Entnehmen Sie die Publikationen der Jahre 2015 und früher von Mitarbeitenden der RMS Foundation der folgenden Liste


Textured and hierarchically structured calcium phosphate ceramic blocks through hydrothermal treatment

Laetitia Galea, Dmitriy Alexeev, Marc Bohner, Nicola Doebelin, André R. Studart, Christos G. Aneziris, Thomas Graule

Synthetic calcium phosphate bone graft substitutes are widely recognized for their biocompatibility and
resorption characteristics in the treatment of large bone defects. However, due to their inherent brittleness,
applications in load-bearing situations always require reinforcement by additional metallic
implants. Improved mechanical stability would eliminate the need for non-resorbable metallic implants.
In this context a new approach to obtain calcium phosphate scaffolds with improved mechanical stability
by texturing the material in specific crystal orientations was evaluated. Texture and reduction of crystal
size was achieved by recrystallizing a-TCP blocks into calcium deficient hydroxyapatite (CDHA) under
hydrothermal conditions. SEM and XRD analysis revealed the formation of fine CDHA needles
(diameter z 0.1e0.5 mm), aligned over several hundreds of micrometers. The obtained microstructures
were remarkably similar to the microstructures of the prismatic layer of mollusk shells or enamel, also
showing organization at 5 hierarchical structure levels. Brazilian disc tests were used to determine the
diametral tensile strength, sdts, and the work-of-fracture, WOF, of the textured materials. Hydrothermal
incubation significantly increased sdts and WOF of the ceramic blocks as compared to sintered blocks.
These improvements were attributed to the fine and entangled crystal structure obtained after incubation,
which reduces the size of strength-determining critical defects and also leads to tortuous crack
propagation. Rupture surfaces revealed intergranular tortuous crack paths, which dissipate much more
energy than transgranular cracks as observed in the sintered samples. Hence, the refined and textured
microstructure achieved through the proposed processing route is an effective way to improve the
strength and particularly the toughness of calcium phosphate-based ceramics.


Phase and size separations occurring during the injection of model pastes composed of b-tricalcium phosphate powder, glass beads and aqueous solutions

S. Tadier, L. Galea, B. Charbonnier, G. Baroud, M. Bohner

Glass beads a few hundred micrometers in size were added to aqueous b-tricalcium phosphate pastes to
simulate the effect of porogens and drug-loaded microspheres on the injectability of calcium phosphate
cements and putties. The composition of the pastes was monitored during the injection process to assess
the effect of glass bead content, glass bead size and paste composition on the paste injectability. The
results revealed that the injection process led to both liquid and glass bead segregations: the liquid
flowed faster than the glass beads, which themselves flowed faster than the b-tricalcium phosphate
microparticles. In fact, even the particle size distribution of the glass beads was modified during injection.
These results reveal that a good design of multiphasic injectable pastes is essential to prevent phase

Growth kinetics of hexagonal sub-micrometric b-tricalcium phosphate particles in ethylene glycol

Laetitia Galea, Marc Bohner, Juerg Thuering, Nicola Doebelin, Terry A. Ring, Christos G. Aneziris, Thomas Graule

Recently, uniform, non-agglomerated, hexagonal b-tricalcium phosphate (b-TCP) platelets (diameter
 400–1700 nm, h  100–200 nm) were obtained at fairly moderate temperatures (90–170 C) by
precipitation in ethylene glycol. Unfortunately, the platelet aspect ratios (diameter/thickness) obtained
in the latter study were too small to optimize the strength of polymer–b-TCP composites. Therefore,
the aim of the present study was to investigate b-TCP platelet crystallization kinetics, and based on this,
to find ways to better control the b-TCP aspect ratio. For that purpose, precipitations were performed at
different temperatures (90–170 C) and precursor concentrations (4, 16 and 32 mM). Solution aliquots
were retrieved at regular intervals (10 s–24 h), and the size of the particles was measured on scanning
electron microscopy images, hence allowing the determination of the particle growth rates. The b-TCP
platelets were observed to nucleate and grow very rapidly. For example, the first crystals were observed
after 30 s at 150 C, and crystallization was complete within 2 min. The crystal growth curves could be
well-fitted with both diffusion- and reaction-controlled equations, but the high activation energies
(100 kJ mol1) pointed towards a reaction-controlled mechanism. The results revealed that the best
way to increase the diameter and aspect ratio of the platelets was to increase the precursor concentration.
Aspect ratios as high as 14 were obtained, but the synthesis of such particles was always associated
with the presence of large fractions of monetite impurities.


