Abstract
The use of 3D scaffolds based on mesoporous bioactive glasses (MBG) enhanced with therapeutic ions, biomolecules and cells is emerging as a strategy to improve bone healing. In this paper, the osteogenic capability of ZnO-enriched MBG scaffolds loaded or not with osteostatin (OST) and human mesenchymal stem cells (MSC) was evaluated after implantation in New Zealand rabbits. Cylindrical meso-macroporous scaffolds with composition (mol %) 82.2SiO2–10.3CaO–3.3P2O5–4.2ZnO (4ZN) were obtained by rapid prototyping and then, coated with gelatin for easy handling and potentiating the release of inorganic ions and OST. Bone defects (7.5 mm diameter, 12 mm depth) were drilled in the distal femoral epiphysis and filled with 4ZN, 4ZN + MSC, 4ZN + OST or 4ZN + MSC + OST materials to evaluate and compare their osteogenic features. Rabbits were sacrificed at 3 months extracting the distal third of bone specimens for necropsy, histological, and microtomography (µCT) evaluations. Systems investigated exhibited bone regeneration capability. Thus, trabecular bone volume density (BV/TV) values obtained from µCT showed that the good bone healing capability of 4ZN was significantly improved by the scaffolds coated with OST and MSC. Our findings in vivo suggest the interest of these MBG complete systems to improve bone repair in the clinical practice.
Similar content being viewed by others
References
Bose S, Roy M, Bandyopadhyay A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 2012;30:546–54.
Salinas AJ, Esbrit P, Vallet-Regí M. A tissue engineering approach based on the use of bioceramics for bone repair. Biomater. Sci. 2013;1:40–51.
Wu SL, Liu XM, Yeung WK, Liu CS, Yang XJ. Biomimetic porous scaffolds for bone tissue engineering. Mater Sci Eng R-Rep. 2014;80:1–36.
Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanisms at the interface of ceramic prosthetic materials. J Biomed Mater Res Symp. 1971;2:117–41.
Li R, Clark AE, Hench LL. An investigation of bioactive glass powders by sol-gel processing. J Appl Biomater. 1991;2:231–9.
Yan X, Yu C, Zhou X, Tang J, Zhao D. Highly ordered mesoporous bioactive glasses with superior in vitro bone forming bioactivities. Angew Chem Int Ed. 2004;43:5980–4.
Vallet-Regí M, Salinas AJ, Arcos D. Tailoring the structure of bioactive glasses: from the nanoscale to macroporous scaffolds. Int J App l Glass Sci. 2016;7:195–205.
Vallet-Regí M, Ragel CV, Salinas AJ. Glasses with medical applications. Eur J Inor Chem. 2003;1:1029–42.
Izquierdo-Barba I, Arcos D, Sakamoto Y, Terasaki O, López-Noriega A, Vallet-Regí M. High-performance mesoporous bioceramics mimicking bone mineralization. Chem Mater. 2008;20:3191–8.
Hench LL. Genetic design of bioactive glass. J Eur Ceram Soc. 2009;29:1257–65.
Kaya S, Cresswell M, Boccaccini AR. Mesoporous silica-based bioactive glasses for antibiotic-free antibacterial applications. Mater Sci Eng C-Mater. 2018;83:99–107.
Yu YQ, Jin GD, Xue Y, Wang DH, Liu XY, Sun J. Multifunctions of dual Zn/Mg ion co-implanted titanium on osteogenesis, angiogenesis and bacteria inhibition for dental implants. Acta Biomater. 2017;49:590–603.
Gittard SD, Perfect JR, Monteiro-Riviere NA, Wei W, Jin CM, Narayan RJ. Assessing the antimicrobial activity of zinc oxide thin films using disk diffusion and biofilm reactor. Appl Surf Sci. 2009;255:5806–11.
Lozano D, Manzano M, Doadrio JC, Salinas AJ, Vallet-Regí M, Gómez-Barrena E, et al. Osteostatin-loaded bioceramics stimulate osteoblastic growth and differentiation. Acta Biomater. 2010;6:797–803.
Esbrit P, Alcaraz MJ. Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies. Biochem Pharmacol. 2013;85:1417–23.
Datta NS, Abou-Samra AB. PTH and PTHrP signalling in osteoblasts. Cell Signal. 2009;21:1245–54.
Lozano D, De Castro LF, Dapía S, Andrade-Zapata I, Manzarbeitia F, Alvarez-Arroyo MV, et al. Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia. Endocrinology. 2009;150:2027–35.
