Fabrication and cytocompatibility of spherical magnesium ammonium phosphate granules Theresa Christel a , Martha Geffers a , Uwe Klammert b , Berthold Nies c , Andreas Höß c , Jürgen Groll a , Alexander C. Kübler b , Uwe Gbureck a, ⁎ a Department for Functional Materials in Medicine and Dentistry, University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany b Department of Cranio-Maxillo-Facial Surgery, University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany c InnoTERE GmbH, Pharmapark Radebeul, Meissner Straße 191, 01455 Radebeul, Germany abstract article info Article history: Received 14 January 2014 Received in revised form 31 March 2014 Accepted 6 May 2014 Available online 22 May 2014 Keywords: Calcium magnesium phosphate cement Struvite Granules Magnesium phosphate compounds, as for example struvite (MgNH 4 PO 4 ·6H 2 O), have comparable charac- teristics to calcium phosphate bone substitutes, but degrade faster under physiological conditions. In the present work, we used a struvite forming calcium doped magnesium phosphate cement with the formulation Ca 0.75 Mg 2.25 (PO 4 ) 2 and an ammonium phosphate containing aqueous solution to produce round-shaped gran- ules. For the fabrication of spherical granules, the cement paste was dispersed in a lipophilic liquid and stabilized by surfactants. The granules were characterized with respect to morphology, size distribution, phase composi- tion, compressive strength, biocompatibility and solubility. In general, it was seen that small granules can hardly be produced by means of emulsification, when the raw material is a hydraulic paste, because long setting times promote coalescence of initially small unhardened cement droplets. Here, this problem was solved by using an aqueous solution containing both the secondary (NH 4 ) 2 HPO 4 and primary ammonium phosphates NH 4 H 2 PO 4 to accelerate the setting reaction. This resulted in granules with 97 wt.% having a size in the range between 200 and 1000 μm. The novel solution composition doubled the compressive strength of the cement to 37 ± 5 MPa without affecting either the conversion to struvite or the cytocompatibility using human fetal osteoblasts. © 2014 Elsevier B.V. All rights reserved. 1. Introduction The use of autografts for the repair of bone defects is considered as “gold standard”, but has several drawbacks such as a lack of avail- ability and its donor site morbidity [1,2]. Alternative synthetic bone replacement materials are mostly based on calcium phosphate chemis- try. Material approaches cover both the use of hydroxyapatite derived from natural resources (e.g. BioOss®) [3] as well as fully synthetic hydroxyapatites (HA) or tricalcium phosphates (TCP) prepared by sintering, precipitation or a cement setting reaction [4]. Depending on the chemical composition and crystal size, these materials are either stable (HA) or are able to slowly degrade in vivo (TCP) by active and passive mechanisms such that host autologous bone can grow into the bone defect [5]. Novel material approaches to enhance the degradation ability of bioceramics for bone replacement involve the use of magne- sium phosphate compounds [6]. Such materials were found to be as cytocompatible as calcium phosphates, but offer a faster chemical degradation due to their higher solubility under physiological condi- tions [7]. Various magnesium phosphate compounds have been in- vestigated in recent studies, e.g. struvite (MgNH 4 PO 4 ·6H 2 O) [8–11], newberyite (MgHPO 4 ·3H 2 O) [12], amorphous magnesium phosphates [13] or magnesium doped calcium phosphates [7,14,15]. The formation of these compounds is often based on a cementitious reaction of either MgO or Mg 3 (PO 4 ) 2 with aqueous sources of phosphate and ammonium salts. The solubility profiles of these cements may be altered by using biphasic calcium magnesium phosphate mixtures. This was already demonstrated by Vorndran et al. [11], who used compounds with the general formula Ca x Mg (3-x) (PO 4 ) 2 allowing to adjust the setting prop- erties as well as the mechanical performance and solubility. By using the formulation Ca 0.75 Mg 2.25 (PO 4 ) 2 together with a 3.5 M (NH 4 ) 2 HPO 4 solu- tion, a good biocompatibility in vitro [11] and in vivo [12], a high me- chanical strength of ~80 MPa and an adequate setting time of 14 min were obtained [11]. In the present work, a cement based on Ca 0.75 Mg 2.25 (PO 4 ) 2 was used to fabricate pre-hardened cement granules since in dental surgery (e.g. sinus lift operation, socket preservation, filling of jaw cysts) the application of bone substitutes in granular form is a typical approach [16]. An easy way to generate granules on the basis of a hydraulic cement paste is the hardening of a cement monolith followed by Materials Science and Engineering C 42 (2014) 130–136 ⁎ Corresponding author. Tel.: +49 931 20173550. E-mail addresses: theresa.christel@fmz.uni-wuerzburg.de (T. Christel), Martha.geffers@fmz.uni-wuerzburg.de (M. Geffers), klammert_u@klinik.uni-wuerzburg (U. Klammert), berthold.nies@innotere.de (B. Nies), andreas.hoess@innotere.de (A. Höß), juergen.groll@fmz.uni-wuerzburg.de (J. Groll), mkg@uni-wuerzburg.de (A.C. Kübler), uwe.gbureck@fmz.uni-wuerzburg.de (U. Gbureck). http://dx.doi.org/10.1016/j.msec.2014.05.023 0928-4931/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec