Sage Journals: Discover world-class research

Abstract

Treatment of bone defects caused by trauma or disease is a major burden on human healthcare systems. Although autologous bone grafts are considered as the gold standard, they are limited in availability and are associated with post-operative complications. Minimally invasive alternatives using injectable bone cements are currently used in certain clinical procedures, such as vertebroplasty and balloon kyphoplasty. Nevertheless, given the high incidence of fractures and pathologies that result in bone voids, there is an unmet need for injectable materials with desired properties for minimally invasive procedures. This paper provides an overview of the most common injectable bone cement materials for clinical use. The emphasis has been placed on calcium phosphate cements and acrylic bone cements, while enabling the readers to compare the opportunities and challenges for these two classes of bone cements. This paper also briefly reviews antibiotic-loaded bone cements used in bone repair and implant fixation, including their efficacy and cost for healthcare systems. A summary of the current challenges and recommendations for future directions has been brought in the concluding section of this paper.

Keywords

Calcium phosphate cement acrylic bone cement fracture repair bone void filler implant fixation

Introduction

Osteoporosis is a condition characterized by low bone mass and can lead to increased susceptibility to fractures in the elderly.¹ Worldwide, fractures resulting from osteoporosis affect approximately one woman in three and one man in five over the age of 50 years.² In addition, approximately 2 million cases of trauma or disease-related bone fractures occur every year in the United States alone, with an estimated annual direct cost of $10 billion.³ The repair rate of a bone defect is dependent on the wound size. When the defect size is greater than the healing capacity of bone, the fibrous connective tissue becomes dominant in the bone defect.^4,5 Bone grafting is considered to be the gold standard for the treatment of traumatic bone defects.⁶ However, bone grafting has the drawback of donor site morbidity and limited availability,⁷ and may be associated with post-operative complications.^8,9

As an alternative to autologous bone grafts, a wide variety of synthetic inorganic/organic or biological materials have been explored as bone graft substitutes for the treatment of bone defects.¹⁰ For thousands of years, humans have made use of seashells, nuts, and so forth as potential bone substitute materials.¹¹ With the introduction of tissue-engineering approach and its successful application in clinical trials,^12,13 the concept of bone graft substitutes has evolved significantly. The scaffold-based tissue engineering aims to restore and maintain normal function in injured and diseased bone.^14–16 A fundamental requirement for tissue-engineered bone grafts is the ability to integrate with the host bone, while providing the capacity for load-bearing and remodeling.¹⁷

Under certain circumstances, such as age-related bone disintegration and osteoporosis, bone reconstruction involving solid scaffolds may not be a feasible approach.^18–20 Therefore, minimally invasive alternatives are sought in certain orthopedic and maxillofacial procedures.^18,21,22 Osteoporotic fracture of vertebral bodies is another example where minimally invasive procedures are sought. Vertebral fractures deform spine and cause chronic pain while limiting patients’ freedom of movement.^23,24 Vertebroplasty (VP) makes use of an injectable bone cement (IBC) to restore the mechanical strength and stiffness of the vertebral body,²³ although its effectiveness as a treatment modality for vertebral compression fractures is yet to be established.²⁵

Injectable biomaterials with appropriate functional properties and self-setting characteristics at physiological temperatures are essential for the success of these interventions. IBCs have been used for bone reconstruction and in a wide range of bone augmentation procedures, such as orthopedic and maxillofacial surgeries.^26–28 Bone cements are obtained by mixing a biomaterial in powder form with a liquid, which can set once implanted as a paste within the body.²⁹ In terms of their chemical composition, IBCs may be regrouped as calcium phosphate cements (CPCs), calcium sulfate cements (CSCs), acrylic bone cements (ABCs), and filamentary composite materials.²⁶ As an alternative, these IBCs can be classified on the basis of their orthopedic applications. While ABCs are used for high and medium load-bearing applications, CPCs and CSCs are generally used for medium and low load-bearing applications.²⁶

Unlike the first-generation biomaterials that were mostly inert, the second-generation bone substitute materials intended for orthopedic applications are expected to elicit a response from the body to favor osseointegration.^30,31 This is true whether the biomaterial is designed for mechanical fixation (e.g., metallic screws) or for the repair or replacement of diseased or injured bone (e.g., bone graft extenders and substitutes).³² Calcium phosphates have been substantially used in the past few decades as second-generation biomaterials.^31,33,34 The chemical composition of CPCs is similar to the natural bone, which means that the release of $C a^{2 +}$ and $P O_{4}^{3 -}$ ions may promote osteoconduction and osteogenesis.^35,36 In addition, calcium phosphates offer fast or slow degradation rates depending on their Ca/P ratio³¹ and the type of filler used.^37–39 Scaffolds made of calcium phosphates have been used in dentistry since the early 1970s and in orthopedics since the 1980s.⁴⁰ Hence, calcium phosphates are gaining a special interest as bone graft substitutes in periodontal and osteochondral regeneration and as potential carriers in controlled release systems.^41–43

As for ABCs, poly(methyl methacrylate) (PMMA) has evolved from ophthalmological and dental applications^44,45 to orthopedics,^46,47 for the fixation of prosthetic implants as well as for remodeling osteoporotic and vertebral fracture repair.^48,49 In addition, PMMA has been used for total joint replacement procedures, including hip, knee, ankle, elbow, and shoulder.^26,50–53 It has been shown that the injection of PMMA can enhance the stability of hip fracture fixation.⁵⁴ Also, it has been shown that an osteoporotic proximal femur can be mechanically stabilized through the injection of PMMA into it.⁵⁵ In general, PMMA bone cement has a relatively high mechanical strength and offers a suitable curing time and ease of application.⁵⁶ The ISO standard 5833 for bone cements requires a compressive strength of ⩾ 70 MPa.⁵⁷

There is a growing body of literature on the development of new bone graft substitutes, making use of synthetic inorganic/organic compounds as well as composites of demineralized bone with various self-setting pastes. Several review papers have provided overviews of the current state-of-the-art in bone cement development and their clinical applications.^48,58–66 This paper briefly covers the main classification of bone graft substitutes for bone reconstruction. The main body of the paper describes the most common injectable bone substitute materials for orthopedic use, placing the emphasis on CPCs and ABCs. Some alternative formulations for these cements have been listed at the end of each section, while discussing the prospect of the new formulations and future directions in the field, including the advantages and drawbacks of antibiotic-loaded bone cements (ALBCs).^28,67–69

Bone graft substitutes

Bone is an organic–inorganic tissue with a hierarchical architecture that makes it a micro-/nano-composite.^11,70 The mineralized bone matrix consists of an organic phase mainly composed of collagen (~35% dry weight), a mineral phase of carbonated apatite (~65% dry weight), as well as other non-collagenous proteins that form a stimulating microenvironment for cellular functions.¹¹ Collagen, a triple helix with a diameter of ~1.5 nm,⁷¹ has a Young’s modulus of 1–2 GPa and an ultimate tensile strength of 50–1000 MPa, whereas the mineral hydroxyapatite (HA) possesses a Young’s modulus of ~130 GPa and an ultimate tensile strength of ~100 MPa.¹¹ The collagen phase is responsible for the rigidity, viscoelasticity, and toughness of bone, while the mineral phase provides structural reinforcement and stiffness.¹¹ The mechanical properties of bone depend on its composition and structural organization, such as mineralization, collagen fiber orientation, porosity, as well as on trabecular vs. cortical bone architecture.^11,72

Autologous bone grafts are considered as the gold standard in orthopedic surgery, but they are limited in availability and associated with post-operative complications.^73–75 A more future-oriented alternative to bone grafting is to make use of synthetic bone graft substitutes.⁷⁶ Despite decades of research attempts to design bio-inspired materials, mimicking the properties of natural bone tissue is not a trivial undertaking.^42,72,77 Nevertheless, according to animal model studies, it has been reported that materials with compressive properties on the low end of human cancellous bone can encourage new tissue growth.^78–80

Synthetic bone graft substitutes are often in the form of granules, typically with diameters ranging between 0.1 and 5 mm, or porous blocks (or sponges) (Figure 1(a) and 1(b)).⁷⁶ Hydraulic cements represent a class of bone graft substitutes that harden after in situ implantation or injection (Figure 1(c)).⁷⁶ This includes cements such as calcium sulfate hemihydrate (plaster of Paris) and CPC,⁷⁶ as well as magnesium phosphate cement.^81,82 Besides granules, porous blocks, and hardening pastes, non-hardening pastes (putty) have also been proposed as bone graft substitutes. These pastes typically consist of a mixture of granules and a highly viscous hydrogel (Figure 1(d)).⁷⁶

Figure 1.

The four main types of bone graft substitutes: (a) granule; (b) block or pre-form; (c) hydraulic cement; and (d) putty. The presence of pores in the size range of 0.1–1.0 mm (as seen in (a) and (b)) is essential for a rapid bone ingrowth. Reproduced with permission from Bohner.⁷⁶ Copyright © 2010 Elsevier Inc.

Table 1(a) provides a summary of some commercially available bone graft substitutes and their mechanisms of action.⁸³ Commercial bone graft substitutes can be classified as (i) allograft based, (ii) ceramic based, (iii) factor based, and (iv) polymer based. Allografts such as demineralized bone matrix (DBM) are osteoinductive⁸⁴ and provide a biological stimulus (proteins and growth factors),⁴¹ but may pose the risk of disease transmission and immunogenicity.^85,86 Ceramics such as calcium phosphates, calcium sulfates, and bioactive glasses have been extensively used as bone graft substitutes.^16,40 Growth factors such as bone morphogenetic proteins (BMPs) have the ability to recruit and signal to mesenchymal progenitor cells to differentiate toward a bone-forming lineage.^40,83 Finally, non-degradable/degradable polymers as well as a variety of their organic/inorganic composite systems make up the market for some commercially available strips and injectable pastes (Table 1(a)). Compositions of some commercially available IBCs are summarized in Table 1(b). This review paper focuses on the two main classes of injectable bone graft substitutes: (i) ceramic based (CPCs) and (ii) polymer based (ABCs).

Table 1.

(a) Summary of selected commercially available bone graft substitutes. Reproduced with permission from Ricciardi and Bostrom.⁸³ Copyright © 2013 Elsevier Inc. (b) Compositions of some commonly used commercially available injectable bone cements. Modified from Lewis.²⁶ Copyright © 2011 Wiley Periodicals, Inc.

(a) Selected commercially available bone graft substitutes.

Class	Commercial Product	Composition	Claimed Mechanism of Action	Formulations
Allograft based	DBX®(Synthes)	DBM with sodium hyaluronate carrier	Osteoinduction, osteoconduction	Putty, paste, mix, injectable, strips
	Grafton®(Medtronic)	DBM fibers w/ w/o cancellous chips	Osteoinduction, osteoconduction, osteogenesis	Putty, strips, crunch, gel, paste
	Orthoblast®(Citagenix)	DBM and cancellous chips in reverse phase medium	Osteinduction, osteoconduction	Putty, paste
Ceramic based	Norian SRS®(Synthes)	Calcium phosphate	Osteoconduction, bioresorbable	Injectable paste
	Vitoss®(Stryker)	Beta-tricalcium phosphate and bioactive glass	Osteoconduction, osteoinductive w bone marrow aspirate, bioresorbable	Putty, strips, injectable, morsels, shapes
	ProOsteon®(Biomet)	Corraline hydroxyapatite and calcium carbonate	Osteconduction, bioresorbable	Injectable granules or block
	BonePlast®(Biomet)	Calcium sulfate	Osteoconductive, bioresorbable	Paste
	Osteoset®(Wright)	Calcium sulfate	Osteoconductive bioresorbable	Pellets
Factor based	Infuse®(Medtronic)	rhBMP-2 on bovine collagen carrier	Osteoinductive	Bovine collagen carrier
Factor based	OP-1®(Stryker)	rhBMP-7 with type I collagen carrier	Osteoinductive	Putty (with carboxymethyl-cellulose addition), paste
Polymer based	Healos®(DePuy)	Crosslinked collagen and HA	Osteoconductive, osteogenic with bone marrow	Strips
Polymer based	Cortoss®(Stryker)	Non-resorbable polymer resin with ceramic particles	Osteoconductive	Injectable paste

(b) Selected commercially available injectable bone cements.