Moisture based three-dimensional printing of calcium phosphate structures for scaffold engineering

A. Butscher, M. Bohner, N. Doebelin, L. Galea, O. Loeffel, R. Müller

Powder based three-dimensional printing (3DP) allows great versatility in material and geometry. These
characteristics make 3DP an interesting method for the production of tissue engineering scaffolds. However,
3DP has major limitations, such as limited resolution and accuracy, hence preventing the widespread
application of this metho engineering. In order to reduce these limitations deeper
understanding of the complex interactions between powder, binder and roller during 3DP is needed.
In the past a lot of effort has been invested to optimize the powder properties for 3DP for a certain layer
thickness. Using a powder optimized for an 88 lm layer thickness, this study systematically quantifies
the surface roughness and geometrical accuracy in printed specimens and assesses their variation upon
changes of different critical parameters such as the moisture application time (0, 5, 10 and 20 s), layer
thickness (44 and 88 lm) and the number of specimens printed per batch (6 and 12). A best surface
roughness value of 25 lm was measured with a moisture application time (using a custom made moisture
application device mounted on a linear stage carrying the print head) of 5 s and a layer thickness of
44 lm. Geometrical accuracy was generally higher for the 88 lm thick layer, due to a less critical powder
bed stability. Moisture application enabled 3DP of a 44 lm thick layer and improved the accuracy even
for a powder initially optimized for 88 lm. Moreover, recycling of the humidified powder was not only
possible but, in terms of reactivity, even beneficial. In conclusion, moisture-based 3DP is a promising
approach for high resolution 3DP of scaffolds

New depowdering-friendly designs for three-dimensional printing of calcium phosphate bone substitutes

A. Butscher, M. Bohner, N. Doebelin, S. Hofmann, R. Müller

Powder-based three-dimensional printing (3DP) is a versatile method that allows creating synthetic calcium
phosphate (CaP) scaffolds of complex shapes and structures. However, one major drawback is the
difficulty of removing all remnants of loose powder from the printed scaffolds, the so-called depowdering
step. In this study, a new design approach was proposed to solve this problem. Specifically, the design of
the printed scaffolds consisted of a cage with windows large enough to enable depowdering while still
trapping loose fillers placed inside the cage. To demonstrate the potential of this new approach, two filler
geometries were used: sandglass and cheese segment. The distance between the fillers was varied and
they were either glued to the cage or free to move after successful depowdering. Depowdering efficiency
was quantified by microstructural morphometry. The results showed that the use of mobile fillers significantly
improved depowdering. Based on this study, large 3DP scaffolds can be realized, which might be a
step towards a broader clinical use of 3D printed CaP scaffolds.

Control of the size, shape and composition of highly uniform, non-agglomerated, sub-micrometer b-tricalcium phosphate and dicalcium phosphate platelets

Laetitia Galea, Marc Bohner, Juerg Thuering, Nicola Doebelin, Christos G. Aneziris, Thomas Graule

Calcium phosphates (CaPs) are widely used as bone graft substitutes but are inherently brittle, hence
restricting their use to mechanically protected environments. Combining them with a tough polymer
matrix could potentially lead to a composite with load-bearing properties. However, the highest mechanical
properties can only be achieved if the CaP particles possess very precise features: they should be
uniform in size and shape, non-agglomerated, elongated and thin. The aim of the present study therefore
was to assess a novel method to produce such particles. This involved the precipitation of CaP particles in
ethylene glycol at moderate temperatures (90e170 C) and the variation of different reaction parameters
(temperature, concentration, pH, etc) to study their influence on particle composition, size, shape and
dispersion was studied. As a result, two main CaP phases were obtained as well-dispersed and highly
uniform platelets in the form of: (i) b-tricalcium phosphate (b-TCP) hexagonal prisms and (ii) monetite
(DCP) flat parallelepipeds. The size dispersion was the narrowest for b-TCP (standard deviation/
mean < 5%) whereas the aspect ratio was the highest for DCP (up to 25). In both cases, the thickness of
the platelets was below 300 nm which should be ideal for the synthesis of strong CaP-based composites


