因骨頭損傷受細菌感染所引發之骨髓炎，須定期且定量將抗生素注入人體，選擇合適之藥物傳遞系統能夠達到有效的治療或是事先預防細菌感染，藥物載體的應用能夠長時間穩定釋放藥物且使療程簡化；而生物活性玻璃因其無毒、生物相容性、生物降解性及生物活性之特性，為一有潛力作為骨植入物及藥物載體的生醫材料。
　　本研究利用造粒技術配製不同重量百分比之聚甲基丙烯酸甲酯 (0、5、10及20 wt%) 及生物活性玻璃混和漿料，透過噴霧乾燥機及燒結熱處理除去聚甲基丙烯酸甲酯等製成生物活性玻璃微球，持溫於37 ℃，以pH 7.4及5.0的磷酸鹽緩衝生理鹽水模擬人體健康及罹患骨髓炎之環境，選用四環黴素作為治療之抗生素以進行體外藥物釋放試驗，另外利用明膠包覆載藥後之生物活性玻璃微球以改善藥物釋放行為，透過X光繞射儀、聚焦型離子束顯微鏡、氮氣吸/脫附分析儀、傅立葉轉換紅外線光譜儀、熱重損失分析儀及全波長吸收光暨螢光複合分析系統進行樣品分析。
　　研究結果顯示利用明膠包覆BG微球的樣品能夠有效地延長藥物釋放時間以利治療；明膠包覆10 wt% PMMA的BG微球樣品於pH 7.4磷酸鹽緩衝生理鹽水的環境下，第一階段釋放速率為最慢的，而第二階段釋放速率為第二快，且於試驗時間120小時仍有持續釋放藥物的趨勢；明膠包覆5 wt% PMMA的BG微球樣品在pH 5.0磷酸鹽緩衝生理鹽水的環境下，第一階段釋放速率為最快的，且於試驗時間48小時可幾乎將藥物釋放。

　　Osteomyelitis caused by bacterial infection due to bone damage, antibiotics must be injected into the human body regularly and quantitatively. Choosing a suitable drug delivery system can achieve an effective therapeutic effect or prevent the risk of infection. However, the application of drug carrier can effectively control the release of the drug and make the treatment easier. Bioactive glass (BG) is a potential biomaterial for bone implants and drug carriers due to the properties of non-toxic, biocompatibility, degradability and bioactivity.
　　In this study, granulation technology was used to prepare poly(methyl methacrylate) (PMMA) and BG mixed slurry with different weight percentage (0, 5, 10 and 20 wt%). The mixed slurry was dried to form microspheres by spray drying and removed PMMA through heat treatment. The environment before and after the bacterial infection is simulated with pH 7.4 and 5.0 of phosphate buffered saline (PBS) solution at 37°C with tetracycline (TC) as therapeutic antibiotic for in vitro drug release test. Using gelatin capsulated BG microspheres with tetracycline loaded to improve drug release behavior. Sample were characterized by X-ray diffraction, dual beam focused ion beam scanning electron microscope, nitrogen adsorption/desorption isotherm, Fourier-transform infrared spectroscopy, thermogravimetric analysis and fluorescence micro-plate reader.
　　The result shows that gelatin capsulated PMMA treated-BG microspheres can prolong the time of drug release. Gelatin capsulated 10wt% PMMA-treated BG microsphere has the slowest release rate of first stage, the second fastest release rate of second stage, and there was still a trend of drug release until 120 h in pH 7.4 of PBS solution. Gelatin capsulated 5 wt% PMMA-treated BG microsphere has the fastest release rate of first stage and the loading TC was almost released at 48 h in pH 5.0 of PBS solution.

[1] N. Rao, B.H. Ziran, B.A. Lipsky, Treating osteomyelitis: antibiotics and surgery, Plastic reconstructive surgery, 127 (2011) 177S-187S.
[2] S.K. Nandi, S. Bandyopadhyay, P. Das, I. Samanta, P. Mukherjee, S. Roy, B. Kundu, Understanding osteomyelitis and its treatment through local drug delivery system, Biotechnology advances, 34 (2016) 1305-1317.
[3] C. Papakostidis, N.K. Kanakaris, J. Pretel, O. Faour, D.J. Morell, P.V. Giannoudis, Prevalence of complications of open tibial shaft fractures stratified as per the Gustilo–Anderson classification, Injury, 42 (2011) 1408-1415.
