Poly (methyl methacrylate) bone cement (also referred to as acrylic bone cement or bone cement) comes in two variants: plain (no antibiotic loaded) and antibiotic-loaded. Arguably, bone cement is the most well-known material in orthopaedic and spinal surgery because it is used in a plethora of applications, which may be collected into six groups. First, to anchor a primary total arthroplasty (PTA) [2]-[4]; second, in local antibiotic delivery systems, such as in antibiotic-loaded cement used to prevent/manage periprosthetic joint infection (PJI) in revision total arthroplasty (RTA) [2][5][6] or prophylactic placement of antibiotic-loaded bone cement discs with tissue expander insertion during a mastectomy [7]; third, to reduce surgical site infections in spine surgery [8]; fourth, for augmentation of osteoporosis-induced vertebral compression fractures (AOVCFs), in particular, percutaneous vertebroplasty (PVP) and percutaneous balloon kyphoplasty (PBK) [9][10]; fifth, for local delivery of chemotherapeutic drugs [11][12] or antimicrobial agents to the site of an infection, as is the case in infected diabetic foot ulcers [13]; and sixth, for bone filling in weight-bearing regions of the body following resection of a tumor [14] or repair of the skull vault defect following a craniectomy or a traumatic head injury [15].

In current clinical practice, the predominant uses of bone cement are for fixation of PTA and RTA (especially, of the hip and the knee), PVP, and BKP. Thus, for example, in 2023, 62%, 78%, and 96% of total knee arthroplasties (TKAs) performed in Australia, United States, and Germany, respectively, were cemented [16], 85% and 96% of total hip arthroplasties (THAs) in Sweden and the Netherlands, respectively, were cemented [17][18], and, based on 2018, 2019, and 2020 volumes [19]-[21] and a rate of increase of volume of 5.6% per year [20], an estimated 44,000 PVP and BKP procedures were performed in the United States in 2025.

Because of its record of widespread use, many aspects of bone cement, such as its composition, polymerization process, attractive features, shortcomings, and complications, are well-known [2][3][22]-[24]. Details of some of these aspects are common to the use of the material in PTA, RTA, PVP, and PBK, while others are specific to each of these uses. The principal attractive features of bone cement are its easy preparation and high injectability. The former simply involves mixing the cement powder and liquid parts, in the ambient operating room environment, until a dough is attained, after which it is inserted in vivo [3]. Plain bone cement and antibiotic-loaded bone cement (ALBC) share a long catalog of shortcomings [2][3][22]-[43], six of which are highlighted here. First, the radiopacifier is a constituent of the powder and comprises micron-sized particles of either BaSO₄ (mBaSO₄) or ZrO₂ (mZrO₂). Each of these inorganic materials has been identified as acting as stress risers in the cured cement and, hence, has a deleterious effect on the mechanical properties (especially, fatigue life) of the cured cement. There are at least two additional concerns when mBaSO₄ is used. One, detached particles may release toxic Ba ions, thereby reducing the biocompatibility of the cement. Two, the mBaSO₄-PMMA matrix is weak, so poor mechanical properties of the cement are obtained. Second, the polymerization process is an exothermic reaction, with, in the case of some cement formulations/commercial brands, a maximum temperature that is high enough to be the cause of or be implicated in thermal necrosis of periprosthetic tissue. Third, leaching of residual monomer constituents, in particular, N,N di-methyl-p-toluidine (DMPT) (the activator or accelerator of the polymerization process), which, it has been postulated, is toxic, and, in some brands, the concentration is high enough to be the cause of or be implicated in chemical necrosis of the periprosthetic tissue. Fourth, it has been postulated that released micron-sized radiopacifier particles cause or are implicated in processes that culminate in bone resorption and, hence, aseptic loosening of the implant. Fifth, the modulus of elasticity of bone cement is so much higher than that of the contiguous cancellous (trabecular) bone (typically, 1500 - 3600 MPa versus 100 - 800 MPa) that there is potential for stress shielding. Additionally, its fracture resistance is low, and, hence, its proneness to fatigue is high. Sixth, the bone cement layer in a cemented total arthroplasty (CTA) lacks (or has limited) bioactivity.