Fenton AJ, Kemp BE, Hammonds RG, Mitchelhill K, Moseley JM, Martin TJ, et al. A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein, PTHrP. Endocrinology. 1991;129:3424–6.
Cornish J, Callon KE, Nicholson GC, Reid IR. Parathyroid hormone-related protein (107–139) inhibits bone resorption in vivo. Endocrinology. 1997;138:1299–304.
Cornish J, Callon KE, Lin C, Xiao C, Moseley JM, Reid IR. Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein. J Bone Mine Res. 1999;14:915–22.
Lozano D, Fernández de Castro LF, Portal-Núñez S, López-Herradón A, Dapía S, Gómez-Barrena E, et al. The C-terminal fragment of parathyroid hormone-related peptide promotes bone formation in diabetic mice with low-turnover osteopenia. Br J Pharmacol. 2011;162:1424–38.
Rihani-Basharat S, Lewinson D. PTHrP(107-111) Inhibits In Vivo Resorption that was Stimulated by PTHrP(1-34) When Applied Intermittently to Neonatal Mice. Calcif Tissue Int. 1997;61:426–8.
Fenton AJ, Kemp BE, Ken GN, Moseley JM, Zheng MH, Rowe DJ, et al. A Carboxyl-Terminal Peptide from the Parathyroid Hormone-Related Protein Inhibits Bone Resorption by Osteoclasts. Endocrinology. 1991;129:1762–8.
De Gortázar AR, Alonso V, Alvarez-Arroyo MV, Esbrit P. Transient Exposure to PTHrP (107–139) Exerts Anabolic Effects through Vascular Endothelial Growth Factor Receptor 2 in Human Osteoblastic Cells in Vitro. Calcif Tissue Int. 2006;79:360–9.
Trejo CG, Lozano D, Manzano M, Doadrio JC, Salinas AJ, Dapía S, et al. The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model. Biomaterials. 2010;31:8564–73.
Lozano D, Trejo CG, Gómez-Barrena E, Manzano M, Doadrio JC, Salinas AJ, et al. Osteostatin-loaded onto mesoporous ceramics improves the earlyphase of bone regeneration in a rabbit osteopenia model. Acta Biomater. 2012;8:2317–23.
Lozano D, Sánchez-Salcedo S, Portal-Nuñez S, Vila M, López-Herradón A, Ardura JA, et al. Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin-glutaraldehyde biopolymer-coated hydroxyapatite. Acta Biomater. 2014;10:3307–16.
Ardura JA, Portal-Núñez S, Lozano D, Gutiérrez-Rojas I, Sánchez-Salcedo S, López-Herradón A, et al. Local delivery of parathyroid hormone-related protein-derived peptides coated onto a hydroxyapatite-based implant enhances bone regeneration in old and diabetic rats. J Biomed Mater Res A. 2016;104:2060–70.
Pérez R, Sanchez-Salcedo S, Lozano D, Heras C, Esbrit P, Vallet-Regí M, et al. Osteogenic Effect of ZnO-Mesoporous Glasses Loaded with Osteostatin. Nanomaterials. 2018;8:592.
Heras C, Sanchez-Salcedo S, Lozano D, Peña J, Esbrit P, Vallet-Regi M, et al. Osteostatin potentiates the bioactivity of mesoporous glass scaffolds containing Zn2+ ions in human mesenchymal stem cells. Acta Biomater. 2019;89:359–71.
Thorpe AA, Creasey S, Sammon C, Le Maitre CL. Hydroxyapatite nanoparticle injectable hydrogel scaffold to support osteogenic differentiation of human mesenchymal stem cells. Eur Cell Mater. 2016;32:1–23.
Lasanios NG, Kanakaris NK, Giannoudis PV. Current management of long bone large segmental defects. J Orthop Trauma. 2009;24:149–63.
Miño-Fariña N, Muñoz-Guzón F, López-Peña M, Ginebra MP, del Valle-Fresno S, Ayala D, et al. Quantitative analysis of the resorption and osteoconduction of a macroporous calcium phosphate bone cement for the repair of a critical size defect in the femoral condyle. Vet J. 2009;179:264–72.
Reichert JC, Saifzadeh S, Wullschleger ME, Epari DR, Schütz MA, Duda GN, et al. The challenge of establishing preclinical models for segmental bone defect research. Biomaterials. 2009;30:2149–63.
Cacchioli A, Spaggiari B, Ravanetti F, Martini FM, Borghetti P, Gabbi C. The critical size bone defect: morphological study of bone healing. Ann Fac Medic Vet Parma. 2006;26:97–100.
