calcium phosphate bone cements- chapter ginebra

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10Calcium phosphate bone cements

M.-P. G I N E B R A, Technical University of Catalonia (UPC), Spain

doi: ••

Abstract: Calcium phosphate cements (CPCs) are self-setting bioactive materials with unique properties for bone regeneration applications. The chapter fi rst describes CPCs and compares them to other orthopaedic cements widely used in clinics, such as acrylic cements. Subsequently, a brief overview of the chemistry of calcium phosphates is presented, together with a classifi cation of the main types of CPCs. The basic physico-chemical, mechanical and biological properties of CPCs are also reviewed and the technological issues most relevant to improving the clinical performance of CPC are described. Finally, the present and potential applications of these materials are discussed.

Key words: calcium phosphate cements, bone cements, bone regeneration, hydroxyapatite, bioceramics.

10.1 Introduction

This chapter focuses on calcium phosphate cements (CPCs), a family of materials that has great potential in bone regeneration, due to their unique properties of bioactivity, injectability and in vivo setting ability. In Section 10.2, a historical perspective is presented, and CPCs are defi ned and com-pared with other orthopaedic cements widely used in clinics, such as acrylic cements. Subsequently, a brief overview of the chemistry of calcium phos-phates is presented, necessary in order to understand the nature of the cementation reaction, together with a classifi cation of the main types of CPCs. Section 10.4 presents the basic properties of the CPCs, and these are compared with conventional high-temperature calcium phosphate ceramics, stressing the advantages of this family of materials. The technological issues relevant to improving the clinical performance of CPCs are the subject of Section 10.5. Another aspect that is also dealt with is the present and poten-tial applications of these materials, both as injectable or pre-set materials – such as bone cavity fi lling, vertebroplasty, scaffolds for tissue engineering or drug delivery. Finally, the new trends and research lines that these materi-als instigate are presented.

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Calcium phosphate bone cements 207

10.2 Historical overview: calcium phosphate cements

versus acrylic cements

When a surgeon uses the term ‘bone cement’ he often refers to acrylic bone cements, widely used in orthopaedic surgery since the 1960s, especially for arthroplasty fi xation.1,2 However, at the beginning of the 1980s a new family of bone cement emerged, namely the CPCs. In common with the acrylic bone cements, this new family could self-set inside the body, which allowed its implantation in a paste form. However, their chemical nature, properties and applications are very different, as summarised in Table 10.1, and described in the following sections.

CPCs are hydraulic cements, which means that water is used as the liquid phase of the cement, and their hardening is not due to a polymerisation reaction, but to a dissolution and precipitation process. Unlike acrylic bone

Table 10.1 Comparison of the nature and properties of acrylic bone cements versus calcium phosphate bone cements

Acrylic bone cementsCalcium phosphate bone cements

Material type Polymer Ceramic

Liquid phase Mainly methyl methacrylate Water or aqueous solutions

Powder component

Polymer beads (PMMA/copolymers)

Some inorganic non-reacting phase can be added as radiopaque agent

Calcium phosphate powders

Setting reaction mechanism

Polymerisation Dissolution and precipitation reaction

Reaction products

Mainly polymethyl methacrylate

Calcium phosphates, usually hydroxyapatite or brushite

Exothermic peak temperature during setting (ISO 5833)

50–90°C 37°C

Stability Non-resorbable Resorbable (low or high resorption rate depending on composition and microstructure)

Bioactivity Non-bioactive Bioactive

Applications Moderate load-bearing applications: arthroplasty fi xation, vertebroplasty

Bone regenerationNon load-bearing

applications


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208 Orthopaedic bone cements

cements, this reaction is not exothermic and therefore it does not evoke problems of necrosis by hyperthermia.3,4 Some of the salient features of CPCs are their excellent biocompatibility, bioactivity with the ability to form a direct bonding with bone, and osteoconductivity. In addition, they can be resorbable, with a resorption rate that depends on their composition and microstructural features. These features confer high bone regeneration potential. On the other hand, they have some limitations related to their poor mechanical properties and solubility. As with most ceramic materials, they are brittle and, in addition, due to the fact that they are intrinsically porous materials, their strength is in general lower than that of acrylic cements. This fact limits their use either to non-load-bearing applications, such as the treatment of maxillofacial defects or in load-bearing applica-tions in combination with metal implants, for example in the treatment of some fracture defects such as wrist fractures.

