In vitro cellular testing of strontium/calcium substituted phosphate glass discs and microspheres shows potential for bone regeneration

Phosphate‐based glasses (PBGs) are ideal materials for regenerative medicine strategies because their composition, degradation rates, and ion release profiles can easily be controlled. Strontium has previously been found to simultaneously affect bone resorption and deposition. Therefore, by combining the inherent properties of resorbable PBG and therapeutic activity of strontium, these glasses could be used as a delivery device of therapeutic factors for the treatment of orthopaedic diseases such as osteoporosis. This study shows the cytocompatibility and osteogenic potential of PBGs where CaO is gradually replaced by SrO in the near invert glass system 40P2O5·(16‐x)CaO·20Na2O·24MgO·xSrO (x = 0, 4, 8, 12, and 16 mol%). Direct seeding of MG63 cells onto glass discs showed no significant difference in cell metabolic activity and DNA amount measurement across the different formulations studied. Cell attachment and spreading was confirmed via scanning electron microscopy (SEM) imaging at Days 3 and 14. Alkaline phosphatase (ALP) activity was similarly maintained across the glass compositions. Follow‐on studies explored the effect of each glass composition in microsphere conformation (size: 63‐125 μm) on human mesenchymal stem cells (hMSCs) in 3D cultures, and analysis of cell metabolic activity and ALP activity showed no significant differences at Day 14 over the compositional range investigated, in line with the observations from MG63 cell culture studies. Environmental SEM and live cell imaging at Day 14 of hMSCs seeded on the microspheres showed cell attachment and colonisation of the microsphere surfaces, confirming these formulations as promising candidates for regenerative medicine strategies addressing compromised musculoskeletal/orthopaedic diseases.

[1]  B. Scammell,et al.  Porous calcium phosphate glass microspheres for orthobiologic applications. , 2018, Acta biomaterialia.

[2]  T. Islam,et al.  Effect of magnesium content on bioactivity of near invert phosphate‐based glasses , 2017 .

[3]  A. Kennedy,et al.  Structural and physico-chemical analysis of calcium/strontium substituted, near-invert phosphate based glasses for biomedical applications. , 2017, Acta biomaterialia.

[4]  G. Bowlin,et al.  In vitro characterization of MG-63 osteoblast-like cells cultured on organic-inorganic lyophilized gelatin sponges for early bone healing. , 2016, Journal of biomedical materials research. Part A.

[5]  Ali Khademhosseini,et al.  Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response. , 2016, Trends in biotechnology.

[6]  Chris D. Rudd,et al.  Structure, viscosity and fibre drawing properties of phosphate-based glasses: effect of boron and iron oxide addition , 2016, Journal of Materials Science.

[7]  A. E. El Haj,et al.  Autonomous magnetic labelling of functional mesenchymal stem cells for improved traceability and spatial control in cell therapy applications , 2016, Journal of tissue engineering and regenerative medicine.

[8]  C. Wen,et al.  Strontium content and collagen-I coating of Magnesium-Zirconia-Strontium implants influence osteogenesis and bone resorption. , 2016, Clinical oral implants research.

[9]  A. Obata,et al.  Dissolution behavior and cell compatibility of alkali-free MgO-CaO-SrO-TiO2-P2O5 glasses for biomedical applications , 2015 .

[10]  M. Gelinsky,et al.  Strontium modified calcium phosphate cements - approaches towards targeted stimulation of bone turnover. , 2015, Journal of materials chemistry. B.

[11]  Cato T Laurencin,et al.  Biomaterials for Bone Regenerative Engineering , 2015, Advanced healthcare materials.

[12]  Nick J. Walters,et al.  Strontium- and calcium-containing, titanium-stabilised phosphate-based glasses with prolonged degradation for orthopaedic tissue engineering , 2015, Journal of biomaterials applications.

[13]  T. Lee,et al.  Fabrication of gelatin–strontium substituted calcium phosphate scaffolds with unidirectional pores for bone tissue engineering , 2015, Journal of Materials Science: Materials in Medicine.

[14]  Ian M. Reaney,et al.  The osteogenic response of mesenchymal stromal cells to strontium‐substituted bioactive glasses , 2015, Journal of tissue engineering and regenerative medicine.

[15]  M. Gazzano,et al.  Combined effect of strontium and zoledronate on hydroxyapatite structure and bone cell responses. , 2014, Biomaterials.

[16]  D. Egan,et al.  In vitro induction of alkaline phosphatase levels predicts in vivo bone forming capacity of human bone marrow stromal cells. , 2014, Stem cell research.

[17]  K. Hankenson,et al.  Mesenchymal Stem Cells in Bone Regeneration. , 2013, Advances in wound care.