Printability of calcium phosphate powders for three-dimensional printing of tissue engineering scaffolds

Andre Butscher, Marc Bohner, Christian Roth, Annika Ernstberger, Roman Heuberger, Nicola Doebelin, Philipp Rudolf von Rohr, Ralph Müller

Three-dimensional printing (3DP) is a versatile method to produce scaffolds for tissue engineering. In 3DP
the solid is created by the reaction of a liquid selectively sprayed onto a powder bed. Despite the importance
of the powder properties, there has to date been a relatively poor understanding of the relation
between the powder properties and the printing outcome. This article aims at improving this understanding
by looking at the link between key powder parameters (particle size, flowability, roughness,
wettability) and printing accuracy. These powder parameters are determined as key factors with a predictive
value for the final 3DP outcome. Promising results can be expected for mean particle size in the
range of 20–35 lm, compaction rate in the range of 1.3–1.4, flowability in the range of 5–7 and powder
bed surface roughness of 10–25 lm. Finally, possible steps and strategies in pushing the physical limits
concerning improved quality in 3DP are addressed and discussed.

Calcium phosphate bone graft substitutes: Failures and hopes

Marc Bohner, Laetitia Galea, Nicola Doebelin

Despite 40 years of efforts, researchers have failed to provide calcium phosphate bone graft substitutes performing well enough to replace bone
grafting procedures: their osteogenesis potential is limited, and calcium phosphates are too brittle. However, there is hope to solve the two aforementioned
problems. First, it is now clear why nacre and bone are very tough despite a high ceramic load. Also, recent studies suggest that calcium
and phosphate ions can trigger osteoinduction. The present article aims: (i) to review our current knowledge in the field of synthetic bone graft
substitutes, (ii) to explain why ceramics and in particular calcium phosphates are still the most promising materials for bone graft substitution, and
(iii) finally to describe the strategy to obtain osteoinductive calcium phosphate bone graft substitutes as strong as cortical bone.


Commentary: Deciphering the link between architecture and biological response of a bone graft substitute

Marc Bohner, Y. Loosli, G. Baroud, D. Lacroix

Hundreds of studies have been devoted to the search for the ideal architecture for bone scaffold. Despite
these efforts, results are often contradictory, and rules derived from these studies are accordingly vague.
In fact, there is enough evidence to postulate that ideal scaffold architecture does not exist. The aim of
this document is to explain this statement and review new approaches to decipher the existing but complex
link between scaffold architecture and in vivo response.

Structural and material approaches to bone tissue engineering in powder-based three-dimensional printing

A. Butscher, Marc Bohner, S. Hofmann, L. Gauckler, R. Müller

This article reviews the current state of knowledge concerning the use of powder-based three-dimensional
printing (3DP) for the synthesis of bone tissue engineering scaffolds. 3DP is a solid free-form fabrication
(SFF) technique building up complex open porous 3D structures layer by layer (a bottom-up
approach). In contrast to traditional fabrication techniques generally subtracting material step by step
(a top-down approach), SFF approaches allow nearly unlimited designs and a large variety of materials
to be used for scaffold engineering. Today’s state of the art materials, as well as the mechanical and structural
requirements for bone scaffolds, are summarized and discussed in relation to the technical feasibility
of their use in 3DP. Advances in the field of 3DP are presented and compared with other SFF methods.
Existing strategies on material and design control of scaffolds are reviewed. Finally, the possibilities and
limiting factors are addressed and potential strategies to improve 3DP for scaffold engineering are


Aqueous impregnation of porous b-tricalcium phosphate scaffolds

C. Stähli, Marc Bohner, M. Bashoor-Zadeh, Nicola Doebelin, G. Baroud

The ability of a porous bone graft substitute to be impregnated with an aqueous solution is of great
importance for tissue engineering and in vivo applications. This study presents an impregnation test
setup and assesses the effect of various synthesis parameters such as sintering temperature, composition,
macroporosity and macropore size on the impregnation properties of porous b-tricalcium phosphate
scaffolds dipped in water. Among those parameters, the macropore size had by far the largest effect; generally,
the bigger the macropore size, the lower the saturation level. The results also showed that impregnation
was less complete when the samples were fully dipped in water than when they were only
partially dipped, owing to the requirement for the system to create air bubbles under water.