Cement Type / Brand Name	Composition / Constituents^a,b	Manufacturer / Supplier
Acrylic bone cements
CMW™1	Powder (40.00 g): 35.54 g PMMA, 3.64 g BaSO₄, 0.82 g BPOLiquid (18.37 g): 18.22 g MMA, 0.15 g DMPT, 25 ppm HQ	DePuy CMW Blackpool, UK
Palacos® R	Powder (40.00 g): 33.55 g poly(methyl acrylate, MMA), 6.13 g ZrO₂, 0.32 g BPO, 1.00 mg chlorophyllLiquid (18.78 g): 18.40 g MMA, 0.38 g DMPT, 0.40 mg chlorophyll	Heraeus Kulzer GmbH, Hanau, Germany
Surgical Simplex® P	Powder (40.00 g): 29.40 g poly(MMA, styrene), 6.00 g MMA, 4.00 g BaSO₄, 0.60 g BPOLiquid (18.79 g): 18.31 g MMA, 0.48 g DMPT, 80 ppm HQ	Stryker, Michigan, USA
Calcium phosphate cements
Biopex®	α-TCP, TTCP, DCPD	Mitsubishi Materials Corp., Tokyo, Japan
Cerament®	Powder: 40% hydroxyapatite (HA), 60% calcium sulfate (CaS)Liquid: iohexol and saline	BoneSupport, Sweden
chronOS Inject®	Powder: 42 wt.% β-TCP, 21 wt.% MCPM, 31 wt.% β-TCP granules, 5 wt.% Mg hydrogen phosphate trihydrate, < 1 wt.% sodium hydrogen pyrophosphate Mg(SO₄)₂ Liquid: 0.5% solution of sodium hyalurone	Oberdorf, Switzerland
Graftys® QuickSet Graftys® HBS	Powder: calcium phosphate salts and HydroxyPropylMethylCellulose (HMPC)Liquid: phosphate-based (Na₂HPO₄) aqueous solution	Graftys, France
Norian® Skeletal Repair System	α-TCP, CaCO₃, MCPM	Synthes, Inc.,West Chester, PA, USA

MMA: methylmethacrylate; BPO: benzoyl peroxide; DMPT: N, N-dimethyl-p-toluidie; HQ: hydroquinone; TCP: tricalcium phosphate; TTCP: tetracalcium phosphate; DCPD: dicalcium phosphate dihydrate; MCPM: monocalcium phosphate monohydrate.

Compositional details for the acrylic bone cements and chronOs Inject^® cement were taken from products’ brochures.

Calcium phosphate cements

Composition and cement formation

Some available calcium phosphates, with their composition, standard abbreviations and solubility data are listed in Table 2.⁸⁷ The clinical potential of calcium phosphate materials further increased when a self-setting CPC was developed in the early 1980s.^88,89 CPCs are generally formed by combining one or more calcium phosphate powders with a liquid phase, which is usually water or an aqueous solution,^90–92 although water-immiscible liquids have also been used to improve handling and cement properties.⁹³ Upon mixing, the produced paste is able to set and harden within the body. Unlike ABCs, which undergo polymerization during hardening, CPCs set as a result of dissolution and precipitation, while the entanglement of the precipitated crystals is responsible for hardening.⁹⁰ A recent study by Mellier et al.⁹⁴ made use of ovine whole blood as a liquid phase for CPCs. The formation of a 3D clot-like network and its interaction with the precipitated apatite crystals resulted in a microstructure that was more sensitive to biological degradation and promoted new bone formation.⁹⁴

Table 2.

Molar ratio (Ca/P)	Compound	Formula	Solubility at 25°C		pH stability (range)
Molar ratio (Ca/P)	Compound	Formula	−logK_s	g l⁻¹	pH stability (range)
0.5	Monocalcium phosphate monohydrate (MCPM)	Ca(H₂PO₄)₂·H₂O	1.14	∼18	0.0–2.0
0.5	Monocalcium phosphate anhydrous(MCPA or MCP)	Ca(H₂PO₄)₂	1.14	∼17	^a
1	Dicalcium phosphate dihydrate(DCPD), mineral brushite	CaHPO₄·2H₂O	6.59	∼0.088	2.0–6.0
1	Dicalcium phosphate anhydrous(DCPA or DCP), mineral monetite	CaHPO₄	6.9	∼0.048	^a
1.33	Octacalcium phosphate (OCP)	Ca₈(HPO₄)₂(PO₄)₄·5H₂O	96.6	∼0.0081	5.5–7.0
1.5	α-Tricalcium phosphate (α-TCP)	α-Ca₃(PO₄)₂	25.5	∼0.0025	^b
1.5	β-Tricalcium phosphate (β-TCP)	β-Ca₃(PO₄)₂	28.9	∼0.0005	^b
1.2–2.2	Amorphous calcium phosphates (ACP)	Ca_xH_y(PO₄)_z·nH₂O, n = 3–4.5, 15–20% H₂O	^c	^c	∼5–12^d
1.5–1.67	Calcium-deficient hydroxyapatite (CDHA or Ca-def HA)^e	Ca₁₀−_x(HPO₄)x(PO₄)₆−x(OH)₂−x (0 < x < 1)	∼85	∼0.0094	6.5–9.5
1.67	Hydroxyapatite (HA, HAp or OHAp)	Ca₁₀(PO₄)₆(OH)₂	116.8	∼0.0003	9.5–12
1.67	Fluorapatite (FA or FAp)	Ca₁₀(PO₄)₆F₂	120	∼0.0002	7–12
1.67	Oxyapatite (OA, OAp or OXA)^f	Ca₁₀(PO₄)₆O	∼69	∼0.087	^b
2	Tetracalcium phosphate (TTCP or TetCP), mineral hilgenstockite	Ca₄(PO₄)₂O	38–44	∼0.0007	^b

Stable at temperatures above 100°C.

These compounds cannot be precipitated from aqueous solutions.

Cannot be measured precisely. However, the following values were found: 25.7 ± 0.1 (pH 7.40), 29.9 ± 0.1 (pH 6.00), 32.7 ± 0.1 (pH 5.28). The comparative extent of dissolution in acidic buffer is: ACP >> α-TCP >> β-TCP > CDHA >> HA > FA.

Always metastable.

Occasionally referred to as “precipitated HA” (PHA).

The existence of OA remains questionable.

As Figure 2 shows, CPCs can be classified by the number of components in the solid phase (single or multiple), type of setting reaction (hydrolysis or acid–base reaction), setting mechanism and microstructure evolution during setting, and the type of end product.⁹⁰ Although a large number of formulations has been used to produce CPCs,^87,95–100 the CPCs developed to date have only two different end products: precipitated HA or brushite (dicalcium phosphate dihydrate, DCPD).⁹⁰ This is anticipated, since HA is the most stable calcium phosphate at pH > 4.2, whereas brushite is the most stable one at pH < 4.2.⁹⁰

Figure 2.

Classification of calcium phosphate cements, with examples of the most common formulations. From top to bottom the cements are classified by the type of end product (apatite or brushite), number of components in the solid phase (single or multiple), type of setting reaction (hydrolysis or acid–base reaction), setting mechanism and microstructure evolution during setting. Scanning electron micrographs of set apatite and brushite cements obtained by the hydrolysis of α tricalcium phosphate (α-TCP) and by reaction of β-TCP with MCPM (monocalcium phosphate monohydrate) respectively, are also shown. Reproduced with permission from Ginebra et al.⁹⁰ Copyright © 2012 Elsevier Inc.

Changing the powder-to-liquid ratios can lead to CPCs with a variety of self-setting times.^101,102 According to ISO/DIS 18531 for CPCs, the setting time is the “time required from the start of powdered agent and liquid agent blending until hardening of the cement.”¹⁰³ Reducing the powder-to-liquid ratio of CPCs increases the injectability¹⁰⁴ while increasing the setting time and affecting the mechanical properties of CPCs after setting.¹⁰⁵ Although CPCs have demonstrated self-setting both in simulated body fluid (SBF) and in vivo in rats, the properties of CPCs set in SBF are expected to differ from those of CPCs set in vivo.¹⁰²

From a biological perspective, CPCs are attractive because they have proven to be biocompatible, osteoconductive, and bioresorbable,^106–110 while they offer an intrinsic microporous structure¹⁰⁰ for the transport of nutrients and metabolic waste products.¹¹¹ Given the excellent biocompatibility and osteoconductivity of CPCs, these cements are great candidates for various clinical applications. For example, CPCs are considered as the most suitable injectable biomaterials to accommodate narrow and irregular bone defects.¹⁸ In addition, CPCs can be injected to form a bioactive scaffold in situ under physiological conditions.¹⁰¹ The lack of macropores is considered a major limitation for the widespread use of CPCs.¹¹² Introducing macropores in CPCs has shown to be beneficial, as macroporous structures can facilitate bone ingrowth and aid in fast resorption of CPCs.¹¹¹ For example, the porosity of CPCs can be enhanced via the use of calcium carbonate,^100,113 polymers,^114,115 and foaming agents.^116,117 In addition, the porosity and microstructure of CPCs can be altered by adjusting the process parameters, such as the liquid-to-powder ratio and the particle size of the powder phase.⁹⁰ Ease of handling is also of paramount importance for the commercial success of injectable bone graft substitute materials.⁷⁶ Some examples of poor handling include the use of non-reproducible or complicated mixing procedures,⁷⁶ poor injectability of a cement paste,^38,91 or the release and migration of fine particles caused by the lack of paste cohesion.^91,118

Cement injectability

Separation of the solid and liquid phases during cement delivery is the primary cause of poor injectability of CPCs.⁸⁹ Some studies have developed theoretical models to gain an in-depth understanding of the solid–liquid phase separation.^119–121 Figure 3 depicts the schematics of the phase separation during paste extrusion and their location in the extruder.⁸⁹ Phase separation mechanisms identified in different studies include: (i) filtration in the barrel, where the drainage of the liquid phase caused by the exerted pressure leads to consolidation of the solid phase;¹²² (ii) suction, caused by dilation of the powder network while flowing into the die;¹¹⁹ and (iii) filtration in the needle (or die land), exacerbated with the formation of solid mats.^89,123 (Figure 3).

Figure 3.

Phase separation mechanisms observed during extrusion of pastes and their location in the extruder. Schematic diagram is not to scale. Reproduced with permission from O’Neill et al.⁸⁹ Copyright © 2017 Elsevier Inc.

Two key aspects should be considered when testing the injectability of CPCs:³⁸ (1) defining a suitable experimental setup for injectability measurements, and (2) investigating adequate compositions and parameters that could affect injectability. The injectability of CPCs is commonly assessed using the syringe ejection method.^124–127 For example, Wang et al.¹²⁷ used a needle with an inner diameter of 1.6 mm for injectability measurements. The as-prepared paste was poured into the syringe 2 min after mixing the cement powder and liquid. Then, 1 kg vertical compressive load was applied on top of the plunger and the expelled paste was collected for 2 min. The following equation was used to calculate the injectability:

$I n j e c t a b i l i t y % = \frac{\begin{array}{l} P a s t e v o l u m e e x p e l l e d \\ f r o m t h e s y r i n g e \end{array}}{\begin{array}{l} T o t a l p a s t e v o l u m e b e f o r e \\ i n j e c t i n g \end{array}}$ (1)

Nevertheless, this method should be used with caution and may lead to inconsistent results, particularly when certain additives are present in the formulation. For example, adding polyvinyl alcohol (PVA) into a cement paste has been shown to highly enhance the injectability of CPCs.¹²⁸ However, this increase of cement injectability in the presence of PVA has been attributed to the increase of setting time only.³⁸ Hence, both the injectability and setting time should be reported, while making sure that the injectability of a cement is measured after a specific time interval (e.g., 50% of the setting time).

In a review paper, Habraken et al.⁹¹ highlighted major research achievements related to calcium phosphate materials in the past 15 years: as biologically active agents, carriers for gene or ion delivery, and bone graft substitutes. In another review paper, Zhang et al.¹²⁹ discussed the role of key processing parameters (e.g., particle size, cement composition, and additives) on the setting properties of CPCs and their handling and mechanical performance.

Some alternative formulations

O’Neill et al.⁸⁹ elaborated on the properties of CPCs that are essential for their clinical success. The paper discusses how the presence of powder or liquid additives can have a positive or detrimental effect on the delivery process of CPCs. For example, the size and proportion of solid additives relative to the bulk calcium phosphate powder can affect its packing ability.⁸⁹ It has been shown that the addition of fine fillers (~1 µm in diameter) alters the packing ability, reduces the water demand, and increases injectability.^89,97 The addition of large glass beads or microspheres of poly(lactic-co-glycolic) acid (PLGA) either decreases or increases injectability depending on the size and wt% of the beads.^95,96 Other additives, such as gelatinized starch, can increase the compressive strength, compressive modulus, and strain energy density of CPCs.¹³⁰

Some studies have aimed at improving the cohesion of CPCs, arguing that these cements can get disintegrated in the presence of water and blood.^18,131 For example, the setting properties of a cement are affected when blood or biological fluids are present at the injection site.¹³¹ Gelling agents have been used in some studies to improve the handling properties and cohesion of CPCs,^131,132 including glycerin, gelatin, cellulose derivatives, alginic acid salts, and chitosan.^131,133 Alternatively, water-immiscible carrier liquids have been proposed to improve the cohesion of injectable CPCs.⁹³ Table 3 shows a selection of studies investigating a few alternative CPC formulations and summarizes the key findings of these studies.

Table 3.

Selection of studies investigating alternative CPC formulations.

Authors	Primary Powder	Additive(s)	Additive Amount (wt%)	Findings
Heinemann et al.⁹³	α-TCP	Castor oil ethoxylate 35 and hexadecyl-phosphate	14.7 and 4.9	The oil-based liquid generated a water-immiscible cement that was injectable and showed improved cohesion, a higher compressive strength, and prolonged shelf life compared with the conventional cement. The product of the setting reaction was identified to be nanocrystalline HA. A resorbability similar to the conventional cement was anticipated because of the identical mineral structure of the set products.
van Houdt et al.¹³⁶	α-TCP	PLGA	30 and 50	PLGA microspheres or milled PLGA particles led to similar CPC porosity and degradation. Increasing the amount of PLGA porogen accelerated the in vitro degradation of CPC/PLGA. Using a distal femoral condyle in vivo model in rats, the CPC/PLGA formulations prepared with milled PLGA showed favorable bone responses, particularly at 50 wt% PLGA.
Smith et al.¹³⁵	α-TCP	Glucose microparticles(GMPs)	10, 20, 30, 40	Glucose microparticles (GMPs) with two sizes ranges (100–150 µm and 150–300 µm) were used as porogens to introduce macroporosity within CPCs. Setting times increased for GMP/CPC formulations compared with control CPC. The local pH was maintained at a neutral pH range over 8-week of in vitro degradation study, but the inclusion of GMPs had a detrimental effect on the compressive strength.
Tödtmann et al.¹³⁸	α-TCP	Mineralized collagen type I	2.5	Cement formulations with mineralized collagen type I, either in combination with osteocalcin or phosphoserine, resulted in an increase of new bone formation in cyst-like jaw defects of minipigs. An increase in the resorption rate was reported for the cement formulations containing osteocalcin and phosphoserine.
Schumacher et al.^98,157	α-TCP	Strontium(Sr)	0.72–2.21	Strontium (II) $(S r^{2 +})$ was introduced into the cement either by adding SrCO₃ to an α-TCP-based cement precursor mixture (A-type) or by substitution of CaCO₃ by SrCO₃ during precursor composition (S-type).The S-type cement (SrCPC) prolonged the setting time and increased the compressive strength by up to 90%, while enabling the release of $S r^{2 +}$ .⁹⁸ SrCPCs appeared to significantly enhance cell proliferation and osteogenic differentiation of hMSCs.¹⁵⁷
Zhu et al.¹⁵⁸	β-TCP/HA	Strontium(Sr)	3–12(molar ratio)	The presence of strontium and its concentration played a significant role in the phase compositions, setting time, compressive strength, in vitro degradation rate and cytotoxicity of the biphasic cement. Pure biphasic cements exhibited a higher stiffness compared with Sr-modified cements. Also, a higher amount of Sr-β-TCP in biphasic cement was associated with a higher degradation rate.
Zheng et al.³⁵	Calcium phosphate silicate(CCPSC)	Carbon fiber (1 µm diameter)	2	Carbon fiber-reinforced CCPSC was reported to possess moderate biodegradability and favorable osteoconductivity. Carbon fibers significantly improved the mechanical properties of the CCPSC cement. A small amount of osteoid found at the heterotopic site 1 month after implantation was attributed to potential short-term osteoinductivity of the cement formulation.

The resorbability of calcium phosphates can be controlled through the regulation of Ca/P ratio (see Table 2). Compounds with Ca/P ratio of less than 1 are not suitable for biological implantation because of the higher speed of hydrolysis with decreasing Ca/P ratio.³¹ While β-tricalcium phosphate (β-TCP) with Ca/P ratio of 1.5 has been classified as a resorbable calcium phosphate material, the resorbability of HA depends on several factors. For example, sintered HA with a stoichiometric Ca/P molar ratio of 1.67 may not show resorbability. Nevertheless, HA becomes resorbable in the presence of certain impurities and structural defects, or when its grain size is reduced to nano-scale.¹³⁴ To enhance resorbability of CPCs, pore-forming additives, such as water-soluble polymers, glucose,¹³⁵ biodegradable polymers (e.g., PLGA^136,137), collagen,¹³⁸ and biphasic calcium phosphate (BCP) granules,¹³⁹ have been proposed. However, these additives may alter the physiochemical characteristics of CPCs, including the setting time, viscosity, dispersibility, and compressive strength.^139,140

Self-setting gelatin-based HA foams have been proposed for the treatment of bone defects.¹¹² The team reported a suitable injectability and cohesion for the formulation, an interconnected porous structure, and good in vivo biocompatibility in rabbits. Additional functionalization with soybean extract slightly reduced the degradation rate and positively influenced bone formation in a critical-size bone defect in rabbits.¹¹² Similarly, an injectable cement made of calcium-deficient HA and foamed gelatin has been shown to promote bone ingrowth.¹⁴¹ The bubble volume caused by foaming appeared to increase the ductility of the cement. Hence, the brittle characteristic of the ceramic was reduced in the presence of the organic phase.¹⁴¹ Incorporation of polylactic acid (PLA) and phosphate glass fibers into CPCs has also been proposed to achieve a less brittle CPC matrix.¹⁴²

A combination of nano-hydroxyapatite (nHA) as the solid phase and a modified sodium phosphate solution as a mixing liquid has been proposed to improve the cohesion of CPCs in aqueous media as well as in human blood.¹⁸ HA has a broad range of clinical applications, has been used in bone cements for the repair of craniofacial and dental defects,^106,143 and has proven to be osteoconductive as a 3D scaffold and bone graft substitute material.^144–151 In particular, nHA has a higher surface area and a higher reactivity¹⁵² favoring cell adhesion and proliferation of mesenchymal stems cells (MSCs), alkaline phosphatase activity, calcium deposition, and osteogenic gene expression.^153–155 Hence, nHA has a greater potential for stimulating new bone growth compared with conventional HA, making it superior for bone reconstruction.^43,150,156

Stimulation of bone formation at the defect site in osteoporotic patients has motivated the development of some new cement formulations. In particular, ionic additives are often considered as viable alternatives to growth factors, not only because they are considerably less expensive, but also there is a lower risk that their delivery would result in adverse effects.¹⁵⁹ For example, strontium (II) $(S r^{2 +})$ can promote bone formation and inhibit bone resorption, and is frequently used in the treatment of osteoporosis.^98,160 A local release of strontium ions into the bone defect site has proven to be a more effective approach than orally administered strontium.^98,161 In vitro trials of strontium-modified cements (SrCPC) have revealed an enhanced cell proliferation and osteogenic differentiation of human bone-marrow-derived MSCs (hMSCs).¹⁵⁷ In a study by Thormann et al.,¹⁶¹ SrCPC-treated rats showed a statistically higher bone volume fraction (BV/TV) compared with the defect areas filled with CPC. Also, there was more bone formation at the bone–cement interface for the SrCPC compared with CPC.

The efficacy of the local bisphosphonate (BP) delivery via calcium-deficient apatite (CDA) granules and CPCs has also been investigated.^110,162 Systemic administration of BPs is the main pharmaceutical treatment option for osteoporosis, as BPs effectively increase bone density and prevent bone loss, and thereby reduce the risk of vertebral and non-vertebral fractures.^110,163 The efficacy of a CPC loaded with BP was evaluated by Verron et al.¹¹⁰ for the local BP delivery in a preclinical large animal model (ewes). To quantify bone formation, the team used three regions of interest (ROI) in microcomputed tomography (µCT). Implantation of CPC ± BP significantly improved bone volume fraction (BV/TV) in each ROI of implanted vertebral bodies compared with non-implanted ones. The BV/TV appeared twice as large on the largest ROI (1.2 mm) in the presence of CPC-BP compared with non-implanted vertebrae. These effects on BV/TV were slightly superior with CPC-BP (e.g. 85% at 1.2 mm) compared with CPC alone (79.5% at 1.2 mm).

Acrylic bone cements

Composition and cement formation

For several decades, ABCs have played an important role in orthopedic surgery.⁴⁸ The commercial ABCs are marketed as a two-component system (see Table 1(b)).²⁶ The powder phase primarily consists of PMMA (82–89 wt%), an inorganic radiopacifying agent such as barium sulfate or zirconium dioxide (10–15 wt%), as well as benzoyl peroxide (BPO; 0.5–2.6 wt%) that acts as a catalyst for the polymerization reaction. The liquid phase is largely methyl methacrylate (MMA) monomer (98 wt%), with 2 wt% N, N-Dimethyl-p-toluidine (DmpT) to accelerate polymerization.¹⁶⁴

The polymerization reaction of an ABC is schematically shown in Figure 4(a–c).¹⁶⁴ During this reaction, the DmpT causes BPO to decompose and produce a benzoyl radical and a benzoyl anion (Figure 4(a)). Then, the benzoyl radicals initiate the polymerization of MMA (Figure 4(b)). The active centers formed at this step combine with additional molecules to form a polymer chain (Figure 4(c)).¹⁶⁴ The paste formed during the reaction is a viscous fluid, which allows the polymerizing cement to be injected by the surgeon into the site of interest (for example, in VP and balloon kyphoplasty (BKP), into a fractured vertebral body),^48,165 or into the prepared bone canal prior to implanting an implant (hip replacement).¹⁶⁴

Figure 4.

Schematic diagram showing (a) the decomposition of BPO leaving a benzoyl radical and a benzoyl anion; (b) how these benzoyl radicals initiate polymerization of MMA; and (c) formation of a polymer chain. Reproduced with permission from Dunne and Ormsby.¹⁶⁴ Copyright © 2011 Dunne and Ormsby. (d) A typical curing curve for PMMA bone cement where T_max is the maximum temperature reached, T_set is the setting temperature and T_amb is the ambient temperature. Reproduced with permission from Dunne and Ormsby.¹⁶⁴ Copyright © 2011 Dunne and Ormsby. (e) Viscosity during setting of three commercial PMMA cements at 37°C. Reproduced with permission from Nicholas et al.¹⁷² Copyright © 2007 Springer.

