Bioactive, Degradable and Tough Hybrids Through Calcium and Phosphate Incorporation

We report the first inorganic/organic hybrids that show outstanding mechanical properties (withstanding cyclic loading) and bone bioactivity. This new hybrid material may fulfil the unmet clinical need for bioactive synthetic bone grafts that can withstand cyclic loading. A SiO2/PTHF/PCL-diCOOH sol-gel hybrid system, that combined inorganic and organic co-networks at the molecular level, previously demonstrated unprecedented synergy of properties, with excellent flexibility and promoted formation of articular cartilage matrix in vitro. Here, for the first time, calcium and phosphate ions were incorporated into the inorganic component of the hybrid network, to impart osteogenic properties. Calcium methoxyethoxide and triethyl phosphate were the calcium and phosphate precursors because they allow for incorporation into the silicate network at low temperature. The hybrid network was characterised with ATR-FTIR, XRD and solid-state Nuclear Magnetic Resonance, which proved calcium and phosphate incorporation and suggested the Ca2+ ions also interacted with PCL-diCOOH through ionic bonds. This resulted in an increased strength (17–64 MPa) and modulus of toughness (2.5–14 MPa) compared to the original SiO2/PTHF/PCL-diCOOH hybrid material (which showed strength of ∼3 MPa and modulus of toughness of ∼0.35 MPa), while also maintaining the ability to withstand cyclic loading. The presence of calcium and phosphates in the silicate network resulted in a more congruent dissolution of the inorganic and organic co-networks in TRIS buffer. This was shown by the presence of silicon, calcium and phosphate ions along with PCL in the TRIS buffer after 1 week, whereas Ca-free hybrids mainly released PCL with negligible Si dissolution. The presence of calcium and phosphates also enabled deposition of hydroxycarbonate apatite following immersion in simulated body fluid, which was not seen on Ca-free hybrid. All hybrids passed cell cytotoxicity tests and supported pre-osteoblast cell attachment. The phosphate-free hybrid showed the best mechanical behaviour and supported better cell attachment, spreading and potentially differentiation of cells. Therefore, the SiO2-CaO/PTHF/PCL-diCOOH hybrid represents a promising biomaterial for use in bone regeneration.

[1]  S. Mello-Castanho,et al.  In vitro bioactivity and antibacterial capacity of 45S5 Bioglass®-based compositions containing alumina and strontium , 2021, Journal of Materials Research and Technology.

[2]  Julian R. Jones,et al.  Scaffold channel size influences stem cell differentiation pathway in 3-D printed silica hybrid scaffolds for cartilage regeneration. , 2020, Biomaterials science.

[3]  Julian R. Jones,et al.  Human mesenchymal stem cells differentiate into an osteogenic lineage in presence of strontium containing bioactive glass nanoparticles. , 2019, Acta biomaterialia.

[4]  Julian R. Jones,et al.  Bouncing and 3D printable hybrids with self-healing properties , 2018 .

[5]  Julian R. Jones,et al.  In vitro osteogenesis by intracellular uptake of strontium containing bioactive glass nanoparticles. , 2018, Acta biomaterialia.

[6]  Julian R. Jones,et al.  Phosphate content affects structure and bioactivity of sol‐gel silicate bioactive glasses , 2017 .

[7]  Richard A. Martin,et al.  The influence of phosphorus precursor on the structure and properties of SiO2–P2O5–CaO bioactive glass , 2017 .

[8]  Julian R. Jones,et al.  Ductile silica/methacrylate hybrids for bone regeneration. , 2016, Journal of materials chemistry. B.

[9]  Julian R. Jones,et al.  Tailoring Mechanical Properties of Sol–Gel Hybrids for Bone Regeneration through Polymer Structure , 2016 .

[10]  Sandra J Shefelbine,et al.  Bone mechanical properties and changes with osteoporosis. , 2016, Injury.