CPCs were discovered by Legeros5, and Brown and Chow6 in the early 1980s. They demonstrated the formation of hydroxyapatite in a monolithic form at room or body temperature by means of a cementitious reaction. This was an important breakthrough in the fi eld of bioceramics research, since it supplied a material that was mouldable, and therefore could adapt to the bone cavity, presenting a good fi xation and an optimum tissue–biomaterial contact, necessary for stimulating the bone ingrowth. Since then, CPCs have attracted much attention and different formulations have been put forward.6–10 Currently many commercial products exist on the market.11

10.3 Chemistry of calcium phosphate cements

In general, all CPCs are formed by a combination of one or more calcium orthophosphates, which upon mixing with a liquid phase, usually water or an aqueous solution, form a paste that is able to set and harden after being implanted within the body. The cement sets as a result of a dissolution and precipitation process, as represented in Fig. 10.1. The entanglement of the precipitated crystals is responsible for cement hardening.

Calcium orthophosphates are the calcium salts derived from orthophos-phoric acid. Their names, abbreviations, chemical formulae and Ca/P molar ratio are summarised in Table 10.2.12 Some of these calcium orthophos-phates can be obtained by precipitation from an aqueous solution at low temperature, while others can only be obtained at high temperature. All of them can be used as reactants for CPCs, and only those calcium orthophos-phates that can precipitate at low temperature in aqueous systems can be theoretically obtained as a result of the CPC setting reaction. However, despite the large number of possible formulations, the CPCs developed up to now have only two different end products, precipitated hydroxyapatite


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(PHA) or brushite (DCPD). This in fact is a predictable situation since hydroxyapatite is the most stable calcium phosphate at pH > 4.2 and brushite the most stable one at pH < 4.2.

The thermodynamics of calcium phosphate salts in an aqueous solution at room or body temperature are the basis for understanding the manufac-turing technology involved in CPCs for clinical applications. The solubility of the different compounds in the ternary system Ca(OH)2-H3PO4-H2O at 37°C is normally represented through solubility diagrams, where the iso-therms of different calcium phosphate salts in equilibrium with their satu-rated solution are plotted.13,14 In these diagrams either the calcium or the phosphate concentration in the saturated solution is represented in a loga-rithmic scale versus pH. It has to be taken into account that these diagrams are applicable to dilute or weakly supersaturated solutions, and CPCs consist of heavily supersaturated systems, far from equilibrium conditions. However, the application of these general concepts allows an understanding of the driving forces controlling dissolution and precipitation reactions, which are related to respective super- or under-saturation levels defi ned with regard to the thermodynamic solubility product.

In fact, in addition to thermodynamic factors,13,14 kinetic factors can control both phase dissolution and the precipitation of PHA, and can deter-mine the fi nal products obtained in a CPC setting reaction.15,16 This means that the thermodynamic conclusions that can be derived from the solubility and relative stability diagrams of the different calcium phosphates must be taken as a fi rst approximation, but never as an exhaustive explanation of what is actually happening during the setting reaction.

10.3.1 Apatite calcium phosphate cements

The relevance of hydroxyapatite as a bone substitute arises from the fact that the mineral phase of bone is precisely a hydroxyapatite. In this sense, it has to be clarifi ed that, even if stoichiometric hydroxyapatite has a fi xed

10.1 Rationale of a calcium phosphate cement.

Liquid

Cement

Powder

Plastic pasteSetting

Hardening

Rigid paste

Solid body

Dissolution

+

Precipitation

atphysiologicaltemperature


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composition, it is well known that the apatitic structure can exist in a range of compositions. Non-stoichiometric or calcium-defi cient hydroxyapatite (CDHA) can be obtained at low temperatures, with a composition that can be expressed as Ca10−x(HPO4)(PO4)6−x(OH)2−x, where x ranges from 0 to 1, being 0 for stoichiometric hydroxyapatite and 1 for fully calcium-defi cient hydroxyapatite. In fact, biological apatite is a carbonate containing calcium-defi cient hydroxyapatite, which in addition contains several other ionic substitutions such as Na+, K+, Mg2+, F− and Cl−.

Apatitic CPCs can form either PHA or CDHA through a precipitation reaction. Their fabrication process allows the incorporation of different ions in its lattice depending on the composition of the starting materials. In general it can be stated that the formation of hydroxyapatite through a cement-type reaction is a biomimetic process, in the sense that it takes place at body temperature and in a physiological environment, as happens when bone is formed or remodelled. This can account for the fact that the hydroxy-apatite formed in the setting of CPCs is much more similar to biological apatites than that obtained when high-temperature sintering processes are applied to fabricate ceramic hydroxyapatite.

