臺灣博碩士論文加值系統

本論文是探討室溫下製備自硬化型的鈣磷酸鹽骨水泥(CPC)經生物礦化後產生具相同組成的氫氧基磷灰石(Hydroxyapatite, Ca10(PO4)6(OH)2, HAp)，也因此理解CPC合成出HAp的溶液化學生成機制，乃對於開發硬骨組織替代物則將有深刻的理解認識。本研究由CaHPO4 (DCPA)與Ca(OH)2粉體顆粒組合成的CPC混合粉體與磷酸氫鈉溶液反應固化生成HAp之反應化學可利用in-situ與long-term (超過150天或3600小時)浸泡時效來觀察。另外，反應物種及其粒子大小、溶液pH變化、無機物質的添加、具生物活性金屬的存在都將對CPC固化及所生成HAp的微結構及機械性質有莫大的影響。因此，我們利用以下分析技術進行以上性質分析：pH、粒子大小分析、磷酸氫鈉鹽溶液之濃度、固化時間之測定、差式掃瞄熱卡計(DSC)、原子吸收光譜儀(AAS)、電子微探針分析(EPMA)、X光繞射、X光吸收光譜、電子顯微鏡(SEM/TEM)、機械強度(DTS及CS))。
對室溫下DCPA/Ca(OH)2/Na2HPO4骨水泥系統而言，固化反應的時間及產物HAp的顯微形貌則強烈的受到Na2HPO4溶液濃度的影響。溶液濃度愈高固化時間較短，殘留反應物較少以及機械強度較高。pH分析則顯示出當CPC固化反應開始，溶液的pH呈現出下降的趨勢，導致有更多的固體粒子在溶液中發生溶解，並於溶液化學中趨近一不變點以求介穩平衡。至於37℃下生成奈米尺寸級HAp的微結構則多以糾結纏繞的棒狀晶體顯微呈現，也因此CPC的固化及硬化則歸功於HAp棒狀晶體在微結構上糾結程度的貢獻。並藉由XRD及FTIR對浸泡已達3600小時的CPC生成產物進行定性與結構分析，則幾乎完全轉換生成HAp，且無其他相組成存在。
根據溶液化學理論，我們發現CPC中固體顆粒不斷地進行溶解並有新的結晶顆粒生成與析出是掌握整個固化反應的進行與否，因此HAp可在37℃下生成。In-situ觀察固化期間，固化反應會首先發生在DCPA與Ca(OH)2固體顆粒的表面區域(液體與固體顆粒間的接觸表面積)，因此控制了其初始溶解，同時，亦傾向析出結晶。在起始固體顆粒溶解階段期間，因為DCPA的溶解度高於HAp，所以初始HAp晶體會傾向生成於DCPA的表面，而HAp晶體的進一步成長則由未反應的DCPA不斷地進行，如此好似自然骨生物礦化的過程一樣。對照引用文獻中的發現，在CPC固化反應早期階段，HAp晶種的存在可促進固化反應，減少內部過渡組成成核；同時，增加DCPA顆粒固化反應的表面區域則對於固體初步的溶解則更具有主導控制反應的效果。
另外在此，將介紹為了改善骨水泥機械強度而提出CPC/Ti複合材料的製備方法。此複合材料是將Ti顆粒加入至DCPA及Ca(OH)2粒子中，利用物理機械混合的方式製備，並將1.0 M的磷酸氫鈉溶液加入，以便合成CPC/Ti骨水泥。由於DCPA, Ca(OH)2及 Ti顆粒可提供給予進行固化反應的表面積增加，因此固化反應就比CPC來的更迅速。XRD證實此此複合材料在符合生理條件環境下經固化3600小時後的產物為具低結晶度的HAp及些許殘留的起始原料於CPC/Ti骨水泥中，而且沒有中間相的存在。因為DCPA具有較高的溶解度，所以認為此創新的骨水泥，相較於磷灰石骨水泥，將可呈現出具較高的體內吸收能力。另外，藉由AAS分析浸泡3600小時的CPC/Ti複合骨水泥，則發現Ca與Ti元素並不存在其所浸泡的溶液中。如此則說明具非常低溶解度的HAp晶體生成於起始原料組成的表面區域，也因此導致CPC/Ti的固化反應逐漸降低，並且DCPA與Ti則隱藏在骨水泥內部。最終CPC/Ti複合骨水泥的機械強度則仰賴轉換生成的HAp晶體及其所建立起的微結構發展，即骨水泥的機械強度取決於生成HAp棒狀晶體其微結構糾結的程度而定。
結論為CPC與CPC/Ti骨水泥的長時效浸泡(研究最長時間的浸泡為10944小時的CPC，及5760小時的CPC/Ti試樣)下其顯微結構穩定度取決於HAp晶體的生成，並強化其顯微架構增加機械性質強度。如此骨水泥應用於整型外科及牙科方面，則應具臨床上的生物可吸收與生物相容性之性質。

Self-setting or self-hardening calcium phosphate cement (CPC) has value in terms of developing synthetic hydroxyapatite [Ca10(PO4)6(OH)2 or HAp], similar in compositions formed by natural mineralization of bone. Understanding the in vitro solution chemistry mechanism of formation of the synthetic composition could produce insights into developing hard tissue analogs. The chemistry of CPC, composed of particulate CaHPO4 (DCPA) and Ca(OH)2, set with sodium hydrogen phosphate solution for formation of HAp were examined by in-situ and long-term aging (over 150 days or 3600 h) observation. In particular, the effects of particle size, pH, reactant species, inorganic salt additives and presence of bioactive metal on the CPC setting and microstructure/mechanical properties of HAp were determined by using the following analytical techniques: pH and setting time measurement, particle size, differential scanning catorimeter (DSC), atomic absorption spectrometer (AAS), electron probe micro-analyzer (EPMA), x-ray diffractometer, x-ray absorption spectrometer, electron microscopy (SEM/TEM), fourier transform infrared spectroscopy (FTIR), solution chemistry, diametrical test strength (DTS) and compressive strength test (CS).
For the DCPA/Ca(OH)2/Na2HPO4 system at room temperature, the setting reaction times and morphologies of the resultant HAp were found to be strongly dependent on the concentration of aqueous solution. Higher concentration of aqueous solution could be diminished the setting time, remnant reactants less, and better mechanical strength. The results revealed the pH of solution has presented drop-down trace when setting reaction happened, leading to more solids dissolved in the solution and approaching to a invariant point for meatstable equilibrium. The microstructure of the resultant HAp typically had entangled, rod-like morphology at 37°C having a nano scale crystalline size. The cement setting/hardening contributed to entanglement at the microstructural level. In the case, t the product set for 3600 h was hydroxyapatite [Ca10(PO4)6(OH)2] determined by XRD and FTIR, and no other intermediates or by-product were formed through the complete transformation.
According to solution chemistry theory, the continually solid dissolution and new crystal precipitation mechanism of CPC was found to control the overall setting reaction and thereby HAp formation at 37°C. During the in-situ observation, the setting reaction was first resulted within the surface area of the DCPA and Ca(OH)2 particulates hence controlling their initial dissolution, and simultaneously preformed to precipitate crystals. During the initial solids dissolution stage, HAp formation initiates preferentially on DCPA surfaces. Further growth of HAp continues progressively by dissolution and precipitation of unreacted DCPA, analogous to natural biomineralization events. Compare to literature cited findings, the presence of HAp seeds increase the setting reaction, eliminating the intrinsic nucleation step; while increasing in the surface area of the DCPA had a more predominant effect on the initial dissolution during the early stage of setting reaction.
CPC/Ti composite approach for improving the mechanical properties of the cement product was introduced. The Composites were prepared by physically incorporating Ti particles with DCPA and Ca(OH)2 particulates. 1.0 M sodium hydrogen phosphate solution, setting modifier, would be added into composite for set to cement block. Because the surface area provided by DCPA, Ca(OH)2 and Ti particles for setting reaction was increase, the reaction occurred faster than CPC. XRD demonstrated that setting product was involved HAp phase, which was low crystalline and remnant starting materials in CPC/Ti cement, no other intermediate phase found until incubation for 3600 h in physiological condition. Due to DCPA with higher solubility, the new cement was considered to exhibit a higher in vivo resorbability in comparison to the apatitic cements. In addition, Ca and Ti elements of composite set for 3600 h did not find in soaking solution by AAS analysis. It was elucidated the very low solubility of the initial HAp crystal layer was formed on the surface area of components, so as the setting reaction of CPC/Ti was getting slow, and then DCPA and Ti were hindering within cement. The mechanical properties of the final composite structure were related to the conversion of calcium phosphate to HAp and porous size.
Summary, The microstructural stability of CPC and/or CPC/Ti could be arrived in the long-term aging for HAp crystallites formation and improved the mechanical strength. Use these cement samples in orthpaedics and dental would be considered as bioresorble and biocompatible with in vivo.