A typical temperature-versus-mixing time curve during the curing of a PMMA bone cement is shown in Figure 4(d),¹⁶⁴ revealing a highly exothermic polymerization reaction. The peak temperature (T_max) is the maximum temperature attained during polymerization (curing) process.¹⁶⁶ This is considered a drawback, as the high temperature during curing may reach up to 110°C.^56,164 High temperatures can lead to thermal necrosis of the bone cells and extensive bone damage,^164,167 since collagen denatures with prolonged exposure to temperatures in excess of 56°C.^168,169 In addition, PMMA bone cement is not absorbable, with no functions of bone conduction or induction.¹⁷⁰

The dough time shown in Figure 4(d) represents the time elapsed between the initial mixing and the time the paste reaches a homogeneous dough-like state. As specified in the British Standard BS 7253 (ISO 5833),⁵⁷ at this point, the cement dough no longer sticks to powderless surgical gloves (typically 2–3 min after initial mixing).¹⁶⁴ The working time is the period between the end of the dough time until the cement can no longer be manipulated.¹⁶⁴ Finally, the setting time of the cement is usually defined as the time when the temperature rise is halfway between the maximum temperature (T_max) and the ambient temperature (T_amb), as described in ISO 5833.⁵⁷

Cement characteristics

Commercially available brands of ABC have similarities and differences on the basis of their chemical composition, bead size of the prepolymerized PMMA in the powder, powder particle size distribution, molecular weight of the powder, and molecular weight of the cured cement (see Table 1(b)).²⁶ The viscosity rise as a function of mixing time differs among the various brands.^26,171–173 Figure 4(e) shows how the viscosities of three commercial PMMA bone cements at 37°C increase with time and reach a maximum of ~75 kPa.s in all three cases, at which the cements turn into an elastic solid.¹⁷² The viscosity can influence the injectability of the cement, as well as its leakage, extent of retention within the vertebral body, and final mechanical properties.^174–176 Several research and review papers have reported on the kinetics of cure reactions for thermosetting resins.^177–181 Studying the effect of experimental factors on the reaction kinetics may guide the development of ABCs, and therefore, the design of experiments can be an effective approach to bone cement design, by enabling the identification of the dominant factors that influence its properties.¹⁸²

There is a limited number of literature reviews on viscoelastic properties of IBCs.^26,183–185 The rheological properties of a cement may play a significant role in the formation of pores during cement mixing and delivery. Such pores could contribute to crack formation and implant loosening over time.¹⁶⁴ In addition, properties such as creep, stress relaxation, and damping can influence the long-term performance of a cemented implant. A recent review paper by Lewis²⁶ has identified the key properties of ABCs for six commercial formulations in orthopedic use. The paper investigated how the viscoelastic properties of the cements were influenced by several relevant parameters, such the monomer-to-polymer ratio, polymerization pressure, cement mixing method, duration of cement mixing, length of aging time, test medium composition, test frequency, and temperature.²⁶ It was reported that the particle size distribution of the powder, as well as the temperature and frequency of the tests, was among the most influential variables affecting the damping behavior of the ABCs.²⁶

Some alternative formulations

Despite the widespread use of commercially available plain PMMA bone cement, mainly due to its outstanding compressive strength and functional performance, it has several major drawbacks. PMMA is not remodeled in the body,^1,6 and the exothermic reaction of PMMA cement fixation can impair fracture healing. Moreover, its high elastic modulus can result in stress shielding and implant loosening.¹⁸⁶ Hence, the use of PMMA cement to stabilize and/or reinforce fractured vertebral body (for example, in VP and BKP) can lead to extensive bone stiffening and potential fractures at the adjacent vertebral bodies.¹⁸⁷ In addition, the mechanical failure of the cement can lead to premature failure of an implant.¹⁸⁸ In a recent review of the literature, Lewis¹⁸⁹ has summarized the properties of some nanofiller-loaded PMMA bone cement composites.

Many studies have aimed at developing alternative formulations that could eliminate these drawbacks. On the basis of the shortcomings addressed in these studies, the new formulations can be grouped into 16 categories as described by Lewis.¹⁹⁰ This review paper focuses on the formulations that aim to reduce the peak temperature, improve the mechanical properties, and impart bioactivity to PMMA cements. For example, adding chitosan or starch-stabilized polyethylene glycol to PMMA bone cement has been shown to reduce the maximum curing temperature of the cement.^56,166 Although chitosan did not appear to affect the tensile properties, it increased the compressive strength of the chitosan/PMMA cement.¹⁶⁶ Chitosan is expected to degrade over time in vivo as the new bone tissue forms, which could enable the generation of a porous network over time for bone ingrowth.

Some studies have investigated the copolymerization of MMA with other materials, such as the hydrophilic acrylic acid (AA)¹⁹¹ as well as 2-hydroxyethyl methacrylate (HEMA) and diethyl 2-(methacryloyloxy)ethyl phosphate (DMP).¹⁹² Copolymers of MMA and AA, modified using 4-iodo phenyl isocyanate and 3,4,5-triiodo phenyl isocyanate as the radiopacifying agents, generated radiopaque composites as bone cement materials.¹⁹¹ Silk sericin has also shown to enhance hydrophilicity of MMA-based copolymers while imparting antibacterial ability.¹⁹³ In another study, the presence of DMP/PHEMA segments improved the thermal behavior of the MMA-based copolymer via reducing the glass transition temperature.¹⁹² Moreover, the incorporation of a commercial block copolymer, Nanostrength^® (NS), into the liquid phase of the PMMA bone cement has been shown to improve the fracture toughness of the cement.¹⁹⁴ Table 4 lists some other alternative PMMA cement formulations and briefly summarizes key findings of the cited studies.

Table 4.

Selection of studies investigating alternative PMMA bone cement formulations to improve the mechanical properties or to impart magnetic or bioactive characteristics.

Author	Additive	Quantity of the additive (wt%)	Findings
Kawashita et al.¹⁹⁵	Magnetite nanoparticles (Fe₃O₄)	40, 50, 60	Increasing the Fe₃O₄ content increased the setting time of the cement and decreased the peak temperature during setting. The cements had a compressive strength of ~90 MPa, adequate for clinical applications. Unlike the standard PMMA cement, the surface temperature of the samples containing 40% and 50% Fe₃O₄ increased rapidly in a magnetic field of 300 Oe (over 70°C within tens of seconds).
Li et al.¹⁹⁶	Magnetite nanoparticles (Fe₃O₄)	30 and 50	The addition of 30% Fe₃O₄ did not significantly alter the compressive strength of the cement or the proliferation of rat fibroblast cells on the cement. The mean diameter of Fe₃O₄ (11–35 nm) appeared to affect the heating capability in AC magnetic fields, depending on the magnetic field (40–300 Oe) and frequency (100 kHz and 600 kHz).
Miola et al.¹⁹⁷	Silver-containing bioactive glass	30	The silver release was greater on the first week, when the rate of infection development was higher, and enabled significant antibacterial effect toward S. aureus strain. The glass acted as a nucleating agent for the precipitation of hydroxyapatite on the surface of the cement by a biomimetic mechanism. Mouse fibroblast L-929 cell line was used to verify the non-cytotoxic effect of the composites.
Mousa et al.¹⁹⁸	Apatite-wollastonite glass ceramic (AW-GC)	50 and 70	Adding 70 wt% dry-silanated AW-GC to PMMA cement maintained or increased the bending strength, fracture toughness, and osteoconductivity, but reduced the elastic strain. Small-diameter PMMA beads improved the handling properties, the mechanical properties and the bioactivity of the PMMA-based cement.
Verné et al.⁶²	Ferrimagnetic bioactive glass ceramic (SC-45)	10–20	The composites supported the growth of hydroxyapatite on their surface after 28 days of immersion in a simulated body fluid (SBF). Iron leaching test revealed a negligible release of iron, while cytotoxicity assays with human osteoblasts indicated good cell viability and biocompatibility.
Serbetci et al.¹⁹⁹	Hydroxyapatite (HA)	7.7 and 14.3	Very few foreign body giant cells were reported for HA-containing cement, which was attributed to the improved in vivo biocompatibility (in rabbits) in the presence of HA. Addition of HA into the PMMA cement also increased the viscosity, improved the workability, decreased the polymerization temperature, and increased the modulus. The changes in the compressive strength depended on the PMMA brand.
Li et al.¹⁸⁶	Nano-HA coated recombinant human collagen	15	The new formulation reduced the elastic modulus from 1.91±0.08 GPa to 1.21±0.12 GPa. The in vivo results in rabbits suggested a significantly higher bone growth for the modified PMMA group when compared with their standard PMMA counterparts.
Arens et al.¹⁸⁷	Bone marrow from sheep and hydroxyapatite (HA)	15 (HA)	The maximum temperature during curing decreased from ~61°C to 38°C and the Young’s modulus decreased from 1830 to 740 MPa by adding 7.5 ml bone marrow to 23 ml cement. The samples had a porosity of up to 51%, with pores ranging between 30 and 250 μm.
Hernández et al.²⁰⁰	Strontium hydroxyapatite (SrHA)	10 and 20	Incorporation of SrHA negatively influenced the handling and mixing properties, emphasizing the need for surface treatment of SrHA particles. The surface-treated particles improved the compressive strength of the cements, although this effect was significant for 20 wt% SrHA only.
Slane et al.²⁰¹	Silver nanoparticles (AgNPs)	0.25–1.0	The cement formulations modified with AgNPs significantly reduced biofilm formation on the surface of the cement, demonstrating a potential for preventing bacterial adhesion, but showed no antimicrobial activity against planktonic bacteria. Mechanical properties were not substantially changed when compared with the standard cement.

Various magnetic materials, such as magnetite (Fe₃O₄), have been shown to generate heat in an alternating magnetic field.^125,195 Hence, these materials have been widely studied for the minimally invasive treatment of cancer through hyperthermia of metastatic bone tumors.^202,203 Adding magnetite has shown to increase the setting time of PMMA cement and decrease the maximum temperature during setting.¹⁹⁵ The addition of 30–50 wt% Fe₃O₄ did not seem to significantly impact the compressive strength of PMMA-based bone cements.^195,196

Reduction of bacterial adhesion on the cement surface can be achieved by favoring the direct bonding of the cement to the bone.¹⁹⁷ One strategy for improving the bone-bonding ability is through the addition of bioactive fillers such as bioactive glasses and glass–ceramics^{62,197,198,204,205} as well as HA.^{199,200,204,206} Bioactive glass acts as a nucleating agent for the precipitation of HA on the surface of PMMA cement.^62,197 It has been well established that HA is an osteoconductive material,^31,147 and thereby can improve the in vivo biocompatibility of PMMA bone cement.^49,199 Biological materials, such as collagen¹⁸⁶ and bone marrow,¹⁸⁷ have also been investigated in combination with bioactive fillers.

Arens et al.¹⁸⁷ studied the effect of adding freshly harvested bone marrow from sheep to a PMMA cement formulation containing 15 wt% HA. Besides a reduction in modulus in the presence of bone marrow, a higher initial cement viscosity immediately after mixing with bone marrow was deemed beneficial, as a result of a reduced risk of leakage upon injection.^{23,187,207,208} In vertebral body augmentation procedures, such as VP and BKP, cement leakage can result in life-threatening cardiac injury²⁰⁹ as well as pulmonary and cerebral embolism.^210–212

Li et al.¹⁸⁶ added 15 wt% recombinant human collagen, coated with HA nanoparticles, to a commercial PMMA cement (C-PMMA) during the early dough stage. Both C-PMMA and the modified cement (MC-PMMA) were implanted in rabbits to examine bone ingrowth and bone affinity index after 4, 12, and 24 weeks. The team reported a significantly higher bone growth for the MC-PMMA group, when compared with their C-PMMA counterparts (p<0.05).¹⁸⁶ Load transfer at the cement–bone interface is mainly influenced by direct contact at this zone. Improving the cement–bone bonding can increase the cement–bone contact area and, hence, lead to a more uniform load transfer in VP and BKP.¹⁸⁶

Drug-loaded bone cements

Silver-containing bioactive agents have been shown to reduce the risk of infection^197,201 while enhancing the bone-bonding ability of the cement.¹⁹⁷ Some new generations of bone cements offer antibiotic-loaded PMMA and CPC formulations.^{26,67,213–217} PMMA bone cement is a good carrier for sustained release of antibiotics in the site of infection.²¹⁴ This is particularly important since chronic infection of joint prostheses requires surgical removal of the implant so as to eradicate the infection.⁴⁸ Several recent papers have reviewed the efficacy and safety of ALBC and highlighted the current state-of-the art in drug-eluting cements.^{28,59–61,218,219} Nevertheless, a recent systematic review comparing deep prosthetic joint infections between total knee arthroplasty patients, treated with either ALBC or plain bone cement, has argued that ALBC would not substantially reduce prosthetic joint infections, and thereby could be considered as an unnecessary cost to the healthcare system.⁶⁸ The cost efficiency profile of ALBC in routine primary hip and knee arthroplasty seems to be different in the United States compared with Europe.²²⁰ A significant hospital overhead cost has been reported in the United States with the use of ALBC, compared with plain bone cement, as ALBC could cost as high as $350–$400 per batch compared with $60–70 per batch of plain bone cement.⁶⁹

It should be noted that CPCs have also been used with other biologically active products (e.g., analgesics and contrast agents). For example, Dupleichs et al.²²¹ have investigated the efficacy of analgesic CPCs loaded with either bupivacaine or ropivacaine. The bupivacaine-loaded cement demonstrated an earlier return to full functional recovery than the ropivacaine-loaded cement, while CPCs retained their mechanical and biological properties. In another study, Le Ferrec et al.²²² loaded CPCs with Xenetix® radiopaque agent and reported that incorporating up to 70 mg/mL of Xenetix® into CPCs did not affect the injectability, setting time, and cohesion of the composite. Upon injection in a bone defect in rats, the Xenetix®-loaded CPC appeared to be biocompatible.²²² A recent review paper by Parent et al.²²³ has elaborated on the design of CPCs for drug delivery applications, with an emphasis on the parameters affecting the loading and release of therapeutic substances. In addition, a paper by Ginebra et al.⁹⁰ provides an overview of drug release from CPCs for low molecular weight drugs (e.g., antibiotics, non-steroidal anti-inflammatories, anti-cancer drugs, and anti-osteoporotics) and for high molecular weight molecules (e.g., growth factors and other proteins). The paper also provides a summary of some CPC formulations intended for ion release (e.g., calcium, phosphate, strontium, silicate, zinc, and magnesium).

Conclusions

An aging population and sports-related injuries have led to a dramatic increase in bone-related diseases and bone fractures.⁷⁶ When biomaterials and medical devices are designed to replace a degenerated or diseased joints, these materials may highly benefit from multi-functional characteristics that can meet the biomechanical and biological requirements of the bone.¹⁶⁴ ABCs composed of PMMA have adequate compressive strength, but suffer from high elastic moduli,¹⁸⁶ high polymerization temperatures,^56,164 and lack of remodeling in the body.^1,6 In addition, cardiac complications and embolism caused by PMMA cement injection and subsequent cement leakage have been reported in several studies.^209–212 Hence, alteration in cement formulation is a rapidly evolving field.²⁰⁹ Bone cement formulations combining PMMA with bone marrow¹⁸⁷ or nano-HA coated human collagen¹⁸⁶ have been proposed to reduce the modulus of PMMA cement while improving its biocompatibility. In addition, porous PMMA cements loaded with bioactive glass have been used to improve osseointegration and provide a better mechanical stability and biological integration.⁴⁸

CPCs are osteoconductive,^106–110 release no heat,¹⁷⁰ and can be shaped arbitrarily because of their self-setting characteristic. However, they are associated with the problems of low strength, high brittleness, and low cohesion in aqueous environment.¹³⁰ These shortcomings hinder their applications as loading-bearing bone substitutes in clinical settings and minimally invasive orthopedic surgeries. Hence, there is an unmet need for tougher and biologically active bone cement materials. Reinforcement of injectable CPCs using different materials such as gelatinized starches,¹³⁰ mixtures of CPCs/PMMA cement,⁹⁹ and composites of nano-HA/PMMA cement⁴⁹ have been considered. The addition of carbon nanotubes has been shown to improve the mechanical properties of CPCs, particularly their fracture strength and toughness.^39,164 In another study, an injectable bone substitute material made of calcium-deficient HA and foamed gelatin has been proposed to promote bone ingrowth.¹⁴¹ Recently, a copper-doped CPC formulation has demonstrated that copper could be a dually effective ion: toxic for bacteria while being beneficial for the healthy cells. This is based on the increased viability of human glial E297 cells, murine osteoblastic K7M2 cells, and human primary lung fibroblasts in the presence of the cement.¹⁵⁹

Both ABC and CPC classes are relatively inadequate in terms of key biological requirements and functional mechanical properties. Taking advantage of the benefits offered by the other class and making use of nanostructured materials can potentially lead to superior bone cement formulations for orthopedics applications. Manufacturing, safety, and regulatory issues should be kept in mind when it comes to nanomaterials.¹⁶⁴ Making use of osteoinductive materials, such as DBM, has also proven to offer a biological stimulus to promote osteogenic differentiation of MSCs and other osteoprogenitor cells.^41,84

Most CPCs have apatite precipitation, which reduces the resorbability under physiological conditions because of the low degradability of HA. Enhancing the bioresorbability of bone cements can pave the way to the development of new bone substitute materials and drug delivery systems.³⁹ The current market for resorbable bone graft substitutes is small compared with the medical device market or the drug market. However, it is a fast-growing field, with materials ranging from metallic alloys to polymers and from injectable cements to complex porous structures.⁷⁶ Rigorous preclinical and clinical trials are necessary to confirm the cost-effectiveness of new injectable bone graft substitutes and assert their benefit-to-risk ratios.⁸³ As for ALBCs, the use of ALBC in routine primary hip and knee arthroplasty appears to remain controversial because of the high cost and limited efficacy reported in some recent studies.^68,220

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The author(s) received no financial support for the research,authorship,and/or publication of this article.

ORCID iD

Azizeh-Mitra Yousefi

References

Heini

Franz

Fankhauser

, et al. Femoroplasty-augmentation of mechanical properties in the osteoporotic proximal femur: A biomechanical investigation of PMMA reinforcement in cadaver bones. Clin Biomech 2004; 19(5): 506–512.

Johnell

Kanis

An estimate of worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17(12): 1726–1733.

Subramanian

Bialorucki

Yildirim-Ayan

Nanofibrous yet injectable polycaprolactone-collagen bone tissue scaffold with osteoprogenitor cells and controlled release of bone morphogenetic protein-2. Mater Sci Eng C 2015; 51: 16–27.

Liu

de Groot

Biomimetic coatings for bone tissue engineering of critical-sized defects. JR Soc Interface 2010; 7: S631–S647.

Schmitz

Hollinger

JO.

The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res 1986; 205: 299–308.

Suhm

Gisep

Injectable bone cement augmentation for the treatment of distal radius fractures: A review. J Orthop Trauma 2008; 22(8 Suppl): S121–S125.

Reichert

Epari

Wullschleger

, et al. Bone tissue engineering. Reconstruction of critical sized segmental bone defects in the ovine tibia. Orthopade 2012; 41(4): 280–287.

Reichert

Wullschleger

Cipitria

, et al. Custom-made composite scaffolds for segmental defect repair in long bones. Int Orthop 2011; 35(8): 1229–1236.

den Boer

Wippermann

Blokhuis

, et al. Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow. J Orthop Res 2003; 21: 521–528.

10.

Schlickewei

The use of bone substitutes in the treatment of bone defects-the clinical view and history. Macromol Symp 2007; 253: 10–23.

11.

Henkel

Woodruff

Epari

, et al. Bone regeneration based on tissue engineering conceptions – A 21st century perspective. Bone Res 2013; 1(3): 216–248.

12.

Vacanti

Langer

Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 1999; 354 Suppl(Suppl 1): SI32–SI34.

13.

Langer

Vacanti

Tissue engineering. Science (80-) 1993; 260: 920–926.

14.

Hutmacher

DW.

Scaffolds in tissue engineering bone and cartilage. Biomaterials 2000; 21(24): 2529–2543.

15.

Hollister

Maddox

Taboas

JM.

Optimal design and fabrication of scaffolds to mimic tissue properties and satisfy biological constraints. Biomaterials 2002; 23(20): 4095–4103.

16.

Jahan

Tabrizian

Composite biopolymers for bone regeneration enhancement in bony defects. Biomater Sci 2016; 4: 25–39.

17.

Bhumiratana

Vunjak-Novakovic

Concise Review: Personalized human bone grafts for reconstructing head and face, stem cells translational medicine. Stem Cells Transl Med 2012; 1: 64–69.

18.

Varma

Garai

Sinha

Synthesis of injectable and cohesive nano hydroxyapatite scaffolds. J Mater Sci Mater Med 2012; 23(4): 913–919.

19.

Youssef

Salas

Loshiavo

Management of painful osteoporotic vertebral fractures: Vertebroplasty and kyphoplasty. Oper Tech Ortho 2003; 13: 222–226.

20.

Bohner

Lemaitre

Cordey

, et al. Potential use of biodegradable bone cement in bone surgery: Holding strength of screws in reinforced osteoporotic bone. Orthop Trans 1992; 16: 401–402.

21.

Wang

Synthesis and property of a novel calcium phosphate cement. J Biomed Mater Res B 2009; 90: 745–751.

22.

Smeets

Marx

Kolk

, et al. In vitro study of adhesive polymethylmethacrylate bone cement bonding to cortical bone in maxillofacial surgery. J Oral Maxillofac Surg 2010; 68(12): 3028–3033.

23.

Zderic

Steinmetz

Benneker

, et al. Bone cement allocation analysis in artificial cancellous bone structures. J Orthop Transl 2017; 8: 40–48.

24.

Wong

McGirt

MJ.

Vertebral compression fractures: A review of current management and multimodal therapy. J Multidiscip Heal 2013; 6: 205–214.

25.

Levin

Anderson

Haas

, et al. Vertebroplasty and return to work for thoracolumbar fractures within the workers’ compensation population. Spine (Phila Pa 1976) 2017; 42(13): 1024–1030.

26.

Lewis

Viscoelastic properties of injectable bone cements for orthopaedic applications: State-of-the-art review. J Biomed Mater Res - Part B Appl Biomater 2011; 98B(1): 171–191.

27.

Shi

Zhang

Liu

, et al. Synergistic effects of citric acid - sodium alginate on physicochemical properties of α-tricalcium phosphate bone cement. Ceram Int 2019; 45(2, Part A): 2146–2152.

28.

Staden

Van and Dicks

LMT

. Calcium orthophosphate-based bone cements ( CPCs ): Applications, antibiotic release and alternatives to antibiotics. J Appl Biomater Funct Mater 2012; 10(1): 2–11.

29.

Ginebra

M-P

Montufar

EB.

Cements as bone repair materials. In: Pawelec

Planell

(eds) Bone Repair Biomaterials (Second Edition). Cambridge, UK: Woodhead Publishing, 2019, pp.233–271.

30.

Ratner

Hoffman

Schoen

, et al. Biomaterials science: An evolving, multidisciplinary endeavor. In: Ratner

Hoffman

Schoen

Lemon

(eds) Biomaterials Science: An Introduction to Materials in Medicine. 3rd Ed. Waltham, MA: Academic Press, 2013, pp.xxv–xxxix.

31.

Hench

Best

SM.

Ceramics, glasses, and glass-ceramics: Basic principles. In: Ratner

Hoffman

Schoen

Lemons

(eds) Biomaterials Science: An Introduction to Materials in Medicine. Third Ed. Elsevier, 2016, pp.128–167.

32.

Campion

Ball

Clarke

, et al. Microstructure and chemistry affects apatite nucleation on calcium phosphate bone graft substitutes. J Mater Sci Mater Med 2013; 24(3): 597–610.

33.

M-H

Lee

P-Y

Chen

W-C

, et al. Comparison of three calcium phosphate bone graft substitutes from biomechanical, histological, and crystallographic perspectives using a rat posterolateral lumbar fusion model. Mater Sci Eng C Mater Biol Appl 2014; 45: 82–88.

34.

Kucko

Herber

R-P

Leeuwenburgh

SCG

, et al. Calcium phosphate bioceramics and cements. In: Atala

Lanza

Mikos

Nerem RBT-P of

(eds) Principles of Regenerative Medicine (Third Edition). Boston: Academic Press, 2019. pp.591–611.

35.

Zheng

Xiao

Gong

, et al. Fabrication and characterization of a novel carbon fiber-reinforced calcium phosphate silicate bone cement with potential osteo-inductivity. Biomed Mater 2015; 11(1): 015003.

36.

Takagi

Quinn

, et al. Fast-setting calcium phosphate scaffolds with tailored macropore formation rates for bone regeneration. J Biomed Mater Res A 2004; 68: 725–734.

37.

Rodriguez

Chari

Aghyarian

, et al. Preparation and characterization of injectable brushite filled-poly (methyl methacrylate) bone cement. Materials (Basel) 2014; 7: 6779–6795.

38.

Bohner

Baroud

Injectability of calcium phosphate pastes. Biomaterials 2005; 26: 1553–1563.

39.

Low

Tan

Hussein

, et al. Calcium phosphate-based composites as injectable bone substitute materials. J Biomed Mater Res B Appl Biomater 2010; 94(1): 273–286.

40.

Nandi

Roy

Mukherjee

, et al. Orthopaedic applications of bone graft & graft substitutes: A review. Indian J Med Res 2010; 132: 15–30.

41.

Jangid

Rakhewar

Nayyar

, et al. Bone grafts and bone graft substitutes in periodontal regeneration: A review. Int J Curr Res Med Sci 2016; 2(8): 1–7.

42.

Yousefi

AM.

Smart functional porous materials for tissue engineering. In: Wang

(ed) Smart Materials for Tissue Engineering: Fundamental Principles. Cambridge: RCS, 2017. pp.358–400.

43.

Yousefi

Hoque

Prasad

RGS

, et al. Current strategies in multiphasic scaffold design for osteochondral tissue engineering: A review. J Biomed Mater Res Part A 2015; 103(7): 2460–2481.

44.

Gad

Abualsaud

Behavior of PMMA denture base materials containing titanium dioxide nanoparticles: A literature review. Int J Biomater 2019; 2019: 6190610.

45.

Shakeri

Nodehi

Atai

PMMA/double-modified organoclay nanocomposites as fillers for denture base materials with improved mechanical properties. J Mech Behav Biomed Mater 2019; 90: 11–19.

46.

Galli

Pedrazzi

Mattioli-Belmonte

, et al. The use of pulsed electromagnetic fields to promote bone responses to biomaterials in vitro and in vivo. Int J Biomater 2018; 2018.

47.

Merolli

Bone repair biomaterials in orthopedic surgery. In: Pawelec

Planell

(eds) Bone Repair Biomaterials (Second Edition) (Woodhead Publishing Series in Biomaterials). Cambridge: Woodhead Publishing, 2019, pp.301–327.

48.

Magnan

Bondi

Maluta

, et al. Acrylic bone cement: Current concept review. Musculoskelet Surg 2013; 97(2): 93–100.

49.

Quan

Tang

Liu

, et al. Effect of modification degree of nanohydroxyapatite on biocompatibility and mechanical property of injectable poly(methyl methacrylate)-based bone cement. J Biomed Mater Res B Appl Biomater 2015; 7: 1–9.

50.

Kuhn

K-D.

Bone cements: Up to date comparison of physical and chemical properties of commercial materials. Berlin: Springer-Verlag, 2000.

51.

Jensen

Linde

Long-term follow-up on 33 TPR ankle joint replacements in 26 patients with rheumatoid arthritis. Foot Ankle Surg 2009; 15: 123–126.

52.

Fevang

Lie

Havelin

, et al. Results after 562 total elbow replacements: A report from Norwegian Arthroplasty Register. J Shoulder Elb Surg 2009; 18: 449–456.

53.

Throckmorton

Zarkadas

Sperling

, et al. Pegged versus keeled glenoid components in total shoulder arthroplasty. J Shoulder Elb Surg 2010; 19: 726–733.

54.

Kramer

Angst

Gasser

, et al. Increasing bone screw anchoring in the femur head by cement administration via the implant–a biomechanical study. Z Orthop Ihre Grenzgeb 2000; 5: 464–469.

55.

Heini

Berlemann

Kaufmann

, et al. Augmentation of mechanical properties in osteoporotic vertebral bones–a biomechanical investigation of vertebroplasty efficacy with different bone cements. Eur Spine J 2001; 2: 164–171.

56.

Krol

Macherzynska Beata Pielichowska

Acrylic bone cements modified with poly (ethylene glycol) -based biocompatible phase-change materials. J Appl Polym Sci 2016; 43898: 1–11.

57.

ISO. International standard 5833/2: Implants for surgery-acrylic resin cements. Orthopaedic Appl. 2002.

58.

Chen

Zhang

Kang

, et al. Recent progress in injectable bone repair materials research. Front Mater Sci 2015; 9(4): 332–345.

59.

Wang

Zhu

Cheng

, et al. A systematic review and meta-analysis of antibiotic- impregnated bone cement use in primary total hip or knee arthroplasty. PLoS One 2013; 8(12): e82745.

60.

Hinarejos

Guirro

Puig-Verdie

, et al. Use of antibiotic-loaded cement in total knee arthroplasty. World J Orthop 2015; 6(11): 877–885.

61.

Bistolfi

Massazza

Vern

, et al. Antibiotic-loaded cement in orthopedic surgery: A review. ISRN Orthop 2011; 2011: 290851.

62.

Verné

Bruno

Miola

, et al. Composite bone cements loaded with a bioactive and ferrimagnetic glass-ceramic: Leaching, bioactivity and cytocompatibility. Mater Sci Eng C 2015; 53: 95–103.

63.

Dorozhkin

SV.

Functional biomaterials self-setting calcium orthophosphate formulations. J Funct Biomater 2013; 4: 209–311.

64.

Bohner

Tadier

van Garderen

, et al. Synthesis of spherical calcium phosphate particles for dental and orthopedic applications. Biomatter 2013; 3(2): e25103.

65.

Canal

Ginebra

MP.

Fibre-reinforced calcium phosphate cements: A review. J Mech Behav Biomed Mater 2011; 4(8): 1658–1671.

66.

Larsson

Hannink

Injectable bone-graft substitutes: Current products, their characteristics and indications, and new developments. Injury 2011; 42: S30–S34.

67.

Qin

López

Öhman

, et al. Enhanced drug delivery of antibiotic-loaded acrylic bone cements using calcium phosphate spheres. J Appl Biomater Funct Mater 2015; 13(3): e241–e247.

68.

King

Hamilton

Jacobs

, et al. The hidden cost of commercial antibiotic-loaded bone cement: A systematic review of clinical results and cost implications following total knee arthroplasty. J Arthroplasty 2018; 33(12): 3789–3792.

69.

Qadir

Sidhu

Ochsner

, et al. Risk stratified usage of antibiotic-loaded bone cement for primary total knee arthroplasty: Short term infection outcomes with a standardized cement protocol. J Arthroplasty 2014; 29(8): 1622–1624.

70.

Zimmermann

Busse

Ritchie

RO.

The fracture mechanics of human bone: Influence of disease and treatment. Bonekey Rep 2015; 4: 743.

71.

Meyers

Chen

P-Y

Lin

AY-M

, et al. Biological materials: Structure and mechanical properties. Prog Mater Sci 2008; 53(1): 1–206.

72.

Wegst

UGK

Bai

Saiz

, et al. Bioinspired structural materials. Nat Mater 2015; 14: 23–36.

73.

Ozturk

Inci

Egri

, et al. The treatment of segmental bone defects in rabbit tibiae with vascular endothelial growth factor (VEGF)-loaded gelatin/hydroxyapatite “cryogel” scaffold. Eur J Orthop Surg Traumatol 2013; 23(7): 767–774.

74.

Jeon

Vaquette

Klein

, et al. Perspectives in multiphasic osteochondral tissue engineering. Anat Rec (Hoboken) 2014; 297(1): 26–35.

75.

Goff

Kanakaris

Giannoudis

PV.

Use of bone graft substitutes in the management of tibial plateau fractures. Injury 2013; 44(Suppl 1): S86-S94.

76.

Bohner

Resorbable biomaterials as bone graft substitutes. Mater Today 2010; 13(1–2): 24–30.

77.

Uth

Mueller

Smucker

, et al. Validation of scaffold design optimization in bone tissue engineering: Finite element modeling versus designed experiments. Biofabrication 2017; 9: 015023.

78.

Robinson

Moglia

Stuebben

, et al. Achieving interconnected pore architecture in injectable polyHIPEs for bone tissue engineering. Tissue Eng Part A 2014; 20(5–6): 1103–1112.

79.

Temenoff

Mikos

Injectable biodegradable materials for orthopedic tissue engineering. Biomaterials 2000; 21: 2405–2412.

80.

Rai

Oest

Dupont

, et al. Combination of platelet-rich plasma with polycaprolactone-tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res Part A 2007; 81(4): 888–899.

81.

Klammert

Reuther

Blank

, et al. Phase composition, mechanical performance and in vitro biocompatibility of hydraulic setting calcium magnesium phosphate cement. Acta Biomater 2010; 6(4): 1529–1535.

82.

Ostrowski

Roy

Kumta

PN.

Magnesium phosphate cement systems for hard tissue applications: A review. ACS Biomater Sci Eng 2016; 2(7): 1067–1683.

83.

Ricciardi

Bostrom

MP.

Bone graft substitutes: Claims and credibility. Semin Arthroplasty 2013; 24(2): 119–123.

84.

Aghdasi

Montgomery

Daubs

, et al. A review of demineralized bone matrices for spinal fusion: The evidence for efficacy. Surgeon 2013; 11(1): 39–48.

85.

Puppi

Chiellini

Piras

, et al. Polymeric materials for bone and cartilage repair. Prog Polym Sci 2010; 35(4): 403–440.

86.

Zhou

Lawrence

Bhaduri

SB.

Fabrication aspects of PLA-CaP/PLGA-CaP composites for orthopedic applications: A review. Acta Biomater 2012; 8(6): 1999–2016.

87.

Dorozhkin

Biphasic, triphasic and multiphasic calcium orthophosphates. Acta Biomater 2012; 8(3): 963–977.

88.

Brown

Chow

A new calcium-phosphate setting cement. J Dent Res 1983; 62: 672.

89.

O’Neill

McCarthy

Montufar

, et al. Critical review: Injectability of calcium phosphate pastes and cements. Acta Biomater 2017; 50: 1–19.

90.

Ginebra

Canal

Pastorino

, et al. Calcium phosphate cements as drug delivery materials. Adv Drug Deliv Rev 2012; 64(12): 1090–1110.

91.

Habraken

Habibovic

Epple

, et al. Calcium phosphates in biomedical applications: Materials for the future? Biochem Pharmacol 2016; 19(2): 69–87.

92.

Pinar

Helgason

Koh

, et al. The effect of water on the mechanical properties of soluble and insoluble ceramic cements. J Mech Behav Biomed Mater 2015; 51: 50–60.

93.

Heinemann

Rössler

Lemm

, et al. Properties of injectable ready-to-use calcium phosphate cement based on water-immiscible liquid. Acta Biomater 2013; 9(4): 6199–6207.

94.

Mellier

Lefèvre

F-X

Fayon

, et al. A straightforward approach to enhance the textural, mechanical and biological properties of injectable calcium phosphate apatitic cements (CPCs): CPC/blood composites, a comprehensive study. Acta Biomater 2017; 62: 328–339.

95.

Tadier

Galea

Charbonnier

, et al. Phase and size separations occurring during the injection of model pastes composed of β-tricalcium phosphate powder, glass beads and aqueous solutions. Acta Biomater 2014; 10(5): 2259–2268.

96.

Mechanical and rheological properties and injectability of calcium phosphate cement containing poly (lactic-co-glycolic acid) microspheres. Mater Sci Eng C 2009; 29(6): 1901–1906.

97.

Gbureck

Spatz

Thull

, et al. Rheological enhancement of mechanically activated α-tricalcium phosphate cements. J Biomed Mater Res Part B Appl Biomater 2005; 73B(1): 1–6.

98.

Schumacher

Henß

Rohnke

, et al. A novel and easy-to-prepare strontium(II) modified calcium phosphate bone cement with enhanced mechanical properties. Acta Biomater 2013; 9(7): 7536–7544.

99.

Yang

Zhang

, et al. Preparation of calcium phosphate cement and polymethyl methacrylate for biological composite bone cements. Med Sci Monit 2015; 21: 1162–1172.

100.

Espanol

Perez

Montufar

, et al. Intrinsic porosity of calcium phosphate cements and its significance for drug delivery and tissue engineering applications. Acta Biomater 2009; 5(7): 2752–2762.

101.

Qiao

Wang

Xie

, et al. Injectable calcium phosphate-alginate-chitosan microencapsulated MC3T3-E1 cell paste for bone tissue engineering in vivo. Mater Sci Eng C 2013; 33(8): 4633–4639.

102.

Ida

Bae

Sekine

, et al. Effects of powder-to-liquid ratio on properties of β-tricalcium-phosphate cements modified using high-energy ball-milling. Dent Mater J 2017; 36(5): 590–599.

103.

ISO/DIS 18531(en) Implants for surgery — Calcium phosphate bioceramics — Characterization of hardening bone paste materials.

104.

Gbureck

Barralet

Spatz

, et al. Ionic modification of calcium phosphate cement viscosity. Part I: hypodermic injection and strength improvement of apatite cement. Biomaterials 2004; 25: 2187–2195.

105.

Barralet

Grover

Gbureck

Ionic modification of calcium phosphate cement viscosity. Part II: hypodermic injection and strength improvement of brushite cement. Biomaterials 2004; 25: 2197–2203.

106.

