Elsevier

Acta Biomaterialia

Volume 50, 1 March 2017, Pages 1-19
Acta Biomaterialia

Review article
Critical review: Injectability of calcium phosphate pastes and cements

https://doi.org/10.1016/j.actbio.2016.11.019Get rights and content

Abstract

Calcium phosphate cements (CPC) have seen clinical success in many dental and orthopaedic applications in recent years. The properties of CPC essential for clinical success are reviewed in this article, which includes properties of the set cement (e.g. bioresorbability, biocompatibility, porosity and mechanical properties) and unset cement (e.g. setting time, cohesion, flow properties and ease of delivery to the surgical site). Emphasis is on the delivery of calcium phosphate (CaP) pastes and CPC, in particular the occurrence of separation of the liquid and solid components of the pastes and cements during injection; and established methods to reduce this phase separation. In addition a review of phase separation mechanisms observed during the extrusion of other biphasic paste systems and the theoretical models used to describe these mechanisms are discussed.

Statement of Significance

Occurrence of phase separation of calcium phosphate pastes and cements during injection limits their full exploitation as a bone substitute in minimally invasive surgical applications. Due to lack of theoretical understanding of the phase separation mechanism(s), optimisation of an injectable CPC that satisfies clinical requirements has proven difficult. However, phase separation of pastes during delivery has been the focus across several research fields. Therefore in addition to a review of methods to reduce phase separation of CPC and the associated constraints, a review of phase separation mechanisms observed during extrusion of other pastes and the theoretical models used to describe these mechanisms is presented. It is anticipated this review will benefit future attempts to develop injectable calcium phosphate based systems.

Introduction

Compounds of calcium phosphate (CaP) have been investigated as bone repair materials since 1920 [1]. However, they saw little use in clinical applications until the 1970s when CaP materials were used as bone substitutes in the form of porous blocks and granules [2], [3], [4]. The clinical potential of CaP materials further increased in the early 1980s with the development of self-setting calcium phosphate cement (CPC) [5]. In addition to its potential to mimic the mineral phase of bone, CPC has the ability to be moulded into bone defects and implant sites, then harden in situ to provide stability. This ability of CPC has shown great potential in percutaneous surgery whereby CPC is injected into the body to fill bone defects and stabilise fractures. Although CPC has shown clinical success in several orthopaedic applications requiring delivery by injection [6], [7], [8], [9], [10], [11], [12], it is thought that several issues currently prevent routine application in clinical applications. This has given rise to a high volume of studies aimed at improving the delivery of CPCs and broadening their clinical use [3].

Many of the studies attempting to optimise CPC for clinical applications focussed on improving the delivery of CPC to the surgical site through injection. A major issue inhibiting successful delivery of CPC is the occurrence of phase separation during injection. If phase separation occurs the extrudate has a higher liquid content than desired, which may cause extravasation from the surgical site and be detrimental to the final properties of the set CPC. The occurrence of phase separation during injection/extrusion of CaP pastes and cements, and methods to reduce it, is the principal focus of this review.

Due to the high volume of studies published concerning CPCs, review articles have proven useful in presenting a summary of recent advances, highlighting current issues and opportunities within CPC research. The focus of recent comprehensive reviews have included: processing techniques [13], mechanical performance [14], methods to reinforce CPCs [15], [16], the role of polymeric additives [17], in vivo degradation and resorption of CaP materials [18], influence of CaP material properties on cell behaviour [19], CaP materials as drug delivery systems [20], [21], [22], stem cell delivery via CPC [23], and the synthesis and application of nanostructured CaP based materials [24], [25], [26], in addition to broader overviews of recent progress in the development of CPC materials [27], [28], [29].

In this article established methods to reduce the phase separation of CaP pastes and cements and the limits of their application are reviewed. Brief discussions relating to the other crucial properties of CPC and their influencing parameters are also included as many established methods to reduce phase separation are detrimental to the other crucial properties, as evident throughout this review. Therefore, when optimising any property of CPC, it is important to consider all the crucial properties. In addition phase separation mechanisms observed during the injection or extrusion of other biphasic paste systems and the theoretical models used to describe these mechanisms are discussed. It is anticipated that including comparisons to work from fields outside of biomaterials will give a new perspective and a greater understanding of the phase separation mechanism of CPC during injection, which will benefit researchers attempting to optimise a fully injectable CPC.