The CPCs leading to the formation of PHA or CDHA can be classifi ed in three groups, taking into account the number and type of calcium phos-phates used in the powder mixture.17

1 Monocomponent CPCs, in which a single calcium phosphate compound hydrolyses to form PHA or CDHA. Since hydroxyapatite is the least soluble phase at pH > 4.2, this means that any other calcium phosphate present in an aqueous solution at that pH range will tend to dissolve, and PHA will tend to precipitate. As a result, H3PO4 or CaOH2 can be released into the solution as a by-product of the hydrolysis reaction. However, in most cases the formation of PHA from the hydrolysis of one calcium phosphate is kinetically very slow, due to a decrease of the super-saturation level, as the reaction proceeds.13 The only cement system that contains a single calcium phosphate was fi rst reported by Monma et al.18,19 and was further optimised and characterised by Ginebra el al.20–25 This system is based on the hydrolysis of α-tricalcium phos-phate (TCP) to CDHA according to equation [10.1]:

3α-Ca3(PO4)2 + H2O → Ca9(HPO4)(PO4)5(OH) [10.1]

Since the Ca/P ratio of the initial and fi nal calcium phosphates is the same, no acid or base is released as by-products.

2 CPCs formed by two calcium phosphates, one acidic and the other one basic, which set following an acid–base reaction. The basic component is normally tetracalcium phosphate (TTCP), since it is the only calcium phosphate having a Ca/P ratio higher than PHA. Therefore, TTCP can



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be combined with one or more calcium phosphates with lower Ca/P ratio to obtain either PHA or CDHA, without the formation of acids or bases as by-products. From a theoretical point of view, any calcium phosphate more acidic than PHA can react directly with TTCP to form PHA or CDHA. The most widely studied combinations are in fact the TTCP + DCPD and TTCP + dicalcium phosphate (DCP) mixtures, which were fi rst developed by Brown and Chow6,26 and have been the object of extensive research.15,16,27–30 These mixtures produce cements that set at body temperature in a pH range around neutral, according to equations [10.2] and [10.3].

Ca4(PO4)2O + CaHPO4 → Ca5(PO4)3OH [10.2]

Ca4(PO4)2O + CaHPO4·2H2O → Ca5(PO4)3OH + 2H2O [10.3]

3 Systems formed by more than two compounds, including calcium phos-phates, and other salts, for example calcium or strontium carbonate, magnesium phosphates among others. An example of this group of CPCs is the product developed by Norian Corporation (Norian SRSTM, Skeletal Repair System),31 where mixtures of calcium phosphates with a Ca/P ratio lower than PHA are used and CaCO3 is added as an addi-tional source of calcium ions. Specifi cally this system is formed by using a mixture of α-TCP, monocalcium phosphate monohyarate (MCPM) and CaCO3. The initial setting process involves the formation of DCPD, while the fi nal setting product is dahllite, a carbonated hydroxyapatite with a Ca/P ratio between 1.67 and 1.69, and with a carbonate ion content similar to bone mineral.31

10.3.2 Brushite calcium phosphate cements

Brushite (DCPD) is an acidic calcium phosphate that has been detected in some physiological sites, for instance in bone,32 fracture callus33 and kidney stones.34 In contrast to hydroxyapatite, brushite is metastable under physi-ological conditions,15 and for this reason brushite CPCs resorb much faster than apatite CPCs, although it has been shown that in vivo DCPD tends to convert into PHA.35 Some CPCs have been designed that give brushite (DCPD) as the end-product. All brushite CPCs are obtained as a result of an acid–base reaction. Several compositions have been proposed for brush-ite cements, e.g. β-TCP + MCPM,36 β-TCP + H3PO4,37,38 and TTCP + MCPM + CaO.35 In the fi rst of these (β-TCP + MCPM), the reaction responsible for the setting of the cement is

β-Ca3(PO4)2 + Ca(H2PO4)2·H2O + 7H2O → 4CaHPO4·2H2O [10.4]

The paste of brushite CPC is acidic during setting because brushite can only precipitate at a pH values lower than 6.12 After setting, the pH of the cement


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paste slowly changes towards the equilibrium pH, which depends on the singular points of the phases present in the cement.39

10.4 Basic properties of calcium phosphate cements

In the late 1960s and early 1970s, the quest for improved biocompatibility of implant materials resulted in a new concept of bioceramic materials that would mimic natural bone tissue.40,41 Because hydroxyapatite, a naturally occurring ceramic mineral, is also the mineral component of bone, it was believed that synthetic hydroxyapatite used for bone replacement would be entirely compatible with the body. It was subsequently shown that these materials were bioactive materials, i.e. they were able to develop a direct bonding with bone, without the formation of a fi brous capsule. Therefore, they were osteoconductive materials, able to guide bone ingrowth on their own surface.

Since then, ceramic calcium phosphates have been used, mainly in the form of sintered hydroxyapatite (SHA) or β-TCP ceramics, as materials for cavity fi lling for bone regeneration, or even as coatings for metallic pros-theses. However, their fabrication method, usually sintering at high tem-perature, represented a signifi cant drawback since it limited the formability of their shape and size. This often caused problems of adaptation and fi xa-tion to the bone cavity where they had to be placed.