[11]  F. Fayon,et al.  Bioactive glass-gelatin hybrids: building scaffolds with enhanced calcium incorporation and controlled porosity for bone regeneration. , 2016, Journal of materials chemistry. B.

[12]  Chikara Ohtsuki,et al.  A unified in vitro evaluation for apatite-forming ability of bioactive glasses and their variants , 2015, Journal of Materials Science: Materials in Medicine.

[13]  Richard A. Martin,et al.  Bioactive organic/inorganic hybrids with improved mechanical performance. , 2015, Journal of materials chemistry. B.

[14]  Julian R. Jones,et al.  A multinuclear solid state NMR spectroscopic study of the structural evolution of disordered calcium silicate sol-gel biomaterials. , 2015, Physical chemistry chemical physics : PCCP.

[15]  F. Baino,et al.  Zirconia-containing radiopaque mesoporous bioactive glasses , 2014 .

[16]  F. Fayon,et al.  Bioactive glass hybrids: a simple route towards the gelatin-SiO₂-CaO system. , 2014, Chemical communications.

[17]  Ting-Yu Shih,et al.  Synthesis and Properties of Biodegradable Segmented Poly-ε-caprolactone , 2014 .

[18]  Julian R. Jones,et al.  Poly(γ-glutamic acid)/Silica Hybrids with Calcium Incorporated in the Silica Network by Use of a Calcium Alkoxide Precursor , 2014, Chemistry.

[19]  Julian R. Jones,et al.  Chemical characterisation and fabrication of chitosan-silica hybrid scaffolds with 3-glycidoxypropyl trimethoxysilane. , 2014, Journal of materials chemistry. B.

[20]  Julian R. Jones,et al.  Preconditioned 70S30C bioactive glass foams promote osteogenesis in vivo. , 2013, Acta biomaterialia.

[21]  H. Morii,et al.  Coordination to divalent cations by calcium-binding proteins studied by FTIR spectroscopy. , 2013, Biochimica et biophysica acta.

[22]  Julian R. Jones,et al.  Bioactivity in silica/poly(γ-glutamic acid) sol-gel hybrids through calcium chelation. , 2013, Acta biomaterialia.

[23]  Julian R. Jones,et al.  Effect of calcium source on structure and properties of sol-gel derived bioactive glasses. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[24]  Hailing Yang,et al.  The Role of Microtubules and Their Dynamics in Cell Migration* , 2012, The Journal of Biological Chemistry.

[25]  Ke-Ke Yang,et al.  Self-healable and recyclable triple-shape PPDO–PTMEG co-network constructed through thermoreversible Diels–Alder reaction , 2012 .

[26]  G. Niebur,et al.  Viscoelastic properties of human cortical bone tissue depend on gender and elastic modulus , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[27]  Julian R. Jones,et al.  Bioactive silica–poly(γ-glutamic acid) hybrids for bone regeneration: effect of covalent coupling on dissolution and mechanical properties and fabrication of porous scaffolds , 2012 .

[28]  S. Yue,et al.  Characterizing the hierarchical structures of bioactive sol–gel silicate glass and hybrid scaffolds for bone regeneration , 2012, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[29]  Julian R. Jones,et al.  Electrospun silica/PLLA hybrid materials for skeletal regeneration , 2011 .

[30]  D. Brauer,et al.  Fluoride-containing bioactive glasses: Fluoride loss during melting and ion release in tris buffer solution , 2011 .

[31]  G. Melinte,et al.  Hydrogen peroxide versus water synthesis of bioglass–nanocrystalline hydroxyapatite composites , 2011 .

[32]  Julian R. Jones,et al.  Softening bioactive glass for bone regeneration: sol–gel hybrid materials , 2011 .

[33]  M. Popall,et al.  Applications of advanced hybrid organic-inorganic nanomaterials: from laboratory to market. , 2011, Chemical Society reviews.

