J O U R N A L O F T H E M E C H A N I C A L B E H AV I O R O F B I O M E D I C A L M AT E R I A L S

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Review article

Fibre-reinforced calcium phosphate cements: A review C. Canal, M.P. Ginebra ∗ Biomaterials, Biomechanics and Tissue Engineering Group, Department of Materials Science and Metallurgical Engineering, Technical University of Catalonia (UPC), Av. Diagonal 647, 08028 Barcelona, Spain Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Maria de Luna 11, Ed. CEEI, 50118 Zaragoza, Spain

A R T I C L E

I N F O

A B S T R A C T

Article history:

Calcium phosphate cements (CPC) consist of one or more calcium orthophosphate pow-

Received 23 April 2011

ders, which upon mixing with water or an aqueous solution, form a paste that is able to set

Received in revised form

and harden after being implanted within the body. Different issues remain still to be im-

18 June 2011

proved in CPC, such as their mechanical properties to more closely mimic those of natural

Accepted 23 June 2011

bone, or their macroporosity to favour osteointegration of the artificial grafts. To this end, blends of CPC with polymer and ceramic fibres in different forms have been investigated. The present work aims at providing an overview of the different approaches taken and

Keywords:

identifying the most significant achievements in the field of fibre-reinforced calcium phos-

Calcium phosphate cement

phate cements for clinical applications, with special focus on their mechanical properties. c 2011 Elsevier Ltd. All rights reserved. ⃝

Fibres Yarns Textile laminar structures Composites Bone substitutes Reinforcement

Contents 1.

Introduction .................................................................................................................................................................................

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2.

General considerations for the design of fibre-reinforced cements...............................................................................................

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3.

CPC composites with non-resorbable fibres..................................................................................................................................

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3.1.

3.2.

Polymer fibres: polyamides ................................................................................................................................................

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3.1.1.

Polyamide 6.6........................................................................................................................................................

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3.1.2.

Aramide................................................................................................................................................................

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Ceramic fibres ....................................................................................................................................................................

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Abbreviations: CPC, calcium phosphate cement; DCPA, dicalcium phosphate anhydrous, CaHPO4 ; DCPD, brushite, dicalcium phosphate dihydrate CaHPO4 ·2H2 O; HA, hydroxyapatite, Ca10 (PO4 )6 (OH)2 ; α-TCP, alpha tricalcium phosphate, α-Ca3 (PO4 )2 ; β-TCP, betatricalcium phosphate, β-Ca3 (PO4 )2 ; TTCP, tetracalcium phosphate, Ca4 (PO4 )2 O; PLA, polylactide; PLLA, poly-L-lactide; PGA, polyglycolide; PLGA, poly (lactide-co-glycolide); PCL, poly-ε-caprolactone; PA, polyamide. ∗ Corresponding author at: Biomaterials, Biomechanics and Tissue Engineering Group, Department of Materials Science and Metallurgical Engineering, Technical University of Catalonia (UPC), Av. Diagonal 647, 08028 Barcelona, Spain. E-mail address: [email protected] (M.P. Ginebra). c 2011 Elsevier Ltd. All rights reserved. 1751-6161/$ - see front matter ⃝ doi:10.1016/j.jmbbm.2011.06.023

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J O U R N A L O F T H E M E C H A N I C A L B E H AV I O R O F B I O M E D I C A L M AT E R I A L S

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3.2.1.

Carbon fibres ........................................................................................................................................................

3.2.2.

Glass fibres ...........................................................................................................................................................

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Calcium phosphate cement composites with resorbable fibres ....................................................................................................

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4.1.

Polylactide (PLA) ................................................................................................................................................................

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4.2.

Polyglycolide/polylactide copolymers ................................................................................................................................ 10

4.3. 5.

(

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4.2.1.

PLGA fibres ........................................................................................................................................................... 10

4.2.2.

PLGA fibres with other additives........................................................................................................................... 10

4.2.3.

PLGA laminar structures....................................................................................................................................... 11

Poly-ε-caprolactone............................................................................................................................................................ 11

Conclusions .................................................................................................................................................................................. 12 Acknowledgments ........................................................................................................................................................................ 12 References .................................................................................................................................................................................... 12

1.