A physical approach to modify the hydraulic reactivity of a-tricalcium phosphate powder

Marc Bohner, Reto Luginbühl, Christian Reber, Nicola Doebelin, Gamal Baroud, Egle Conforto

A microsized a-tricalcium phosphate (a-TCP) powder was calcined at various temperatures (350 C < T < 800 C) for various durations
(1–24 h) and the resulting physico-chemical and reactivity changes were measured. Without calcination, the a-TCP powder started
reacting within minutes after contacting a 0.2 M Na2HPO4 solution as measured by isothermal calorimetry. The overall reaction was
finished within a few days. After calcination at 350 C 6 T 6 550 C for 24 h, no significant changes in the crystalline composition, crystallite
size, particle size or specific surface area were noticed. However, the powder reactivity was progressively changed. More specifically,
the hydraulic reaction of the powders calcined at 500 and 550 C only started after 2–3 h whereas the overall hydraulic reaction was
only slightly postponed, suggesting that physical or chemical changes had occurred at the particle surface. As mainly physical changes
were detected at the particle surface during calcination at 500 C, it was speculated that the appearance of this reaction delay (= induction
time) was due to the disappearance of surface defects during the calcination step, i.e. to the need to create surface defects to induce
dissolution and hence reaction.

Silicon-substituted calcium phosphates – A critical view

Marc Bohner

Nowadays, the scientific community widely accepts the statement that silicon-substituted calcium
phosphates have better biological properties compared to pure calcium phosphates. For example, a review
published in this journal in 2007 started with the sentence ‘‘Silicon (Si) substitution in the crystal
structures of calcium phosphate (CaP) ceramics such as hydroxyapatite (HA) and tricalcium phosphate
(TCP) generates materials with superior biological performance to stoichiometric counterparts’’ [1]. A
critical look at published articles demonstrates that this sentence is controversial and somehow
misleading, because there is no experimental evidence that Si ions are released from Si-substituted calcium
phosphates at therapeutic concentrations, and because there is no study linking the improved biological
performance of Si-substituted calcium phosphates to Si release. The aim of this article is to explain this
statement in more details.


Bone substitute: Transforming b-tricalcium phosphate porous scaffolds into monetite

Laetitia G. Galea, Marc Bohner, Jacques Lemaître, Thomas Kohler, Ralph Müller

The goal of the present study was to assess the possibility to change the composition of a calcium
phosphate scaffold from a high-temperature phase to a phase only stable at or close to room temperature
without macrostructural changes. For that purpose, macroporous b-TCP scaffolds were converted into
a-TCP by high-temperature thermal treatment and then dipped into a phosphoric acid solution to obtain
a more acidic calcium phosphate phase called monetite or dicalcium phosphate (DCP; CaHPO4). Two
different solid-to-liquid ratios (SLR: 0.067 and 0.200 g/mL) and three different temperatures (T: 37,
60 and 80 C) were used. The reaction was followed by measuring the change of sample size and weight,
by determining the compositional changes by X-ray diffraction (Rietveld analysis), and by looking at the
micro- and macrostructural changes by scanning electron microscopy and micro-computed tomography.
The results revealed that the transformation proceeded faster at a higher temperature and a higher SLR
value but was achieved within a few days in all cases. Morphologically, the porosity decreased by 10%,
the pore size distribution became wider and the mean macro pore size was reduced from 0.28 to
0.19 mm. The fastest conversion and the highest compressive strength (9 MPa) were measured using an
incubation temperature of 80 C and an SLR value of 0.2 g/mL.