Table of Contents
Page
Acknowledgements
Abstract
Table of Contents i
List of Figures iv
List of Tables vii

Chapter 1 Introduction 1
1.1. General Introduction 1
1.2. The Objective of the Study 5

Chapter 2 Background and Literature 7
2.1. Biomaterials 7
2.2. Bio-ceramics 8
2.3. Bone 10
2.3.1. Properties and Structures 10
2.3.2. Bone Formation 13
2.3.3. Bone Substitutes 16
2.3.4. Properties and functions of Bone Substitutes 17
2.4. Synthetic Bone Substitutes 19
2.4.1. Bio-ceramics as Synthetic Bone Substitutes 19
2.4.1.1 Hydroxyapatite (HAp) 20
2.4.1.2 Self-Hardening Calcium-Phosphate Cements 22
2.5. Aqueous Stability of Calcium Phosphate Salt solids at 37 °C 23
2.6. Hydroxyapatite Formation from Cementation of Calcium
Phosphate Systems 26
2.7. Hydroxyapatite Formation via Setting and Soaking of
Dicalcium Phosphate Anhydrous (DCPA) and Calcium
Hydroxide (Ca(OH)2) 31

Chapter 3 The different concentration of Na2HPO4 solution on Calcium
Phosphate Salts System in forming Hydroxyapatite (HAp) 47
Abstract 47
3.1 Introduction 48
3.2 Materials and Methods 50
3.2.1 The Precursor Preparation and Cementation Processing 50
3.2.2 Characterization 51
3.2.2.1 Powder characterization:
(1) Particles Size analysis
(2) Energy Probe Microanalysis (EPMA) 51
51
51
3.2.2.2 Setting Time Measurement 52
3.2.2.3 pH Measurement and Mechanical Testing 52
3.2.2.4 X-ray Diffraction Analysis and Microstructure
Observeration 53
3.2.2.5 FTIR analysis 54
3.3 Results and Discussion 54
3.3.1 Powder Characteristics 54
3.3.2 Setting reaction of CPC 55
3.3.3 pH variations and Mechanical property 58
3.3.4 Structural Analysis 60
3.4 Conclusion 62

Chapter 4 In-situ Observation on the transformation from Calcium
Phosphate Cement to Hydroxyapatite 73
Abstract 73
4.1 Introduction 73
4.2 Materials and Methods 74
4.3 Results 76
4.4 Discussion 79
4.5 Conslusion 81

Chapter 5 Structural Stability of Calcium Phosphate Cement During Aging in
Water 89
Abstract 89
5.1 Introduction 89
5.2 Experimental 91
5.3 Results and Discussion 92
5.4 Conclusion 95

Chapter 6 Strengthening Calcium Phosphate Cement via Ti-particles
Addition 104
Abstract 104
6.1 Introduction 105
6.2 Materials and Methods 106
(1) CPC and CPC/Ti in-situ observation 106
(2) Cement long-term incubation 107
6.3 Results and Discussion 108
6.3.1 Preliminary Ceemnt Setting Observation 108
6.3.2 Chemistry and Structure Analysis 109
(1) Solution chemistry Analysis 109
(2) XRD Analysis 110
6.3.3 Compressive Strength 113
6.4 Conclusion 114

Chapter 7 Conclusion 130
Chapter 8 Future Work 133
References 134

Reference

1.Clemson Advisory Board for Biomaterials “Definition of the word biomaterial,” The 6th Annnal Intermalionel Biomaterial Symposium, April pp.20-24, 1974.
2.Driessens F. C. M., Verbeeck R. M. H., editor. "Biominerals". New York: CRC Press, 1990.
3.LeGeros RZ "Calcium phosphates in oral biology and medicine" Karger, Basel, New York, 1991.
4.Silver FH "Biomaterials, medical devices, and tissue engineering: an integrated approach". 1st ed. Chapman & Hall, London, New York, 1994.
5.Skinner HCW "Biominerals" Mineralogical Magazine 69(5), 621-641(2005).
6.Craig RG, O''Brien WJ, Powers JM "Dental materials: properties and manipulation". 2nd ed. St. Louis: Mosby, 1979.
7.Byrom D "Biomaterials: novel materials from biological sources" Macmillan, Stockton Press, London, New York:, 1991.
8.PL Felgner Cambridge Healthtech Institute. "Artificial self-assembling systems for gene delivery". American Chemical Society, Washington, DC, 1996.
9.Paul JP, "Biomaterials in artificial organs. London: Scientific and Medical Division", Macmillan Press; Deerfield Beach, FL: Distribution for USA and Canada, VCH, 1984.
10.Smith DC, Williams DF, "Biocompatibility of preventive dental materials and bonding agents" CRC Press, Boca Raton, Fla., 1982.
11.N Ogata "Advanced biomaterials in biomedical engineering and drug delivery systems". Springer, Tokyo, New York, 1996.
12.Park JB, Lakes RS, "Biomaterials: an introduction" Plenum Press, 2nd Ed. New York, 1992.
13.Ratner BD, "Biomaterials science: an introduction to materials in medicine" Academic Press, San Diego, 1996.