Four shortcomings of ALBC brands approved by relevant regulatory agencies, such as the European Medicines Agency, for use in CTA, are often cited [4][33][41][43]-[46]. First, elution of the loaded antibiotic (usually, gentamicin, vancomycin, clindamycin, or a combination of the second and the third) is characterized by an initial burst, followed by a steady-state zone, and, finally, exhaustion all within, typically, 6 - 10 hours of deployment in an in vitro test (simulated body fluid (SBF), held at 37˚C ± 1˚C). Second, the eluate demonstrates reduced efficacy against certain bacterial species that are widely considered to be the causes of or are implicated in PJI, such as Staphylococcus aureus and Staphylococcus epidermidis. When used in a CTA, two complications of an ALBC are noted. One is bone cement implantation syndrome, which is characterized by presentations that include hypotension and cardiac instability (or, even, arrest) during various stages during CTA, particularly during cemented THA and TKA [29][47]. Two, because the cement is not degradable in vivo, cement debris that accumulates on the periprosthetic tissue, over the in vivo life of the arthroplasty, may cause chronic inflammation or cause or be implicated in prosthesis loosening and, eventually, osteolysis. When bone cement is used in PVP and BKP, two issues are highlighted. One is its high modulus, which may lead or contribute to the fracture of vertebra(e) adjacent to the treated one(s). The other is the possibility of cement leakage into paraveteral tissues (in particular, the lungs), which, in some cases, is fatal [48][49]. A common complication with the cement is its involvement in the fracture of vertebral body/bodies adjacent to the treated one(s) [50]-[52].

Although there are many reviews of the literature on studies that address the stated shortcomings, concerns, and complications of plain and antibiotic-loaded bone cement in their use in CTA and plain bone cement in its use in AOVCFs [22]-[44][53], only a few include coverage of studies on alternative radiopacifiers [22]-[25][29][36][38][39][41][53]. Among these studies, there are four issues. First, the coverage is either short [22]-[24][29][36] or moderate [25][38][39]. Second, in the case of one review [41], alternative radiopacifiers were mentioned in the context of the use of bone cement in drug delivery , not arthroplasty or vertebral augmentation . Third, the review was not on bone cement specifically, but rather, on polymeric biomaterials that are used in many other implant applications apart from CTA and AOVCF, examples being coronary artery stents and internal bone fracture fixation systems, and the coverage on enhancement of radiopacity was short [38][53]. Fourth, each of the reviews that contained a section on enhancement of radiopacity [22]-[24] did not include a critical appraisal of the cited studies.

The purpose of the present work was to give a detailed review in which the exclusive focus is on studies of alternative radiopacifiers for bone cement for use in CTAs and AOVCFs. The review is organized in seven sections. The period of the search for relevant articles and the strategy used to conduct the search (that is, the criteria used to include or exclude items) are described in the second section. In the third section, the rationale given in the cited studies for the selection of the various alternative radiopacifiers is discussed. Salient aspects of the methods used to determine radiopacity are presented in the fourth section. The focus of the fifth section is the introduction of the concept of an index of effectiveness of an alternative radiopacifier (IEAR), calculation of IEAR using radiopacity results given in the various literature studies, and a discussion of the trends in IEAR. The sixth section is devoted to highlighting shortcomings of the literature and, hence, suggestions for future studies. A summary of the key points made in the review is presented in the seventh section.

The first step involved searching several relevant databases, such as Google Scholar, PubMed, Scopus, and Web of Science, for items published between January 1996 and June 2026 in which one or more of the search terms appeared. Those terms were “PMMA bone cement”, “radiopacity”, and “alternative radiopacifier.” In the second step, inclusion and exclusion criteria were applied to all the items obtained in the first step. Inclusion criteria were that the item is a peer-reviewed article and is written in English. Exclusion criteria were that the item was an abstract or a conference presentation. The third step involved manually reviewing the reference lists of each of the articles that met the inclusion criteria for additional articles. In the fourth step, the stated inclusion and exclusion criteria were applied to the additional articles. Through this four-step process, 35 articles were finally selected. Thus, the present review is of these articles.

