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Bone–cement fixation: glass–ionomer cements
11
Bone±cement fixation: glass±ionomer cements P V H A T T O N , V R K E A R N S and I M B R O O K , University of Sheffield, UK
11.1
Introduction
Glass±ionomer cements (GICs) have been employed extensively in the repair of tooth tissue since the 1970s, and this long history suggests that they are among the most biocompatible dental materials available. Their apparent safety and history of good biocompatibility led scientists and clinicians to consider them for wider surgical uses in the 1980s and 1990s, and much of this early work has been reviewed (Brook and Hatton, 1998; Kenny and Buggy, 2003; Hatton et al., 2006). This chapter in many ways represents the first attempt to connect the data in published studies and reviews to our current technical knowledge of GICs, their setting chemistry and structure±property relationships.
11.2
Structure and properties of glass±ionomer cements
Conventional GICs are formed from the combination of high molecular weight polymeric acids (e.g. polyacrylic acid), a basic fluoroaluminsilicate glass powder and water. Many compositions include tartaric acid to extend the working time. The properties of GICs result from these components and their setting reaction, surface chemistry, physical structure and bulk composition. Set GICs may be described as composites with inorganic glass particles set in a relatively insoluble hydrogel matrix (see Fig. 11.1). Freshly mixed, unset GIC is able to chemically bond to both bone (apatite) and metals (McLean, 1988; Wilson and McLean, 1988). This is advantageous as it means that fixation is not achieved with mechanical interlocking alone. In simple terms, GICs set in stages. First, carboxylic acid residues on the polymeric acid ionise in the presence of water. Protons then react with the surface of the basic glass particles to liberate cations. Specific ions such as Ca2+ and Al3+ are then able to crosslink the ionised carboxylic acid residues, setting the cement. Although at reduced concentrations relative to the parent ionomer glasses (Hatton and Brook, 1992a), many of the component ions remain very mobile long after initial setting, leading to the
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11.1 Transmission electron photomicrographs of (a) a G338 glass particle in a set glass±ionomer cement and (b) a glass particle in set Ketac-cem. Field width approximately 5 m.
potential for complex `curing' and leaching of ions. The setting reaction is not exothermic, unlike acrylics. This is highly beneficial as it does not cause thermal damage to tissues at the site of implant, or to any temperature-sensitive drugs that may be incorporated into the matrix phase of the cement. In addition, there is no significant shrinkage of the cement on setting (Wood and Hill, 1991a). The mechanical properties of GICs are generally considered inferior to those of acrylic cements, but are sufficient for low to intermediate load-bearing applications with some potential for improvements with the use of different components. The mechanical properties of the GIC may be controlled to a degree by varying the volume fraction of the glass and hydrogel phases, enabling some properties to be matched with those of the surrounding bone.
11.3
Biological evaluation
11.3.1 Ion release and bioactivity The osteoconductivity exhibited by specific GICs is of particular interest. It has been suggested that this is due to ion exchange with the biological environment (Brook et al., 1991a, Wood and Hill, 1991a, Hatton and Brook, 1992b, Hatton et al., 2006). The ability of the material surface to bind certain biological factors that may recruit and regulate osteogenic cells could also assist the formation of a more stable bone±implant interface and thus improve the potential for clinical success. Immunohistochemical studies of implanted GIC have shown close association of the non-collagenous extracellular matrix proteins of bone (osteopontin, fibronectin and tenascin) with the GIC surface (Carter et al., 1991; Johal et al., 1996). These factors, which are believed to play an important role in ontogenesis and the osseointegration of biomaterials (Weiss and Reddi, 1981; Clark et al., 1982; Mackie et al., 1987; Carter et al., 1991; Bagambisa et al., 1993, 1994) together with the hydrophilic surface of GIC, may explain the osteoconductive properties of implanted GIC (Jonck et al., 1989a,b; Brook et al., 1991a,b, 1992; Doherty, 1991; Nicholson et al., 1991; Hatton and Brook, 1992b; Sasanaluckit et al., 1993; Hill et al., 1995; Johal et al., 1995).
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The bulk composition of GIC acts as a reservoir for ion release (Nicholson et al., 1991; Wood and Hill, 1991b; Sasanaluckit et al., 1993; Hill et al., 1995; Johal et al., 1995). As mentioned previously, certain ions released from the glass particles during the gelation process remain mobile once setting is complete. Studies have reported the presence of such ions in the matrix of the cement (Hatton and Brook, 1992a) and in adjacent bone (Hatton and Brook, 1992b), with exchange of ions taking place with the (aqueous) environment (McLean, 1988; El Mallakh and Sarkar, 1990, Forsten, 1991). Glass composition (Johal et al., 1995) determines ion release, as well as the biochemical environment of the implant bed (Devlin et al., 1994). Fluoride ion release from GIC has been comprehensively reported, although the majority of studies have related to the use of GIC in dental applications (Wilson and McLean, 1988; El Mallakh and Sarkar, 1990; Forsten, 1991). Even though caution must be exercised when interpreting the results, due in the main to poor standardisation and incomplete reporting of methods, it is clear that relatively large quantities of fluoride are released from GICs for periods of up to one year. It was originally proposed that fluoride release was the most significant factor affecting biocompatibility of glass±ionomers. Whereas the absence of fluoride has been reported to result in the least in vitro toxicity (although this material contained no phosphate, complicating interpretation of results) (Brook et al., 1991a), it also produced the lowest osteoconductivity and integration in vivo (Brook et al., 1991b, Johal et al., 1995). The effect of fluoride ions appears to be dose-dependent. Although high fluoride concentrations result in enzyme inhibition in vitro, bone-forming cells exhibit increased proliferation and alkaline phosphatise activity in vivo (Farley et al., 1983; Lundy et al., 1986; Turner et al., 1989; Brook et al., 1991b). Fluoride is also used to treat bone resorption in patients with osteoporosis (Pak et al., 1989; Sùgaard et al., 1995), owing to its ability to increase the density of trabecular bone. Studies have reported a greater volume of bone formation associated with GIC than with more inert ceramic bone substitutes and, more recently, related increased fluoride release with bone formation (Brook et al., 1991b; Johal et al., 1995). It is speculated that this is because fluoride release from GIC during bone formation results in mineralisation containing fluorapatite, which is more resistant to resorption. The release of other ions from GIC is less well reported, although it has been proposed that ion release is a major factor in the bioactivity of different GICs (Brook et al., 1991a, 1992; Doherty, 1991; Nicholson et al., 1991; Hatton and Brook, 1992b; Sasanaluckit et al., 1993). Ion exchange with the tissues of the implant bed has been confirmed to be a significant determinant in the bioactivity of a GIC (Devlin et al., 1994; Johal et al., 1995). Aluminium ion release is particularly important and plays a somewhat controversial role (Nicholson et al., 1991), particularly following reports of four cases of post-otoneurosurgery aluminium encephalopathy and deaths among patients treated with a glass±
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ionomer bone cement (Renard et al., 1994; Reusche et al., 2001). Data published to date suggest that aluminium leaching occurs only in the initial period following setting (Crisp et al., 1980; Wilson and McLean, 1988). Increased aluminium ion content and release result in decreased biocompatibility in vitro (Devlin et al., 1994) and may be a more significant factor in biocompatibility than fluoride, although it may have a similarly complex effect. No reports have identified aluminium ions as the sole cause of in vitro cytotoxicity. Low concentrations of aluminium ions have been shown to stimulate the proliferation of osteoblasts in vitro and new bone formation (Quarles et al., 1990; Meyer et al., 1993). Additionally, aluminium particles have been observed inside cultured osteoblasts cells without any detrimental effect on the cells or impairment of bone formation (Blumenthal and Posner, 1984; Hatton and Brook, 1992b; Szulczewski et al., 1993). Aluminium ion release increased the amount of osteoid formation in vivo but interferes with the early stages of bone mineralisation (Blumenthal and Posner, 1984; Quarles, 1991; Meyer et al., 1993), resulting in a reduction of this process. Collagen synthesis is also inhibited (Goodman, 1985; Goodman and O'Connor, 1991). Aluminium also mediates mobilisation of calcium from bone by a cell-independent mechanism. Further research is required into the role of metal ions on osteogenesis. Calcium and phosphate ions may be expected to enhance this process, whereas the effect of other ions is less clear. It is likely that the combination of various factors, particularly the combination and relative concentration of ionic species and their interaction with each other and the biological environment, will result in different outcomes (El Mallakh and Sarkar, 1990; Forsten, 1991; Lau et al., 1991; Nicholson et al., 1991; Devlin et al., 1994; Johal et al., 1995).