The development of CPCs at the beginning of the 1980s brought to light several advantages in comparison with the use of ceramic calcium phos-phates. These can be summarised as follows:

(a) in vivo self-setting ability;(b) injectability, which allows cement implantation by means of minimally

invasive surgical techniques, less aggressive than the traditional surgical techniques;

(c) perfect fi t at the implant site, which assures good bone–material contact, even in geometrically complex defects; this allows for an optimum tissue–biomaterial contact, necessary for stimulating bone ingrowth;

(d) reaction products chemically and structurally more similar to the bio-logical hydroxyapatite (in the case of apatite cements) due to the fact that the setting reaction is a low-temperature dissolution–precipitation process; this contributes to an increased reactivity of CPCs as compared with calcium phosphate ceramics;

(e) the possibility of incorporating different drugs – given the fact that the setting reaction takes place at low temperature, from antibiotics and anti-infl ammatory drugs to growth factors which are able to stimulate certain biological responses.


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10.4.1 Processing parameters

The properties of a cement system depend on, and therefore can be tailored by, several processing parameters, which are summarised in Table 10.3. The composition of the solid phase varies with the setting reactions desired. Normally, the solid phase is chosen from the orthophosphate family, listed in Table 10.2. On the other hand, those calcium orthophosphates containing biocompatible components such as Na+, K+, Mg2+, Zn2+, CO3

2−, SO42− or Cl−

are also suitable as constituents of CPC powders, and calcium carbonate is also added in some formulations.

The particle size of the starting powder plays an important role in the setting and fi nal properties of the cement. As mentioned before, the setting reaction occurs through a dissolution–precipitation process. Hence, fi neness of the powder will increase the rate of hardening since smaller particles will dissolve faster than bigger particles and the precipitation of a new phase will begin earlier.25

Another strategy that can be used to produce cement with good setting characteristics is the use of seed crystals to act as a ‘nucleator’ for the pre-cipitation reaction. Several parameters can be modifi ed, such as the amount of seed added, its crystallinity and crystal size. Although the effects of seeds under different conditions have not been entirely clarifi ed, it seems that their main effect is to reduce the setting time of the cement.

The primary role of the liquid phase is to function as a vehicle for dissolu-tion of the reactants and precipitation of products. The liquid phase in CPCs is always water or an aqueous solution. Water solutions ranging from plain water to simulated body fl uid have been used. In some cases, some soluble phosphate salts such as NaH2PO4 and/or Na2HPO4 are added as a source of phosphate ions in solution, because it is known that common ions can

Table 10.3 Processing parameters that affect the properties of a calcium phosphate cement

Powder phase Chemical composition Relative proportion of the constituentsAdditives (seeds, acelerants, retarders, etc.)Particle size distribution of the powder

Liquid phase Additives (acelerants, retarders, cohesion promoters)pH

Mixing parameters Liquid/powder ratioMixing protocol (time, speed, etc.)

Environmental factors TemperatureHumiditypH


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have an accelerating effect on the setting reaction.42 Therefore, neutral salts dissolved in the liquid phase can be used to shorten the setting time exhib-ited by the cement, for instance in apatitic cements.23 In some cases, water-soluble polymers can be added with the scope of modifying the cohesion of the cement paste or its rheological properties.

The liquid/powder ratio is a factor that affects the initial plasticity of the paste and consequently its injectability and setting times. In addition, the fi nal strength is affected by this parameter since the porosity of the set specimen is directly correlated to the liquid/powder ratio used. Therefore, reducing the liquid/powder ratio within the limits of workability would be a means of improving the strength of CPCs.

Several properties must be taken into account in relation to the applica-bility of the CPCs as bone substitutes. Among them, we can mention the setting and cohesion times, the injectability, the hardening rate, the mechan-ical strength and the pH evolution during setting. All of these properties depend on the composition and the processing parameters that are chosen for each formulation.