14.Groot Kd., "Bioceramics of calcium phosphate" CRC Press, Boca Raton, Fla., 1983.
15.Black J, Hastings GW, "Handbook of biomaterial properties. 1st ed., Chapman & Hall, London ; New York, 1998.
16.Hill D "Design engineering of biomaterials for medical devices" John Wiley & Sons, Chichester, New York, 1998.
17.Hideki Aoki “Science and Medical Applications of Hydroxyapatite” Ishiyaku EuroAmerica, Inc. Tokey, St. Louis, 1994.
18.Chow LC “Calcium Phosphate materials: Reactor Response” Adv. Deny. Res. 2(1), 181-184, (1998).
19.Mathew M and Takagi S "Structures of Biological Minerals in Dental Research" J. Res. Natl. Inst. Stand. Technol. 106(6), 1035-1044, 2001.
20.LeGeros RZ "Calcium phosphates in oral biology and medicine" Karger, Basel, New York, 1991.
21.Hench LL, Ethridge EC “Biomaterial”, A Cademic Press. Inc. , 1982.
22.Bills PM, Wheeler EJ “Bone-a composite material” J. Ed. Mod. Mater. Sci. Eng. 4, 395-455 (1982).
23.Walker MM, Katz JL “Mechanisms for the bonding of bone to dense hydroxyapatite,” In Transactions of Society of Biomaterials Vol.7, Society for Biomaterials, Birmingham, AL, pp. 152, 1984.
24.Posner AS “Crystal chemistry of bone” Physiol. Rev. 49, 760-792 (1969).
25.Holliger J, McAllister B “Bone and its Repair” In Bioceramics, J Wilson, LL Hench, D Greenspan (Eds.), Pergamon Press, Ponte V edra, FL, 1995.
26.Bills PM, Wheeler EJ “Bone-a composite material” J. Ed. Mod. Mater. Sci. Eng. 4, 395-455 (1982).
27.LeGeros RZ “Apatites in biological systems” Prog. Crystals Growths Characts. 4, 1-45 (1981).
28.LeGeros RZ In Calcium phosphates in Oral Biological and Medicine. Monographs in Oral Science, vol 15 HM Myers (Eds.), S Karger, Basel, Switzerland, 1991.
29.LeGeros RZ, LeGeros JP “Phosphate Minerals in Human Tissue,” In Phosphate Minerals, JO Nriagu, P. B. Moore (Eds.), Springer-Verlag, pp. 351-385, New York, 1984.
30.McLean FC, Urist MR In Bone: An introduction to the Physiology of Skeletal tissue, University of Chicago Press, 1995.
31.McLean FC, Urist MR In Bone: An introduction to the Physiology of Skeletal tissue, University of Chicago Press, 1995.
32.Wuthier E “A review of the primary mechanism of endochondral calcification with special emphasis on the role of cells, mitochondria and matrix vesicles” Clin. Orthop. 169, 219-242 (1982).
33.Veis A, sharkey M, Dickson L “Non-collagenous proteins of bone and dentin extracellular matrix and their role in organized mineral deposition” In Calcium Binding Proteins and Calcium Function, RH Wasserman (Ed.), New York, Elsevier, North Holland, pp. 409-418, 1977
34.Ennever J, Boyan-Salyers B, Rigger LJ “Proteolipid and matrix calcification in vivo” J. Dent. Res. 56, 140-142 (1977).
35.Termine JD, Belcourt AB, Conn KM, Kleinman HK “ Mineral and collagen-binding proteins of fetal calf bone” J. Biol. Chem. 256, 10403-10408 (1981).
36.Bosky AL “Current concepts in physiology and biochemistry of calcification” Clin. Orthop. Rel. Res. 157, 225-257(1981).
37.Boskey AL “Overview of cellular elements and macro molecules im[licated in the initiation of mineralization” In the Chemistry and Biology of Mineralized Tissues. WT Butler (Ed.), BSCO Media, pp.335-343, Birmingham, 1985.
38.Neuman WF, Neuman MW “The chemical dynamics of bone mineral” Univ. of Chicage Press, Chicago, 1958.
39.Brown WE “A mechanism for growth of apatitic crystals” In Tooth Enamel, MV Stack, RW Feamhead (Eds.), John Wright, pp. 11-14, Bristol, 1965.
40.Glimcher MJ “Recent studies of the early mineral deposits in bone and enamel, and of the organic matrix of enamel,” Calc. Tiss. Res. Suppl.: I (1968).
41.Brown WE, Chow LC “Chemical Properties of Bone Mineral” Annual Review of Materials Science, 6, 213-236 (1976).