11.3.2 In vitro evaluation Glass±ionomers have been tested extensively in vitro and interpretation of these studies demonstrates that these materials should be classed as `bioactive'. Consideration of the results should therefore take into account that bioactive materials often perform less well than more inert materials in vitro (Gross et al., 1987). Furthermore, the in vitro model should attempt to replicate the clinical situation as far as possible. Many studies have evaluated GICs and other bone cements in terms of the migration of osteoblasts onto their surfaces. Appropriate cell source and culture conditions can also be manipulated to induce formation of a bone-like tissue in vitro. Standard cytotoxicity tests involving a variety of cell types (osteoblasts, osteoclasts, fibroblasts, neonate rat calvaria) have been carried out. Positive interactions between certain types of GIC and bone cells have been reported (Brook et al., 1991a, 1992; Doherty, 1991; Meyer et al., 1993; Szulczewski et al., 1993). Cultured cells are particularly sensitive to wet cements; studies in which wet cements were placed in direct contact with neonate rat calvaria resulted in cell death (Brook et al., 1991a). This makes this
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method of study unsuitable for investigating unset cements. Any observed toxicity of set cements has been attributed to the presence of a toxic leachate or the rough surface of the cement. The effect of fluoride, aluminium ion leaching has been discussed in detail above. The low pH of GICs (due to release of protons) while setting and maturing has been proposed as a cause of cyto- and neurotoxicity (Gross et al., 1987; Loescher et al., 1994a; Brook and Hatton, 1998). In summary, the mechanisms responsible for in vitro cytotoxicity are complex and may be unrelated to their in vivo and clinical performance. It might in the future be beneficial to evaluate GICs in vitro following the pre-treatments described for bioactive glasses, but no detailed studies that add substantially to the knowledge reviewed here have been reported.
11.3.3 In vivo evaluation In vivo evaluation allows more meaningful testing of GICs than in vitro methods. Encouraging results have been reported from testing of set cements. In vivo osteoconduction has been widely reported (Jonck et al., 1989a,b; Brook et al., 1991b; Johal et al., 1995). The first preclinical studies into the use of GIC for orthopaedic surgery involved implantation into baboon tibia and gave promising results (Jonck et al., 1989a,b). In one study, GICs with certain compositions were found to support new bone formation six weeks following implantation in rat femora, with the tissue stable over the course of one year. Another important finding of this study was the demonstration that in vitro studies are not always a reliable predictor of the performance of GICs in vivo, as one composition (fluoride- and phosphate-free) that was considered to be biocompatible failed to achieve osseo-integration. Direct bone±cement contact was observed only with fluoride-containing glasses, with the formation of a stable interface (Hatton and Brook, 1992b). The GIC±bone interface morphology varies, ranging from a lamina limitans-like interface shown in Fig. 11.2 (Brook et al., 1991a,b), which mimics the normal boundary of bone with osteocyte lacunae (Van Blitterswijk et al., 1985) to an interdigitation of collagen fibres with the GIC (Brook et al., 1992). The latter of these represents a more bioactive bond, reported on specimens that have not been distorted by decalcification (Jarcho et al., 1977; Kotani et al., 1991). Once the initial post-implantation inflammatory response to a material, which is inevitable, has subsided, the medium-term biological response can be evaluated. GICs demonstrate their osteoconductive potential, unlike poly(methylmethacrylate) (PMMA) cements. Evidence of the bioactive properties of GICs was reported (Fischer, 1986; Carter et al., 1997); no incidence of fibrous encapsulation was observed. Unfortunately, the issue of aluminium ion release appeared to influence the results of in vivo implantation. Two independent studies demonstrated that the new bone tissue that formed rapidly on the surface suffered from defective mineralisation, and that this was associated with the
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11.2 Transmission electron photomicrograph of interface (arrowed) between new bone tissue (B) and a set glass±ionomer cement with glass particles (G) and matrix (M). Field width approximately 10 m.
localisation of aluminium in the tissue (Blades et al., 1991, Carter et al., 1991). Despite this concern, a study of the use of particulate GICs as a bone allograft expander concluded that there were no adverse effects on bone remodelling or recovery or the performance of the bone allograft. GIC implanted into the tibia of baboons (Jonck et al., 1989b; Brook et al., 1991a) had previously generated favourable results, leading to the limited clinical application in orthopaedics noted above (Jonck and Grobbelaar, 1990). While numerous reports describe the response of bone to set GICs, very few studies investigating the response to freshly mixed GICs have been reported, and in general the less encouraging tissue responses are observed when GICs are placed `wet' during setting. Studies based on diffusion chambers containing a glass±ionomer and bone marrow, implanted into baboon femora for up to three years demonstrated that the cement promoted osteoblastic activity, with no inhibitory effect on bone tissue. The relevance of these results is limited, however, owing to the separation of host and material by the diffusion chamber. Although freshly mixed glass±ionomers placed on the rat femur suggested initial bone bonding, evidence of a pronounced periosteal reaction and sub-periosteal resorption was found at 6 and 12 weeks. New bone formation was, however, observed at 12 weeks (Brook et al., 1991b; Hatton and Brook, 1992b). Additionally, there was a short-term inflammatory response, likely to be the result of either reduction of tissue pH, causing local tissue necrosis, or release of free glass particles and metal ions from unset cement contaminated by tissue fluid or blood. Water has an adverse effect on the setting reaction and the unfavourable in vivo response to unset cements highlights the importance of avoiding excess moisture during surgery.
11.3.4 Clinical evaluation GICs have been used in various surgical applications. Favourable outcomes have been reported when GICs have been used in granule or cement form in orthopaedic cases where conventional care had failed (Jonck and Grobbelaar,
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1990), but it is the opinion of the authors that these materials are not suitable for situations in which the strength of the cement is critical to the outcome. The use of GIC to reinforce osteoporotic femoral heads has been reported to improve the primary stability of dynamic hip screws (McElveen, 1994), although long-term data or additional information on bone mineral density was not reported. GICs have been particularly successful in otological surgery, being used as a cement or formed into prosthetic implants (Babighian, 1992; Ramsden et al., 1992; Geyer and Helms, 1993; Muller et al., 1993, 1994; Babighian et al., 1994). GIC is the highest-performing material in terms of clinical efficacy in ossicular chain reconstruction, where the cement is used to repair bony ossicles in their normal position, and in cementation of cochlear implants (Babighian, 1992; Ramsden et al., 1992; Muller et al., 1993; Babighian et al., 1994). One study reported 167 patients who had been treated with GIC in middle ear surgery (Geyer and Helms, 1990). Another study reported a 94% four-year success rate for 945 instances of GIC ossicular implant placement (Geyer and Helms, 1993). Furthermore, out of 74 cases of posterior canal wall repair using GIC, only 12 cases required revision surgery (Geyer and Helms, 1993). Oral surgical procedures may also involve GIC, in particular as a bone substitute to prevent bone loss following tooth extraction and as a filler for graft donor sites and cyst cavities (Nordenvall, 1992). GIC are also used as a surgical dressing following exposure of teeth prior to orthodontic alignment (Nordenvall, 1992). The successful outcomes following the use of GIC in various surgical procedures led to their application in neuro-otological and skull base surgery and repair of cerebrospinal fluid (CSF) fistulas and skull defects (Ramsden et al., 1992; Helms and Geyer, 1994). At the same time, evaluation of GIC in terms of their biocompatibility with neural tissue was being carried out. Although seemingly biocompatible, clinical data reported that exposure to viscous GIC resulted in a potentially irreversible block in nerve conduction (Loescher et al., 1994a,b). It was already recommended that unset GIC should not come into contact with soft tissue and that it should be placed in a `dry field', but the results of these studies lead to a further restriction ± that GIC bone cement should not be allowed to come into contact with neural tissue. Sadly, these warnings came too late to prevent four cases of post-otoneurosurgery aluminium encephalopathy, resulting in two deaths (Renard et al., 1994). The issues surrounding these cases are complex, but it is likely that the release of polyacid during the setting reaction and disruption of the setting reaction due to exposure to body fluid/blood, led to the release of large quantities of metal ions and glass particles with disastrous results. It is notable that no deaths resulted from operations where the brain was protected from contact with the cement, and it might be concluded that correct surgical technique is essential when using modern `bioactive' medical materials. Overall, the story of the development of glass±ionomer bone cements is a salient reminder of some of the key points of biomaterials science: biocompatibility is application-specific, and the ultimate
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behaviour of a medical device in the body is as much related to the expertise and experience of the surgeon as it is to the properties of the biomaterials used.
11.4
Future trends
The incorporation of antibiotics into acrylic cements is associated with a reduction in the incidence of post-operative infection following orthopaedic surgery. Early studies trying to replicate this success using drug-loaded GIC were less successful (Wijnbergen Buijen Van Weelderen et al., 1983), although the release of biologically active chlorhexidine was reported from two dental cements (Ribeiro and Ericson, 1991). The Sheffield group also reported that GICs provided a favourable matrix for the release of potential biologically active molecules such as proteins (Wittwer et al., 1994). Given the promising properties reported here, it appears advisable to revisit GICs for use as a matrix for drug delivery in bone tissue. GICs have some advantages for orthopaedic applications, including their truly adhesive nature and non-exothermic setting reaction, which does not result in shrinkage and may improve the release of incorporated therapeutic compounds. Their mechanical properties are, however, inferior to those of acrylic bone cements, limiting their load-bearing capacity. It is their interaction with the biological environment that is both encouraging and problematic in equal measure. Biological evaluation has provided some encouraging results, for example the so-called bioactive nature of GICs, by which a composition, site and tissue-dependent ion exchange has encouraged an appropriate host response. More worryingly, the release of aluminium has also been associated with a mineral defect in bone tissue following the use of GICs in orthopaedic applications, and in extreme examples the incorrect placement of the cement has been associated with the death of patients. Concerns regarding aluminium release from glass±ionomers have led recently to the development of aluminium-free GICs, where the Al2O3 was substituted entirely with Fe2O3 (Hurrell-Gillingham et al., 2005, 2006). Further work is ongoing on these promising compositions to establish whether or not they represent a practical alternative to the conventional GIC bone cements already used successfully in ear, nose and throat (ENT) surgery. However, a more radical approach to biomaterial design will be required if glass±ionomer bone cements are to be used successfully for the fixation of medical devices in total joint replacement.
11.5
References
Babighian, G. (1992) Use of a glass ionomer cement in otological surgery: a preliminary report. Journal of Laryngology and Otology, 106, 954±959. Babighian, G., Dominguez, M., Pantano, N. & Tomasi, P. (1994) Multichannel cochlear implant: personal experience. L'impianto cocleare multicanale. Nostra esperienza, Acta Otorhinolaryngol Ital. Mar±Apri 14, 107±125.
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Bagambisa, F. B., Joos, U. & Schilli, W. (1993) Mechanisms and structure of the bond between bone and hydroxyapatite ceramics. Journal of Biomedical Materials Research, 27, 1047±1055. Bagambisa, F. B., Kappert, H. F. & Schilli, W. (1994) Cellular and molecular biological events at the implant interface. Journal of Cranio-Maxillo-Facial Surgery, 22, 12±17. Blades M. C., Moore D. P., Revell P. A. & Hill R. (1991) In vivo skeletal response and biomechanical assessment of two novel polyalkenoate cements following femoral implantation in the female New Zealand white rabbit. Journal of Materials Science: Materials in Medicine, 9, 701±706. Blumenthal, N. C. & Posner, A. S. (1984) In vitro model of aluminium-induced osteomalacia: inhibition of hydroxyapatite formation and growth. Calcified Tissue International, 36, 439±441. Brook, I. M. & Hatton, P. V. (1998) Glass±ionomers: bioactive implant materials. Biomaterials, 19, 565±571. Brook, I. M., Craig, G. T. & Lamb, D. J. (1991a) In vitro interaction between primary bone organ cultures, glass±ionomer cements and hydroxyapatite/tricalcium phosphate ceramics. Biomaterials, 12, 179±186. Brook, I. M., Craig, G. T. & Lamb, D. J. (1991b) Initial in-vivo evaluation of glass± ionomer cements for use as alveolar bone substitutes. Clinical Materials, 7, 295± 300. Brook, I. M., Craig, G. T., Hatton, P. V. & Jonck, L. M. (1992) Bone cell interactions with a granular glass±ionomer bone substitute material: in vivo and in vitro culture models. Biomaterials, 13, 721±725. Carter, D. H., Sloan, P. & Aaron, J. E. (1991) Immunolocalization of collagen Types I and III, tenascin, and fibronectin in intramembranous bone. Journal of Histochemistry and Cytochemistry, 39, 599±606. Carter, D. H., Sloan, P., Brook, I. M. & Hatton, P. V. (1997) Role of aluminium in the integration of ionomeric (glass polyalkenoate) bone substitutes. Biomaterials, 18, 459±466. Clark, R. A. F., Lanigan, J. M., Dellapelle, P., Manseau, E., Dvorak, H. F. & Colvin, R. B. (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. Journal of Investigative Dermatology, 79, 264±269. Crisp, S., Lewis, B. G. & Wilson, A. D. (1980) Characterization of glass±ionomer cements. 6. A study of erosion and water absorption in both neutral and acidic media. Journal of Dentistry, 8, 68±74. Devlin, A. J., Hatton, P. V., Hill, R., Henn, G., De Barra, E., Craig, G. T. & Brook, I. M. (1994) Initial investigation of ion release from novel polyalkenoate cements related to in vitro biocompatibility. 11th European Conference on Biomaterials. Pisa, Italy, Tipographia Vigo Cursi. Doherty, P. J. (1991) Biocompatibility evaluation of glass ionomer cement using cell culture techniques. Clinical Materials, 7, 335±340. El Mallakh, B. F. & Sarkar, N. K. (1990) Fluoride release from glass±ionomer cements in de-ionized water and artificial saliva. Dental Materials: Official Publication of the Academy of Dental Materials, 6, 118±122. Farley, J. R., Wergedal, J. E. & Baylink, D. J. (1983) Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science, 222, 330±332. Fischer, A. A. (1986) Reactions to acrylic bone cement in orthopaedic surgeons and patients. Cutis, 37, 425±426.
Bone±cement fixation: glass±ionomer cements
261
Forsten, L. (1991) Fluoride release and uptake by glass ionomers. Scandinavian Journal of Dental Research, 99, 241±245. Geyer, G. & Helms, J. (1990) Reconstructive measures in the middle ear and mastoid using a biocompatible cement ± preliminary clinical experience. In Heimke, E., Soltese, U. & Lee, A. J. C. (Eds) Advances in Biomaterials. Amsterdam, The Netherlands, Elsevier. Geyer, G. & Helms, J. (1993) Ionomer-based bone substitute in otologic surgery. European Archives of Oto-Rhino-Laryngology, 250, 253±256. Goodman, W. (1985) Bone disease and aluminum: pathogenic considerations. American Journal of Kidney Diseases, 6, 330±335. Goodman, W. G. & O'Connor, J. (1991) Aluminum alters calcium influx and efflux from bone in vitro. Kidney International, 39, 602±607. Gross, U., Schmitz, H. J., Kinne, R., Fendler, F. R. & Struntz, V. (1987) Tissue or cell culture versus in vivo testing of surface reactive biomaterials. In Pizzoferrato, A., Ravaglioli, A. & Lee, A. J. C. (Eds) Biomaterials and Clinical Applications. Amsterdam, The Netherlands, Elsevier Science. Hatton, P. V. & Brook, I. M. (1992a) Characterisation of the ultrastructure of glass± ionomer (poly-alkenoate) cement. British Dental Journal, 173, 275±277. Hatton, P. V. & Brook, I. M. (1992b) X-ray microanalysis of bone and implanted bone substitutes. Micron and Microscopica Acta, 23, 363±364. Hatton P.V., Hurrell-Gillingham, K. & Brook I. M. (2006) Biocompatibility of glass± ionomer bone cements. Journal of Dentistry, 34, 598±601. Helms, J. & Geyer, G. (1994) Closure of the petrous apex of the temporal bone with ionomeric cement following translabyrinthine removal of an acoustic neuroma. Journal of Laryngology and Otology, 108, 202±205. Hill, R., Hatton, P. V. & Brook, I. (1995) Factors influencing the biocompatibility of glass polyalkenoate (ionomer) cements with bone tissue. In Ravaglioli, A. (Ed.) Proceedings of the Ceramics Cells and Tissues. Faenza, Italy, Gruppo Editoriale. Hurrell-Gillingham, K., Reaney, I. M., Brook, I. & Hatton, P. V. (2005) Novel Fe2O3containing glass ionomer cements: Glass characterisation. Key Engineering Materials, 284±286, 799±802. Hurrell-Gillingham, K., Reaney, I. M., Brook, I. & Hatton, P. V. (2006) In vitro biocompatibility of a novel Fe2O3 based glass ionomer cement. Journal of Dentistry, 34, 533±538. Jarcho, M., Kay, J. F., Gumaer, K. I., Doremus, R. H. & Drobeck, H. P. (1977) Tissue, cellular and subcellular events at a bone±ceramic hydroxyapatite interface. Journal of Bioengineering, 1, 79±92. Johal, K. K., Craig, G. T., Devlin, A. J., Brook, I. M. & Hill, R. (1995) In vivo response of ionomeric cements: effect of glass composition, increasing soda or calcium fluoride content. Journal of Materials Science: Materials in Medicine, 6, 690±694. Johal, K., Carter, D. H., Hatton, P. V., Sloan, P. & Brook, I. (1996) The interaction of bone extracellular matrix proteins with ionomeric implants increasing in sodium content. Journal of Dental Research, 75, 1152. Jonck, L. M. & Grobbelaar, C. J. (1990) Ionos bone cement (glass±ionomer): an experimental and clinical evaluation in joint replacement. Clinical Materials, 6, 323±359. Jonck, L. M., Grobbelaar, C. J. & Strating, H. (1989a) The biocompatibility of glass± ionomer cement in joint replacement: bulk testing. Clinical Materials, 4, 85±107. Jonck, L. M., Grobbelaar, C. J. & Strating, H. (1989b) Biological evaluation of glass± ionomer cement (Ketac-0) as an interface material in total joint replacement. A
262
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screening test. Clinical Materials, 4, 201±224. Kenny, S. M. & Buggy, M. (2003) Bone cements and fillers: a review. Journal of Materials Science: Materials in Medicine, 14, 923±938. Kotani, S., Fujita, Y., Kitsugi, T., Nakamura, T., Yamamuro, T., Ohtsuki, C. & Kokubo, T. (1991) Bone bonding mechanism of tricalcium phosphate. Journal of Biomedical Materials Research, 25, 1303±1315. Lau, K. H. W., Yoo, A. & Wang, S. P. (1991) Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride. Molecular and Cellular Biochemistry, 105, 93±105. Loescher, A. R., Robinson, P. P. & Brook, I. M. (1994a) The effects of implanted ionomeric and acrylic bone cements on peripheral nerve function. Journal of Materials Science: Materials in Medicine, 5, 108±112. Loescher, A. R., Robinson, P. P. & Brook, I. M. (1994b) The immediate effects of ionomeric and acrylic bone cements on peripheral nerve function. Journal of Materials Science: Materials in Medicine, 5, 551±556. Lundy, M. W., Farley, J. R. & Baylink, D. J. (1986) Characterization of a rapidly responding animal model for fluoride-stimulated bone formation. Bone, 7, 289±293. Mackie, E. J., Thesleff, I. & Chiquet-Ehrismann, R. (1987) Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro. Journal of Cell Biology, 105, 2569±2579. McElveen Jr, J. T. (1994) Ossiculoplasty with polymaleinate ionomeric prostheses. Otolaryngologic Clinics of North America, 27, 777±784. McLean, J. W. (1988) Glass±ionomer cements. British Dental Journal, 164, 293±300. Meyer, U., Szulczewski, D. H., Barckhaus, R. H., Atkinson, M. & Jones, D. B. (1993) Biological evaluation of an ionomeric bone cement by osteoblast cell culture methods. Biomaterials, 14, 917±924. Muller, J., Geyer, G. & Helms, J. (1993) Ionomer-based cement in cochlear implant surgery. Laryngo-Rhino-Otologie, 72, 36±38. Muller, J., Geyer, G. & Helms, J. (1994) Good audiological results by reconstruction of defects of the incudo-stapedial joint in the middle ear by reconstructing the ossicles in their normal position. Laryngo-Rhino-Otologie, 73, 160±163. Nicholson, J. W., Braybrook, J. H. & Wasson, E. A. (1991) The biocompatibility of glass±poly(alkenoate) (glass±ionomer) cements: a review. Journal of biomaterials science. Polymer edition, 2, 277±285. Nordenvall, K. J. (1992) Glass ionomer cement used as surgical dressing after radical surgical exposure of impacted teeth. Swedish Dental Journal, 16, 87±92. Pak, C. Y. C., Sakhaee, K., Zerwekh, J. E., Parcel, C., Peterson, R. & Johnson, K. (1989) Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone mass and inhibition of fractures. Journal of Clinical Endocrinology and Metabolism, 68, 150±159. Quarles, L. D. (1991) Paradoxical toxic and trophic osseous actions of aluminum: potential explanations. Mineral and Electrolyte Metabolism, 17, 233±239. Quarles, L. D., Murphy, G., Vogler, J. B. & Drezner, M. K. (1990) Aluminum-induced neo-osteogenesis: a generalized process affecting trabecular networking in the axial skeleton. Journal of Bone and Mineral Research, 5, 625±635. Ramsden, R. T., Herdman, R. C. D. & Lye, R. H. (1992) Ionomeric bone cement in neuro-otological surgery. Journal of Laryngology and Otology, 106, 949±953. Renard, J. L., Felten, D. & Bequet, D. (1994) Post-otoneurosurgery aluminium encephalopathy [15]. Lancet, 344, 63±64. Reusche, E., Pilz, P., Oberascher, G., Lindner, B., Egensperger, R., Gloeckner, K.,
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Trinka, E. & Iglseder, B. (2001) Subacute fatal aluminum encephalopathy after reconstructive otoneurosurgery: a case report. Human Pathology, 32, 1136±1140. Ribeiro, J. & Ericson, D. (1991) In vitro antibacterial effect of chlorhexidine added to glass±ionomer cements. Scandinavian Journal of Dental Research, 99, 533±540. Sasanaluckit, P., Albustany, K. R., Doherty, P. J. & Williams, D. F. (1993) Biocompatibility of glass ionomer cements. Biomaterials, 14, 906±916. Sùgaard, C. H., Mosekilde, L., Schwartz, W., Leidig, G., Minne, H. W. & Ziegler, R. (1995) Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone, 16, 163±169. Szulczewski, D. H., Meyer, U., Moller, K., Stratmann, U., Doty, S. D. & Jones, D. B. (1993) Characterisation of bovine osteoclasts on an ionomeric cement in vitro. Cells and Materials, 3, 83±92. Turner, R. T., Francis, R., Brown, D., Garand, J., Hannon, K. S. & Bell, N. H. (1989) The effects of fluoride on bone and implant histomorphometry in growing rats. Journal of Bone and Mineral Research, 4, 477±484. Van Blitterswijk, C. A., Grote, J. J. & Kuypers, W. (1985) Bioreactions at the tissue/ hydroxyapatite interface. Biomaterials, 6, 243±251. Weiss, R. E. & Reddi, A. H. (1981) Role of fibronectin in collagenous matrix-induced mesenchymal cell proliferation and differentiation in vivo. Experimental Cell Research, 133, 247±254. Wijnbergen Buijen Van Weelderen, M., Van Mullem, P. J. & De Wijn, J. R. (1983) Release of an anti-inflammatory drug from some dental cements. Biomaterials, 4, 52±54. Wilson, A. D. & Mclean, J. W. (1988) Glass±Ionomer Cement. Chicago, Quintessence Publishing Co. Wittwer, C., Devlin, A. J., Hatton, P. V., Brook, I. M. & Downes, S. (1994). Release of serum proteins and dye from glass±ionomer (polyalkenoate) cements. Journal of Materials Science: Materials in Medicine 5, 108±112. Wood, D. & Hill, R. (1991a) Glass ceramic approach to controlling the properties of a glass±ionomer bone cement. Biomaterials, 12, 164±170. Wood, D. & Hill, R. (1991b) Structure±property relationships in ionomer glasses. Clinical Materials, 7, 301±312.