10.4.2 The setting time of calcium phosphate cements

The time required for the initial setting of the cement paste, which is refl ected in a loss of plasticity, is called the setting time. Usually it is mea-sured following mechanical methods, as a quick way of determining whether a reaction occurs upon making a paste of the mixture of reactants with water. The most common methods are based on the assessment of the ability of the cement paste to resist a mechanical load applied to its surface. Two examples are the Vicat needle and the two Gillmore needles. In the fi rst, a single needle is applied on the cement surface. The rationale for the two Gillmore needles, as proposed by Ginebra et al.22 is that with the light-and-wide needle one can measure the initial setting time, which indicates the end of mouldability, without serious damage to the cement structure, whereas with the heavy-and-fi ne needle one can measure the fi nal setting time, beyond which it is possible to touch the cement without causing serious damage. As far as clinical applications are concerned, the proposed ranges were 4 min < I < 8 min for the initial setting time, I, and 10 min < F < 15 min for the fi nal setting time, F.22

In general, setting times of apatite CPCs are too long and several strate-gies have to be applied to reach the clinical requirements.43 Among the parameters that can be adjusted to accelerate the setting of apatitic cements are: (a) the liquid/powder ratio (a smaller amount of liquid reduces the setting time); (b) the reduction of the powder size (smaller size leads to shorter setting time); (c) the addition of calcium or phosphate ions either pre-dissolved in the liquid phase or as highly soluble salt (common ion


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effect: the higher the concentration, the shorter the setting time); (d) the addition of seed materials, which act as crystal nuclei (the greater the number of nuclei, the shorter the setting time).

On the other hand, brushite CPCs tend to set too fast. The setting time of brushite CPCs is controlled by the solubility of the basic phase: the higher the solubility, the faster the setting time.36 In brushite CPCs setting retarders are often used, and a common approach to increase the setting time is the addition of inhibitors of DCPD crystal growth.44

10.4.3 Cohesion time

CPCs are materials designed to be implanted while in a paste state. This means that the paste is in contact with blood or other physiological fl uids. Cohesion can be defi ned as the capacity of a CPC to set in a fl uid without disintegrating. It has to be clarifi ed that, in fact, several terms have been used to describe this property – such as non-decay ability, anti-washout, compliance, swelling or stability – and some studies have been devoted to this topic.45–51 In general this property has been evaluated by an immersion test in water, Ringer’s solution or simulated body fl uid. The addition of some water-soluble polymers has been proven to be very effective in enhancing the cohesion of CPC pastes.48,49

However, the approach is very empirical, and in fact there is a need for more understanding of the underlying mechanisms concerning cohesion. It is indeed an important topic since if a CPC has no cohesion at all it will not be able to form a solid body when implanted, or, in the case of poor cohe-sion, calcium phosphate particles can be released, which can elicit harmful reactions such as infl ammation or blood clotting.50,51

10.4.4 Injectability

The ability to inject the cement in the surgical site is an important property since it can minimise surgical invasion and allow for complex-shaped defects to be fi lled adequately. Although all CPCs are mouldable materials, not all of them can be injected, since in some formulations the viscosity of the paste is too high. The injectability of a CPC paste can be defi ned as its ability to be extruded through a needle without demixing. This will, of course, depend on the diameter and length of the needle (2 mm diameter and 10 mm length can be illustrative values).52 A common problem with CPC injection is demixing or fi lter pressing, which occurs when the mixing liquid separates from the powder phase, i.e. it is expelled through the needle without the CaP particles. Khairoun et al.53 defi ned an injectability coeffi cient as the percentage by weight of the amount of a CPC paste that could be extruded from a syringe with respect to the total mass of the cement introduced in the syringe, when it was extruded at a compression rate of 15 mm min−1 up


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to a maximum force of 100 N. Injectability depends on the rheological properties of the paste. The characterisation of the rheological properties of CPCs is a complex issue, since they have transient rheological properties due to the setting reaction that is taking place from the beginning of the mixing of the liquid and the powder.54 There are several ways of modifying the viscosity of a CPC paste, which in turn will affect its injectability. The most relevant are the liquid/powder ratio, the particle size of the powder phase and the addition of ionic and non-ionic additives. For example, some studies have been performed on the effect of citric acid and its salts on the rheological properties of CPCs.55,56 Citric acid and sodium citrate have been shown to make the surface charge of the particles more negative, acting as a dispersant of the paste and acting as a liquefying agent. This allows a reduction in the amount of water used in the cement, and therefore signifi -cantly decreases the porosity and improves the mechanical properties. Another approach is based on the addition of soluble polymers, such as polysaccharides – i.e. sodium alginate, sodium hyaluronate or chondroitin sulphate11,50,57 – or even some polymeric drugs.58

10.4.5 Microstructure and porosity

Chemically, the setting reaction of a CPC consists of fi rstly the dissolution of one or more constituents of the cement powder and secondly the pre-cipitation of a different calcium phosphate. Physically, it takes place by the entanglement of the crystals of the precipitating calcium phosphate. A precipitation reaction will only lead to considerable strength in these materials on the following two conditions: (a) the precipitate grows in the form of clusters of crystals that have a fair degree of rigidity and (b) the morphology of the crystals of the precipitate enable the entanglement of the clusters.43