Wagoner Johnson

Herschler

. A review of the mechanical behavior of CaP and CaP/polymer composites for applications in bone replacement and repair. Acta Biomater 2011; 7(1): 16–30.

107.

Ooms

Wolke

JGC

Heuvel

Van De , et al. Histological evaluation of the bone response to calcium phosphate cement implanted in cortical bone. Biomaterials 2003; 24: 989–1000.

108.

Willem

Hoekstra

, et al. The in vivo performance of CaP/PLGA composites with varied PLGA microsphere sizes and inorganic compositions. Acta Biomater 2013; 9(7): 7518–7526.

109.

Kanter

Geffers

Ignatius

, et al. Control of in vivo mineral bone cement degradation. Acta Biomater 2014; 10(7): 3279–3287.

110.

Verron

Pissonnier

Lesoeur

, et al. Vertebroplasty using bisphosphonate-loaded calcium phosphate cement in a standardized vertebral body bone defect in an osteoporotic sheep model. Acta Biomater 2014; 10(11): 4887–4895.

111.

Zhang

Liu

Gauthier

, et al. A simple and effective approach to prepare injectable macroporous calcium phosphate cement for bone repair: Syringe-foaming using a viscous hydrophilic polymeric solution. Acta Biomater 2016; 31: 326–338.

112.

Kovtun

Goeckelmann

Niclas

, et al. In vivo performance of novel soybean/gelatin-based bioactive and injectable hydroxyapatite foams. Acta Biomater 2015; 12: 242–249.

113.

Hesaraki

Zamanian

Moztarzadeh

. The influence of the acidic component of the gas-foaming porogen used in preparing an injectable porous calcium phosphate cement on its properties: Acetic acid versus citric acid. J Biomed Mater Res Part B Appl Biomater 20081; 86B(1): 208–216.

114.

Shariff

Tsuru

Ishikawa

Fabrication of interconnected pore forming α-tricalcium phosphate foam granules cement. J Biomater Appl 2016; 30(6): 838–845.

115.

Sipaut

Jafarzadeh

Sundang

, et al. Size control in porosity of hydroxyapatite using a mold of polyurethane foam. J Inorg Organomet Polym Mater 2016; 26(5): 1066–1074.

116.

Almirall

Delgado

Ginebra

, et al. Effect of albumen as protein-based foaming agent in a calcium phosphate bone cement. Key Eng Mater 2004; 254: 253–256.

117.

Engel

Asin

Delgado

, et al. Cell behaviour of calcium phosphate bone cement modified with a protein-based foaming agent. Key Eng Mater 2005; 284: 117–120.

118.

Bohner

Doebelin

Baroud

Theoretical and experimental approach to test the cohesion of calcium phosphate pastes. Eur Cell Mater 2006; 12: 26–35.

119.

Patel

Blackburn

andWilson

DI.

Modelling of paste flows subject to liquid phase migration. Int J Numer Meth Eng 2007; 72: 1157–1180.

120.

Kheli

Perrot

Lecompte

, et al. Prediction of extrusion load and liquid phase filtration during ram extrusion of high solid volume fraction pastes. Powder Technol 2013; 249: 258–268.

121.

Rough

Wilson

Bridgwater

A model describing liquid phase migration within an extruding microcrystalline cellulose paste. Chem Eng Res Des 2002; 80(7): 701–714.

122.

Zhang

Rough

Ward

, et al. A comparison of ram extrusion by single-holed and multi-holed dies for extrusion – spheronisation of microcrystalline-based pastes. Int J Pharm 2011; 416(1): 210–222.

123.

Yaras

Kalyon

PDM

Yilmazer

Flow instabilities in capillary flow of concentrated suspensions. Rheol Acta 1994; 48–59.

124.

Khairoun

Boltong

Driessens

, et al. Some factors controlling the injectability of calcium phosphate bone cements. J Mater Sci 1998; 9(8): 425–428.

125.

Portela

Vasconcelos

Branco

, et al. An in vitro and in vivo investigation of the biological behavior of a ferrimagnetic cement for highly focalized thermotherapy. J Mater Sci Mater Med 2010; 21(8): 2413–2423.

126.

Sarda

Fernández

Llorens

, et al. Rheological properties of an apatitic bone cement during initial setting. J Mater Sci Mater Med 2001; 2: 905–909.

127.

Wang

Effects of additives on the rheological properties and injectability of a calcium phosphate bone substitute material. J Biomed Mater Res Part B Appl Biomater 2006; 78: 259–264.

128.

Borzacchiello

Sanginario

Ambrosio

, et al. Characterization of an injectable hydrogel composite for orthopedic applications. In: Proceedings of the Second International Conference on New Biomedical Materials, April 6–8, Cardiff, UK, 2003.

129.

Zhang

Liu

Schnitzler

, et al. Calcium phosphate cements for bone substitution: Chemistry, handling and mechanical properties. Acta Biomater 2014; 10(3): 1035–1049.

130.

Liu

Guan

Wei

, et al. Reinforcement of injectable calcium phosphate cement by gelatinized starches. J Biomed Mater Res B Appl Biomater 2016; 104(3): 615–625.

131.

Komath

Varma

HK.

Development of a fully injectable calcium phosphate cement for orthopedic and dental applications. Bull Mater Sci 2003; 26(4): 415–422.

132.

Khairoun

Driessens

FCM

Boltong

, et al. Addition of cohesion promotors to calcium phosphate cements. Biomaterials 1999; 20(4): 393–398.

133.

O’Mahony

Garigapati

Wai

, et al. Post irradiation shelf-stable dual paste direct injectable bone cement precursor systems and methods of making same. U.S. Patent 8,722,073, 2014.

134.

Sakai

Anada

Tsuchiya

, et al. Comparative study on the resorbability and dissolution behavior of octacalcium phosphate, β-tricalcium phosphate, and hydroxyapatite under physiological conditions. Dent Mater J 2016; 35(2): 216–224.

135.

Smith

Santoro

Grosfeld

, et al. Incorporation of fast dissolving glucose porogens into an injectable calcium phosphate cement for bone tissue engineering. Acta Biomater 2017; 50: 68–77.

136.

van Houdt

Preethanath

van Oirschot

, et al. Toward accelerated bone regeneration by altering poly(d,l-lactic-co-glycolic) acid porogen content in calcium phosphate cement. J Biomed Mater Res A 2016; 104(2): 483–492.

137.

Lopez-Heredia

Sariibrahimoglu

Yang

, et al. Influence of the pore generator on the evolution of the mechanical properties and the porosity and interconnectivity of a calcium phosphate cement. Acta Biomater 2012; 8(1): 404–414.

138.

Tödtmann

Lode

Mann

, et al. Influence of different modifications of a calcium phosphate cement on resorption and new bone formation: An in vivo study in the minipig. J Biomed Mater Res - Part B Appl Biomater 2013; 101(8): 1410–1418.

139.

Lee

Makkar

Paul

, et al. Incorporation of BMP-2 loaded collagen conjugated BCP granules in calcium phosphate cement based injectable bone substitutes for improved bone regeneration. Mater Sci Eng C 2017; 77: 713–724.

140.

Chen

Tien

, et al. Osteoregenerative capacities of dicalcium phosphate-rich calcium phosphate bone cement. J Biomed Mater Res - Part A 2015; 103(1): 203–210.

141.

Dessì

Alvarez-Perez

De Santis

, et al. Bioactivation of calcium deficient hydroxyapatite with foamed gelatin gel. A new injectable self-setting bone analogue. J Mater Sci Mater Med 2014; 25(2): 283–295.

142.

Hasan

Carpenter

Wei

, et al. Effects of adding resorbable phosphate glass fibres and PLA to calcium phosphate bone cements. J Appl Biomater Funct Mater 2014; 12(3): 203–209.

143.

Sharifi

Almasi

Sudin

Bin , et al. Enhancement of the mechanical properties of hydroxyapatite/sulphonated poly ether ether ketone treated layer for orthopaedic and dental implant application. Int J Biomater 2018; 2018: ID 9607195.

144.

Liao

Cui

FZ.

In vitro and in vivo degradation of mineralized collagen-based composite scaffold: nanohydroxyapatite/collagen/poly(L-lactide). Tissue Eng 2004; 10(1–2): 73–80.

145.

Webster

Ergun

Doremus

, et al. Specific proteins mediate enhanced osteoblast adhesion on nanophase ceramics. J Biomed Mater Res 2000; 51(3): 475–483.

146.

Minton

Janney

Akbarzadeh

, et al. Solvent-free polymer/bioceramic scaffolds for bone tissue engineering: Fabrication, analysis, and cell growth. J Biomater Sci Polym Ed 2014; 25(16): 1856–1874.

147.

Coutu

Cuerquis

El Ayoubi

, et al. Hierarchical scaffold design for mesenchymal stem cell-based gene therapy of hemophilia B. Biomaterials 2011; 32(1): 295–305.

148.

Coutu

Yousefi

Galipeau

Three-dimensional porous scaffolds at the crossroads of tissue engineering and cell-based gene therapy. J Cell Biochem 2009; 108(3): 537–546.

149.

Yousefi

James

Akbarzadeh

, et al. Prospect of stem cells in bone tissue engineering: A review. Stem Cells Int 2016; 2016: 6180487.

150.

Yousefi

Oudadesse

Akbarzadeh

, et al. Physical and biological characteristics of nanohydroxyapatite and bioactive glasses used for bone tissue engineering. Nanotechnol Rev 2014; 3(6): 527–552.

151.

Akbarzadeh

Yousefi

AM.

Effects of processing parameters in thermally induced phase separation technique on porous architecture of scaffolds for bone tissue engineering. J Biomed Mater Res B Appl Biomater 2014; 102(6): 1304–1315.

152.

Shi

Huang

Cai

, et al. Size effect of hydroxyapatite nanoparticles on proliferation and apoptosis of osteoblast-like cells. Acta Biomater 2009; 5: 338–345.

153.

Kim

Dean

, et al. Early osteogenic signal expression of rat bone marrow stromal cells is influenced by both hydroxyapatite nanoparticle content and initial cell seeding density in biodegradable nanocomposite scaffolds. Acta Biomater 2011; 7: 1249–1264.

154.

Lock

Nguyen

TYT

Liu

, et al. Nanophase hydroxyapatite and poly(lactide-co-glycolide) composites promote human mesenchymal stem cell adhesion and osteogenic differentiation in vitro. J Mater Sci Mater Med 2012; 23(10): 2543–2552.

155.

Sethuraman

Nair

El-Amin

, et al. Development and characterization of biodegradable nanocomposite injectables for orthopaedic applications based on polyphosphazenes. J Biomater Sci Polym Ed 2010; 22(4–6): 733–752.

156.

W-W

Elkasabi

Chen

H-Y

, et al. The use of reactive polymer coatings to facilitate gene delivery from poly (epsilon-caprolactone) scaffolds. Biomaterials 2009; 30(29): 5785–5792.

157.

Schumacher

Lode

Helth

, et al. A novel strontium(II)-modified calcium phosphate bone cement stimulates human-bone-marrow-derived mesenchymal stem cell proliferation and osteogenic differentiation in vitro. Acta Biomater 2013; 9(12): 9547–9557.

158.

Zhu

Guo

, et al. Development of Sr-incorporated biphasic calcium phosphate bone cement. Biomed Mater 2017; 12(1): 015016.

159.

Rau

Graziani

, et al. The bone building blues: Self-hardening copper-doped calcium phosphate cement and its in vitro assessment against mammalian cells and bacteria. Mater Sci Eng C 2017; 79: 270–279.

160.

Bonnelye

Chabadel

Saltel

, et al. Dual effect of strontium ranelate: Stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 2008; 42(1): 129–138.

161.

Thormann

Ray

Sommer

, et al. Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats. Biomaterials 2013; 34(34): 8589–8598.

162.

Faucheux

Verron

Soueidan

, et al. Controlled release of bisphosphonate from a calcium phosphate biomaterial inhibits osteoclastic resorption in vitro. J Biomed Mater Res A 2009; 89(1): 46–56.

163.

McClung

Bisphosphonates in osteoporosis: Recent clinical experience. Expert Opin Pharmacother 2000; 1: 225–238.

164.

Dunne

Ormsby

RW.

MWCNT used in orthopaedic bone cements. In: Naraghi

(ed) Carbon nanotubes – growth and applications. IntechOpen, 2011, pp.337–392.

165.