42.Robinson RA, Watson ML “Crystal-collagen relationships in bone as observed in the electron microscope. III Crystal and collagen morphology as function of age” Ann. New York Academic Society 60, 596-628 (1955)
43.Harper RA, Posner AS “Measurement of non-crystalline calcium phosphate in bone mineral” Proc. Soc. Exptl. Biol. Med. 122, 137-142 (1966).
44.Termine JD, Posner AS “Amorphous/crystalline interrelationships in bone mineral” Calc. Tiss. Res. 1, 8-23, (1967).
45.Fleisch H “Role of nucleation and inhibition in calcification,” Clin. Orthoped. 32, 170-180 (1964).
46.Bosky AL “Current concepts in physiology and biochemistry of calcification” Clin. Orthop. Rel. Res. 157, 165-174(1980).
47.Glimcher MJ “Molecular biological of mineralized tissues with reference to bone” Rev. Mod. Phys. 31, 359-393 (1959).
48.Roviller C “Collagen Fibers of Connective tissue” In The biochemistry and Physiology of bone, Academic Press, New York, 1956.
49.Herring GM “The organic matrix of bone In The Biochemistry and Physiological of Bone, GH Bonne (Ed.) Academic Pres, pp. 128-196, New York, 1972.
50.Strates B, Neuman WF “On the mechanism of calcification” proc. Soc. Exptl. Biol. Med. 97, 688-691 (1958).
51.Fleisch H “Role of nucleation and inhibition in calcification” Clin. Orthoped. 32, 170-18- (1964).
52.Dreesmann H “Uber knochenplombierubg” Beitr. Klin. Chir. 9, 804-810 (1892).
53.Bahn SL “Plaster: a bone substitute” Oral Surg. Oral. Med. Pathol. 21, 672-681 (1966).
54.Peltier LF, Jonse RH “Treatment of unicmarael bonecsyst by curettage and packing with Plaster of Paris” J. Bone Jt. Surg. 60A, 820-822 (1978).
55.Peltier LF “The use of plaster of Paris to fill large defects in bone” Clin. Orthop. 21, 1-29 (1961).
56.Jarcho M “Calcium phosphate ceramics as hard tissue prosthetics” Clin. Orthop. Relat. Res. 157, 259-278 (1981).
57.Jarcho M “Calcium phosphate ceramics as hard tissue prosthetics” Clin. Orthop. Relat. Res. 157, 259-278 (1981).
58.Dennisen JW, De Groot K, Makkes PC “Tissue response to dense apatite implants in rats” J. Biomed. Mater. Res. 14, 713-721 (1980).
59.Hench LL “Bioactive implants” In Transactions of Society of Biomaterials Vol. 8, Society for Biomaterials, pp. 25, Birmingham, AL, 1985.
60.Boyne PJ, Fremmmg BD, Walsh R, Jarcho M “Evaluation of ceramic hydroylapatite in femoral defects” J. Dent. Res. 57A, 108-(1978).
61.Dennisen HW, De Groot K “Immediate dental root implants from synthetic dense calcium HA” J. Prosthet. Dent. 42, 551-556 (1979).
62.Saylor KR, Holmes R, Johns D “Replamineform porous hydroxyapatite as bone substitute in craniofacial osseous reconstruction” J. Dent. Res. 56B, 173 (1977).
63.Frame JW, Brady CL “Augmentation of an atrophic edentulous mandible by interpositional grafting with HAp” J. Oral. Maxillofac. Surg. 42, 89-92 (1984).
64.Jarcho M, Kay JF, Gumaer KI, Doremus RH, Drobeck HP “Tissue cellular and subcellular events at bone-ceramic hydroxyapatite interface” J. Bioeng. 1, 79-92 (1977).
65.Jarcho M “Calcium phosphate ceramics as hard tissue prosthetics” Clin. Orthoop. Relat. Res. 157, 259-278 (1981).
66.Kent JN, Quinn JH, Zide MF, Guerra LR, Boyne PJ “Alveolar ridge augmentation using nonresorabale hydroxyapatite with or without autogeneous cancellous” J. Oral. Maxillofac. Surg. 41, 629-642 (1983).
67.Baker RD, Terry BC, Davis WH, Connole PW “Long-term results of alveolar ridge aubementation” J. Oral Surg. 37, 486-489 (1979).
68.Brown WE “ Solubilities of phosphate and other sparingly soluble compounds” In Environmental Phosphorous Handbook, EJ Griffeth, EJ Griffith and A Beeton (Eds.), John wiley & Sons, pp.203-239, New York, 1973.
69.Brown PW, Hocker N, Hoyle S “ Variations in solution chemistry during the low-temperature formation of hydroxyapatite” J. Am. Ceram. Soc. 74, 1848-1854 (1991).