It is interesting to note that, in fact, as previously mentioned, many apa-titic cements involve a reaction in water between acidic dicalcium phos-phates (DCP or DCPD) and basic TTCP or α-TCP. No water is consumed during the setting of these CPCs, as can be seen in equations [10.2] and [10.3], and liquid is required only to make the reactants workable and to allow a homogeneous reaction. In other cases, when a hydration reaction takes place (see for instance equation [10.1]), some water is consumed, but much less than the total amount added to make a workable paste. Hence, water is a major contributor to the origin of porosity in this system, and therefore CPCs are intrinsically porous materials. Figure 10.2 shows the microstructure of an apatitic cement after setting and it can be clearly seen that CPCs develop a highly micro-/nanoporous structure. The porosity of the set CPCs is closely related to the liquid/powder ratio used, and it nor-mally varies between 30% and 50%, although even higher values can be reached. The pores are normally micro- or nanometric in size, and the par-


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ticle size distribution of the starting powder can modify the size of the pre-cipitated crystals, and also the pore size distribution.25 A typical pore size distribution diagram of an apatitic CPC obtained by Hg-porosimetry is shown in Fig. 10.3.

10.4.6 Mechanical strength

For adequate performance of CPCs as biomaterials, some physical proper-ties such as compressive strength, diametral tensile strength and fracture

10 μm

10.2 Scanning electron microscopy image showing the microstructure of an apatitic cement after setting. Scale bar corresponds to 10 μm.

0.6

0.5

0.4

dV/d

log D

0.3

0.2

0.1

00.001 0.01 0.1 1

Entrance pore diameter (μm)

10 100 1000

10.3 Hg-porosimetry diagram of an apatitic CPC after setting. The starting powder consists of α-TCP and the liquid/powder ratio is 0.35 ml/g, showing open porosity centred around 10 nm, and pore size below 0.5 μm. This CPC had a total porosity of 32%. dV/d log D is the log differential intrusion volume versus diameter.


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toughness may be important. The main mechanical property has been described to assess the quality of CPCs is the compressive strength.59 Since these materials are conceived as bone substitutes, it is important to keep in mind as reference values that, according to different studies, the compres-sive strength of human cortical bone ranges between 90 and 209 MPa,60,61 and that of the cancellous bone ranges between 1.5 and 45 MPa.62

Owing to the intrinsic porosity of CPCs, their strength is lower than that of calcium phosphate ceramics.13 The liquid/powder ratio, the particle size of the reactants, the crystallinity and amount of seed, and the use of liquid accelerators are factors that affect the strength of the CPCs. A wide range of values can be found in the literature, depending on the composition and processing parameters, and it is diffi cult to make comparisons between them due to a lack of consistency in specimen dimensions, testing protocols and sample pre-treatments. As indicative values, the compressive strength of apatite cements normally ranges between 20 and 50 MPa,8,20,25,46–49 although lower and higher values for some formulations have also been reported.63 The compressive strength of some commercial formulations of apatitic CPCs are summarised in Table 10.4. Brushite CPCs are in general weaker than apatite CPCs and compressive strengths of 25 MPa have been reported.64

Different models have been proposed to describe the strength depen-dence on porosity, in ceramics. Among them, Ryshkewitch65 claimed that strength varies as an exponential function of porosity, as described by

s = s0 exp(−bP) [10.5]

Table 10.4 Compressive strength of some commercial apatitic calcium phosphate cements

Cement name Company Powder composition

Compressive strength (MPa)

α-BSM ETEX ACP, DCPD 12Biopex Mitsubishi

materialsα-TCP, TTCP, DCPD, HA 60–90

Cementek Tecknimed α-TCP, TTCP, Na-glycerophosphate

15–25

Calcibon Biomet α-TCP, DCP, CaCO3, PHA 60Mimix Biomet TTCP, α-TCP, C6H5O7Na3·2H2O 24Mimix QS Biomet — 22Norian SRS Synthes-Norian α-TCP, CaCO3, MCPM 50Norian CRS Synthes-Norian — 30


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where s is strength, s0 is strength at zero porosity, P is porosity and b is a parameter characteristic of each material. This model was fi tted to the compressive strength of apatitic CPCs with different liquid/powder ratios,66 and a value of 408 MPa was obtained for s0, which is in good agreement with the compressive strength reported in the literature for dense, sintered hydroxyapatite.67