Combining particle size distribution and isothermal calorimetry data to determine the reaction kinetics of a-tricalcium phosphate–water mixtures

Marc Bohner, Anna K. Malsy, Christopher L. Camiré, Uwe Gbureck

Many calcium phosphate bone substitutes are based on the use of a-tricalcium phosphate (a-TCP) powder. This compound has been
intensively studied, but some aspects of a-TCP reactivity are still controversial. The goal of this study was to determine the setting kinetics
of a-TCP based on a new approach that compared particle size distribution data to isothermal calorimetry data. Results indicated
that a-TCP conversion is mostly controlled by surface reactions, with at later stages a diffusion-controlled mechanism. The presence of
an X-ray amorphous a-TCP fraction in the crystalline a-TCP powder increased the dissolution rate threefold, without modifying the
reaction mechanism.

In vivo behavior of calcium phosphate scaffolds with four different pore sizes

Marie-Cécile von Doernberg, Brigitte von Rechenberg, Marc Bohner, Sonja Grünenfelder, G Harry van Lenthe, Ralph Müller, Beat Gasser, Robert Mathys, Gamal Baroud, Jörg Auer

The goal of the present study was to assess the effect of macropore size on the in vivo behavior of ceramic scaffolds. For that purpose,
b-tricalcium phosphate (b-TCP) cylinders with four different macropore sizes (150, 260, 510, and 1220 mm) were implanted into drill hole
defects in cancellous bone of sheep and their resorption behavior was followed for 6, 12 and 24 weeks. The scaffolds were evaluated for
biocompatibility, and new bone formation was observed macroscopically, histologically and histomorphometrically. Histomorphometrical
measurements were performed for the whole defect area and for the area subdivided into three concentric rings (outer, medial, and
inner ring). All implants were tolerated very well as evidenced by the low amount of inflammatory cells and the absence of macroscopic
signs of inflammation. Resorption proceeded fast since less than 5% ceramic remained at 24-week implantation. Hardly any effect of
macropore size was observed on the in vivo response. Samples with an intermediate macropore size (510 mm) were resorbed significantly
faster than samples with smaller macropore sizes (150 and 260 mm). However, this fast resorption was associated with a lower bone
content and a higher soft tissue content. At 12 and 24 weeks, the latter differences had disappeared. Bone was more abundant in the outer
ring than in the rest of the blocks at 6 weeks, and in the outer and medial ring compared to the inner ring at 12 weeks.


Injectability of calcium phosphate pastes

Marc Bohner, Gamal Baroud

A theoretical model was developed to assess ways to improve the injectability of calcium phosphate pastes. The theoretical results
were then compared to experimental data obtained on calcium phosphate slips. The theoretical approach predicted that the
injectability of a cement paste could be improved by an increase of the liquid-to-powder ratio, and a decrease of the particle size and
the plastic limit (PL) of the powder. The theoretical results were confirmed by experimental data. Interestingly, an increase of the
viscosity of the mixing liquid with small additions of xanthan had a positive effect on the paste injectability. This effect could be due
to a change of the PL of the powder or to the lubricating effect of the polymer.

Synthesis and characterization of porous b-tricalcium phosphate blocks

Marc Bohner, G.H. van Lenthe, S. Grünenfelder, W. Hirsiger, R. Evison, R. Müller

Porous b-tricalcium phosphate (b-TCP) blocks with four different macropore sizes (pore larger than 50 mm) were synthesized
using ‘‘calcium phosphate emulsions’’, and characterized by optical, geometrical, gravimetric, and radiological methods. The
reproducibility of the synthesis method was excellent. Moreover, the macropore size could be easily controlled without modifying
the microporosity (pore smaller than 50 mm) or the total porosity (microporosity+macroporosity). Based on the initial composition
of the blocks and their final apparent density, the microporosity, macroporosity, and the total block porosity were calculated to be
close to 21%, 54%, and 75%, respectively. These values were confirmed by microcomputed tomography (mCT). The mean
macropore diameters were close to 150, 260, 510 and 1220 mm, as measured optically. Consistenly lower values (25% lower) were
obtained by mCT, but the linear correlation between mCT and optical method was high (r240:97). The macropore size distribution
calculated from mCT scans appears to be narrow and normally distributed. The very good correlation between the results of the
various methods and the possibility to determine the pore size distribution suggest that mCT is an ideal tool to non-destructively
characterize macroporous calcium phosphate bone substitutes.

Technological issues for the development of more efficient calcium phosphate bone cements: A critical assessment

Marc Bohner, U. Gbureck, J.E. Barralet

The first calcium phosphate cements (CPCs) were discovered in the 1980s. Two decades later, the interest for these materials is still
rising. The goal of the present document is to review the most recent achievements in the field and to analyze future directions in
research and development.


New hydraulic cements based on a-tricalcium phosphate–calcium sulfate dihydrate mixtures

Marc Bohner

Calcium sulfate dihydrate (CSD) powder was added to a cement consisting of a-tricalcium phosphate (a-TCP) and water. The
changes ofthe physico-chemical properties of the cement were investigated as a function ofthe CSD amount, the phosphate
concentration in the mixing solution, and the solution volume. An increase ofthe phosphate concentration in the mixing liquid and
small additions ofCSD powder strongly reduced the cement setting time. Simultaneously, the fraction of unreacted a-TCP powder
present after 1 day of incubation increased, indicating that a-TCP hydrolysis was inhibited. The effects of the CSD amount and the
phosphate concentration were synergetic, i.e. the effect of CSD powder was increased with an increase of the phosphate
concentration and vice versa. Interestingly, none of the factors affected the cement diametral tensile strength. The present results
were explained based on solubility calculations. The present study shows that the use ofCSD crystals in combination with
phosphate ions is an easy and interesting way to control the setting time of a-TCP–water mixtures, in particular, because the
mechanical properties ofthe cement are not modified.

Theoretical model to determine the effects of geometrical factors on the resorption of calcium phosphate bone substitutes

Marc Bohner, F. Baumgart

A theoretical approach was used to determine the effect of geometrical factors on the resorption rate of calcium phosphate bone
substitutes that are either dense, microporous, and/or contain spherical macropores. Two cases were considered: (a) macroporous
blocks that can be invaded by resorbing cells either directly because the structure is fully open-porous, or indirectly after some
resorption of the macropores walls and/or interconnections. (b) Microporous or dense blocks/granules that cannot be invaded by
resorbing cells, i.e. can only be resorbed from the outside to the inside, layer by layer. The theoretical approach was based on five
assumptions: (i) the pores are spherical; (ii) the pores are ordered according to a face-centered cubic packing; (iii) the resorption is
surface-controlled; (iv) the resorption is only possible if the surface can be accessed by blood vessels of 50 mm in diameter; and (v) the
resorption time of a given amount of calcium phosphate is proportional to the net amount of material. Based on these assumptions,
the calculations showed that the resorption time of a macroporous block could be minimized at a specific pore radius. This pore
radius depended (i) on the size of the bone substitute and (ii) on the interpore distance. Typical radii were in the range of 100–
400 mm. These values are similar to the numerous pore size optima mentioned in the scientific literature. For microporous or dense
blocks/granules, the model suggested that a relatively small radius should be preferred. Such a radius leads to an optimum
combination of a high surface area favorizing resorption and the presence of large intergranular gaps favorizing blood vessel
ingrowth. In that case, the optimum of granule radius is around 100–200 mm. Finally, a very good agreement was found between the
predictions of the model and experimental data, i.e. the model explained in all but two cases the results with an accuracy superior to
80%. In conclusion, the model appears to be a useful tool to better understand in vivo results, and possibly better define the
geometry and distribution of the pores as well as the size of a bone substitute.


Theoretical and experimental model to describe the injection of a polymethylmethacrylate cement into a porous structure

Marc Bohner, B. Gasser, G. Baroud, P. Heini

A theoretical approach was used to determine the distribution of a poly(methylmethacrylate) cement after its injection into a
porous structure. The predictions of the model were then compared to experimental results obtained by injecting a
polymethylmethacrylate cement into an open-porous ceramic filter. The goal was to define a model that could predict what
factors affect the risk of cement extravasation and hence how the risk of cement extravasation can be minimized. The calculations
were based on two important rheological laws: the law of Hagen–Poiseuille and the law of Darcy. The law of Hagen–Poiseuille
describes the flow of a fluid in a cylindrical tube. The law of Darcy describes the flow of a fluid through a porous media. The model
predicted that the extravasation risk was decreased when the cement viscosity, the bone pore size, the bone permeability and the
bone porosity were increased, and when the diameter of the extravasation path and the viscosity of the marrow were decreased.
Experimentally, the effect of the marrow viscosity and extravasation path could be evidenced. Therefore, the model was believed to
be an adequate approximation of the experimental behavior. In conclusion, the experimental results demonstrated that the model
was adequate and that the best practical way to decrease the risk of extravasation is to increase the cement viscosity.