[4] U. Posadowska, M. Brzychczy-Włoch, E. Pamuła, Gentamicin loaded PLGA nanoparticles as local drug delivery system for the osteomyelitis treatment, Acta of bioengineering biomechanics, 17 (2015) 41-48.
[5] S.B. Levy, B. Marshall, Antibacterial resistance worldwide: causes, challenges and responses, Nature medicine, 10 (2004) S122.
[6] A.N. Sapadin, R. Fleischmajer, Tetracyclines: nonantibiotic properties and their clinical implications, Journal of the american academy of dermatology, 54 (2006) 258-265.
[7] M.A. Jennifer, Determination of minimum inhibitory concentrations, Journal of antimicrobial chemotherapy, 48 (2001) 5-16.
[8] B.S. Speer, N.B. Shoemaker, A.A. Salyers, Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance, Clinical microbiology reviews, 5 (1992) 387-399.
[9] C.G. Zalavras, M.J. Patzakis, P. Holtom, Local antibiotic therapy in the treatment of open fractures and osteomyelitis, Clinical orthopaedics related research, 427 (2004) 86-93.
[10] J. Siepmann, R.A. Siegel, M.J. Rathbone, Fundamentals and applications of controlled release drug delivery, New York: Springer, 2012, pp. 1-43
[11] P.I. Lee, J.X. Li, Evolution of oral controlled release dosage forms, Oral controlled release formulation design drug delivery, John Wiley Sons, Inc, (2010) 21-31.
[12] Y.H. Yun, B.K. Lee, K. Park, Controlled drug delivery: historical perspective for the next generation, Journal of controlled release, 219 (2015) 2-7.
[13] J.H. Lee, Y. Yeo, Controlled drug release from pharmaceutical nanocarriers, Chemical engineering science, 125 (2015) 75-84.
[14] G. Kaur, Clinical Applications of Biomaterials: State-of-the-Art Progress, Trends, and Novel Approaches, Springer, 2017, pp. 287-311.
[15] S. Freiberg, X. Zhu, Polymer microspheres for controlled drug release, International journal of pharmaceutics, 282 (2004) 1-18.
[16] J.M. Anderson, M.S. Shive, Biodegradation and biocompatibility of PLA and PLGA microspheres, Advanced drug delivery reviews, 28 (1997) 5-24.
[17] M. Manzano, M. Vallet-Regí, Revisiting bioceramics: bone regenerative and local drug delivery systems, Progress in solid state chemistry, 40 (2012) 17-30.
[18] A.S. Mistry, A.G. Mikos, Tissue engineering strategies for bone regeneration, Regenerative medicine II, Springer, Berlin, Heidelberg, 2005, pp. 1-22.
[19] A. Bettencourt, A.J. Almeida, Poly (methyl methacrylate) particulate carriers in drug delivery, Journal of microencapsulation, 29 (2012) 353-367.
[20] J.A. DiPisa, G.S. Sih, A.T. Berman, The temperature problem at the bone-acrylic cement interface of the total hip replacement, Clinical orthopaedics related research, (1976) 95-98.
[21] K.A. Athanasiou, G.G. Niederauer, C.M. Agrawal, Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers, Biomaterials, 17 (1996) 93-102.
[22] L. Brannon-Peppas, Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery, International journal of pharmaceutics, 116 (1995) 1-9.
[23] M.I.A. Echazú, M.V. Tuttolomondo, M.L. Foglia, A.M. Mebert, G.S. Alvarez, M.F. Desimone, Advances in collagen, chitosan and silica biomaterials for oral tissue regeneration: from basics to clinical trials, Journal of materials chemistry B, 4 (2016) 6913-6929.
[24] H.K. Kleinman, R.J. Klebe, G.R. Martin, Role of collagenous matrices in the adhesion and growth of cells, The journal of cell biology, 88 (1981) 473-485.
[25] L. Kostopoulos, T. Karring, Augmentation of the rat mandible using guided tissue regeneration, Clinical oral implants research, 5 (1994) 75-82.
[26] H.L. Wang, L. Boyapati, “PASS” principles for predictable bone regeneration, Implant dentistry, 15 (2006) 8-17.
[27] M. Van der Rest, R. Garrone, Collagen family of proteins, The FASEB journal, 5 (1991) 2814-2823.
[28] X.J. Yang, P.J. Zheng, Z.D. Cui, N.Q. Zhao, Y.F. Wang, K. De Yao, Swelling behaviour and elastic properties of gelatin gels, Polymer international, 44 (1997) 448-452.