The reduction of porosity in CPCs has been explored as a way of increas-ing their strength. Reducing the amount of added water and improving particle packaging can reduce the porosity of the cements. Compaction of the cement paste during setting has been demonstrated to increase the compressive strength of apatitic CPCs,68–70 and values as high as 118 MPa have been reported.70 The addition of water-reducing or liquefying agents, such as sodium citrate, allows for a further densifi cation of the paste and compressive strength values of 180 MPa in wet conditions have been reported.70 However, it has to be considered that this compaction cannot be applied if the cement is implanted or injected within the bone tissue, and therefore at present it can be used only to fabricate pre-set substrates or scaffolds for bone regeneration. A two-step protocol, including pre-compaction of a paste followed by a conventional application has been suggested as an alternative for potential clinical use.70

The evolution of the strength of the CPC after implantation has also been studied. The mechanical properties of apatite CPCs are reported to increase,71 while those of brushite CPCs tend to decrease72 due to the higher solubility of DCPD compared with that of PHA. Only after a few weeks of implantation, when bone growth is signifi cant, do the mechanical properties of brushite CPCs increase.72

10.4.7 In vivo behaviour

Since their discovery, numerous studies have been devoted to the charac-terisation of the in vivo behaviour of CPCs, showing that that they are highly biocompatible and osteoconductive materials, which can stimulate tissue regeneration.8,35,73–82 Most of the apatitic cements are resorbed via cell-mediated processes. In these processes osteoclastic cells degrade the materials layer by layer, starting at the bone–cement interphase throughout its inner core. The biodegradability of apatite CPCs is greater than that of sintered hydroxyapatite, but it is still slow. It has been shown for instance that some CPCs could remain for as long as 78 weeks when implanted in dog femurs.78 There are several factors that affect the degradation rate of apatitic CPCs, with the crystallinity of the PHA being especially relevant, and also the specifi c surface area and the porosity of the set cement. One strategy proposed in recent years in a bid to accelerate resorption of apatite


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CPCs is the incorporation of macroporosity, and this will be described in the next section.

Brushite CPCs are resorbed much faster than apatitic cements,79–81 owing to the fact that brushite is metastable in physiological conditions. However, it has been reported that brushite CPCs tend to transform to PHA in vivo, this transformation reducing its overall degradation rate. The addition of magnesium salts can be used to avoid, or at least delay, this transformation.82

10.5 Applications of calcium phosphate cements:

present and future perspectives

10.5.1 Present applications

The fi rst commercial apatitic CPCs were introduced in the market in the 1990s, and subsequently brushite cements were also commercialised. They are used for different bone regeneration applications, such as: (a) maxillo-facial and craniofacial reconstruction (cranioplasty, cranial recontouring, cranial fl ap augmentation, augmentation genioplasty, on-lay grafting, skull base defect repair);83 (b) treatment of several fracture defects – such as distal radius, proximal and distal tibia, calcaneus, proximal and distal femur, proximal humerus, acetabulum;84 (c) treatment of surgically or traumati-cally created osseous defects, fi lling of cystic lesions and augmentation of screws; (d) more recently, they are being used for the treatment of spinal fractures and vertebroplasty (with or without the aid of a kyphoplasty balloon).85–87

10.5.2 Macroporous calcium phosphate cements

As mentioned in Section 10.4.7, although apatitic cements have the ability to slowly be replaced by bone, one of the weaknesses in their clinical per-formance is their slow rate of resorption. The introduction of macroporosity in CPCs is envisaged as a method to facilitate bone ingrowth not only from the external surface but throughout the whole bulk of the material. This would accelerate its resorption and its transformation in newly formed bone tissue. Presently, two different strategies have been adopted to introduce macroporosity in CPCs. The fi rst approach aims to produce the macropores after the setting of the cement. Different porogenic agents have been sug-gested, which are added within the CPC paste and, after the setting, degrade faster than the cement itself, creating the macroporosity; for example, sugars,88,89 PLA fi bres or particles90,91 or frozen sodium phosphate solution particles.92 However, it is necessary to add a large amount of porogenic


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agent to guarantee interconnectivity of the porosity, thus compromising the excellent bioactivity and biocompatibility of CPCs. In a second approach, macroporosity is created before the setting of the cement. The cement paste is foamed while it has a viscous consistency, and on setting a solid macro-porous construct is created. The macroporosity can be produced by two main routes: (a) the addition of some gas-generating compounds, such as hydrogen peroxide93 or sodium bicarbonate,94–96 although it has to be taken into account that the liberation of gas after the implantation of the cement paste could have harmful effects for the organism; (b) the use of biocompat-ible foaming agents.97,98 This last approach has allowed the development of injectable macroporous CPCs, which maintain the macroporosity after injection.97 Figure 10.4 shows the macroporous structure of a foamed CPC. In vivo studies have shown that this strategy can be effective in accelerating the resorption of CPCs.98

10.5.3 Pre-set granules and bone tissue engineering scaffolds

CPCs can be used to fabricate pre-set granules and blocks, which can have some advantages in comparison with ceramic granules or blocks. The advan-tages arise from the low-temperature and wet processing method intrinsic to CPCs. Indeed, the apatite CPCs products are micro-/nanocrystalline and have high specifi c surface area, and therefore are much more reactive than sintered ceramics. In addition CPCs enable the fabrication of low-temperature calcium phosphates – such as DCPD, octacalcium phosphate

1 mm

10.4 Scanning electron microscopy image of a macroporous CPC. Scale bar corresponds to 1 mm.


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(OCP) or CDHA – which cannot be obtained by high-temperature sinter-ing, and which are much more close to the calcium phosphates found in living tissues.