In an approved cement brand (which, herein, is defined as a patented commercial-prepared formulation that is approved by a relevant regulatory agency, such as the US Food and Drug Administration and the European Medicines Agency, for use in a specified clinical procedure, such as cemented primary arthroplasty, cemented revision arthroplasty, PVP, and PBK), the radiopacifier comprises either mBaSO₄ or mZrO₂ particles added to the cement powder. Herein, these particles are referred to as the gold standard radiopacifiers. Examples of these brands with the accompanying gold standard radiopacifier and its loading are given in Table 1. In experimental bone cement formulations, an alternative radiopacifier (that is, one that is not mBaSO₄ or mZrO₂) is used.

Table 1.Gold standard radiopacifier (mBaSO₄ or mZrO₂ particles) and loading in a sample of plain and antibiotic-loaded bone cement brands for use in cemented primary and revision arthroplasties.

^aALBC: antibiotic-loaded bone cement; mBaSO₄: micron-sized barium sulfate particles; mZrO₂: micron-sized zirconium dioxide particles. ^bManufacturer/distributor: Biomet Orthopaedics Switzerland GmbH, Ried b. Kerzers, Switzerland/Zimmer Biomet, Warsaw, IN, USA. ^cManufacturer: Tecres SpA., Sommacampagna, Verona, Italy. ^dManufacturer: Heraeus Medical GmbH, Wehrheim, Germany. ^eManufacturer: Stryker Howmedica Osteonics, Mahwah, NJ, USA. ^fManufacturer/distributor: DePuy International Ltd., Blackpool, UK/DePuy Synthes.

Various alternative radiopacifiers were the subject of the studies selected for review [54]-[88]. In the preponderance of these studies, the radiopacifier was blended with the powder of the cement formulation, examples being 2,5 diiodo-8-8-hydroquinone, iodixanol (an iodine-containing agent), micron-sized SrTiO₃, graphene oxide-embedded baghdadite particles, and BiInSn powder (Table 2). In six studies, the radiopacifier was blended with the liquid of the control formulation, these being triphenyl bismuth, 2[2',3',5'-triiodobenzoyl] ethyl methacrylate (TIBMA), 3,5-diiodine salicyclic methacrylate (DISMA), and nanoTiO₂ particles (Table 2). In many of the literature reports, the rationale for the choice of the alternative radiopacifier used in the study is given. A summary of this information is presented in Table 3.

Table 2.Alternative radiopacifiers used in experimental bone cement formulations in literature studies.

Table 3.Stated rationale for selection of alternative radiopacifiers.

In the present work, an index of effectiveness of an alternative radiopacifier (IEAR) is introduced. IEAR is defined as the % increase in the radiopacity of a specimen (R) fabricated using an alternative radiopacifier compared to that of a specimen when a radiopaque control cement was used for the fabrication. Thus, an acceptable alternative radiopacfier is one for which IEAR > 0. The following stratification of effectiveness of radiopacifier is offered: low (1% < IEAR ≤ 30%), moderate (31% ≤ IEAR ≤ 70%), high (71 ≤ IEAR ≤ 90%), and very high (IEAR > 91%). It is to be noted that two additional requirements for an alternative radiopacifier to be deemed acceptable are 1) that its radiopacity determined under clinically-relevant test conditions meets a defined clinical or regulatory visibility threshold and 2) it does not have adverse effects on clinically-relevant cement properties, notably fatigue life, hemolysis, and cytotoxicity.

The steps used to calculate IEAR are now described. The first step was to assemble a first sub-set of literature studies as those in which R results were presented in quantitative terms. The second step involved identifying a second sub-set of literature studies as those in the first sub-set in which x-radiography was used to determine R and, for the determination, the tube voltage (V_t) used was in the order of 75 - 80 kV. It is pointed out that, in THA and TKA, almost invariably, x-radiography is carried out using the stated range of V_t [61].

The IEAR values, as calculated from the second sub-set of studies (8), are presented in Table 10, from it is seen that among the 23 radiopacifiers used in this sub-set of studies (yielding 27 values of IEAR), 19 may be classified as having low effectiveness, 4 as being moderately effective, 2 as being highly effective, and 2 as being very highly effective.

Two methodologies were used to determine measures of centrality and dispersion of the population of IEARs. First, a test of normality (the Anderson-Darling (AD) Test) was conducted to see if the population followed a normal distribution. It was found that this was not the case (AD statistic = 2.750; critical value of the AD statistic (AD*) = 2.835; level of significance (p) ≤ 0.0005). Thus, an appropriate method to use to determine the stated statistical measures is the three-parameter Weibull method. When this was done, the minimum value, the Weibull modulus, and the characteristic value of IEAR were determined to be 2.45%, 0.714 and 25.98%, respectively. With these values, the Weibull median (a measure of centrality) and the Weibull standard deviation (a measure of dispersion) of the IEAR population were calculated to be 18% and 46%, respectively.