[34]  Molly M. Stevens,et al.  Silica‐Gelatin Hybrids with Tailorable Degradation and Mechanical Properties for Tissue Regeneration , 2010 .

[35]  Julian R. Jones,et al.  Synthesis of bioactive class II poly(γ-glutamic acid)/silica hybrids for bone regeneration , 2010 .

[36]  K. Kikuta,et al.  In vitro apatite formation on organic–inorganic hybrids in the CaO–SiO2–PO5/2–poly(tetramethylene oxide) system , 2010, Journal of materials science. Materials in medicine.

[37]  P. Nayak,et al.  Synthesis of chitosan-polycaprolactone blend for control delivery of ofloxacin drug , 2010 .

[38]  Julian R. Jones,et al.  Differentiation of fetal osteoblasts and formation of mineralized bone nodules by 45S5 Bioglass conditioned medium in the absence of osteogenic supplements. , 2009, Biomaterials.

[39]  Jacques Besson,et al.  Mullins effect and cyclic stress softening of filled elastomers by internal sliding and friction thermodynamics model , 2009 .

[40]  Julian R. Jones.  New trends in bioactive scaffolds: The importance of nanostructure , 2009 .

[41]  D. Hutmacher,et al.  The return of a forgotten polymer : Polycaprolactone in the 21st century , 2009 .

[42]  Julian R. Jones,et al.  Nanostructure evolution and calcium distribution in sol-gel derived bioactive glass , 2009 .

[43]  Jonathan C. Knowles,et al.  Preparation, structural characterisation and antibacterial properties of Ga-doped sol–gel phosphate-based glass , 2009 .

[44]  S. Yannopoulos,et al.  Vibrational spectroscopic and computational studies of sol–gel derived CaO–MgO–SiO2 binary and ternary bioactive glasses , 2008 .

[45]  A. Tilocca,et al.  Structural effects of phosphorus inclusion in bioactive silicate glasses. , 2007, The journal of physical chemistry. B.

[46]  B. Lim,et al.  Comparative in vitro and in vivo studies using a bioactive poly(epsilon-caprolactone)-organosiloxane nanohybrid containing calcium salt. , 2007, Journal of biomedical materials research. Part B, Applied biomaterials.

[47]  Yiyong Wu,et al.  Structural characterization of sol–gel composites using TEOS/MEMO as precursors , 2007 .

[48]  Larry L. Hench,et al.  The story of Bioglass® , 2006, Journal of materials science. Materials in medicine.

[49]  María Vallet-Regí,et al.  Bioactive Star Gels , 2006 .

[50]  Tadashi Kokubo,et al.  How useful is SBF in predicting in vivo bone bioactivity? , 2006, Biomaterials.

[51]  M. Popall,et al.  Applications of hybrid organic–inorganic nanocomposites , 2005 .

[52]  L. Hench,et al.  The use of advanced diffraction methods in the study of the structure of a bioactive calcia: silica sol-gel glass. , 2005, Journal of materials science. Materials in medicine.

[53]  M. Bosetti,et al.  The effect of bioactive glasses on bone marrow stromal cells differentiation. , 2005, Biomaterials.

[54]  J. Mano.  Viscoelastic properties of bone: Mechanical spectroscopy studies on a chicken model , 2005 .

[55]  L. Hench,et al.  Tailoring of bioactive glasses for the release of nitric oxide as an osteogenic stimulus , 2004 .

[56]  B. Lim,et al.  Evaluation of a novel poly(epsilon-caprolactone)-organosiloxane hybrid material for the potential application as a bioactive and degradable bone substitute. , 2004, Biomacromolecules.

[57]  Philippe Dumas,et al.  FTIR study of polycaprolactone chain organization at interfaces. , 2004, Journal of colloid and interface science.

[58]  S. Rhee,et al.  Evaluations of bioactivity and mechanical properties of poly (ε-caprolactone)/silica nanocomposite following heat treatment , 2004 .

