Injectable and Rapid-Setting Calcium Phosphate Bone Cement with Dicalcium Phosphate Dihydrate Elena F. Burguera,1 Hockin H. K. Xu,2 Michael D. Weir2 1 Instituto de Cera´ mica de Galicia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain 2 Paffenbarger Research Center, American Dental Association Foundation, National Institute of Standards and Technology, Gaithersburg, Maryland 20899-8546 Received 31 March 2005; revised 3 June 2005; accepted 8 June 2005 Published online 23 September 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.b.30403 Abstract: Calcium phosphate cement (CPC) sets in situ with intimate adaptation to the contours of defect surfaces, and forms an implant having a structure and composition similar to hydroxyapatite, the putative mineral in teeth and bones. The objective of the present study was to develop an injectable CPC using dicalcium phosphate dihydrate (DCPD) with a high solubility for rapid setting. Two agents were incorporated to impart injectability and fast- hardening to the cement: a hardening accelerator (sodium phosphate) and a gelling agent (hydroxypropyl methylcellulose, HPMC). The cement with DCPD was designated as CPCD, and the conventional cement was referred to as CPCA. Using water without sodium phosphate, ؎ CPCA had a setting time of 82 6 min. In contrast, CPCD exhibited rapid setting with a time ؎ ؎ of 17 1 min. At 0.2 mol/L sodium phosphate, setting time for CPCD was 15 1 min, ؎ significantly faster than 40 2 min for CPCA (Tukey’s at 0.95). Sodium phosphate decreased the paste injectability (measured as the paste mass extruded from the syringe divided by the original paste mass inside the syringe). However, the addition of HPMC dramatically in- ؎ creased the paste injectability. For CPCD, the injectability was increased from 65% 12% ؎ without HPMC to 98% 1% with 1% HPMC. Injectability of CPCA was also doubled to 99% ؎ 1%. The injectable and rapid-setting CPCD possessed flexural strength and elastic modulus values overlapping the reported values for sintered porous hydroxyapatite implants and cancellous bone. In summary, the rapid setting and relatively high strength and elastic modulus of CPCD should help the graft to quickly attain strength and geometrical integrity within a short period of time postoperatively. Furthermore, the injectability of CPCD may have potential for procedures involving defects with limited accessibility or narrow cavities, when there is a need for precise placement of the paste, and when using minimally invasive surgical techniques. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 77B: 126–134, 2006 Keywords: calcium phosphate cement; hydroxyapatite; injectability; rapid setting; bone repair INTRODUCTION jection and disease transmission. These factors are providing much of the driving force for the development of synthetic Approximately one million bone grafts are performed each biomaterials. Calcium phosphate biomaterials have gained year in the United States to treat osseous defects.1,2 This need clinical acceptance for bone substitution and augmenta- is increasing dramatically as the world population ages.3 tion.4–11 Porous calcium phosphate scaffolds have been de- Autograft, the gold standard in bone repair, is restricted by veloped to facilitate tissue ingrowth12–14 by using controlled bone availability, donor site morbidity, and contouring diffi- pore architectures15 and three-dimensional fabrication tech- culty. Allografts and xenografts raise concerns of immunore- niques.16 Calcium phosphate cements can be easily manipulated and shaped, provide intimate adaptation to the contours of defect Correspondence to: H. Xu, (e-mail: [email protected]) E. F. Burguera is now with Materials Science and Engineering Department, Vir- surfaces, and set in situ in the bone cavity to form a solid ginia Polytechnic Institute and State University, Blacksburg, VA. restoration.17 The concept of calcium phosphates as possible Contract grant sponsor: USPHS NIH; contract grant number: R01 DE14190 18 Contract grant sponsor: NIST cement materials was first introduced in 1982. The first Contract grant sponsor: ADAF calcium phosphate cement (CPC) was reported in 1987.17 17,19–22 © 2005 Wiley Periodicals, Inc. Since then, many compositions have been formulated. 