In light of the aforementioned caveats as well as the fact that among the 8 studies (23 different alternative radiopacifiers) whose results were used to calculate IEAR, different radiopacity determination methods were used and different specimen testing environments were used, the present methodology used to calculate IEAR should be taken as exploratory, rather than definitive. Thus, the IEAR values and the associated stratification of the radiopacifiers based on IEAR must be treated cautiously.

Table 10. Calculated values of index of effectiveness of alternative radiopacifiers.

^aIDX: iodixanol; Bgh: baghdadite; GO: graphene oxide-encapsulated baghdadite. ^bRelative to mBaSO₄-containing control cement. ^cRelative to mZrO₂-containing control cement. ^dDetermined with specimen in air. ^eDetermined with specimen under water. ^fRelative to Palacos^®R (radiopaque control cement). ^gRelative to Cemex^®Isoplastic (radiopaque control cement). ^hDetermined using x-ray tube voltage of 75 kV.

Eleven shortcomings of the literature and suggestions for future studies to address them are highlighted.

First, in some studies in which the focus was determination of the influence of radiopacifier on cement properties, radiopacity was not among the properties determined [57][63][64][67][70][71][86]. This deficiency must be avoided in future studies.

Second, the case in which the alternative radiopacifier was dissolved in the liquid of the cement was the subject of only a few studies [54][56][58][72][73]. Thus, there is an opportunity to develop and synthesize more alternative radiopacifiers that would be suited to be dissolved in the liquid.

Third, in some studies, a control cement was not included [54][77][81] or a control cement was used but it was radiolucent [59][68][82]. In other studies, the control cement was radiopaque and was formulated specifically for the use in the study [58][65][78][80][84][88] rather than an approved cement brand. An experimental ALBC formulation (antibiotic: vancomycin) was used in one study [83] and a commercial-prepared ALBC (Cemteq^®; antibiotic: vancomycin) was used in another [86]. In some studies, the control cement was an approved cement brand, namely CMW^®1R1 [56]; C-ment^®3 [62][63]; Cemex^®Isoplastic [78]; Cemteq^®Cement [86]; CMW^®1 [67][72][73]; CMW^®3 [85]; Model 1230^® (Tecres) [88]; Palacos^®MV [89]; Palacos^®R [64][78]; Simplex^® P [83]; and Vertaplex^TM [74]. In future studies, a radiopaque control cement must be used, preferably an appropriate approved cement brand.

Fourth, in only three of the studies on bone cements that are designed for use CTAs were the cement powder and liquid vacuum mixed (“the combination”) to prepare test specimens [55][60][61]. It is well-known that cement mixing method exerts a strong influence on cement properties. For example, for specimens of one commercial-prepared bone cement (Palacos^®MV), when mixing was carried out using a bowl open to the atmosphere and in a vacuum cartridge (vacuum level = 86.7 kPa), the mean porosities were ~2.3 and ~0.3%, respectively, and the mean quasi-static compressive strengths were ~105 MPa and ~115 MPa, respectively [89]. Additionally, in contemporary CTA practice, the combination is mixed and delivered under vacuum to the prepared bone bed [3]. Thus, in future studies, the combination should be vacuum mixed.