70.Brown PW, Fulmer MT “Kinetics of hydroxyaptite formation at low-temperature” J. Am. Ceram. Soc. 74, 934-940 (1990).
71.Fulmer MT, Martin RI, Brown PW “Formation of calacium deficient hydroxyapatite at near-physiological temperature” J. Mater. Sci.: Mater. Med. 3, 299-305 (1992).
72.Chow LC, Eanes ED “Octacalcium Phosphate” Monogr. Oral. Sci., Karger, Basel, vol.18, pp.1-14, 2001.
73.Desai TD, Bhaduri SB, Tas AC “A self-setting, Monetite (CaHPO4) cement for skeletal repair” in Advan. Bioceram. Biocomp. II, Mineo Mizumo Ed., Andrew Wereszczak and Edgar Lara-Curizo (vol. Ed.), J. Wiley & Sons, N.Y., pp. 61-70, 2007
74.Monma H, Kanazawa T “Wet-process formation of nonstoichiometric hydroxyapatite from tricalcium phosphate” Yogyo Kyokai Shi 86, 73-76 (1978).
75.Monma H, Ueno S, Tsutsumi M “Effects of water-soluble additives on the properties of hardened apatite” Gypsum and Lime 156, 190-195 (1978).
76.Monma H, Ueno S, Kanazawa T “Properties of hydroxyapatite prepared by the hydrolysis of tricalcium phosphate” J. chem. Tech. Biotech. 31, 15-24 (1981).
77.Monma H, Goto M, Kohmura T “Effect of additives on hydration and hardening of tricalcium phosphate” Gypsum and Lime 188, 11-16 (1984).
78.Fernandez E, Boltong MG, Ginebra MP, Bermudez O., Driessens FCM, Planell JA “Common ion effect on some calcium phosphate cements” Clin. Mater. 16, 99-103 (1994).
79.Ginebra MP, Fernandez E, Driessens FCM, Boltong MG, Muntasell J, Font J, Planell JA “The effects of temperature on the behavior of an apatitic calcium phosphate cement” J. Mat. Sci.: Mater. Med. 6, 857-860 (1995).
80.Yoshikawa M, Hayami S, Toda T, Mandai Y “Effects of tannic acid in alpha-tricalcium phosphate cement for the physical properties and tissue respones” Bioceramics 14, 365-368 (2002).
81.Sarda S, Fernandez E, Nilsson M, Balcells M, Planell JA “Kinetics study of citric acid influence on calcium phosphate bone cements as water-reducing agent” J. Biomed. Mater. Res. 61, 653-659 (2002).
82.Muroyama K “Effect of addition of arylamide on hydaulic hardening of calcium phosphate” Maki Materiara 5, 31-36 (1998).
83.Fini M, Giavaresi G, Aldini NN, Torricelli P, Botter R, Beruto D, Giardino R “A bone substitute composed of polymethylmethacrykate and alphs-tricalcium phosphate: results in terms of osteoblast function and bone tissue formation” Biomaterials 23, 4523-4531 (2002).
84.Oreffo ROC, Driessends FCM, planell JA, Triffitt JT “Growth and differentiation of human bone marrow osteoprogenitors on novel calcium phosphate cements” Biomaterials 19, 1845-1854 (1998).
85.Mayer-Wohlfart U, Fiedler J, Gunther KP, Puhl W, Kessler S “Proliferation and differentiation rates of a human osteoblast-like cell line (SaOS-2) in contact with different bone substitute materials” J. Biomed. Meter. Res. 57, 132-139 (2001).
86.Knabe C, Driessens FCM, Planell JA, Gildenhaar R, Berger G, Reif D, Fitzner R, Radlanski RJ, Gross U “Evaluation of calcium phosphates and experimental calcium phosphate bone cements using osteogenic cultures” J. Biomed. Mater. Res. 52, 498-508 (2000).
87.Kurashina K, Ogiso A, Kotani A, Takeuchi H, Hirano M “Histological and microradiographis evaluation of hydrated and hardened alpha-tricalcium phosphate calcium-phosphate dibasic mixtures” Biomaterials 15, 429-432 (1996).
88.Yuan H, Li Y, De Bruijn JD, De Groot K, Zhang X “Tissue responses of calcium phosphate cement: a study in dogs” Biomaterials 21, 1283-1290 (2000).
89.Niedhart C, Maus U, edmann E, Siebert CH “In vivo testing of an new in situ setting β-tricalcium phosphate cement for osseous reconstruction” J. Biomed. Mater. Res. 55, 530-537 (2001).
90.Jupiter JB, Winters S, Sigman S, Lowe C, Pappas C, Ladd AL, Van Wagoner M, Smith ST “Repair of five distal radius fractures with an investigational cancellous bone cement: a preliminary report” J. Orthop. Trauma 11, 11, 110-116 (1997).
91.Kopylov P, Runnqvist K, Jonsson K, Aspenberg P”Norian SRS versus external fixation in redisplaced distal radial fractures. A randomized study in 40 patients” Acta Orthop. Scand 70, 1-5 (1999).
92.Kurashina K, Ogiso A, Kotani A, Takeuchi H, Hirano M “Histological and microradiographis evaluation of hydrated and hardened alpha-tricalcium phosphate calcium-phosphate dibasic mixtures” Biomaterials 15, 429-432 (1996).
93.Nagase M, Chen RB, Asada Y, Nakaima T “Radiographic and microscopic evaluation of subperiosteally implanted blocks of hydrated and hardened α-tricalcium phosphate in rabbits” J. Oral. Maxillofac. Surg. 47, 582-586 (1989).
94.Driessens FCM, Boltong MG, De Maeyer EAP, Wenz R, Nies B, Planell JA “The Ca/P range of nanoapatitic calcium phosphate cements” Biomaterials 23, 4011–4017 (2002).
95.Barralet JE, Tremayne M, Lilley KJ, Gbureck U, "Modification of calcium phophate cement with alpha-hydroxy acids and their salts", Chem. Mater. 17, 1313-1319 (2005).
96.TenHuisen KS, Brown PW “Formation of calcium-deficient hydroxyapatite from α-tricalcium phosphate” Biomaterials 19, 2209-2217 (1998).
97.Manuel CM, Ferraz1 MP, Monteiro FJ “Synthesis of Hydroxyapatite and Tricalcium Phosphate Nanoparticles-Preliminary Studies” Key Engineering Materials Vols. 240-242, 555-558 (2003).
98.Chow LC “Calcium Phosphate materials: Reactor Response” Adv. Dent. Res. 2(1), 181-184 (1998).
99.Driessens FCM, Verbeeck RK “Biominerals” CRC Press, New York, 1990.
100.Ambard AJ, Mueninghoff L “Calcium Phosphate Cement: Review of Mechanical and Biological Properties” J. Prosthodontics 15(5) 321-328 (2006).
101.Ginebra MP, Traykova T, Planell JA “Calcium phosphate cements as bone drug delivery systems: A review” Journal of Controlled Release 113, 102 – 110 (2006).
102.Amjad Z “Calcium Phosphates in Biological and Industrial Systems” Kluwer Academic Publisher, 1998.
103.Driessens FCM, Boltong MG, De Maeyer EAP, R. Verbeeck RMH, Wenz R, J. Mater. Sci.: Mater. Med. 11(7), 453-457 (2000).
104.Serraj S, Boudeville P, Terol A, J. Mater. Sci.: Mater. in Med. 12, 45-50 (2001).
105.Ginebra MP, Driessens FCM, Planell JA, Biomaterials 25, 3453-3462 (2004).
106.Sun L, Xu HHK, Takagi S, Chow LC, J. Biomater. Appl. 21, 299-315 (2007).
107.Ginebra MP, Fernandez E, De Maeyerl EAP, Verbeeck RMH, Boltong MG, Ginebra J, Driessens FCM, Planell JA, J. Dent. Res. 76(4), 905-912 (1997).
108.Miyamoto Y, Ishikawa K, Fukao H, Sawada M, Nagayama M, Kon M, Asaoka K, Biomaterials 16, 855-860 (1995).
109.Miyamoto Y, Ishikawa K, Takechi M, Toh T, Yoshida Y, Nagayama M, Kon M, Asaoka K, J. Biomed. Mater. Res. 37, 457–464 (1997).
110.Yang Q, Troczynski T, Liu DM, Biomaterials 23, 2751-2760 (2002).
111.Gbureck U, Grolms O, Barralet JE, Grover LM, Thull R, Biomaterials 24, 4123-4131 (2003).
112.Dorozhkina EI, Dorozhkin SV, Chem. Mater. 14, 4267-4272 (2002).
113.Hsu HC, Chiu CY, Tuan WH, Lee HY, Mater. Sci. & Eng. C: 28 (2008) 429–433.
114.Hench LL, Wilson J, An introduction to bioceramics, Word Scitific, 1993.
115.Chow LC, Eanes ED, Octacalcium phosphate, S. Karger AG, Basel, 2001.
116.Brown WE, Chow LC. J. Dent. Res., 63, pp.672 (1983).
117.Brown WE, Chow LC, in Cement Research Progress, P. W. Brow (ed.), American Ceramic Society, Westerville, Ohio, p.352 (1986).
118.Costantino PD, Friedman CD, Jones K, Chow LC, Sisson GA. Plastic Reconstr. Surg. 90, pp.174 (1992).