Bone±cement fixation: glass±ionomer cements P V H A T T O N , V R K E A R N S and I M B R O O K , University of Sheffield, UK
11.1
Introduction
Glass±ionomer cements (GICs) have been employed extensively in the repair of tooth tissue since the 1970s, and this long history suggests that they are among the most biocompatible dental materials available. Their apparent safety and history of good biocompatibility led scientists and clinicians to consider them for wider surgical uses in the 1980s and 1990s, and much of this early work has been reviewed (Brook and Hatton, 1998; Kenny and Buggy, 2003; Hatton et al., 2006). This chapter in many ways represents the first attempt to connect the data in published studies and reviews to our current technical knowledge of GICs, their setting chemistry and structure±property relationships.
11.2
Structure and properties of glass±ionomer cements
Conventional GICs are formed from the combination of high molecular weight polymeric acids (e.g. polyacrylic acid), a basic fluoroaluminsilicate glass powder and water. Many compositions include tartaric acid to extend the working time. The properties of GICs result from these components and their setting reaction, surface chemistry, physical structure and bulk composition. Set GICs may be described as composites with inorganic glass particles set in a relatively insoluble hydrogel matrix (see Fig. 11.1). Freshly mixed, unset GIC is able to chemically bond to both bone (apatite) and metals (McLean, 1988; Wilson and McLean, 1988). This is advantageous as it means that fixation is not achieved with mechanical interlocking alone. In simple terms, GICs set in stages. First, carboxylic acid residues on the polymeric acid ionise in the presence of water. Protons then react with the surface of the basic glass particles to liberate cations. Specific ions such as Ca2+ and Al3+ are then able to crosslink the ionised carboxylic acid residues, setting the cement. Although at reduced concentrations relative to the parent ionomer glasses (Hatton and Brook, 1992a), many of the component ions remain very mobile long after initial setting, leading to the
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11.1 Transmission electron photomicrographs of (a) a G338 glass particle in a set glass±ionomer cement and (b) a glass particle in set Ketac-cem. Field width approximately 5 m.
potential for complex `curing' and leaching of ions. The setting reaction is not exothermic, unlike acrylics. This is highly beneficial as it does not cause thermal damage to tissues at the site of implant, or to any temperature-sensitive drugs that may be incorporated into the matrix phase of the cement. In addition, there is no significant shrinkage of the cement on setting (Wood and Hill, 1991a). The mechanical properties of GICs are generally considered inferior to those of acrylic cements, but are sufficient for low to intermediate load-bearing applications with some potential for improvements with the use of different components. The mechanical properties of the GIC may be controlled to a degree by varying the volume fraction of the glass and hydrogel phases, enabling some properties to be matched with those of the surrounding bone.
11.3
Biological evaluation
11.3.1 Ion release and bioactivity The osteoconductivity exhibited by specific GICs is of particular interest. It has been suggested that this is due to ion exchange with the biological environment (Brook et al., 1991a, Wood and Hill, 1991a, Hatton and Brook, 1992b, Hatton et al., 2006). The ability of the material surface to bind certain biological factors that may recruit and regulate osteogenic cells could also assist the formation of a more stable bone±implant interface and thus improve the potential for clinical success. Immunohistochemical studies of implanted GIC have shown close association of the non-collagenous extracellular matrix proteins of bone (osteopontin, fibronectin and tenascin) with the GIC surface (Carter et al., 1991; Johal et al., 1996). These factors, which are believed to play an important role in ontogenesis and the osseointegration of biomaterials (Weiss and Reddi, 1981; Clark et al., 1982; Mackie et al., 1987; Carter et al., 1991; Bagambisa et al., 1993, 1994) together with the hydrophilic surface of GIC, may explain the osteoconductive properties of implanted GIC (Jonck et al., 1989a,b; Brook et al., 1991a,b, 1992; Doherty, 1991; Nicholson et al., 1991; Hatton and Brook, 1992b; Sasanaluckit et al., 1993; Hill et al., 1995; Johal et al., 1995).
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The bulk composition of GIC acts as a reservoir for ion release (Nicholson et al., 1991; Wood and Hill, 1991b; Sasanaluckit et al., 1993; Hill et al., 1995; Johal et al., 1995). As mentioned previously, certain ions released from the glass particles during the gelation process remain mobile once setting is complete. Studies have reported the presence of such ions in the matrix of the cement (Hatton and Brook, 1992a) and in adjacent bone (Hatton and Brook, 1992b), with exchange of ions taking place with the (aqueous) environment (McLean, 1988; El Mallakh and Sarkar, 1990, Forsten, 1991). Glass composition (Johal et al., 1995) determines ion release, as well as the biochemical environment of the implant bed (Devlin et al., 1994). Fluoride ion release from GIC has been comprehensively reported, although the majority of studies have related to the use of GIC in dental applications (Wilson and McLean, 1988; El Mallakh and Sarkar, 1990; Forsten, 1991). Even though caution must be exercised when interpreting the results, due in the main to poor standardisation and incomplete reporting of methods, it is clear that relatively large quantities of fluoride are released from GICs for periods of up to one year. It was originally proposed that fluoride release was the most significant factor affecting biocompatibility of glass±ionomers. Whereas the absence of fluoride has been reported to result in the least in vitro toxicity (although this material contained no phosphate, complicating interpretation of results) (Brook et al., 1991a), it also produced the lowest osteoconductivity and integration in vivo (Brook et al., 1991b, Johal et al., 1995). The effect of fluoride ions appears to be dose-dependent. Although high fluoride concentrations result in enzyme inhibition in vitro, bone-forming cells exhibit increased proliferation and alkaline phosphatise activity in vivo (Farley et al., 1983; Lundy et al., 1986; Turner et al., 1989; Brook et al., 1991b). Fluoride is also used to treat bone resorption in patients with osteoporosis (Pak et al., 1989; Sùgaard et al., 1995), owing to its ability to increase the density of trabecular bone. Studies have reported a greater volume of bone formation associated with GIC than with more inert ceramic bone substitutes and, more recently, related increased fluoride release with bone formation (Brook et al., 1991b; Johal et al., 1995). It is speculated that this is because fluoride release from GIC during bone formation results in mineralisation containing fluorapatite, which is more resistant to resorption. The release of other ions from GIC is less well reported, although it has been proposed that ion release is a major factor in the bioactivity of different GICs (Brook et al., 1991a, 1992; Doherty, 1991; Nicholson et al., 1991; Hatton and Brook, 1992b; Sasanaluckit et al., 1993). Ion exchange with the tissues of the implant bed has been confirmed to be a significant determinant in the bioactivity of a GIC (Devlin et al., 1994; Johal et al., 1995). Aluminium ion release is particularly important and plays a somewhat controversial role (Nicholson et al., 1991), particularly following reports of four cases of post-otoneurosurgery aluminium encephalopathy and deaths among patients treated with a glass±
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ionomer bone cement (Renard et al., 1994; Reusche et al., 2001). Data published to date suggest that aluminium leaching occurs only in the initial period following setting (Crisp et al., 1980; Wilson and McLean, 1988). Increased aluminium ion content and release result in decreased biocompatibility in vitro (Devlin et al., 1994) and may be a more significant factor in biocompatibility than fluoride, although it may have a similarly complex effect. No reports have identified aluminium ions as the sole cause of in vitro cytotoxicity. Low concentrations of aluminium ions have been shown to stimulate the proliferation of osteoblasts in vitro and new bone formation (Quarles et al., 1990; Meyer et al., 1993). Additionally, aluminium particles have been observed inside cultured osteoblasts cells without any detrimental effect on the cells or impairment of bone formation (Blumenthal and Posner, 1984; Hatton and Brook, 1992b; Szulczewski et al., 1993). Aluminium ion release increased the amount of osteoid formation in vivo but interferes with the early stages of bone mineralisation (Blumenthal and Posner, 1984; Quarles, 1991; Meyer et al., 1993), resulting in a reduction of this process. Collagen synthesis is also inhibited (Goodman, 1985; Goodman and O'Connor, 1991). Aluminium also mediates mobilisation of calcium from bone by a cell-independent mechanism. Further research is required into the role of metal ions on osteogenesis. Calcium and phosphate ions may be expected to enhance this process, whereas the effect of other ions is less clear. It is likely that the combination of various factors, particularly the combination and relative concentration of ionic species and their interaction with each other and the biological environment, will result in different outcomes (El Mallakh and Sarkar, 1990; Forsten, 1991; Lau et al., 1991; Nicholson et al., 1991; Devlin et al., 1994; Johal et al., 1995).