Fifth, many different methods were used to determine radiopacity of bone cement, as detailed in Section 4. This makes interstudy comparison of results challenging. Although there is a Standard for determining radiopacity (ASTM F640-23), it suffers from two shortcomings. One, it is generic in the sense that it is for materials, products, or parts of a product intended for use as a medical device in the body, rather than for bone cement specifically. Two, the determination was done in ambient laboratory air, rather than in a biosimulating medium (such as SBF). Thus, there is scope to develop a standard for determining radiopacity in which the protocol is simple and covers all relevant aspects, such as specimen preparation conditions (medium and temperature), specimen configuration, specimen size, specimen aging conditions (medium, temperature of medium, and duration in medium), test equipment, and method of analysis of test results. In this regard, efforts should be made to ensure that four aspects are covered. First, the cost of the stipulated test equipment is modest so that the Standard could be adopted in many countries regardless of per capita income level. Second, the method should allow for determining radiopacity in a short time. Third, it should be possible to use the Standard to evaluate test specimens as well as animal models into which cement dough is delivered. Fourth, the test protocol should include features that are clinically relevant. Work on this aspect could build on the study by Kjellson et al. [61]. Cognizant of the first three aforementioned points, the recommendation is that a very-low-cost high-quality cone beam CT (VLCHQCBCT) be adopted as the equipment for use in this Standard after results using it have been validated using a counterpart standard cone beam CT (CBCT) that is in contemporary clinical use. Suggested settings for various parameters to be used are voltage = 100 kV, current = 900 mA, focal distance = 0.5 m, dose area product = 2200 mGy.cm², and exposure time = 0.5 s. A challenge of this recommendation is the need to design a VLCHQCBCT which, among other features, should have the advantages of clinical-quality CBCT but none of its shortcomings. Thus, image acquisition time should be short (in order of 5 - 10 min) and spatial resolution of image should be in the sub-mm range but should not have beam hardening artifacts or be susceptible to scattering of radiation. Delivering this design should interest research and development professionals in fields such as radiation physics and biomedical engineering. A benefit that should accrue from employing this Standard would be a robust calculation of an index of effectiveness of a radiopacifier.

Sixth, in some studies [54][58][62][74][76][85], radiopacity results were expressed in qualitative terms (visual observations), an approach that is viewer-dependent. In future studies, radiopacity results must be expressed in quantitative terms.

Seventh, cements intended for use in AOVCF were the subject of only a few studies and, in each of them, the target uses were PVP and BKP [59][74][79]-[82][84][85][88]. Recent developments in the field of vertebral augmentation include third-generation implantable vertebral augmentation devices (TGIVADs) and innovative surgical techniques. The goal of each is to create an expanded and stable space within the fractured vertebral bodies in which the bolus of cement dough is injected. Examples of TGIVADs are Osseofix System, Sky Bone Expander System, SpineJack, and vertebral body stenting [90][91]. Three examples of an innovative technique are percutaneous curvature kyphoplasty [90], the pedicle-to-pedicle technique [92], and a curved cement delivery system in VP [93]. In future studies, this paucity of research attention should be addressed through inclusion of at least one cement from three categories. One, those that are in current clinical use for PVP and BKP, such as Osteopal^®V or VertePlex^®. Two, novel formulations designed for use in PVP and BKP, examples being iodine-containing spheres-reinforced PMMA bone cement [74], a poly(dimethyl siloxane)-enhanced cement [85], a demineralized bone matrix-augmented PMMA bone cement [94], and a PMMA bone cement augmented with chitosan and human-derived bone powder [95].

Eighth, in many studies, statistical analysis of the results was not reported [54][58][61][62][65][74][77][79][81][82][84][87][88]. In many other studies, a parametric test of significance between the means of the populations (datasets) was used without any mention of a priori investigation to establish whether or not the conditions for using the test were satisfied (namely, normality and homogeneity of variance). In these studies, the parametric tests used were the t test [69] and analysis of variance (ANOVA) [59][68][72][76][83], ANOVA with the Bonferroni correction [66], and ANOVA in conjunction with another test (Tukey B rank-order test [73] and Tukey multiple comparisons test [85]). In only one study was a check for normality of the populations to be compared conducted first (Shapiro-Wilk test) and, if normality was shown, ANOVA was used, but, if deviation from normality was shown, a non-parametric test (Kruskal-Wallis test) was used followed by Dunn’s post hoc test [78]. In one study, both ANOVA and a non-parametric test (Mann-Whitney U test) were used [80]. In future studies, the results must be statistically analyzed using a non-parametric method.

Ninth, in only seven studies was determination of radiopacity conducted in an animal model, namely, defect created in the femoral condyles of New Zealand White rabbits (12 wk; 3 kg) [76], defect created in the proximal femur of Wistar rats (male; 4 mo; 0.24 kg) [83], sheep vertebrae [81][84][88], porcine lumbar vertebrae [85], and femurs from fresh pigs obtained from a licensed commercial market [87]. However, in four of these studies, some relevant information of the model was not provided, such as the breed of the sheep and the spinal level of the vertebrae [81][84][88] and the spinal level of the vertebrae [85]. In future studies, radiopacity should be determined both in vitro and in suitable animal models. For the latter, many details should be given, such as rationale for the selected model and anatomical location of the injected cement bolus.

