stem cell transplantation, Stem cells, Tissue engineering, umbilical vein, upregulation, Vascular endothelial growth factor (VEGF), X ray analysis, Young Adult},
	isbn = {01429612 (ISSN)},
	url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-67349213598\&partnerID=40\&md5=0190ab2a91dc0dc3527ffd9f86fabf63},
	author = {Grellier, M. and Granja, P.L. and Fricain, J.-C. and Bidarra, S.J. and Renard, M. and Bareille, R. and Bourget, C. and Am{\'e}d{\'e}e, J. and Barbosa, M.A.}
}