11.3.2 In vitro evaluation Glass±ionomers have been tested extensively in vitro and interpretation of these studies demonstrates that these materials should be classed as `bioactive'. Consideration of the results should therefore take into account that bioactive materials often perform less well than more inert materials in vitro (Gross et al., 1987). Furthermore, the in vitro model should attempt to replicate the clinical situation as far as possible. Many studies have evaluated GICs and other bone cements in terms of the migration of osteoblasts onto their surfaces. Appropriate cell source and culture conditions can also be manipulated to induce formation of a bone-like tissue in vitro. Standard cytotoxicity tests involving a variety of cell types (osteoblasts, osteoclasts, fibroblasts, neonate rat calvaria) have been carried out. Positive interactions between certain types of GIC and bone cells have been reported (Brook et al., 1991a, 1992; Doherty, 1991; Meyer et al., 1993; Szulczewski et al., 1993). Cultured cells are particularly sensitive to wet cements; studies in which wet cements were placed in direct contact with neonate rat calvaria resulted in cell death (Brook et al., 1991a). This makes this
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method of study unsuitable for investigating unset cements. Any observed toxicity of set cements has been attributed to the presence of a toxic leachate or the rough surface of the cement. The effect of fluoride, aluminium ion leaching has been discussed in detail above. The low pH of GICs (due to release of protons) while setting and maturing has been proposed as a cause of cyto- and neurotoxicity (Gross et al., 1987; Loescher et al., 1994a; Brook and Hatton, 1998). In summary, the mechanisms responsible for in vitro cytotoxicity are complex and may be unrelated to their in vivo and clinical performance. It might in the future be beneficial to evaluate GICs in vitro following the pre-treatments described for bioactive glasses, but no detailed studies that add substantially to the knowledge reviewed here have been reported.
11.3.3 In vivo evaluation In vivo evaluation allows more meaningful testing of GICs than in vitro methods. Encouraging results have been reported from testing of set cements. In vivo osteoconduction has been widely reported (Jonck et al., 1989a,b; Brook et al., 1991b; Johal et al., 1995). The first preclinical studies into the use of GIC for orthopaedic surgery involved implantation into baboon tibia and gave promising results (Jonck et al., 1989a,b). In one study, GICs with certain compositions were found to support new bone formation six weeks following implantation in rat femora, with the tissue stable over the course of one year. Another important finding of this study was the demonstration that in vitro studies are not always a reliable predictor of the performance of GICs in vivo, as one composition (fluoride- and phosphate-free) that was considered to be biocompatible failed to achieve osseo-integration. Direct bone±cement contact was observed only with fluoride-containing glasses, with the formation of a stable interface (Hatton and Brook, 1992b). The GIC±bone interface morphology varies, ranging from a lamina limitans-like interface shown in Fig. 11.2 (Brook et al., 1991a,b), which mimics the normal boundary of bone with osteocyte lacunae (Van Blitterswijk et al., 1985) to an interdigitation of collagen fibres with the GIC (Brook et al., 1992). The latter of these represents a more bioactive bond, reported on specimens that have not been distorted by decalcification (Jarcho et al., 1977; Kotani et al., 1991). Once the initial post-implantation inflammatory response to a material, which is inevitable, has subsided, the medium-term biological response can be evaluated. GICs demonstrate their osteoconductive potential, unlike poly(methylmethacrylate) (PMMA) cements. Evidence of the bioactive properties of GICs was reported (Fischer, 1986; Carter et al., 1997); no incidence of fibrous encapsulation was observed. Unfortunately, the issue of aluminium ion release appeared to influence the results of in vivo implantation. Two independent studies demonstrated that the new bone tissue that formed rapidly on the surface suffered from defective mineralisation, and that this was associated with the
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11.2 Transmission electron photomicrograph of interface (arrowed) between new bone tissue (B) and a set glass±ionomer cement with glass particles (G) and matrix (M). Field width approximately 10 m.
localisation of aluminium in the tissue (Blades et al., 1991, Carter et al., 1991). Despite this concern, a study of the use of particulate GICs as a bone allograft expander concluded that there were no adverse effects on bone remodelling or recovery or the performance of the bone allograft. GIC implanted into the tibia of baboons (Jonck et al., 1989b; Brook et al., 1991a) had previously generated favourable results, leading to the limited clinical application in orthopaedics noted above (Jonck and Grobbelaar, 1990). While numerous reports describe the response of bone to set GICs, very few studies investigating the response to freshly mixed GICs have been reported, and in general the less encouraging tissue responses are observed when GICs are placed `wet' during setting. Studies based on diffusion chambers containing a glass±ionomer and bone marrow, implanted into baboon femora for up to three years demonstrated that the cement promoted osteoblastic activity, with no inhibitory effect on bone tissue. The relevance of these results is limited, however, owing to the separation of host and material by the diffusion chamber. Although freshly mixed glass±ionomers placed on the rat femur suggested initial bone bonding, evidence of a pronounced periosteal reaction and sub-periosteal resorption was found at 6 and 12 weeks. New bone formation was, however, observed at 12 weeks (Brook et al., 1991b; Hatton and Brook, 1992b). Additionally, there was a short-term inflammatory response, likely to be the result of either reduction of tissue pH, causing local tissue necrosis, or release of free glass particles and metal ions from unset cement contaminated by tissue fluid or blood. Water has an adverse effect on the setting reaction and the unfavourable in vivo response to unset cements highlights the importance of avoiding excess moisture during surgery.
11.3.4 Clinical evaluation GICs have been used in various surgical applications. Favourable outcomes have been reported when GICs have been used in granule or cement form in orthopaedic cases where conventional care had failed (Jonck and Grobbelaar,
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1990), but it is the opinion of the authors that these materials are not suitable for situations in which the strength of the cement is critical to the outcome. The use of GIC to reinforce osteoporotic femoral heads has been reported to improve the primary stability of dynamic hip screws (McElveen, 1994), although long-term data or additional information on bone mineral density was not reported. GICs have been particularly successful in otological surgery, being used as a cement or formed into prosthetic implants (Babighian, 1992; Ramsden et al., 1992; Geyer and Helms, 1993; Muller et al., 1993, 1994; Babighian et al., 1994). GIC is the highest-performing material in terms of clinical efficacy in ossicular chain reconstruction, where the cement is used to repair bony ossicles in their normal position, and in cementation of cochlear implants (Babighian, 1992; Ramsden et al., 1992; Muller et al., 1993; Babighian et al., 1994). One study reported 167 patients who had been treated with GIC in middle ear surgery (Geyer and Helms, 1990). Another study reported a 94% four-year success rate for 945 instances of GIC ossicular implant placement (Geyer and Helms, 1993). Furthermore, out of 74 cases of posterior canal wall repair using GIC, only 12 cases required revision surgery (Geyer and Helms, 1993). Oral surgical procedures may also involve GIC, in particular as a bone substitute to prevent bone loss following tooth extraction and as a filler for graft donor sites and cyst cavities (Nordenvall, 1992). GIC are also used as a surgical dressing following exposure of teeth prior to orthodontic alignment (Nordenvall, 1992). The successful outcomes following the use of GIC in various surgical procedures led to their application in neuro-otological and skull base surgery and repair of cerebrospinal fluid (CSF) fistulas and skull defects (Ramsden et al., 1992; Helms and Geyer, 1994). At the same time, evaluation of GIC in terms of their biocompatibility with neural tissue was being carried out. Although seemingly biocompatible, clinical data reported that exposure to viscous GIC resulted in a potentially irreversible block in nerve conduction (Loescher et al., 1994a,b). It was already recommended that unset GIC should not come into contact with soft tissue and that it should be placed in a `dry field', but the results of these studies lead to a further restriction ± that GIC bone cement should not be allowed to come into contact with neural tissue. Sadly, these warnings came too late to prevent four cases of post-otoneurosurgery aluminium encephalopathy, resulting in two deaths (Renard et al., 1994). The issues surrounding these cases are complex, but it is likely that the release of polyacid during the setting reaction and disruption of the setting reaction due to exposure to body fluid/blood, led to the release of large quantities of metal ions and glass particles with disastrous results. It is notable that no deaths resulted from operations where the brain was protected from contact with the cement, and it might be concluded that correct surgical technique is essential when using modern `bioactive' medical materials. Overall, the story of the development of glass±ionomer bone cements is a salient reminder of some of the key points of biomaterials science: biocompatibility is application-specific, and the ultimate
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behaviour of a medical device in the body is as much related to the expertise and experience of the surgeon as it is to the properties of the biomaterials used.