Tenth, the following four categories of experimental cement formulations should be evaluated in future studies. One, those that include alternative radiopacifiers and have been the subject of studies in which the radiopacity was not determined or radiopacity was expressed in qualitative terms. Examples of these formulations are ones in which the radiopacifiers were PMMA-coated ZrO₂ fibers [70], an iodine-containing methacrylic copolymer [55][63][64][71], I microspheres and IC microspheres [74], a commercial formulation of poly(dimethyl siloxane) (PDMS) [85], Ca tungstate [86], bismuth oxychloride [86], and BiInSn particles [87]. Two, novel/emerging plain formulations in which the influence of replacing a gold standard radiopacifier with an alternative radiopacifier on radiopacity has not been explored. Examples are a formulation that includes chemically functionalized graphene powder [96], a formulation that includes chitosan microgel to increase quasi-static properties of the cement [97], and a formulation that includes Ca₂MgSi₂O₇ (akermanite) and graphene oxide to impart bioactivity and increase quasi-static compressive properties and cellular response [98]. Three, novel/emerging ALBCs in which the influence of replacing a gold standard radiopacifier with an alternative radiopacifier on radiopacity has not been explored. Examples are a formulation that includes natural antibacterial agents, such as extracts of Aloe vera and Calendura [15], a formulation that contains a combination of a well-known antibiotic (vancomycin) and a lesser-known antibiotic (ceftazidime) [99], and a formulation that includes a combination of gentamicin and vancomycin (both of which are well-known antibiotics) and trimethoprim (a lesser-known antibiotic) [100]. Four, novel/emerging bone cements for use in AOVCFs, an example being a formulation that includes MoS₂nanosheets to impart antibacterial activity to the cement [110].

Eleventh, the literature is uneven in terms of determination of radiopacities. For example, radiopacity was not determined (7 studies), radiopacity was reported in a qualitative manner (11 studies), and quantitative measures of radiopacity were reported but a radiopaque control cement was not among those used in the study (4 studies). A consequence of this unevenness is that in the present work, IEAR could not be determined for the alternative radiopacifiers used in the aforementioned studies. The affected alternative radiopacifiers include triphenyl bismuth (TPB), 2,5 diiodo-8-quinolyl methacrylate (IHQM), polydimethyl siloxane (PDMS), calcium tungstate, and micron-sized SrTiO₃. This underscores the need for improved design of future studies.

Twelfth, there are no reports on first-principles design of alternative radiopacifiers. Such a design would entail deriving the composition of an alternative radiopacifier subject to desirable values of a varied list of properties in addition to radiopacity. For example, for radiopacifiers to be incorporated in ALBCs, at the minimum, the following additional cement properties must be considered: dough time (t_d); setting time (t_s); maximum temperature reached during cement polymerization (T_max); injectability (INJ); quasi-static compressive strength in SBF, at 37˚C; quasi-static four-point flexural strength in SBF, at 37˚C; fracture toughness, in SBF, at 37˚C (K_IC); multiaxial fatigue life, at 3 Hz, in SBF, at 37˚C; fatigue crack growth rate, in SBF, at 37˚C (FCGR); measures of in vitro biocompatibility and osteogenic activity (especially, attachment, proliferation, and differentiation of precursor osteoblast cell line, such as MC3T3-E1 and L929, and human osteoblasts, such as CRL-1137); blood compatibility (expressed as % hemolysis); a measure of in vitro bioactivity (for example, amount of apatite-like deposits formed on surface of a test specimen in SBF, at 37˚C, for 7 days); a measure of osteoconductivity in a relevant animal model (especially, volume of bone tissue formed around and within the implanted cement bolus); profile of the elution of the antibiotic from an ALBC, especially, duration of burst phase and time-to-exhaustion. For alternative radiopacifiers for use in cements intended for AOVCFs, at the minimum, the following additional cement properties should be considered: t_d; t_s; T_max; INJ, K_IC; compression-compression fatigue life, at 3 Hz, in SBF, at 37˚C; FCGR; rate of cement leakage; measures of in vitro biocompatibility; a measure of in vitro biocompatibility; and a measure of osteoconductivity in a relevant animal model. It is suggested that artificial intelligence methods (such as machine learning models) be used in these design studies [111][112].

