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Critical Role of Silicon in Directing the Bio-inspired Mineralization of Gelatin in the Presence of Hydroxyapatite

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Abstract

Significant progress has been made on understanding the critical role of organic components in directing the collagen mineralization. We hypothesize that the inorganic trace elements might also play important role in the mineralization of collagenous matrix. To this aim, we systematically compared the in-vitro biomineralization behaviors of gelatin, gelatin-HA and gelatin-SiHA electrospun membranes. The results indicated that the presence of Si ions played a striking influence on the nucleation behaviors and mineralized structures. The gelatin-SiHA samples demonstrated more homogeneous nucleation within the gelatin fiber and growth along the fiber direction, in comparison with the heterogeneous nucleation and growth of spherulitic clusters on top of the nanofiber surface, i.e. extrafibrillar mineralization. The likely shift of the nucleation mode to the intrafibrillar mineralization in the presence of Si ions led to good alignment of apatite c-axis with the long axis of the nanofiber, resulting in a mineralization process and microstructure that were closer to those in natural bone. Cellular response analysis indicated that Si incorporation improved the MSC attachment and cytoskeleton organization. Such findings might have important implication in both understanding the complex mechanisms involved in collagen mineralization and optimal designing of advanced bio-inspired materials with potential superior mechanical and biological properties.

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References

  1. Fratzl, P., Gupta, H. S., Paschalis, E. P., & Roschger, P. (2004). Structure and mechanical quality of the collagen-mineral nano-composite in bone. Journal of Materials Chemistry, 14, 2115–2123.

    Article  Google Scholar 

  2. Barth, H. D., Zimmermann, E. A., Schaible, E., Tang, S. Y., Alliston, T., & Ritchie, R. O. (2011). Characterization of the effects of X-Ray irradiation on the hierarchical structure and mechanical properties of human cortical bone. Biomaterials, 32, 8892–8904.

    Article  Google Scholar 

  3. Ding, C. M., Chen, Z. X., & Li, J. S. (2017). From molecules to macrostructures: recent development of bioinspired hard tissue repair. Biomaterials Science, 5, 1435–1449.

    Article  Google Scholar 

  4. Niu, L., Jee, S. E., Jiao, K., Tonggu, L., Li, M., Wang, L. G., Yang, Y. D., Bian, J. H., Breschi, L., Jang, S. S., Chen, J. H., Pashley, D. H., & Tay, F. R. (2017). Collagen intrafibrillar mineralisation as a result of the balance between osmotic equilibrium and electroneutrality. Nature Materials, 16, 370–378.

    Article  Google Scholar 

  5. Smith, L. J., Deymier, A. C., Boyle, J. J., Li, Z., Linderman, S. W., Pasteris, J. D., Xia, Y. N., Genin, G. M., & Thomopoulos, S. (2016). Tunability of collagen matrix mechanical properties via multiple modes of mineralization. Interface Focus, 6, 2042–2053.

    Article  Google Scholar 

  6. Antonietti, M., Breulmann, M., Göltner, C. G., Clfen, H., Wong, K. K. W., Walsh, D., & Mann, S. (2015). Inorganic/organic mesostructures with complex architectures: precipitation of calcium phosphate in the presence of double-hydrophilic block copolymers. Chemistry-A European Journal, 4, 2493–2500.

    Article  Google Scholar 

  7. Gay, C. V. (1977). The ulstrastructure of the extracellular phase of bone as observed in frozen thin sections. Calcified Tissue Research, 23, 215–223.

    Article  Google Scholar 

  8. Yoreo, D. J. J., Gilbert, P. U., Sommerdijk, N. A., Penn, R. L., & Dove, P. M. (2015). Crystallization by particle attachment in synthetic, biogenic, and geologic environments. Science, 349, 6760–6770.

    Article  Google Scholar 

  9. Gebauer, D., Volkel, A., & Colfen, H. (2008). Stable prenucleation calcium carbonate clusters. Science, 322, 1819–1822.

    Article  Google Scholar 

  10. Tidhar, Y., Weissman, H., Tworowski, D., & Rybtchinski, B. (2014). Mechanism of crystalline self-assembly in aqueous medium: a combined cryo-TEM/kinetic study. Chemistry, 20, 10332–10342.

    Article  Google Scholar 

  11. Kim, Y. Y., Douglas, E. P., & Gower, L. B. (2007). Patterning inorganic (CaCO3) thin films via a polymer-induced liquid-precursor Process. Langmuir, 23, 4862–4870.