Section snippets

Types of calcium phosphate cements

Due to the high level of interest and research into CPC, many different formulations of CPC have been developed. They can be divided into two principal groups: (1) apatite (hydroxyapatite, HA, and calcium-deficient HA, CDHA) and (2) brushite cements (dicalcium phosphate dihydrate, DCPD) [30]. Both apatite and brushite CPC are produced by mixing a powder component consisting of one or more calcium orthophosphates with an aqueous solution. The mixing of these two phases induces the dissolution of

Properties of calcium phosphate cement

When designing CPC for orthopaedic applications the properties of the unset and set cement require careful consideration to ensure clinical success. The hardened cement must be biocompatible and have sufficient mechanical integrity to stabilise the fracture or implant site. Ideally the hardened CPC should have a suitable composition and adequate porosity to be bioresorbed and replaced by host tissue. The cement prior to setting has to be easily prepared and handled during the surgical

Properties and delivery of unset calcium phosphate cement

The method by which the CPC is delivered to the surgical site, can directly impact the properties previously discussed in Sections 3.1 Bioresorbability and biocompatibility, 3.2 Porosity, 3.3 Mechanical properties. The unset CPC should be easily loaded into a syringe and injected into the body to the surgical site through a cannulated needle. The needles used in percutaneous surgeries such as PVP and BKP usually range from 13 to 8-gauge (internal diameters of 1.80–3.43 mm) [69] and from 100 to

Improving injectability of calcium phosphate cement

Phase separation of CPC is believed to be a result of high extrusion pressure relative to liquid filtration pressure [80]. Improvement methods would therefore include: (i) reducing the extrusion pressure, i.e. increasing the flowability (reducing the pressure required to cause the paste to flow), and (ii) increasing the pressure (PPS) required to force the liquid through the powder network (Eq. (4)), i.e. reducing the permeability (k) of the paste system.PPS=QμlLkAwhere Q and μl are flow rate

Theoretical consideration of injectability for calcium phosphate paste

Bohner and Baroud [80] applied a theoretical approach to investigate the effect of several variables on injectability of a CaP paste. They developed a model that combined the Hagen-Poiseuille equation (Eq. (6)), describing the flow of the CaP paste through a cannulated needle, and a derivative of Darcy’s law (Eq. (7)), representing the filtration of the liquid phase though the powder network:Pi=128μpLnQpπDn4where Pi is injection pressure, Ln and Dn are length and diameter of the needle, and Qp

Limitations of ‘injectability’ as a measurement

The model proposed by Bohner and Baroud [80] was the first attempt at relating important characteristics: namely, rheological and permeability properties and extrusion parameters of the paste system to injectability and phase separation of CaP materials. In doing so, Bohner and Baroud highlighted the lack of knowledge across these areas. Although dozens of investigations have been performed, the exact mechanism of phase separation and its effect on the permeability and flow properties of the

Permeability of calcium phosphate powders

Habib also investigated the correlation between injectability and permeability properties of CaP pastes [114]. Using the Blaine apparatus (ASTM C:204), Habib determined the permeability of β-TCP powders of various PSD [114]. To vary the PSD, finer plasma treated β-TCP and HA powders at various wt% were added to a commercial β-TCP powder. It was observed that decreasing voidage and increasing the wt% of fines (HA powder, 3 wt% max. and plasma treated β-TCP, 10 wt% max.) reduced permeability. To

Rheology of calcium phosphate pastes and cements

The rheological properties of dilute suspensions are relatively well understood. In contrast, concentrated suspensions and pastes with a relatively high SVF, such as CPC for orthopaedic applications, exhibit an apparent viscosity far higher than that of the liquid component due to complex particles interactions. The rheology of these materials have received less attention and are therefore less understood [115].

Due to the complexity and inherent heterogeneity of pastes it is difficult to obtain

Extrusion of pastes: Benbow-Bridgwater approach

Faced with the considerations outlined above, Benbow and Bridgwater [135] developed a semi-empirical approach to describe paste flow into and along a die that enables useful rheological parameters to be obtained from extrusion testing of pastes. The parameters obtained could be applied to other extrusion configurations, for design, as well as allowing the effect of extrusion conditions and paste formulation to be compared.

The model assumes the pressure (Pex) required to extrude the paste

Phase separation during extrusion of pastes

Phase separation is not limited to CaP based cements and pastes. It has also been encountered during extrusion of various biphasic pastes in the chemical, food and pharmaceutical sectors. Phase separation is not only detrimental to the quality of extrudate; it can also be very damaging to the extrusion system, depending on materials used and extrusion pressure. These factors have stimulated numerous investigations into how to reduce phase separation for all the above sectors. The approaches

Phase separation mechanism of calcium phosphate pastes and cements

Considering the different possibilities reviewed above, it is evident that knowledge of the phase separation mechanism is required when applying theoretical approaches to describe experimental observations. A better theoretical understanding is essential to enable efficient optimisation of CaP pastes and CPC systems and to fully satisfy clinical requirements for surgical applications requiring extrusion or injection.

When investigations into the injectability and phase separation of CaP pastes

Concluding remarks

CPC have seen clinical success in many dental and orthopaedic applications due to their ability to be moulded into bone defects and implant sites, then harden in situ to provide stability. However, there is limited clinical use of CPC in surgical applications requiring extrusion or injection due to their relatively poor injectability.

Poor injectability of CPC primarily arises from the separation of the solid and liquid phases during cement delivery from a syringe/cannulated needle arrangement,

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