[18]  Xiaolei Li,et al.  A simple sol–gel route for preparing the Barium Strontium Calcium Titanate-Magnesium Oxide composite powders and the sintering/dielectric properties of the ceramics , 2013, Journal of Materials Science: Materials in Electronics.

[19]  Jiang Chang,et al.  Strontium substituted hydroxyapatite porous microspheres: Surfactant-free hydrothermal synthesis, enhanced biological response and sustained drug release , 2013 .

[20]  G. Cerrato,et al.  Sr-containing hydroxyapatite: morphologies of HA crystals and bioactivity on osteoblast cells. , 2013, Materials science & engineering. C, Materials for biological applications.

[21]  Zhenguo Liu,et al.  Porous microsphere and its applications , 2013, International journal of nanomedicine.

[22]  Richard A. Martin,et al.  Titanium phosphate glass microspheres for bone tissue engineering. , 2012, Acta biomaterialia.

[23]  A. Clare,et al.  Bio-glasses : an introduction , 2012 .

[24]  Younan Xia,et al.  Biodegradable porous beads and their potential applications in regenerative medicine , 2012 .

[25]  W. Lu,et al.  The effect of strontium incorporation into hydroxyapatites on their physical and biological properties. , 2012, Journal of biomedical materials research. Part B, Applied biomaterials.

[26]  Lintao Cai,et al.  Strontium Enhances Osteogenic Differentiation of Mesenchymal Stem Cells and In Vivo Bone Formation by Activating Wnt/Catenin Signaling , 2011, Stem cells.

[27]  Vehid Salih,et al.  Titanium and Strontium-doped Phosphate Glasses as Vehicles for Strontium Ion Delivery to Cells , 2011, Journal of biomaterials applications.

[28]  Aldo R Boccaccini,et al.  A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. , 2011, Biomaterials.

[29]  S. Yue,et al.  Bioactive glass scaffolds for bone regeneration and their hierarchical characterisation , 2010, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[30]  Gavin Jell,et al.  The effects of strontium-substituted bioactive glasses on osteoblasts and osteoclasts in vitro. , 2010, Biomaterials.

[31]  M. Rybchyn,et al.  Osteoblasts play key roles in the mechanisms of action of strontium ranelate , 2009, British journal of pharmacology.

[32]  M. Gazzano,et al.  Interaction of Sr-doped hydroxyapatite nanocrystals with osteoclast and osteoblast-like cells. , 2009, Journal of biomedical materials research. Part A.

[33]  Wojciech Chrzanowski,et al.  Structure and properties of strontium-doped phosphate-based glasses , 2009, Journal of The Royal Society Interface.

[34]  K. Boesze-Battaglia,et al.  The role of alkaline phosphatase in mineralization , 2007 .

[35]  J. Glenn,et al.  Effect of ternary phosphate-based glass compositions on osteoblast and osteoblast-like proliferation, differentiation and death in vitro. , 2007, Acta biomaterialia.

[36]  G. Blake,et al.  Strontium ranelate: a novel treatment for postmenopausal osteoporosis: a review of safety and efficacy , 2006, Clinical interventions in aging.

[37]  Junzo Tanaka,et al.  The effect of calcium ion concentration on osteoblast viability, proliferation and differentiation in monolayer and 3D culture. , 2005, Biomaterials.

[38]  I Olsen,et al.  Processing, characterisation and biocompatibility of iron-phosphate glass fibres for tissue engineering. , 2004, Biomaterials.

[39]  P. Marie,et al.  The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. , 1996, Bone.

[40]  G. Stein,et al.  Relationship of cell growth to the regulation of tissue‐specific gene expression during osteoblast differentiation , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  Ke Yang,et al.  Tailoring the degradation and biological response of a magnesium-strontium alloy for potential bone substitute application. , 2016, Materials science & engineering. C, Materials for biological applications.

[42]  T. Hanawa,et al.  New bone formation induced by surface strontium-modified ceramic bone graft substitute. , 2016, Oral diseases.

[43]  L. Dürselen,et al.  Effects of macroporous, strontium loaded xerogel-scaffolds on new bone formation in critical-size metaphyseal fracture defects in ovariectomized rats. , 2016, Injury.

[44]  M. Brandi,et al.  Mechanism of action of strontium ranelate: what are the facts? , 2010, Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases.

[45]  D. W. Pack,et al.  Microspheres for Drug Delivery , 2006, BioMEMS and Biomedical Nanotechnology.

[46]  P. Ammann.  Strontium ranelate: A novel mode of action leading to renewed bone quality , 2004, Osteoporosis International.