    Article  Google Scholar 

  12. Olszta, M. J., Gajjeraman, S., Kaufman, M., & Gower, L. B. (2004). Nanofibrous calcite synthesized via a solution-precursor-solid mechanism. Chemistry of Materials, 16, 2355–2362.

    Article  Google Scholar 

  13. Olszta, M. J., Cheng, X. G., Jee, S. S., Kumar, R., Kim, Y. Y., Kaufman, M. J., Douglas, E. P., & Gower, L. B. (2007). Bone structure and formation: a new perspective. Materials Science and Engineering R, 58, 77–116.

    Article  Google Scholar 

  14. Nudelman, F., Pieterse, K., George, A., Bomans, P. H. H., Friedrich, H., Brylka, L. J., Hilbers, P. A. J., With, G. D., & Sommerdijk, N. A. J. M. (2010). The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nature Materials, 9, 1004–1009.

    Article  Google Scholar 

  15. Landis, W. J., Song, M. J., Leith, A., Mcewen, L., & Mcewen, B. F. (1993). Mineral and organic matrix interaction in normally calcifying tendon visualized in three dimensions by high-voltage electron microscopic tomography and graphic image reconstruction. Journal of Structural Biology, 110, 39–54.

    Article  Google Scholar 

  16. Nudelman, F., Lausch, A. J., Sommerdijk, N. A. J. M., & Sone, E. D. (2013). In vitro models of collagen biomineralization. Journal of Structural Biology, 183, 258–269.

    Article  Google Scholar 

  17. Toroian, D., Lim, J. E., & Price, P. A. (2007). The size exclusion characteristics of type I collagen: Implications for the role of noncollagenous bone constituents in mineralization. Journal of Structural Biology, 282, 22437–22447.

    Google Scholar 

  18. Takahashi, M., Nakajima, M., Tagami, J., Scheffel, D. L. S., Carvalho, R. M., Mazzoni, A., & Cadenaro, M. (2013). The importance of size-exclusion characteristics of type I collagen in bonding to dentin matrices. Acta Biomaterialia, 9, 9522–9528.

    Article  Google Scholar 

  19. Toroian, D., & Price, P. A. (2008). The essential role of fetuin in the serum-induced calcification of collagen. Calcified Tissue International, 82, 116–126.

    Article  Google Scholar 

  20. Shih, Y. V., & Varghese, S. (2019). Tissue engineered bone mimetics to study bone disorders ex vivo: Role of bioinspired materials. Biomaterials, 198, 107–121.

    Article  Google Scholar 

  21. Öfkeli, F., Demir, D., & Bölgen, N. (2020). Biomimetic mineralization of chitosan/gelatin cryogels and in vivo biocompatibility assessments for bone tissue engineering. Journal of Applied Polymer Science, 138, 50337.

    Article  Google Scholar 

  22. Zhao, Y. Q., & Tang, R. K. (2020). Improvement of organisms by biomimetic mineralization: A material incorporation strategy for biological modification. Acta Biomaterialia., 120, 57–80.

    Article  Google Scholar 

  23. Li, B., Gao, P., Zhang, H. Q., Guo, Z., Zheng, Y. F., & Han, Y. (2018). Osteoimmunomodulation, osseointegration, and in vivo mechanical integrity of pure Mg coated with HA nanorod/pore-sealed MgO bilayer. Biomaterials Science, 6, 3202–3218.

    Article  Google Scholar 

  24. Stipniece, L., Wilson, S., Curran, J. M., & Chen, R. (2021). Strontium substituted hydroxyapatite promotes direct primary human osteoblast maturation. Ceramics International, 47, 3368–3379.

    Article  Google Scholar 

  25. You, Y. H., Ma, W. Z., Wang, F. A., Jiao, G. J., Zhang, L., Zhou, H., Wu, W. L., Wang, H. L., & Chen, Y. (2021). Ortho-silicic acid enhances osteogenesis of osteoblasts through the upregulation of miR-130b which directly targets PTEN. Life Sciences, 264, 118680.

    Article  Google Scholar 

  26. Carlisle, E. M. (1970). Silicon: A possible factor in bone calcification. Science, 167, 279–280.

    Article  Google Scholar 

  27. Carlisle, E. M. (1981). Silicon: A requirement in bone formation independent of vitamin D1. Calcified Tissue International, 33, 27–34.

    Article  Google Scholar 

  28. Hench, L. L., & Paschall, H. A. (1973). Direct chemical bond of bioactive glass-ceramic materials to bone and muscle. Journal of Biomedical Materials Research Part A, 7, 25–42.