11.4
Future trends
The incorporation of antibiotics into acrylic cements is associated with a reduction in the incidence of post-operative infection following orthopaedic surgery. Early studies trying to replicate this success using drug-loaded GIC were less successful (Wijnbergen Buijen Van Weelderen et al., 1983), although the release of biologically active chlorhexidine was reported from two dental cements (Ribeiro and Ericson, 1991). The Sheffield group also reported that GICs provided a favourable matrix for the release of potential biologically active molecules such as proteins (Wittwer et al., 1994). Given the promising properties reported here, it appears advisable to revisit GICs for use as a matrix for drug delivery in bone tissue. GICs have some advantages for orthopaedic applications, including their truly adhesive nature and non-exothermic setting reaction, which does not result in shrinkage and may improve the release of incorporated therapeutic compounds. Their mechanical properties are, however, inferior to those of acrylic bone cements, limiting their load-bearing capacity. It is their interaction with the biological environment that is both encouraging and problematic in equal measure. Biological evaluation has provided some encouraging results, for example the so-called bioactive nature of GICs, by which a composition, site and tissue-dependent ion exchange has encouraged an appropriate host response. More worryingly, the release of aluminium has also been associated with a mineral defect in bone tissue following the use of GICs in orthopaedic applications, and in extreme examples the incorrect placement of the cement has been associated with the death of patients. Concerns regarding aluminium release from glass±ionomers have led recently to the development of aluminium-free GICs, where the Al2O3 was substituted entirely with Fe2O3 (Hurrell-Gillingham et al., 2005, 2006). Further work is ongoing on these promising compositions to establish whether or not they represent a practical alternative to the conventional GIC bone cements already used successfully in ear, nose and throat (ENT) surgery. However, a more radical approach to biomaterial design will be required if glass±ionomer bone cements are to be used successfully for the fixation of medical devices in total joint replacement.
11.5
References
Babighian, G. (1992) Use of a glass ionomer cement in otological surgery: a preliminary report. Journal of Laryngology and Otology, 106, 954±959. Babighian, G., Dominguez, M., Pantano, N. & Tomasi, P. (1994) Multichannel cochlear implant: personal experience. L'impianto cocleare multicanale. Nostra esperienza, Acta Otorhinolaryngol Ital. Mar±Apri 14, 107±125.
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Bagambisa, F. B., Joos, U. & Schilli, W. (1993) Mechanisms and structure of the bond between bone and hydroxyapatite ceramics. Journal of Biomedical Materials Research, 27, 1047±1055. Bagambisa, F. B., Kappert, H. F. & Schilli, W. (1994) Cellular and molecular biological events at the implant interface. Journal of Cranio-Maxillo-Facial Surgery, 22, 12±17. Blades M. C., Moore D. P., Revell P. A. & Hill R. (1991) In vivo skeletal response and biomechanical assessment of two novel polyalkenoate cements following femoral implantation in the female New Zealand white rabbit. Journal of Materials Science: Materials in Medicine, 9, 701±706. Blumenthal, N. C. & Posner, A. S. (1984) In vitro model of aluminium-induced osteomalacia: inhibition of hydroxyapatite formation and growth. Calcified Tissue International, 36, 439±441. Brook, I. M. & Hatton, P. V. (1998) Glass±ionomers: bioactive implant materials. Biomaterials, 19, 565±571. Brook, I. M., Craig, G. T. & Lamb, D. J. (1991a) In vitro interaction between primary bone organ cultures, glass±ionomer cements and hydroxyapatite/tricalcium phosphate ceramics. Biomaterials, 12, 179±186. Brook, I. M., Craig, G. T. & Lamb, D. J. (1991b) Initial in-vivo evaluation of glass± ionomer cements for use as alveolar bone substitutes. Clinical Materials, 7, 295± 300. Brook, I. M., Craig, G. T., Hatton, P. V. & Jonck, L. M. (1992) Bone cell interactions with a granular glass±ionomer bone substitute material: in vivo and in vitro culture models. Biomaterials, 13, 721±725. Carter, D. H., Sloan, P. & Aaron, J. E. (1991) Immunolocalization of collagen Types I and III, tenascin, and fibronectin in intramembranous bone. Journal of Histochemistry and Cytochemistry, 39, 599±606. Carter, D. H., Sloan, P., Brook, I. M. & Hatton, P. V. (1997) Role of aluminium in the integration of ionomeric (glass polyalkenoate) bone substitutes. Biomaterials, 18, 459±466. Clark, R. A. F., Lanigan, J. M., Dellapelle, P., Manseau, E., Dvorak, H. F. & Colvin, R. B. (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. Journal of Investigative Dermatology, 79, 264±269. Crisp, S., Lewis, B. G. & Wilson, A. D. (1980) Characterization of glass±ionomer cements. 6. A study of erosion and water absorption in both neutral and acidic media. Journal of Dentistry, 8, 68±74. Devlin, A. J., Hatton, P. V., Hill, R., Henn, G., De Barra, E., Craig, G. T. & Brook, I. M. (1994) Initial investigation of ion release from novel polyalkenoate cements related to in vitro biocompatibility. 11th European Conference on Biomaterials. Pisa, Italy, Tipographia Vigo Cursi. Doherty, P. J. (1991) Biocompatibility evaluation of glass ionomer cement using cell culture techniques. Clinical Materials, 7, 335±340. El Mallakh, B. F. & Sarkar, N. K. (1990) Fluoride release from glass±ionomer cements in de-ionized water and artificial saliva. Dental Materials: Official Publication of the Academy of Dental Materials, 6, 118±122. Farley, J. R., Wergedal, J. E. & Baylink, D. J. (1983) Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science, 222, 330±332. Fischer, A. A. (1986) Reactions to acrylic bone cement in orthopaedic surgeons and patients. Cutis, 37, 425±426.