[29] M.S.P. Abdullah, M.I. Noordin, S.I.M. Ismail, N.M. Mustapha, M. Jasamai, M.F. Danik, W.A.W. Ismail, A.F. Shamsuddin, Recent Advances in the Use of Animal-Sourced Gelatine as Natural Polymers for Food, Cosmetics and Pharmaceutical Applications, Sains malaysiana, 47 (2018) 323-336.
[30] S. Gorgieva, V. Kokol, Collagen-vs. gelatine-based biomaterials and their biocompatibility: review and perspectives, Biomaterials applications for nanomedicine, 2011, pp. 17-52.
[31] A. Asghar, R. Henrickson, Chemical, biochemical, functional, and nutritional characteristics of collagen in food systems, Advances in food research, Academic Press, 1982, pp. 231-372.
[32] M. Santoro, A.M. Tatara, A.G. Mikos, Gelatin carriers for drug and cell delivery in tissue engineering, Journal of controlled release, 190 (2014) 210-218.
[33] Y.C. Chen, W.Y. Su, S.H. Yang, A. Gefen, F.H. Lin, In situ forming hydrogels composed of oxidized high molecular weight hyaluronic acid and gelatin for nucleus pulposus regeneration, Acta biomaterialia, 9 (2013) 5181-5193.
[34] M. Usta, D. Piech, R. MacCrone, W. Hillig, Behavior and properties of neat and filled gelatins, Biomaterials, 24 (2003) 165-172.
[35] D. Arcos, M. Vallet-Regí, Bioceramics for drug delivery, Acta materialia, 61 (2013) 890-911.
[36] K. Wang, C. Zhou, Y. Hong, X. Zhang, A review of protein adsorption on bioceramics, Interface focus, 2 (2012) 259-277.
[37] L.L. Hench, J.M. Polak, Third-generation biomedical materials, Science, 295 (2002) 1014-1017.
[38] M. Dreßler, F. Dombrowski, U. Simon, J. Börnstein, V.-D. Hodoroaba, M. Feigl, S. Grunow, R. Gildenhaar, M. Neumann, Influence of gelatin coatings on compressive strength of porous hydroxyapatite ceramics, Journal of the european ceramic society, 31 (2011) 523-529.
[39] L.L. Hench, The story of Bioglass®, Journal of materials science: materials in medicine, 17 (2006) 967-978.
[40] L.L. Hench, Bioactive ceramics: Theory and clinical applications, Bioceramics, Pergamon, 1994, pp. 3-14.
[41] L.L. Hench, Bioceramics: from concept to clinic, Journal of the american ceramic society, 74 (1991) 1487-1510.
[42] L. Zhao, X. Yan, X. Zhou, L. Zhou, H. Wang, J. Tang, C. Yu, Mesoporous bioactive glasses for controlled drug release, Microporous mesoporous materials, 109 (2008) 210-215.
[43] A. Kirsten, A. Hausmann, M. Weber, J. Fischer, H. Fischer, Bioactive and thermally compatible glass coating on zirconia dental implants, Journal of dental research, 94 (2015) 297-303.
[44] A. Salinas, S. Shruti, G. Malavasi, L. Menabue, M. Vallet-Regí, Substitutions of cerium, gallium and zinc in ordered mesoporous bioactive glasses, Acta biomaterialia, 7 (2011) 3452-3458.
[45] A. Clark Jr, C. Pantano Jr, L.L. Hench, Auger spectroscopic analysis of bioglass corrosion films, Journal of the american ceramic society, 59 (1976) 37-39.
[46] D. Sanders, L.L. Hench, Mechanisms of glass corrosion, Journal of the american ceramic society, 56 (1973) 373-377.
[47] P. Ducheyne, Bioceramics: material characteristics versus in vivo behavior, Journal of biomedical materials research, 21 (1987) 219.
[48] R. Li, A. Clark, L.L. Hench, An investigation of bioactive glass powders by sol‐gel processing, Journal of applied biomaterials, 2 (1991) 231-239.
[49] Y.J. Chou, C.W. Hsiao, N.T. Tsou, M.H. Wu, S.J. Shih, Preparation and in Vitro Bioactivity of Micron-sized Bioactive Glass Particles Using Spray Drying Method, Applied sciences, 9 (2019) 19.
[50] B.J. Hong, S.J. Shih, Novel pore-forming agent to prepare of mesoporous bioactive glass using one-step spray pyrolysis, Ceramics international, 43 (2017) S771-S775.