In this context, CPCs have been used to fabricate pre-set hydroxyapatite porous blocks to act as scaffolds for guiding in vitro or in vivo tissue regen-eration, which in fact is one of the main goals of tissue engineering.92,93 These three-dimensional macroporous constructs satisfy several requirements, such as osteoconductivity, adequate mechanical properties, formability and high interconnected macroporosity to ensure cell colonisation and fl ow transport of nutrients and metabolic waste. In addition, the apatite foams combine the interconnected macroporosity with the intrinsically high micro-/nanoporosity of CPCs.93 Recently it has also been shown that CPCs can be used in rapid prototyping techniques, and specifi cally low-temperature three-dimensional powder printing can be used to fabricate calcium phosphate structures with simultaneous control of geometry and organic molecule incorporation in three dimensions.99

10.5.4 Drug delivery

Although most drug-delivery materials are polymeric in nature, calcium phosphate-based materials have an added value owing to their bioactive character in the specifi c fi eld of the pharmacological treatment of skeletal disorders. Moreover, another important property of calcium phosphates is their unique ability to adsorb different chemical species on their surfaces. This property has been exploited in hydroxyapatite chromatography, which has proved to be very effi cient for the purifi cation and separation of pro-teins, enzymes, nucleic acids and other macromolecules. This great affi nity of hydroxyapatite for these various active molecules can extend the applica-tion of CPCs not only as bone substitutes, but as carriers for local and con-trolled supply of drugs in the treatment of different skeletal diseases – such as bone tumours, osteoporosis or osteomyelitis – which normally require long and painful therapies.100

Unlike calcium phosphate ceramics employed as drug-delivery systems, where the drugs are usually absorbed on the surface, in CPCs the drugs can be incorporated throughout the whole material volume, by adding them into one of the two cement phases. This fact can facilitate the release of drugs for a more prolonged period. Certain factors need to be taken into consideration with reference to the incorporation of drugs in CPC cements. In the fi rst instance, it is necessary to verify that the addition of the drug (either to the liquid or the solid phases of the cement) does not interfere with the setting reaction, modifying the physico-chemical properties, not only in terms of the setting and hardening mechanisms, but also with respect to the rheological behaviour. Secondly, it is necessary to characterise the


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kinetics of drug release in vitro. Subsequently, the effectiveness of the cement in acting as a carrier for drug delivery in vivo, must be assessed. Finally, the clinical performance of the drug-delivery system must be evalu-ated. To date, the fi rst three factors have been extensively studied, but the application of CPCs as drug-delivery systems has not yet reached clinical applications.

Over the last decade, several studies related to the application of both commercial and experimental CPCs as drug carriers have been published.101 Major attention has been paid to antibiotics, due to their wide area of application: either as prophylactics to prevent infections produced during surgical interventions, or in general in the treatment of bone infections. Other types of drugs incorporated in cements include anti-infl ammatory drugs and anticancer drugs, and even hormones have been studied. In recent years the inclusion of growth factors that are able to stimulate bone regeneration, such as bone morphogenetic proteins (BMPs) or transform-ing growth factor β (TGF-β) have been considered for controlled delivery from CPC cements.

The research that has been carried out in the past, especially the in vitro studies, has highlighted the great potential of CPCs as carriers for con-trolled release and vectoring of drugs in the skeletal system. However, the industrial use of CPCs for drug delivery is not yet a reality, and in fact two main underlying problems can be identifi ed. First, implant companies selling CPCs do not generally have the expertise to deal with drugs, and pharma-ceutical companies do not have any expertise with CPCs. Secondly, infec-tions are not always produced by the same microorganisms and, therefore, it would be necessary to design versatile systems that could combine a given CPC with many different drugs, in such a way that the surgeon could choose the drug just before implantation. However, as mentioned previously, various drugs have various effects on CPC properties, and this represents a serious drawback for the implementation of the technology. Therefore, a lot of work has still to be done to be able to adjust the use of CPCs to different therapeutical needs and to obtain reproducible and predictable drug-delivery systems.

10.6 References

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