Introduction

Calcium phosphate cements (CPC) are able to harden in vivo, through a low-temperature setting reaction. The products formed in this setting reaction have many similarities with the mineral phase that constitutes 70 wt% of the bone tissue. However, their mechanical properties are far from those of the cortical or even the cancellous bone. Not only in terms of strength, but especially in terms of toughness, ductility and fatigue resistance. The similitude of CPC with the bone mineral arises from their origin. Both are obtained by precipitation in aqueous solutions at physiological temperature. When set, CPC consist of a network of calcium phosphate crystals, with a chemical composition and crystal size that can be tailored to closely resemble the biological hydroxyapatite occurring in living bone (Morgan et al., 1997; Ginebra et al., 2010). A number of CPC formulations are currently available. They consist of mixture of one or several calcium phosphate powders with water or an aqueous solution. Either hydroxyapatite (HA: Ca10 (PO4 )6 (OH)2 ) or brushite (dicalcium phosphate dihydrate; DCPD: CaHPO4 .2H2 O) can be formed in the cement setting reaction. One of the main advantages of CPC is their in vivo hardening ability. Bone defects can be reconstructed by filling with CPC mouldable pastes, which in some instances can be injected in the surgical site by minimally invasive surgical procedures (Ginebra et al., 2001; Ishikawa, 2008), with significant benefits for several clinical situations such as the treatment of osteoporosis related fractures, unstable fractures, maxillofacial defects and deformities, and more recently for other specific applications such as vertebroplasty (Lewis, 2006). Moreover, the possibility of loading them with drugs or growth factors has open new perspectives in their application as drug delivery systems (Ginebra et al., 2006). However, their poor mechanical performance has limited their applicability to non-stress-bearing applications. Their compressive strength, when no pre-compaction is applied, ranges from 10 to 90 MPa (Ginebra, 2008), the apatitic cements being stronger than brushite cements. These values overcome those of trabecular bone, which range between 1.5 and 45 MPa (Carter and Hayes, 1977), or fall in the lower range of the compressive strength of cortical bone, that varies between 90 and 209 MPa (Ontañón et al., 2000; Burstein et al., 1977). Nonetheless, the major constraints of the mechanical performance of CPC arise from the intrinsic brittleness derived from their composition and microstructure. CPC are

in fact intrinsically porous ceramics, with porosities that vary between 20% and 50% depending on the liquid to powder ratio used in their preparation (Espanol et al., 2009). Thus, the bending strength values reported for CPC, typically in the range of 5–15 MPa (Martin and Brown, 1995; Ginebra et al., 2001) are well below that of cortical bone, which is close to 200 MPa (Currey and Butler, 1975). With respect to the fracture properties of CPC, Morgan et al. (1997) reported a fracture toughness of 0.14 MPa m1/2 for a carbonated apatite CPC, comparable to other brittle cellular materials such as chalk or Portland cement (Maiti et al., 1984), and far from the fracture toughness of human cortical bone, 2–5 MPa m1/2 (Nalla et al., 2003). The development of CPC with enhanced toughness would considerably broaden the field of potential applications, such as the repair of multiple fractures of long bones, fixing of cemented articulation prostheses or substitution of vertebral bodies among others (Dos Santos et al., 2000). It is true that the mechanical limitations of CPC can be balanced with the effects of progressive remodelling that eventually is expected to lead to the replacement of the CPC with new bone. However, even if the material is completely transformed in newly formed tissue, at the initial stages after implantation it would be desirable to have CPC with enhanced mechanical properties. This has led to the development of fibre-reinforced CPC. In fact, fibre reinforcement has been extensively explored in the field of hydraulic cements and concretes for civil engineering and building applications. The incorporation of fibres into a brittle cement matrix has been proven to increase the fracture toughness of the composite by the resultant crack arresting processes as well as the tensile and flexural strengths (Beaudoin, 1990). Fibre reinforcement has proven also to be effective in other types of brittle cements, such as the acrylic bone cements used for orthopaedic or dental applications (Schreiber, 1974; Pal and Saha, 1982; Puska et al., 2004). However, in cements intended for medical applications such as CPC, specific requirements arise in the selection of the fibres; on one hand, they must be biocompatible. On the other hand, they can be used not only as a reinforcement for the cement matrix but also as pore-generating agents. In this second approach, fibres, in addition to being biocompatible, must also be biodegradable. It is the aim of the present work to provide an overview of the different approaches taken in the development of fibrereinforced CPC for clinical applications and to identify the kind of fibres used and the most significant achievements.

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Table 1 – Fibre classification (adapted from Needles, 1981). The fibres that have been used in calcium phosphate cement composites are listed in the last column. Natural fibres Animal origin

Chemical or man-made fibres Natural polymers

Silk

Alginate

Wool

Natural rubber

Hair (Alpaca, Mohair)

Regenerated cellulose

Plant origin

Cellulose ester

Seed (Cotton, Cocoa . . . )

Chitosan

Liberian (Linen, Jute)

Polylactide

Leaf (Alpaca, Sisal)

Reference

Zuo et al., 2010

Synthetic polymers

Mineral origin

Polyolefins

Asbestos

Polyvinyl derivatives Polyurethane Polyamide (polyamide 6.6, p-aramide)

Dos Santos et al., 2000; Xu et al., 2000, 2001

Polyester (poly-ε-caprolactone, polyglycolide)

Zuo et al., 2010; Xu and Quinn, 2002; Xu et al., 2004; Xu and Simon, 2004; Xu et al., 2006, 2007a,b; Burguera et al., 2005; Gorst et al., 2006; Zhang and Xu, 2005; Zhao et al., 2010a,b; Von Gonten et al., 2000; Weir et al., 2006; Weir and Xu, 2010

Polyisoprene Ceramics Carbon

Xu et al., 2000; Wang et al., 2007

Glass

Xu et al., 2000; Nezafati et al., 2010

Metals

2. General considerations for the design of fibre-reinforced cements Fibre reinforced cement and concrete composites have long been used in numerous applications in traditional fields such as civil engineering. In such applications, the fibres are often discontinuous and randomly oriented and distributed within the volume of the composite. Natural fibres (such as cellulose, sisal, jute, bamboo, asbestos, rock-wool, etc.) and man-made fibres (such as steel, titanium, glass, carbon, polymers, etc.) (Table 1) have been used for the purpose of enhancing the cement mechanical properties, among which are cracking and microcracking, resistance in tension, shear and bending, ductility, and energy absorption capacity (Naaman, 2007). A high fibre tensile strength is essential for a substantial reinforcing action. A high ratio of fibre elastic modulus to matrix elastic modulus facilitates stress transfer from the matrix to the fibre. Fibres having large values of failure strain give high extensibility in composites (Beaudoin, 1990). However, not only fibre type is important. Other factors, such as fibre length, volume fraction, orientation or fibre/matrix adhesion among others, determine the final properties of the composite. Some of them have been investigated in fibre–CPC literature and will be detailed in the following sections, while others, such as the adhesive mechanisms between fibre and the CPC matrix, have not been systematically covered. For the purpose of this work, the distinction between fibres and yarns will be made. A yarn can be defined as a continuous strand of twisted fibres of natural or synthetic material, which is then the basis for woven or knitted fabrics. The blending of fibres with the cement paste or precursor powder can be carried out using different structures of the fibrous materials, as shown in Fig. 1. Fibres can be introduced in the cements

as short staple fibres (Fig. 1(a)), or as long fibres forming a random bundle (Fig. 1(b)). The random bundles can also be cut into small pieces and dispersed in the cement matrix (Fig. 1(c)). If fibres are spun into yarns, the latter can also be cut and introduced randomly into the cement (Fig. 1(a), (b)), oriented (Fig. 1(e)), or may be woven or knitted into laminar textile structures (Fig. 1(d)). Both the fibre and the matrix are assumed to work together, and provide the synergism needed to make an effective composite (Naaman, 2007). The load is transferred through the matrix to the fibre by shear deformation at the fibre–matrix interface. It is known that the adhesive force between the matrix and the fibre surface has a significant influence on the efficient stress transfer between the two phases. In a cement system, where the fibres are incorporated to a hydraulic cement paste, the wettability of the fibres is a relevant parameter, since it can influence fibre integration and also the fibre/cement bonding. Moreover, it has to be taken into account that cement matrices are brittle porous bodies containing pores of varying diameters, and this affects not only the properties of the matrix but also the intrinsic properties of the fibre–matrix interface. Indeed, porosity at the fibre–matrix interface results in a reduction of the number of solid–solid contacts between fibre and matrix. However, no systematic studies regarding adhesion at the interface have been carried out in CPC–fibre composites. The incorporation of fibres into a brittle solid, in this case a brittle cement matrix is expected to increase the fracture toughness of the composite, and also the tensile and flexural strengths. For discontinuous fibre composites, simple two phase mixture rules have been employed as the basis for the prediction of cement-composite properties. Equations