    Article  Google Scholar 

  29. Hing, K. A., Revell, P. A., Smith, N., & Buckland, T. (2006). Effect of silicon level on rate, quality and progression of bone healing within silicate-substituted porous hydroxyapatite scaffolds. Biomaterials, 27, 5014–5026.

    Article  Google Scholar 

  30. Thian, E. S., Huang, J., Best, S. M., Barber, Z. H., Brooks, R. A., Rushton, N., & Bonfield, W. (2006). The response of osteoblasts to nanocrystalline silicon-substituted hydroxyapatite thin films. Biomaterials, 27, 2692–2698.

    Article  Google Scholar 

  31. Henstock, J. R., Canham, L. T., & Anderson, S. I. (2015). Silicon: The evolution of its use in biomaterials. Acta Biomaterialia, 11, 17–26.

    Article  Google Scholar 

  32. Bohner, M. (2009). Silicon-substituted calcium phosphates-A critical view. Biomaterials, 30, 6403–6406.

    Article  Google Scholar 

  33. Ahmed, F. E., Lalia, B. S., & Hashaikeh, R. (2015). A review on electrospinning for membrane fabrication: Challenges and applications. Desalination, 356, 15–30.

    Article  Google Scholar 

  34. Hinderer, S., Layland, S. L., & Schenke-Layland, K. (2016). ECM and ECM-like materials-biomaterials for applications in regenerative medicine and cancer therapy. Advanced Drug Delivery Reviews, 97, 260–269.

    Article  Google Scholar 

  35. Gouma, P. I., & Han, D. (2006). Electrospun bioscaffolds that mimic the topology of extracellular matrix. Nanomedicine: Nanotechnology Biology and Medicine, 2, 37–41.

    Article  Google Scholar 

  36. Huang, T., Xiao, Y. F., Wang, S. L., Huang, Y., Liu, X. G., Wu, F., & Gu, Z. W. (2011). Nanostructured Si, Mg, CO32− substituted hydroxyapatite coatings deposited by liquid precursor plasma spraying: Synthesis and characterization. Journal of Thermal Spray Technology, 20, 829–836.

    Article  Google Scholar 

  37. Jiao, K., Niu, L. N., Ma, C. F., Huang, X. Q., Pei, D. D., Luo, T., Huang, Q., Chen, J. H., & Tay, F. R. (2016). Complementarity and uncertainty in intrafibrillar mineralization of collagen. Advanced Functional Materials, 26, 6858–6875.

    Article  Google Scholar 

  38. Deshpande, A. S., & Beniash, E. (2008). Bio-inspired synthesis of mineralized collagen fibrils. Crystal Growth & Design, 8, 3084–3090.

    Article  Google Scholar 

  39. Rodriguez, D. E., Thulamata, T., Toro, E. J., Yeh, Y. W., & Gower, L. B. (2014). Multifunctional role of osteopontin in directing intrafibrillar mineralization of collagen and activation of osteoclasts. Acta Biomaterialia, 10, 494–507.

    Article  Google Scholar 

  40. Li, Y. P., Thula, T. T., Jee, S., Perkins, S. L., Aparicio, C., Douglas, E. P., & Gower, L. B. (2012). Biomimetic mineralization of woven bone-like nanocomposites: role of collagen cross-links. Biomacromolecules, 13, 49–59.

    Article  Google Scholar 

  41. Marelli, B., Ghezzi, C. E., Zhang, Y. L., Rouiller, I., Barralet, J. E., & Nazhat, S. N. (2015). Fibril formation pH controls intrafibrillar collagen biomineralization invitro and invivo. Biomaterials, 37, 252–259.

    Article  Google Scholar 

  42. Xu, Z. J., Yang, Y., Zhao, W. L., Wang, Z. Q., Landis, W. J., Cui, Q., & Sahai, N. (2015). Molecular mechanisms for intrafibrillar collagen mineralization in skeletal tissues. Biomaterials, 39, 59–66.

    Article  Google Scholar 

  43. Janning, C., Willbold, E., Vogt, C., Nellesen, J., Lindenberg, A. M., Windhagen, H., Thorey, F., & Witte, F. (2010). Magnesium hydroxide temporarily enhancing osteoblast activity and decreasing the osteoclast number in peri-implant bone remodelling. Acta Biomaterialia, 6, 1861–1868.