[51] L.L. Hench, R.J. Splinter, W. Allen, T. Greenlee, Bonding mechanisms at the interface of ceramic prosthetic materials, Journal of biomedical materials research, 5 (1971) 117-141.
[52] Y.J. Chou, Microstructure and bioactivity correlation of one-step synthesized bioactive glass, Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei, 2013.
[53] S.J. Shih, Y.J. Chou, I.C. Chien, One-step synthesis of bioactive glass by spray pyrolysis, Journal of nanoparticle research, 14 (2012) 1299.
[54] S.J. Shih, Y.Y. Wu, K.B. Borisenko, Control of morphology and dopant distribution in yttrium-doped ceria nanoparticles, Journal of nanoparticle research, 13 (2011) 7021-7028.
[55] R. Vehring, Pharmaceutical particle engineering via spray drying, Pharmaceutical research, 25 (2008) 999-1022.
[56] A. Sosnik, K.P. Seremeta, Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers, Advances in colloid interface science, 223 (2015) 40-54.
[57] H.S. An, K.S. Lim, D.J. Kwak, B.S. You, S.H. Lee, Device for reducing pressure loss of cyclone dust collector, U.S. Patent No 6,679,930, 2004.
[58] B.J. Hong, Surfactant-free synthesis of mesoporous bioactive glass for drug delivery, Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei, 2018.
[59] Z. Yang, Y. Zhang, Z. Schnepp, Soft and hard templating of graphitic carbon nitride, Journal of materials chemistry A, 3 (2015) 14081-14092.
[60] S.J. Shih, Y.Y. Wu, C.Y. Chen, C.Y. Yu, Morphology and formation mechanism of ceria nanoparticles by spray pyrolysis, Journal of nanoparticle research, 14 (2012) 879.
[61] X. Yan, C. Yu, X. Zhou, J. Tang, D. Zhao, Highly ordered mesoporous bioactive glasses with superior in vitro bone‐forming bioactivities, Angewandte chemie international edition, 43 (2004) 5980-5984.
[62] Y. Ma, L. Qi, Solution-phase synthesis of inorganic hollow structures by templating strategies, Journal of colloid interface science, 335 (2009) 1-10.
[63] Y. Li, Y. Fan, J. Ma, Thermal, physical and chemical stability of porous polystyrene-type beads with different degrees of crosslinking, Polymer degradation stability, 73 (2001) 163-167.
[64] S.M. Iveson, J.D. Litster, K. Hapgood, B.J. Ennis, Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review, Powder technology, 117 (2001) 3-39.
[65] E. Hansuld, L. Briens, A review of monitoring methods for pharmaceutical wet granulation, International journal of pharmaceutics, 472 (2014) 192-201.
[66] Y. Makovskaya, M. Gordienko, N. Menshutina, INFLUENCE OF STARCH TYPE AND METHOD OF BINDER INPUT ON GRANULATION QUALITY, 17th International Drying Symposium (IDS 2010), Magdeburg, Germany, 2010.
[67] T. Kokubo, H. Kushitani, S. Sakka, T. Kitsugi, T. Yamamuro, Solutions able to reproduce in vivo surface‐structure changes in bioactive glass‐ceramic A‐W3, Journal of biomedical materials research, 24 (1990) 721-734.
[68] M.F. Chung, W.T. Chia, H.Y. Liu, C.W. Hsiao, H.C. Hsiao, C.M. Yang, H.W. Sung, Inflammation‐Induced Drug Release by using a pH‐Responsive Gas‐Generating Hollow‐Microsphere System for the Treatment of Osteomyelitis, Advanced healthcare materials, 3 (2014) 1854-1861.
[69] J. Zhang, M. Zhao, X. Tian, X. Lv, Z. Chen, K. Zhou, X. Ren, P. Zhang, X. Mei, Protein-mediated mineralization of edaravone into injectable, pH-sensitive microspheres used for potential minimally invasive treatment of osteomyelitis, New journal of chemistry, 42 (2018) 5447-5455.
[70] F. Qu, G. Zhu, H. Lin, W. Zhang, J. Sun, S. Li, S. Qiu, A controlled release of ibuprofen by systematically tailoring the morphology of mesoporous silica materials, Journal of solid state chemistry, 179 (2006) 2027-2035.
[71] L. L. Hench, An Introduction to Bioceramics, 2nd Edition, London: Imperial College Press, 2013, pp.1-9.