Cugala Z, Gogolewski S. Regeneration of segmental diaphyseal defects in sheep tibiae using resorbable polymeric membranes: a preliminary study. J Orthop Trauma. 1999;13:187–95.
Gil-Albarova J, Garrido-Lahiguera R, Salinas AJ, Roman J, Bueno-Lozano AL, Gil-Albarova R, et al. The in vivo performance of a sol–gel glass and a glass-ceramic in the treatment of limited bone defects. Biomaterials. 2004;25:4639–45.
Gil-Albarova J, Vila M, Badiola-Vargas J, Sánchez-Salcedo S, Herrera A, Vallet-Regi M. In vivo osteointegration of three-dimensional crosslinked gelatin-coated hydroxyapatite foams. Acta Biomater. 2012;8:3777–83.
Shors EC. Coraline bone graft substitutes. Orthop Clin North Am. 1999;30:599–613.
Bauer TW, Muschler GF. Bone graft materials: an overview of the basic science. Clin Orthop. 2000;71:10–27.
Gao T, Aro HT, Ylänen H, Vuorio E. Silica-based bioactive glasses modulate expression of bone morphogenetic protein-2 mRNA in Saos-2 osteoblasts in vitro. Biomaterials. 2001;22:1475–83.
Wai-Ching L, Irina SR, Rikin P, Ming CL, Velez M, Chu TM. The effects of 3D bioactive glass scaffolds and BMP-2 on bone formation in rat femoral critical size defects and adjacent bones. Biomed Mater. 2014;9:045013.
Caramella C, Conti B, Modena T, Ferrari F, Bonferoni MC, Genta I, et al. Controlled delivery systems for tissue repair and regeneration. J Drug Deliv Sci Technol. 2016;32:206–28.
Liu D, Nie W, Li D, Wang W, Zheng L, Zhang J, et al. 3D printed PCL/SrHA scaffold for enhanced bone regeneration. Chem Eng J. 2019;362:269–79.
Begam H, Nandi SK, Chanda A, Kundu B. Effect of bone morphogenetic protein on Zn-HAp and Zn-HAp/collagen composite: a systematic in vivo study. Res Vet Sci. 2017;115:1–9.
Dias MR, Guedes JM, Flanagan CL, Hollister SJ, Fernandes PR. Optimization of scaffold design for bone tissue engineering: a computational and experimental study. Med Eng Phys. 2014;36:448–57.
Barceloux DGJ. Zinc. Toxicol, Clin Toxicol. 1999;37:279–92.
van der Stok J, Lozano D, Chai YC, Amin YS, Bastidas CAP, Verhaar JA, et al. Osteostatin-coated porous titanium can improve early bone regeneration of cortical bone defects in rats. Tissue Eng Part A. 2015;21:1495–506.
Xie E, Hu Y, Chen X, Bai X, Li D, Ren L, et al. In vivo bone regeneration using a novel porous bioactive composite. Appl Surf Sci. 2008;255:545–7.
Hadley KB, Newman SM, Hunt JR. Dietary zinc reduces osteoclast resorption activities and increases markers of osteoblast differentiation, matrix maturation, and mineralization in the long bones of growing rats. J Nutr Biochem. 2010;2:297–303.
Yamaguchi M, Weitzmann MN. Zinc stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-kB activation. Mol Cell Biochem. 2011;355:179–86.
Acknowledgements
This research was funded by Instituto de Salud Carlos III, grant number PI15/00978 co-financed with the European Union FEDER funds, the European Research Council, Advanced Grant Verdi-Proposal No. 694160 (ERC-2015-AdG).
Author information
Authors and Affiliations
Contributions
Conceptualization, DL, JGA, and AJS; Funding acquisition, MVR and AJS; Investigation, DL, CH, SSS, EGP, and AGB; Methodology, JGA, CH, EGP, AGB and JCD; Supervision, JGA, MVR and AJS; Validation, DL and JGA; Visualization, DL and JGA; Writing–original draft, DL and JGA; Writing–review & editing, DL, JGA, CH, SSS, and AJS. All authors have read and agreed to the published version of the paper.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Lozano, D., Gil-Albarova, J., Heras, C. et al. ZnO-mesoporous glass scaffolds loaded with osteostatin and mesenchymal cells improve bone healing in a rabbit bone defect. J Mater Sci: Mater Med 31, 100 (2020). https://doi.org/10.1007/s10856-020-06439-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10856-020-06439-w