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a

b

Short fibres or yarns

Long fibres or yarns – random bundle

c

d

Cut random bundle of long fibres

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e

Knitted or woven structures

Yarns – oriented

Fig. 1 – Disposition of the fibres in fibre-reinforced calcium phosphate cement composites.

predicting modulus of elasticity of the composite (Ec ) and its tensile or flexural strength (σc ) are generally of the form (Beaudoin, 1990): Ec = φi Ef Vf + Em Vm

(1) Fig. 2 – Chemical structure of polyamide 6.6.

and σc = φi σf Vf + σm Vm

(2)

where Vf and Vm are volume fractions of the fibres and the matrix, respectively. Elastic moduli of fibres and matrix are denoted by Ef and Em respectively, and σf and σm are the corresponding tensile strengths. The composite efficiency factor (φi ) accounts for the reduction in composite mechanical property values due to such factors as fibre length, orientation, defects and fibre–fibre interaction. When the fibres are continuous, aligned, and parallel to the direction of the applied load, φi = 1. This factor includes the Krenchel correction factor (ηo ) which is an orientation efficiency factor and a fibre-length correction factor (ηL ) (O’Regan et al., 1999): φi = ηL ηo .

(3)

The expression of the Krenchel factor is given by the general form:  afn cos4 αn  n  a fn = 1 (4) , where ηo = afn n n

where afn is the ratio between the cross-sectional area presented by a group of fibres orientated at an angle αn to the applied load direction and the total area of all the fibres at a given cross-section of the composite. In the following section, we present an overview of the fibre–CPC composites reported in the literature, focusing specifically on their mechanical properties. They are classified in two groups, (i) CPC composites with non-resorbable fibres, where the function of the fibres is the mechanical reinforcement of the cement, and (ii) CPC composites with resorbable/biodegradable fibres, where the addition of fibres to the cement seeks an initial reinforcement followed by the creation of macroporosity in the cement matrix after fibre degradation.

3.

apatitic CPC. The reinforcing efficiency of different short non-resorbable fibres distributed randomly in an apatitic CPC matrix was analysed by Xu et al. (2000). For a given fibre length and fibre content, the strength of the composite was shown to depend linearly on fibre strength, according to Eq. (2). Specifically, for a 5.7 vol% of short (25 mm) random fibres, the bending strength of the composite (σc ) was related to fibre strength (σf ) according to σc = 12.5 + 0.0082σf . A summary of the fibre features, CPC composition and mechanical properties of the composites can be found in Table 2.

CPC composites with non-resorbable fibres

Different types of non-resorbable fibres, both polymeric and ceramic, have been investigated as reinforcing phases of

3.1.

Polymer fibres: polyamides

Polyamide fibres are chemical fibres formed by a linear macromolecule polymer in which amide groups are a constant part of the chain, where a minimum of 85% are bonded to aliphatic or cycloaliphatic carbons (Rouette, 2001). Due to their chemical structure, polyamides are moderately hydrophilic (Canal et al., 2004).

3.1.1.

Polyamide 6.6

Polyamide 6.6 (PA6.6) fibres (Fig. 2) are widely used in many conventional textile applications. They have high failure strain (13%–15%), and low elastic modulus (4.0 GPa) (Beaudoin, 1990), the combination of both parameters leading to a high work of fracture. Dos Santos et al. (2000) investigated the influence of polyamide 6.6 fibres in the mechanical resistance of CPC based on α-TCP (for details of composition see Table 2). Short PA6.6 fibres of 3 mm length were added to the cement in percentages between 0.2 and 1.6 wt%. The porosity and water absorption decreased with increasing PA6.6 content. The mechanical properties were evaluated only in compression, reporting a 30% increase of the compressive strength, from 9.5 to 12.5 MPa, when up to 0.8 wt% of PA66 fibres were added. No information was provided on the flexural properties of the cement.