Bongio

Beucken

JJJP

Van Den Leeuwenburgh

SCG

, et al. Preclinical evaluation of injectable bone substitute materials. J Tissue Eng Regen Med 2015; 9(3): 191–209.

166.

Endogan

Kiziltay

Kose

, et al. Acrylic bone cements: Effects of the poly(methyl methacrylate) powder size and chitosan addition on their properties. J Appl Polym Sci 2014; 131(3): 39662.

167.

Liptáková

Lelovics

Necas

Variations of temperature of acrylic bone cements prepared by hand and vacuum mixing during their polymerization. Acta Bioeng Biomech 2009; 11(3): 47–51.

168.

Webb

Spencer

The role of polymethylmethacrylate bone cement in modern orthopaedic surgery. J Bone Jt Surg 2007; 89: 851–857.

169.

Saleh

Othmani

MM El

Tzeng

, et al. Acrylic bone cement in total joint arthroplasty: A review. J Orthop Res 2016; 34: 737–744.

170.

Axrap

Wang

Liu

, et al. Study on adhesion, proliferation and differentiation of osteoblasts promoted by new absorbable bioactive glass injection in vitro. Eur Rev Med Pharmacol Sci 2016; 20: 4677–4681.

171.

Lewis

Carroll

Rheological properties of acrylic bone cement during curing and the role of the size of the powder particles. J Biomed Mater Res - Part A 2002; 63(2): 191–199.

172.

Nicholas

MKD

Waters

MGJ

Holford

, et al. Analysis of rheological properties of bone cements. J Mater Sci Mater Med 2007; 18: 1407–1412.

173.

Hernández

Gurruchaga

Goñi

Influence of powder particle size distribution on complex viscosity and other properties of acrylic bone cement for vertebroplasty and kyphoplasty. J Biomed Mater Res - Part B Appl Biomater 2006; 77(1): 98–103.

174.

Craig

Dunne

Biomechanics of vertebroplasty: Effect of cement viscosity on mechanical behaviour. Key Eng Mater 2014; 587: 416–421.

175.

Zhang

Wang

Feng

, et al. A comparison of high viscosity bone cement and low viscosity bone cement vertebroplasty for severe osteoporotic vertebral compression fractures. Clin Neurol Neurosurg 2015; 129: 10–16.

176.

Pelletier

Waites

Lau

, et al. Viscosity of bone cement influences effectiveness of vacuum mixing. Int J Polym Mater Polym Biomater 2013; 62(2): 95–100.

177.

Yousefi

Lafleur

Gauvin

Kinetic studies of thermoset cure reactions: A review. Polym Compos 1997; 18(2): 157–168.

178.

Yousefi

Cure analysis of promoted polyester and vinylester reinforced composites and heat transfer in RTM molds. PhD dissertation, Ecole Polytechnique de Montreal, 1996.

179.

Kamal

Sourour

Kinetics and thermal characterization of thermoset cure. Polym Eng Sci 1973; 13(1): 59–64.

180.

Strachan

Molecular scale simulations on thermoset polymers: A review. J Polym Sci Part B Polym Phys 2015; 53(2): 103–122.

181.

Pomrink

DiCicco

Clineff

, et al. Evaluation of the reaction kinetics of CORTOSSTM, a thermoset cortical bone void filler. Biomaterials 2003; 24(6): 1023–1031.

182.

Clements

Walker

Pentlavalli

, et al. Optimisation of a two-liquid component pre-filled acrylic bone cement system: A design of experiments approach to optimise cement final properties. J Mater Sci Mater Med 2014; 25(10): 2287–2296.

183.

Saha

Pal

Mechanical properties of bone cement: A review. J Biomed Mater Res 1984; 18: 435–462.

184.

Boesel

Reis

A review on the polymer properties of hydrophilic, partially degradable and bioactive acrylic cements. Prog Polym Sci 2008; 33: 180–190.

185.

Lewis

Properties of acrylic bone cement: State-of-the-art review. J Biomed Mater Res Appl Biomater 1997; 38(2): 155–182.

186.

Weng

Bian

, et al. Influence of nano-HA coated bone collagen to acrylic (polymethylmethacrylate) bone cement on mechanical properties and bioactivity. PLoS One 2015; 10(6): e0129018.

187.

Arens

Rothstock

Windolf

, et al. Bone marrow modified acrylic bone cement for augmentation of osteoporotic cancellous bone. J Mech Behav Biomed Mater 2011; 4(8): 2081–2089.

188.

Slane

Vivanco

Meyer

, et al. Modification of acrylic bone cement with mesoporous silica nanoparticles: Effects on mechanical, fatigue and absorption properties. J Mech Behav Biomed Mater 2014; 29: 451–461.

189.

Lewis

Properties of nanofiller-loaded poly (methyl methacrylate) bone cement composites for orthopedic applications: A review. J Biomed Mater Res Part B Appl Biomater 2017; 105(5): 1260–1284.

190.

Lewis

Alternative acrylic bone cement formulations for cemented arthroplasties: Present status, key issues, and future prospects. J Biomed Mater Res - Part B Appl Biomater 2008; 84(2): 301–319.

191.

Shiralizadeh

Nasr-Isfahani

Keivanloo

, et al. Radiopaque nanocomposites based on biocompatible iodinated N-phenyl amide-modified methyl methacrylate/acrylic acid copolymer. J Polym Res 2017; 24(11): 186.

192.

Peng

Y-F

Tsai

Huang

M-H.

Synthesis and thermal investigation of phosphate-functionalized acrylic materials. Polym J 2018; 50(10): 967–974.

193.

Wang

, et al. Preparation of a bio-composite of sericin-g-PMMA via HRP-mediated graft copolymerization. Int J Biol Macromol 2018; 117: 323–330.

194.

Paz

Abenojar

Ballesteros

, et al. Mechanical and thermal behaviour of an acrylic bone cement modified with a triblock copolymer. J Mater Sci Mater Med 2016; 27(4): 72.

195.

Kawashita

Kawamura

PMMA-based bone cements containing magnetite particles for the hyperthermia of cancer. Acta Biomater 2010; 6: 3187–3192.

196.

Kawamura

Kawashita

, et al. In vitro assessment of poly (methylmethacrylate)-based bone cement containing magnetite nanoparticles for hyperthermia treatment of bone tumor. J Biomed Mater Res A 2012; 100A: 2537–2345.

197.

Miola

Fucale

Maina

, et al. Composites bone cements with different viscosities loaded with a bioactive and antibacterial glass. J Mater Sci 2017; 5133–5146.

198.

Mousa

Kobayashi

Shinzato

, et al. Biological and mechanical properties of PMMA-based bioactive bone cements. Biomaterials 2000; 21: 2137–2146.

199.

Serbetci

Korkusuz

Hasirci

Thermal and mechanical properties of hydroxyapatite impregnated acrylic bone cements. Polym Test 2004; 23: 145–155.

200.

Hernández

Gurruchaga

Goñi

Injectable acrylic bone cements for vertebroplasty based on a radiopaque hydroxyapatite. Formulation and rheological behaviour. J Mater Sci Mater Med 2009; 20(1): 89–97.

201.

Slane

Vivanco

Rose

, et al. Mechanical, material, and antimicrobial properties of acrylic bone cement impregnated with silver nanoparticles. Mater Sci Eng C 2015; 48: 188–196.

202.

Ito

Kobayashi

Intracellular hyperthermia using magnetic nanoparticles: A novel method for hyperthermia clinical applications. Therm Med 2008; 24: 113–129.

203.

Matsumine

Kusuzaki

Matsubara

, et al. Novel hyperthermia for metastatic bone tumors with magnetic materials by generating an alternating electromagnetic field. Clin Exp Metas 2007; 24: 191–200.

204.

Heikkila

Aho

Kangasniemi

, et al. Polymethylmethacrylate composites: Disturbed bone formation at the surface of bioactive glass and hydroxyapatite. Biomaterials 1996; 17: 1755–1760.

205.

Miola

Bruno

Maina

, et al. Antibiotic-free composite bone cements with antibacterial and bioactive properties. A preliminary study. Mater Sci Eng C 2014; 43: 65–75.

206.

Lam

Pan

Fong

, et al. In vitro characterization of low modulus linoleic acid coated strontium-substituted hydroxyapatite containing PMMA bone cement. J Biomed Mater Res - Part B Appl Biomater 2011; 96: 76–83.

207.

Baroud

Crookshank

Bohner

High-viscosity cement significantly enhances uniformity of cement filling in vertebroplasty: An experimental model and study on cement leakage. Spine (Phila Pa 1976) 2006; 31: 2562–2568.

208.

Kolmeder

Lion

Landgraf

, et al. Thermophysical properties and material modelling of acrylic bone cements used in vertebroplasty. J Therm Anal Calorim 2011; 105(2): 705–718.

209.

Shridhar

Chen

Khalil

, et al. A review of PMMA bone cement and intra-cardiac embolism. Materials (Basel) 2016; 9(10): 821.

210.

Jang

Lee

Jung

Pulmonary embolism of polymethylmethacrylate after percutaneous vertebroplasty: A report of three cases. Spine (Phila Pa 1976) 2002; 27: E416–E418.

211.

Scroop

Eskridge

Britz

Paradoxical cerebral arterial embolization of cement during intraoperative vertebroplasty: Case report. AJNR Am J Neuroradiol 2002; 23: 868–870.

212.

Lewis

Percutaneous vertebroplasty and kyphoplasty for the stand-alone augmentation of osteoporosis-induced vertebral compression fractures: Present status and future directions. J Biomed Mater Res - Part B Appl Biomater 2007; 81(2): 371–386.

213.

Lee

Tai

Chen

, et al. Elution and mechanical strength of vancomycin-loaded bone cement: In vitro study of the influence of brand combination. PLoS One 2016; 11(11): e0166545.

214.

Gálvez-López

Peña-Monje

Antelo-Lorenzo

, et al. Elution kinetics, antimicrobial activity, and mechanical properties of 11 different antibiotic loaded acrylic bone cement. Diagn Microbiol Infect Dis 2014; 78(1): 70–74.

215.

Moojen

DJF

Hentenaar

Vogely

, et al. In vitro release of antibiotics from commercial PMMA beads and articulating hip spacers. J Arthroplasty 2008; 23(8): 1152–1156.

216.

Liu

Wong

Fong

, et al. Gentamicin-loaded strontium-containing hydroxyapatite bioactive bone cement — An efficient bioactive antibiotic drug delivery system. J Biomed Mater Res B Appl Biomater 2010; 95B: 397–406.

217.

Wang

Qiu

G-X

Lin

, et al. Antibiotic bone cement cannot reduce deep infection after primary total knee arthroplasty. Orthopedics 2015; 38(6): e462–e466.

218.

Lewis

Properties of antibiotic-loaded acrylic bone cements for use in cemented arthroplasties: A state-of-the-art review. J Biomed Mater Res - Part B Appl Biomater 2009; 89B: 558–574.

219.

Hake

Young

Hak

, et al. Local antibiotic therapy strategies in orthopaedic trauma: Practical tips and tricks and review of the literature. Injury 2015; 46: 1447–1456.

220.

Suleiman

Mesko

Nam

Intraoperative considerations for treatment/prevention of prosthetic joint infection. Curr Rev Musculoskelet Med 2018; 11(3): 401–408.

221.

Dupleichs

Masson

Gauthier

, et al. Pain management after bone reconstruction surgery using an analgesic bone cement: A functional noninvasive in vivo study using gait analysis. J Pain 2018; 19(10): 1169–1180.

222.

Le Ferrec

Mellier

Boukhechba

, et al. Design and properties of a novel radiopaque injectable apatitic calcium phosphate cement, suitable for image-guided implantation. J Biomed Mater Res Part B Appl Biomater 2018; 106(8): 2786–2795.

223.

Parent

Baradari

Champion

, et al. Design of calcium phosphate ceramics for drug delivery applications in bone diseases: A review of the parameters affecting the loading and release of the therapeutic substance. J Control Release 2017; 252: 1–17.

A review of calcium phosphate cements and acrylic bone cements as injectable materials for bone repair and implant fixation

Abstract

Keywords

Introduction

Bone graft substitutes

Calcium phosphate cements

Composition and cement formation

Cement injectability

Some alternative formulations

Acrylic bone cements

Composition and cement formation

Cement characteristics

Some alternative formulations

Drug-loaded bone cements

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References