[59]  N. Miyata,et al.  Apatite-forming ability and mechanical properties of CaO-free poly(tetramethylene oxide) (PTMO)-TiO2 hybrids treated with hot water. , 2003, Biomaterials.

[60]  NMR nomenclature: nuclear spin properties and conventions for chemical shifts. IUPAC recommendations 2001. Prepared for publication by Robin K. Harris, Edwin D. Becker, Sonia M. Cabral de Menezes, Robin Goodfellow and Pierre Granger Magn. Reson. Chem. 2002; 40: 489–505 , 2002 .

[61]  N. Miyata,et al.  Apatite-forming ability and mechanical properties of PTMO-modified CaO-SiO2 hybrids prepared by sol-gel processing: effect of CaO and PTMO contents. , 2002, Biomaterials.

[62]  P. Granger,et al.  NMR nomenclature: nuclear spin properties and conventions for chemical shifts. IUPAC Recommendations 2001. International Union of Pure and Applied Chemistry. Physical Chemistry Division. Commission on Molecular Structure and Spectroscopy , 2002 .

[63]  Larry L Hench,et al.  Third-Generation Biomedical Materials , 2002, Science.

[64]  L L Hench,et al.  Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass 45S5 dissolution. , 2001, Journal of biomedical materials research.

[65]  P Zioupos,et al.  Mechanical properties and the hierarchical structure of bone. , 1998, Medical engineering & physics.

[66]  M. Mizuguchi,et al.  FT-IR study of the Ca2+-binding to bovine alpha-lactalbumin. Relationships between the type of coordination and characteristics of the bands due to the Asp COO- groups in the Ca2+-binding site. , 1997, FEBS letters.

[67]  A. Bantjes,et al.  In vivo testing of crosslinked polyethers. II. Weight loss, IR analysis, and swelling behavior after implantation. , 1996, Journal of biomedical materials research.

[68]  A. Bantjes,et al.  In vivo testing of crosslinked polyethers. I. Tissue reactions and biodegradation. , 1996, Journal of biomedical materials research.

[69]  M. Tanokura,et al.  Infrared studies of interaction between metal ions and Ca2+‐binding proteins Marker bands for identifying the types of coordination of the side‐chain COO− groups to metal ions in pike parvalbumin (pI = 4.10) , 1994, FEBS letters.

[70]  Bruce M. Novak,et al.  Hybrid nanocomposite materials―between inorganic glasses and organic polymers , 1993 .

[71]  B. Piriou,et al.  Study of sodium silicate melt and glass by infrared reflectance spectroscopy , 1983 .

[72]  R. Stolen,et al.  Water and its relation to broken bond defects in fused silica , 1976 .

[73]  Larry L. Hench,et al.  Bonding mechanisms at the interface of ceramic prosthetic materials , 1971 .

[74]  R. Legeros,et al.  Apatite Crystallites: Effects of Carbonate on Morphology , 1967, Science.

[75]  G. Kickelbick.  Hybrid Materials – Past, Present and Future. , 2014 .

[76]  Julian R Jones,et al.  Review of bioactive glass: from Hench to hybrids. , 2013, Acta biomaterialia.

[77]  T. Wecker,et al.  Substrate rigidity modulates cell matrix interactions and protein expression in human trabecular meshwork cells. , 2008, Investigative ophthalmology & visual science.

[78]  N. Miyata,et al.  Apatite-forming ability and mechanical properties of PTMO-modified CaO-SiO2-TiO2 hybrids derived from sol-gel processing. , 2004, Biomaterials.

[79]  Larry L. Hench,et al.  Gene-expression profiling of human osteoblasts following treatment with the ionic products of Bioglass t 45 S 5 dissolution , 2000 .

[80]  M Martens,et al.  Aging of bone tissue: mechanical properties. , 1976, The Journal of bone and joint surgery. American volume.