Fibre (wt%)

Fibre length (mm)

Fibre diameter (µm)

30 nm

3–200 16 ± 2 Undetermined 10 MPa. It was shown that increasing thickness of the fibre-containing layer resulted in a linear increase of the flexural strength and the elastic modulus of the whole material, and maximum values above 20 MPa and 2 GPa were achieved, respectively. A pre-mixed CPC-25% PLGA yarn composite scaffold was developed by Xu et al. (2007b). Pre-mixed calcium phosphate cements are designed with the goal to have an already prepared paste, which can be stored until use. A non-aqueous yet water-miscible liquid is used to prepare the paste, which would not harden until it is delivered into the defect site. Inside the body, the physiological fluid is exchanged with the liquid, producing the cement hardening. In the formulation proposed by Xu et al. glycerol was used as the non-aqueous phase, and mannitol was added as porogen. An increase of the bending strength was reported with fibre addition. Both the composite and the pristine CPC were non-cytotoxic in cell culture studies with osteoblast cells, and no significant differences in cell proliferation were observed among them. Injectability of a CPC paste can be defined as its ability to be extruded through a needle without demixing. The ability to inject the cement in the surgical site is an important property since it can minimize surgical invasion and allow for complex-shaped defects to be filled adequately (Ginebra, 2008). The injectability of fibre–CPC composites with 5 mm length PGA yarns at 2.5%–7.5% vol/vol was tested by Xu et al. (2006). Hydroxypropyl methylcellulose (HPMC) was added as gelling agent (Table 2). The injection force tended to increase with the incorporation of the yarns in the cement paste, but no significant differences were observed between 2.5% and 7.5%, with forces ranging from 6 to 10 N. Higher yarn volume percentages did not allow proper injectability. In a step forward, with views on stem cell-based tissue engineering, the incorporation of stem cells into the CPC composites is starting to receive attention. Human Bone Marrow Stem Cells (hBMSCs) (Weir and Xu, 2010) and Human Umbilical Cord Mesenchymal Stem Cells (hUCMSCs) (Zhao et al., 2010a,b) were seeded in the fibre–CPC composites. hUCMSCs seeded on pristine CPC and 20% PLGA fibre–CPC composites with chitosan (Zhao et al., 2010a) showed good attachment, adhesion, proliferation and viability, equivalent on both materials. To protect hUCMSCs or hBMSCs from pH changes during setting reaction, cells were encapsulated with an hydrogel and blended with the composites (Zhao et al., 2010b; Weir and Xu, 2010). The presence of the alginate beads responsible of cell encapsulation in the fibre–CPC composite decreased its mechanical properties, bringing the elastic modulus to 2 GPa and flexural strength to 10 MPa. Both

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Fig. 6 – Chemical structure of poly-ε-caprolactone.

kinds of cells showed good viability (70%–80%), were able to differentiate and to synthesize poorly crystalline apatite.

4.2.3.

PLGA laminar structures

Von Gonten et al. (2000) studied the incorporation of one layer of PLGA woven or knitted fabrics (Fig. 1(d)) on the tensile side of TTCP:DCPA cements (Table 2). The toughening fibremesh was incorporated into only one surface since it was assumed that clinical loading of implants on wide surfaces such as a cranial plate would occur in such a manner as to create the highest tensile stresses on the internal surface of shell-like structures. The dense structure of woven materials did not allow cement penetration, while knitted structures significantly improved work of fracture of the initially brittle CPC by 100 times (from 0.31 to 22.65 N cm), and this was comparable to the mechanical behaviour of acrylate resins. After 28 days the degradation of PLGA fibres introduced porosity on one side of the material and therefore lowering the mechanical properties of the composite. Weir et al. (2006) prepared a fibre–CPC composite with either 1 or 3 layers of PLGA mesh according to Fig. 1(d) which showed improved mechanical properties (Table 2) but slightly lower cell viability than the CPC composite without fibres. Similar CPC composition (Xu et al., 2004) incorporated up to 13 layers of superimposed absorbable PLGA knitted fabrics (meshes). The presence of the meshes improved the mechanical properties allowing frictional sliding and stretching during pullout, which contributed to the resistance of the material to crack propagation. The elastic modulus of the CPC decreased with the incorporation of the knitted PGA materials but in the combined chitosan–fibre–CPC composite it increased above that of cancellous bone (0.30 GPa (O’Kelly et al., 1996)) but still below cortical bone (12.8 GPa (Broz et al., 1997)). After 84 days the knitted PLGA fabrics were degraded, and therefore linear interconnected macropores appeared in the cement, which still retained higher flexural strength (5.3 MPa) and WOF than the pristine CPC (Xu et al., 2004).