126 INJECTABLE AND RAPID-SETTING CALCIUM PHOSPHATE CEMENT 127 CPC is comprised of a mixture of tetracalcium phosphate NJ), which were mixed and heated at 1500°C for6hina 17 [TTCP: Ca4(PO4)2O] and dicalcium phosphate anhydrous furnace (Model 51333, Lindberg, Watertown, WI). The 17 (DCPA: CaHPO4). The CPC powder can be mixed with an heated mixture was quenched to room temperature and aqueous liquid to form a paste23–26 where the water provides ground dry in a ball mill (Retsch PM4, Brinkman, NY). The a vehicle for the dissolution of the reactants and the precip- TTCP powder was then sieved using a standard testing sieve itation of the product. The set cement has a structure and (W. S. Tyler Inc., Mentor, OH) with openings of 38 ␮mto composition similar to hydroxyapatite, the putative mineral remove the large particles. The TTCP powder that went ϩ 3 in teeth and bones: 2Ca4(PO4)2O 2CaHPO4 through the sieve was collected and analyzed. The particle 17,26 Ca10(PO4)6(OH)2. Due to its excellent osteoconductivity size distribution was measured by a sedimentation method and bone replacement capability, CPC is highly promising for with the use of a centrifugal particle analyzer (SA-CP3, a wide variety of clinical applications.17,23–26 Shimazu, Kyoto, Japan), which yielded a TTCP particle size In other in vitro studies, dicalcium phosphate dihydrate range of about 1 ␮mto60␮m and a median particle size of ⅐ ␮ (DCPD, CaHPO4 2H2O), a compound with a relatively high 20 m. The commercial DCPA powder was ground and then solubility, was used to replace the DCPA component in CPC analyzed using the same particle size analyzer, which re- 27,28 ϩ ⅐ ␮ ␮ to form hydroxyapatite : 2Ca4(PO4)2O 2CaHPO4 ported a particle size range of 0.4 mto6 m and a median 3 ϩ ␮ 2H2O Ca10(PO4)6(OH)2 4H2O. The conventional ce- particle size of 1.2 m. The TTCP and DCPA powders were ment from DCPA–TTCP was referred to as CPCA, and the mixed in a micromill (Bel-Alert Products, Pequannock, NJ) 28 cement from DCPD–TTCP was termed CPCD. The high in equimolar amounts to form the powder for the cement solubility of DCPD resulted in faster setting and higher early designated as CPCA. 28 strength for CPCD. Thirty minutes after powder and liquid Commercial DCPD powders were first used in our pilot 27 mixing, CPCD developed a flexural strength of 4.2 MPa, studies, but the resulting TTCP–DCPD pastes exhibited 28 Ͼ while CPCA was not set and consequently had no strength. undesirable long setting times of 1 h. This was likely due Fast setting is desirable because a long setting time can result to unidentified impurities in the commercial powders.27 in the crumbling of the inserted paste when it comes in early Hence DCPD in the present study was prepared in our labo- contact with physiological fluids, or when bleeding occurs ratory. To synthesize DCPD, the pH of a DCPD–monocal- due to the difficulty to achieve complete hemostasis in some cium phosphate monohydrate singular point solution (pH ϭ 21,29,30 27,28 cases. High early strength is needed to prevent early- 1.9, 4°C) was slowly raised via the addition of CaCO3. stage implant failure or disintegration.28 DCPD that precipitated before the pH reached 3.5, which is In addition to rapid setting and early strength, the inject- significantly below the hydroxyapatite–DCPD singular point ability of a CPC paste is also an important property. This is of 4.2, was collected to avoid possible contamination of the especially true in procedures involving defects with limited DCPD by hydroxyapatite.27,28 The DCPD was ground and accessibility or narrow cavities, when there is a need for then analyzed using the same particle size analyzer that precise placement of the paste to conform to a defect area, showed a particle size range of 0.5 ␮mto4␮m and a median and when using minimally invasive surgical techniques.31–37 particle size of 1.3 ␮m. The DCPD powder was then mixed Several factors affecting the injectability of a number of with the TTCP powder at a molar ratio of 1:1 to form the 31–37 calcium phosphate cements have been examined. How- powder for the cement referred to as CPCD. 27,28 ever, the injectability of the high early-strength CPCD remains to be investigated. Cement Liquids The objective of the present study was to investigate the injectability of CPCD in comparison with the conventional Two types of liquid were used: (1) aqueous sodium phosphate CPCA, and to examine the effects of incorporating a harden- solution and (2) aqueous sodium phosphate–hydroxypropyl ing accelerator and a gelling agent. The tested hypotheses methylcellulose solution. The sodium phosphate solutions were: (1) incorporating sodium phosphate into the cement were prepared by diluting a 3 mol/L phosphate solution liquid would impart rapid setting to the cement, but would (Na2HPO4 and NaH2PO4, Abbott Laboratories, North Chi- decrease the paste’s injectability; (2) incorporating hy- cago, IL) with distilled water at the following sodium phos- droxypropyl methylcellulose would improve the paste’s in- phate concentrations: 0 mol/L (distilled water without sodium jectability, without compromising the mechanical strength; phosphate), 0.1 mol/L, 0.2 mol/L, 0.3 mol/L, 0.4 mol/L, and and (3) the use of DCPD with its high solubility for rapid 0.5 mol/L. In a previous study,30 sodium phosphate imparted setting would not reduce the paste’s injectability compared to fast setting to CPCA. But the very fast-setting property might DCPA.