Compositional changes of a dicalcium phosphate dihydrate cement after implantation in sheep

Marc Bohner, F. Theiss, D. Apelt, W. Hirsiger, R. Houriet, G. Rizzoli, E. Gnos, C. Frei, J.A. Auer, B. von Rechenberg

A hydraulic calcium phosphate cement having dicalcium phosphate dihydrate (DCPD) as end-product of the setting reaction was
implanted in a cylindrical defect in the diaphysis of sheep for up to 6 months. The composition of the cement was investigated as a
function of time. After setting,the cement composition consisted essentially of a mixture of DCPD and b-tricalcium phosphate
(b-TCP). In the first few weeks of implantation,the edges of the cement samples became depleted in DCPD,suggesting a selective
dissolution of DCPD,possibly due to low pH conditions. The cement resorption at this stage was high. After 8 weeks,the resorption
rate slowed down. Simultaneously,a change of the color and density of the cement center was observed. These changes were due to
the conversion of DCPD into a poorly crystalline apatite. Precipitation started after 6–8 weeks and progressed rapidly. At 9 weeks,
the colored central zone reached its maximal size. The fraction of b-TCP in the cement was constant at all time. Therefore,this study
demonstrates that the resorption rate of DCPD cement is more pronounced as long as DCPD is not transformed in vivo.


Calcium orthophosphates in medicine: from ceramics to calcium phosphate cements

Marc Bohner

Calcium phosphate (Cal’) compounds are becoming of
increasingly great importance in the field of biomaterials
and, in particular, as bone substitutes. Recent discoveries
have accelerated this process, but have simultaneously
rendered the field more complicated for the
everyday user. Subtle differences in composition and
structure of CaP compounds may have a profound effect
on their in vivo behaviour. Therefore, the main goal
of this article is to provide a simple, but comprehensive
presentation of Cal’ compounds. Reference is made to
the most important commercial products.

Gentamicin-Loaded Hydraulic Calcium Phosphate Bone Cement as Antibiotic Delivery System


hydraulic calcium phosphate cement made of â-tricalcium
phosphate [â-Ca3(PO4)2], monocalcium phosphate monohydrate [Ca(H2-
PO4)2âH2O], and water was used as a delivery system for the antibiotic
gentamicin sulfate (GS). GS, added as powder or as aqueous solution,
was very beneficial to the physicochemical properties of the cement. The
setting time increased from 2 to 4.5 min with 3% (w/w) GS and then
slowly decreased to 3.75 min with 16% (w/w) GS. The tensile strength
increased from 0.4 to 1.6 MPa with 16% (w/w) GS. These effects were
attributed to the presence of sulfate ions in GS. The release of GS from
the cement was measured in a pH 7.4 phosphate-buffered saline solution
at 37 °C by USP paddle method. Factors such as cement porosity, GS
content and presence of sulfate ions or polymeric additives were
investigated. The amount of GS released was roughly proportional to
the square root of time up to 50% release. Afterwards, the release
rate markedly slowed down to zero. In all but two cement formulations,
the total dose of GS was released within 7 days, indicating that no
irreversible binding occurred between the cement paste and the antibiotic.
When small amounts of hydroxypropylcellulose or poly(acrylic acid) were
added to the cement, the maximum fraction released was a few percent
lower than the total GS dose, suggesting some binding between the
polymer and GS. The GS release rate was strongly influenced by the
presence of sulfate ions in the cement paste and by the cement porosity.
The higher the sulfate ion content of the cement paste, the lower the GS
release rate. This influence was attributed to the finer cement microstructure
induced by the presence of sulfate ions. Furthermore, when
the initial cement porosity was increased from 38 to 69%, the release
rate almost tripled (0.16 to 0.45 h-1/2). Finally, the biological activity of
GS in the cement was maintained, as measured by assaying the release

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