Bone±cement fixation: glass±ionomer cements
261
Forsten, L. (1991) Fluoride release and uptake by glass ionomers. Scandinavian Journal of Dental Research, 99, 241±245. Geyer, G. & Helms, J. (1990) Reconstructive measures in the middle ear and mastoid using a biocompatible cement ± preliminary clinical experience. In Heimke, E., Soltese, U. & Lee, A. J. C. (Eds) Advances in Biomaterials. Amsterdam, The Netherlands, Elsevier. Geyer, G. & Helms, J. (1993) Ionomer-based bone substitute in otologic surgery. European Archives of Oto-Rhino-Laryngology, 250, 253±256. Goodman, W. (1985) Bone disease and aluminum: pathogenic considerations. American Journal of Kidney Diseases, 6, 330±335. Goodman, W. G. & O'Connor, J. (1991) Aluminum alters calcium influx and efflux from bone in vitro. Kidney International, 39, 602±607. Gross, U., Schmitz, H. J., Kinne, R., Fendler, F. R. & Struntz, V. (1987) Tissue or cell culture versus in vivo testing of surface reactive biomaterials. In Pizzoferrato, A., Ravaglioli, A. & Lee, A. J. C. (Eds) Biomaterials and Clinical Applications. Amsterdam, The Netherlands, Elsevier Science. Hatton, P. V. & Brook, I. M. (1992a) Characterisation of the ultrastructure of glass± ionomer (poly-alkenoate) cement. British Dental Journal, 173, 275±277. Hatton, P. V. & Brook, I. M. (1992b) X-ray microanalysis of bone and implanted bone substitutes. Micron and Microscopica Acta, 23, 363±364. Hatton P.V., Hurrell-Gillingham, K. & Brook I. M. (2006) Biocompatibility of glass± ionomer bone cements. Journal of Dentistry, 34, 598±601. Helms, J. & Geyer, G. (1994) Closure of the petrous apex of the temporal bone with ionomeric cement following translabyrinthine removal of an acoustic neuroma. Journal of Laryngology and Otology, 108, 202±205. Hill, R., Hatton, P. V. & Brook, I. (1995) Factors influencing the biocompatibility of glass polyalkenoate (ionomer) cements with bone tissue. In Ravaglioli, A. (Ed.) Proceedings of the Ceramics Cells and Tissues. Faenza, Italy, Gruppo Editoriale. Hurrell-Gillingham, K., Reaney, I. M., Brook, I. & Hatton, P. V. (2005) Novel Fe2O3containing glass ionomer cements: Glass characterisation. Key Engineering Materials, 284±286, 799±802. Hurrell-Gillingham, K., Reaney, I. M., Brook, I. & Hatton, P. V. (2006) In vitro biocompatibility of a novel Fe2O3 based glass ionomer cement. Journal of Dentistry, 34, 533±538. Jarcho, M., Kay, J. F., Gumaer, K. I., Doremus, R. H. & Drobeck, H. P. (1977) Tissue, cellular and subcellular events at a bone±ceramic hydroxyapatite interface. Journal of Bioengineering, 1, 79±92. Johal, K. K., Craig, G. T., Devlin, A. J., Brook, I. M. & Hill, R. (1995) In vivo response of ionomeric cements: effect of glass composition, increasing soda or calcium fluoride content. Journal of Materials Science: Materials in Medicine, 6, 690±694. Johal, K., Carter, D. H., Hatton, P. V., Sloan, P. & Brook, I. (1996) The interaction of bone extracellular matrix proteins with ionomeric implants increasing in sodium content. Journal of Dental Research, 75, 1152. Jonck, L. M. & Grobbelaar, C. J. (1990) Ionos bone cement (glass±ionomer): an experimental and clinical evaluation in joint replacement. Clinical Materials, 6, 323±359. Jonck, L. M., Grobbelaar, C. J. & Strating, H. (1989a) The biocompatibility of glass± ionomer cement in joint replacement: bulk testing. Clinical Materials, 4, 85±107. Jonck, L. M., Grobbelaar, C. J. & Strating, H. (1989b) Biological evaluation of glass± ionomer cement (Ketac-0) as an interface material in total joint replacement. A
262
Joint replacement technology
screening test. Clinical Materials, 4, 201±224. Kenny, S. M. & Buggy, M. (2003) Bone cements and fillers: a review. Journal of Materials Science: Materials in Medicine, 14, 923±938. Kotani, S., Fujita, Y., Kitsugi, T., Nakamura, T., Yamamuro, T., Ohtsuki, C. & Kokubo, T. (1991) Bone bonding mechanism of tricalcium phosphate. Journal of Biomedical Materials Research, 25, 1303±1315. Lau, K. H. W., Yoo, A. & Wang, S. P. (1991) Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride. Molecular and Cellular Biochemistry, 105, 93±105. Loescher, A. R., Robinson, P. P. & Brook, I. M. (1994a) The effects of implanted ionomeric and acrylic bone cements on peripheral nerve function. Journal of Materials Science: Materials in Medicine, 5, 108±112. Loescher, A. R., Robinson, P. P. & Brook, I. M. (1994b) The immediate effects of ionomeric and acrylic bone cements on peripheral nerve function. Journal of Materials Science: Materials in Medicine, 5, 551±556. Lundy, M. W., Farley, J. R. & Baylink, D. J. (1986) Characterization of a rapidly responding animal model for fluoride-stimulated bone formation. Bone, 7, 289±293. Mackie, E. J., Thesleff, I. & Chiquet-Ehrismann, R. (1987) Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro. Journal of Cell Biology, 105, 2569±2579. McElveen Jr, J. T. (1994) Ossiculoplasty with polymaleinate ionomeric prostheses. Otolaryngologic Clinics of North America, 27, 777±784. McLean, J. W. (1988) Glass±ionomer cements. British Dental Journal, 164, 293±300. Meyer, U., Szulczewski, D. H., Barckhaus, R. H., Atkinson, M. & Jones, D. B. (1993) Biological evaluation of an ionomeric bone cement by osteoblast cell culture methods. Biomaterials, 14, 917±924. Muller, J., Geyer, G. & Helms, J. (1993) Ionomer-based cement in cochlear implant surgery. Laryngo-Rhino-Otologie, 72, 36±38. Muller, J., Geyer, G. & Helms, J. (1994) Good audiological results by reconstruction of defects of the incudo-stapedial joint in the middle ear by reconstructing the ossicles in their normal position. Laryngo-Rhino-Otologie, 73, 160±163. Nicholson, J. W., Braybrook, J. H. & Wasson, E. A. (1991) The biocompatibility of glass±poly(alkenoate) (glass±ionomer) cements: a review. Journal of biomaterials science. Polymer edition, 2, 277±285. Nordenvall, K. J. (1992) Glass ionomer cement used as surgical dressing after radical surgical exposure of impacted teeth. Swedish Dental Journal, 16, 87±92. Pak, C. Y. C., Sakhaee, K., Zerwekh, J. E., Parcel, C., Peterson, R. & Johnson, K. (1989) Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone mass and inhibition of fractures. Journal of Clinical Endocrinology and Metabolism, 68, 150±159. Quarles, L. D. (1991) Paradoxical toxic and trophic osseous actions of aluminum: potential explanations. Mineral and Electrolyte Metabolism, 17, 233±239. Quarles, L. D., Murphy, G., Vogler, J. B. & Drezner, M. K. (1990) Aluminum-induced neo-osteogenesis: a generalized process affecting trabecular networking in the axial skeleton. Journal of Bone and Mineral Research, 5, 625±635. Ramsden, R. T., Herdman, R. C. D. & Lye, R. H. (1992) Ionomeric bone cement in neuro-otological surgery. Journal of Laryngology and Otology, 106, 949±953. Renard, J. L., Felten, D. & Bequet, D. (1994) Post-otoneurosurgery aluminium encephalopathy [15]. Lancet, 344, 63±64. Reusche, E., Pilz, P., Oberascher, G., Lindner, B., Egensperger, R., Gloeckner, K.,
Bone±cement fixation: glass±ionomer cements
263
Trinka, E. & Iglseder, B. (2001) Subacute fatal aluminum encephalopathy after reconstructive otoneurosurgery: a case report. Human Pathology, 32, 1136±1140. Ribeiro, J. & Ericson, D. (1991) In vitro antibacterial effect of chlorhexidine added to glass±ionomer cements. Scandinavian Journal of Dental Research, 99, 533±540. Sasanaluckit, P., Albustany, K. R., Doherty, P. J. & Williams, D. F. (1993) Biocompatibility of glass ionomer cements. Biomaterials, 14, 906±916. Sùgaard, C. H., Mosekilde, L., Schwartz, W., Leidig, G., Minne, H. W. & Ziegler, R. (1995) Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone, 16, 163±169. Szulczewski, D. H., Meyer, U., Moller, K., Stratmann, U., Doty, S. D. & Jones, D. B. (1993) Characterisation of bovine osteoclasts on an ionomeric cement in vitro. Cells and Materials, 3, 83±92. Turner, R. T., Francis, R., Brown, D., Garand, J., Hannon, K. S. & Bell, N. H. (1989) The effects of fluoride on bone and implant histomorphometry in growing rats. Journal of Bone and Mineral Research, 4, 477±484. Van Blitterswijk, C. A., Grote, J. J. & Kuypers, W. (1985) Bioreactions at the tissue/ hydroxyapatite interface. Biomaterials, 6, 243±251. Weiss, R. E. & Reddi, A. H. (1981) Role of fibronectin in collagenous matrix-induced mesenchymal cell proliferation and differentiation in vivo. Experimental Cell Research, 133, 247±254. Wijnbergen Buijen Van Weelderen, M., Van Mullem, P. J. & De Wijn, J. R. (1983) Release of an anti-inflammatory drug from some dental cements. Biomaterials, 4, 52±54. Wilson, A. D. & Mclean, J. W. (1988) Glass±Ionomer Cement. Chicago, Quintessence Publishing Co. Wittwer, C., Devlin, A. J., Hatton, P. V., Brook, I. M. & Downes, S. (1994). Release of serum proteins and dye from glass±ionomer (polyalkenoate) cements. Journal of Materials Science: Materials in Medicine 5, 108±112. Wood, D. & Hill, R. (1991a) Glass ceramic approach to controlling the properties of a glass±ionomer bone cement. Biomaterials, 12, 164±170. Wood, D. & Hill, R. (1991b) Structure±property relationships in ionomer glasses. Clinical Materials, 7, 301±312.