The following is a summary of the main points made in the present work:

Poly (methyl methacrylate) bone cement (“bone cement”) has a multitude of uses in surgery, ranging from providing the anchoring/grouting bed of an implant in an arthroplasty and augmentation of osteoporotic vertebral compression fracture(s) (for example, balloon kyphoplasty (BKP)) to delivery of chemotherapeutic drugs and filling of a bone void. The most common use is in primary and revision total hip arthroplasty (THA) and knee arthroplasty (TKA). Bone cement has many shortcomings. Three of them are (i) problems associated with the gold standard radiopacifier (micron-sized particles of BaSO₄ (mBaSO₄) or ZrO₂ (mZrO₂), which is a constituent of the powder of the cement), (ii) high temperature reached when the powder and liquid are mixed to form a dough (which, it has been postulated, may cause or be implicated in thermal necrosis of periprosthetic tissue), and (iii) lack of or very limited bioactivity. Although the synthesis and characterization of bone cements that contain an alternative radiopacifier to mBaSO₄ and mZrO₂ have been the subject of many reports in the literature, a review of this body of work is lacking. The present contribution fills this gap. Ten key points made in this review are now highlighted. First, in the vast majority of studies, the alternative radiopacifier was added to the powder of the cement. Examples of these radiopacifiers are micron-sized particles of TaC, nano-sized particles of MgO, and an iodine-containing methacrylate. Second, in several of the studies, radiopaque control bone cement specimens were not used. Third, in some of the studies, radiopacity was not determined. Fourth, in studies where radiopacity was determined, several combinations of instrumentation and methods were used. Examples are x-radiography and the equivalent Al thickness method, computed tomography, and a densitometer. Fifth, the concept of an index of effectiveness of an alternative radiopacifier (IEAR) was introduced as the percentage increase in radiopacity when specimens of an alternative radiopacifier were used compared to when radiopaque control bone cement specimens were used. IEAR ranged from 3% when 25 wt./wt.% of yttria-stabilized ZrO₂ particles were added to the cement powder to 187% when 10 wt./wt.% of nano-sized BaSO₄ particles (particle size: 80 - 500 nm) were added to the cement powder. The Weibull median IEAR was 18%. Sixth, in many studies, statistical analysis of radiopacities was not reported or, in cases where it was, an inappropriate method was used (namely, analysis of variance (ANOVA method)). Seventh, radiopacities of specimens of antibiotic-loaded bone cements (ALBCs) were determined in only a few studies even though ALBCs are very widely used to prevent/manage peri-prosthetic joint infections in revision total hip and knee arthroplasties. Eighth, radiopacities of specimens of cements for use in vertebroplasty and balloon kyphoplasty (BKP) were determined in only a few studies. Ninth, in nearly all the studies, radiopacity was determined with the test specimen being in ambient laboratory atmosphere rather than in a biosimulating solution, such as simulated body fluid. Tenth, radiopacity was not determined for any specimens of novel/emerging plain or antibiotic-loaded bone cements, which have been the subject of recent reports in the literature. The shortcomings of the literature, as indicated above, suggest twelve areas for future work, four of which are summarized here. First, the development and validation of a test standard for the determination of radiopacity of bone cement specimens. Second, determination of radiopacity of a large collection of specimens fabricated from (i) commercial-prepared plain bone cements, commercial-prepared ALBCs, and experimental plain bone cements that were not included in the studies reviewed, (ii) novel/emerging experimental plain bone cements, and (iii) novel/emerging experimental ALBCs. Third, determination of radiopacity when bone cement dough/specimen is placed in appropriate anatomical locations in animal models, such as the thurl of a cow (for cements to be used in, for example, THA or TKA) and the third vertebra in the lumbar spine of a sheep (for cements to be used in, for example, BKP). Fourth, in every study, (i) radiopaque control bone cement specimens should be included and they must be immersed in a biosimulating solution and (ii) an appropriate statistical method should be used to analyze study results, an example being the Kruskal-Wallis method.

The author thanks Dr. Samira Ghadar, Department of Mechanical Engineering, The University of Memphis, for formatting the List of References.