119.Gruninger SE, Siew C., Chow LC, Brown AO, Brown WE, J. Dent. Res. 63, pp.200 (1984).
120.Fuhkase Y, Eanes ED, Takag S, Chow LC, Brown WE, J. Dent. Res. 69, pp.1852 (1990).
121.Ishikawa K, Eanes ED, J. Dent. Res. 72 pp.474 (1993).
122.Chohayeb AA, Chow LC, Tsaknis P, J. Endodont. 13, pp.384 (1987).
123.Liu C, Shen W, Gu Y, Hu L, J. Biomed. Mat. Res. 35, pp.75 (1997).
124.Fukase Y, Eanes ED, Takag S, Chow LC, Brown WE. J. Dent. Res. 69, pp.1852 (1990).
125.Moreno EC, Gregory TM, Brown WE,. J. Res. Nat. Bureau Stand. U.S. 72A, pp.773 (1968).
126.Tas AC, Bhaduri SB. J. Am. Cerm. Soc. 87, pp.2195 (2004).
127.Fulmer MT, Brown PW, J. Mat. Sci.: Mat. In Med. 9, pp.197 (1998).
128.Eichert D, Salome M, Banu M, Susini J, Rey C, Spectrochimica Acta Part B 60, pp.850 (2005).
129.Bezjak A, Jelenic I, Cem. Concr. Res. 10, pp.553 (1980).
130.Jinawath S, Pongkao D, Yoshimura M, J. Mat. Sci.: Mat. In Med. 13, pp.491 (2002).
131.Lu X, Leng Y, Biomaterials 26, pp.1097 (2005).
132.Burguera EF, Guitian F, Chow LC, J. Biomed. Mater. Res. 71A, pp.275 (2004).
133.Fulmer MT, Martin RI, Brown PW “Formation of calacium deficient hydroxyapatite at near-physiological temperature” J. Mater. Sci.: Mater. Med. 3, 299-305 (1992).
134.Dennisen JW, De Groot K, Makkes PC “Tissue response to dense apatite implants in rats” J. Biomed. Mater. Res. 14, 713-721 (1980).
135.Suzuki T, Arai K, Goto H, Hanano M, Watanabe J, Tomono K “Dissolution Tests for Self-Setting Calcium Phosphate Cement-Containing Nifedipine” Chem. Pharm. Bull. 50(6), 741—743 (2002).
136.Amjad Z “Calcium Phosphates in Biological and Industrial Systems” Kluwer Academic Publisher, 1998.
137.Ahmed El-Ghannam “Bone reconstruction: from bioceramics to tissue engineering” Expert Review of Medical Devices 2(1), 87-101 (2005).
138.Iwatsubo T, Sumaru K, Kanamori T, Shinbo T, Yamaguchi T “Construction of a New Artificial Biomineralization System” Biomacromolecules 7, 95-100 (2006).
139.Şerbetçi K, Korkusuz F, Hasirci N “Mechanical and thermal properties of hydroxyapatite impregnated bone cement” Turk. Journal Med. Sci. 30, 543-549 (2000).
140.Radić M, Ignjatović N, Nedić Z, Mitrić M, Miličević D, Uskoković D “Synthesis and Characterization of Biphasic Calcium Phosphate/Poly-(DL-Lactide-Co-Glycolide) Biocomposite” Materials Science Forum Vol. 494, pp. 537-542 (2005).
141.Evis Z, Doremus R “A study of phase stability and mechanical properties of hydroxylapatite–nanosize α-alumina composites” Materials Science and Engineering C 27, 421 – 425(2007)
142.Maeda H, Kasuga T, Nogami M “Apatite formation on titania–vaterite powders in simulated body uid” J. Eur. Ceram. Soc. 24, 2125–2130 (2004).
143.Kubarev OL, Komlev VS, Maitz M, Barinov SM “Bioactive composite ceramics in the hydroxyapatite-tricalcium phosphate system” Doklady Chemistry 413(1), 72-74 (2007).
144.Smirnov V, Egorov A, Barinov S, Shvorneva L “Composite calcium phosphate bone cements reinforced by particulate titanium” Doklady Chemistry 413(4), 489–492 (2007).
145.Zhang H, Li S, Yan Y “Dissolution behavior of hydroxyapatite powder in hydrothermal solution” Ceramics International 27, 45-454 (2001).
146.Wu J, Wang M, Osaka A “Bioactive Composite Coating on Titanium Implants for Hard Tissue Repair” Key Engineering Materials Vols. 334-335, 1249-1252 (2007).
147.Chow LC, Eanes ED (eds): Octacalcium Phosphate. Monogr Oral Sci. Basel, Karger, vol. 18, 2001.