    Article  Google Scholar 

  44. Castellani, C., Lindtner, R. A., Hausbrandt, P., Tschegg, E., Stanzl-Tschegg, S. E., Zanoni, G., Beck, S., & Weinberg, A. M. (2011). Bone–implant interface strength and osseointegration: Biodegradable magnesium alloy versus standard titanium control. Acta Biomaterialia, 7, 432–440.

    Article  Google Scholar 

  45. Marie, P. J., Felsenberg, D., & Brandi, M. L. (2011). How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporosis International, 22, 1659–1667.

    Article  Google Scholar 

  46. Zhu, P. X., Masuda, Y., & Koumoto, K. (2004). The effect of surface charge on hydroxyapatite nucleation. Biomaterials, 25, 3915–3921.

    Article  Google Scholar 

  47. Takeuchi, A., Ohtsuki, C., Miyazaki, T., Kamitakahara, M., Ogata, S., Yamazaki, M., Furutani, Y., Kinoshita, H., & Tanihara, M. (2005). Heterogeneous nucleation of hydroxyapatite on protein: Structural effect of silk sericin. Journal of the Royal Society Interface, 2, 373–378.

    Article  Google Scholar 

  48. Eastoe, J. E., & Eastoe, B. (1954). The organic constituents of mammalian compact bone. Biochemical Journal, 57, 453–459.

    Article  Google Scholar 

  49. Thula, T. T., Rodriguez, D. E., Lee, M. H., Pendi, L., Podschun, J., & Gower, L. B. (2011). In vitro mineralization of dense collagen substrates: A biomimetic approach toward the development of bone-graft materials. Acta Biomaterialia, 7, 3158–3169.

    Article  Google Scholar 

  50. Landis, W. J., & Robin, J. (2013). Association of calcium and phosphate ions with collagen in the mineralization of vertebrate tissues. Calcified Tissue International, 93, 329–337.

    Article  Google Scholar 

  51. Nair, A. K., Gautieri, A., Chang, S. W., & Buehler, M. J. (2013). Molecular mechanics of mineralized collagen fibrils in bone. Nature Communications, 4, 1724–1732.

    Article  Google Scholar 

  52. Biomineralization, C. H. (2010). A crystal-clear view. Nature Materials, 9, 960–961.

    Article  Google Scholar 

  53. Chakkalakal, D. A. (1989). Mechanoelectric transduction in bone. Journal of Materials Research, 4, 1034–1046.

    Article  Google Scholar 

  54. Jee, S. S., Dimasi, E., Kasinath, R. K., & Kim, Y. Y. (2011). Oriented hydroxyapatite in turkey tendon mineralized via the polymer-induced liquid-precursor (PILP) process. CrystEngComm, 13, 2077–2083.

    Article  Google Scholar 

  55. Nudelman, F., Bomans, P. H. H., George, A., With, G. D., & Sommerdijk, N. A. J. M. (2012). The role of the amorphous phase on the biomimetic mineralization of collagen. Faraday Discussions, 159, 357–370.

    Article  Google Scholar 

  56. Olszta, M. J., Odom, D. J., Douglas, E. P., & Gower, L. B. (2009). A new paradigm for biomineral formation: Mineralization via an amorphous liquid-phase precursor. Connective Tissue Research, 44, 326–334.

    Article  Google Scholar 

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Acknowledgements

The present research was supported by the National Natural Science Foundation of China [Nos. 81671826 and 31971257], Key Research and Development Project of the 13th Five-Year Plan [No. 2016YFC1101903] and China Postdoctoral Science Foundation [No. 2018T110975]. We would like to thank the Analytical & Testing Center of Sichuan University for using different analytic facilities.

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  1. Ruijuan Yao and Yao Wang contributed equally to this work.

Authors and Affiliations

  1. National Engineering Research Centre for Biomaterials, Sichuan University, Chengdu, 610064, China

    Ruijuan Yao, Yao Wang, Bo Zhang, Juan Liu, Nihui Zhang, Jing He, Guolong Meng, Bo Jiang & Fang Wu

  2. Analytical and Testing Center, Sichuan University, Chengdu, 601165, China

    Shanling Wang

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  1. Ruijuan Yao
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  2. Yao Wang
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Yao, R., Wang, Y., Zhang, B. et al. Critical Role of Silicon in Directing the Bio-inspired Mineralization of Gelatin in the Presence of Hydroxyapatite. J Bionic Eng 18, 1413–1429 (2021). https://doi.org/10.1007/s42235-021-00084-x

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