4.3.

Poly-ε-caprolactone

Polycaprolactone (PCL) is a polyester (Fig. 6) which is degraded by hydrolysis of its ester linkages in physiological conditions. It has received a great deal of attention for use as an implantable biomaterial. In particular, it is especially interesting for the preparation of long term implantable devices, owing to its degradation which is even slower than that of polylactide. PCL is a Food and Drug Administration (FDA) approved material for use in drug delivery devices, sutures, or adhesion barriers. PCL fibre–CPC composites were studied through the introduction of electrospun PCL fibre bundles in CPC made of 61% α-TCP as described in Table 2 (Zuo et al., 2010). Depending on the concentration of the PCL solution prior to electrospinning, different fibre diameters were obtained (1.14–1.91 µm) forming fibre bundles of 0.18–0.20 mm width

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which were introduced in the cement cut to 3 mm length pieces as in Fig. 1(c). Introduction of PCL fibre bundles decreased the initial and final setting times of the CPC. Total porosity and macroporosity progressively increased with fibre weight fraction in the composite, while fibre diameter had no influence in this parameter, as most electrospun fibres were fused with each other when forming the bundles introduced in the cement, so the width of the bundles determined macroporosity. The work of fracture increased with the addition of the microfibres in the CPC. The improved flexibility was attributed to the flexibility of the polymeric fibres which allowed the set cements to consume more energy due to elongation or distortion of these fibres during frictional pull-out, and also to the frictional sliding of fibres in the matrix during deformation. However, flexural strength and elastic modulus of CPC decreased with the introduction of the fibre bundles (with lower strength than the matrix), which were not well integrated in the cement due to their hydrophobic surface, similarly as their homologues with PLLA bundles (Zuo et al., 2010).

5.

Conclusions

Calcium phosphate cements are of great interest in the field of biomaterials for bone repair due to their bioactivity, mouldability and capacity of self-setting in vivo, allowing minimally invasive surgical techniques. However, their brittleness has limited their applicability to non-stressbearing applications. This has been addressed by reinforcing CPC with fibres. The random dispersion of non-resorbable fibres such as polyamides (polyamide 6.6., p-aramide), carbon or glass fibres in the cement matrix resulted in an increased bending strength and work of fracture. Higher reinforcement was associated with longer fibres, although the problems associated with their mixing and wetting with the cement paste, resulted in less homogeneous composites. It is known that a highly porous and interconnected pore structure generally favours bone regeneration. However, a material generally weakens as its porosity increases, which poses a major challenge in developing porous load-bearing CPC for bone tissue engineering. Porous fibre–CPC composites were developed with resorbable polymer fibres and fibre constructs such as yarns, nonwovens, woven and knitted fabrics (meshes). A twofold objective was intended; the temporary reinforcement of CPC prior to fibre degradation, and the subsequent pore formation, upon fibre degradation, to allow for tissue colonization. The degradable polymers evaluated were mainly polyglycolide, polylactide and poly εcaprolactone. The suitability of porous fibre–CPC composites for stem-cell based tissue engineering, was assessed, showing that they are able to sustain cell growth. The field of CPC–fibre composites has relevant points still to be tackled, such as improving adhesion between the fibres and the CPC matrix to further improve mechanical properties, improving injectability wherever possible, or evaluating their in vitro and in vivo behaviour, among others. Moreover, although numerous scientific articles have proven the efficiency or fibre reinforcement in CPC, most of those studies are based only in 3 or 4-point bending tests. There is still a lot to be done to reach a better understanding of

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the mechanical properties and fracture processes of fibrereinforced CPC.

Acknowledgments The authors acknowledge the MICINN for the Juan de la Cierva fellowship of CC and the financial support in the MAT 2009-13547 project. The research leading to these results has received funding from the European Commission Seventh Framework Programme (FP7/2007-2013) under Grant agreement no. 241879, REBORNE project.

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