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Developments in Biocompatible Glass Compositions

The use of bioactive glasses has shown promise in promoting tissue repair and regeneration.

David C. Greenspan

Ceramic materials, including glasses, have enjoyed numerous uses in the healthcare industry for quite some time, especially outside the body. Eyeglasses, thermometers, containers for sterile saline, and tissue-culture flasks are just a few examples. In dentistry, porcelain crowns, silica fillers in composite resins, and glass-ionomer cements have also had a long and successful history of use. The use of bioceramic materials—of which bioactive glasses are a subset—as implants, however, has only developed during the past 30 years.

Through the mid-1960s, the goal of biomaterials development was the creation of materials that were as chemically inert as possible.¹ It was only by minimizing the materials' interaction with the host that biocompatibility and long-term survival of implants was achieved. The materials used at this time were primarily metallic and were subject to corrosion and eventual failure caused by the highly aggressive nature of body fluids. This led to a search for materials that were better able to withstand the chemical attack of the body.

In the late 1960s and early 1970s, the quest for better biocompatibility of implant materials resulted in a new concept: bioceramic materials that would mimic natural bone tissue.^2,3 Because hydroxyapatite (HA), a naturally occurring ceramic mineral, is also the mineral component of bone, it was believed that synthetic HA used for bone replacement would be entirely compatible with the body. At the same time, Hench developed the concept of using a silicate-based material with calcium and phosphate—in proportions identical to natural bone—as an implant material.^4,5 It was found that after implantation in bone tissue, these glass materials resisted removal from the implant site and were, in effect, "bonded to bone." Hench used the term "bioactive glass" to describe this interfacial bond that developed between the implant and host tissue. The term bioactive was later applied to the synthetic HA materials to encompass the field of biomaterials science known as bioactive ceramics. As a result of this early research, four general categories of implant materials were identified and their attachment mechanisms described, as shown in Table I.

Table I. Bioceramic implant types and mechanisms of tissue attachment.

The class of bioactive materials, including bioactive glasses and hydroxyapatites, have in common a surface activity that is directly responsible for the formation of the interfacial bond. A bioactive material has thus been defined as one that "elicits a specific biological response at the interface of the material which results in the formation of a bond between the tissues and the material."⁶ Another common characteristic of these materials is the formation of a hydroxycarbonate apatite (HCA) surface layer, first described by Hench¹ and, later, by Davies.⁷

BIOACTIVE GLASS SURFACE REACTIVITY

The unique surface reactivity of bioactive glasses has been described extensively by Hench^2,5,6 and others.^8–10 Figure 2 summarizes the various reactions that transpire at the bioactive glass—tissue surface, with stages 1 through 5 occurring ostensibly in sequence. The first stage is the loss of sodium ions (Na⁺) from the surface of the glass via ion exchange with hydrogen (H⁺ or H₃O⁺). This reaction occurs very rapidly, within minutes of material exposure to bodily fluids, and creates a dealkalinization of the surface layer with a net negative surface charge.

During these first minutes of exposure of a bioactive glass to an aqueous environment, the loss of sodium causes a localized breakdown of the silica network with the resultant formation of silanol (Si(OH)₄) groups, which then repolymerize into the silica-rich surface layer. This surface is highly porous on a microscopic scale, with average pore diameter on the order of 30 to 50 Å and an effective surface area of up to 100 m²/g. Hench has proposed that the loss of soluble silica from the surface of bioactive glasses might be at least partially responsible for stimulating the proliferation of bone-forming cells in the area of the glass surface.¹¹

Following the formation of the silica-rich layer, an amorphous calcium phosphate layer will form on the glass surface (stages 4 and 5) and incorporate the biologic moieties—for example, blood proteins, growth factors, and collagen. The adsorption of proteins and other biologic moities occurs concurrently with the first four reaction stages and is believed to contribute to the biological nature of the HCA layer. Within approximately 3 to 6 hours in vitro, this calcium phosphate layer will crystallize into the hydroxycarbonate apatite layer, which has been described as the bonding layer.⁶ Because this surface is chemically and structurally nearly identical to natural bone mineral, the body's tissues are able to attach directly to it. As the reactivity continues, this surface HCA layer grows in thickness to form a bonding zone of 100–150 µm—a mechanically compliant interface that is essential for maintaining the bioactive bonding of the implant to the natural tissue.

These surface reactions occur within the first 12 to 24 hours of implantation. Thus by the time osteogenic cells, such as osteoblasts or mesenchymal stem cells, infiltrate a bony defect—which normally takes 24 to 72 hours—they will encounter a bonelike surface, complete with organic components, and not a foreign material. It is this sequence of events, in which the bioactive glass participates in the repair process, that allows for the creation of a direct bond of the material to tissue.

The body's normal healing and regeneration processes (stages 7–11) begin after these surface layers have begun to form. As will be described below, bioactive glasses appear to minimize the duration of the macrophage and inflammatory responses that accompany any trauma, including surgery.^5,6,11,12 Thus, stages 8 through 11 in Table II can occur more rapidly than has been seen with implantation of other synthetic materials.

CLINICAL RESPONSE OF BIOACTIVE GLASSES

The first clinical use of bioactive glass was for the reconstruction of the bony ossicular chain of the middle ear in the treatment of conductive hearing loss. There are numerous indications for the surgical restoration of the ossicular chain. These include formation of cholesterol crystals, which can exert pressure on the surrounding tissue; chronic inflammation of the middle ear, which attacks the bone structure, resulting in hearing loss; and osteosclerosis, a hereditary disorder causing deafness due to an overgrowth of the mastoid bone. Details of the various disease states are beyond the scope of this article, but a review of clinical performance of bioactive glass has been published by Hench and Wilson.⁶

Until the use of bioactive glasses for ossicular replacement was attempted, the long-term prognosis for surgical success was not very good. Ceravital (E. Leitz Wetzlar GmBh; Wetzlar, Germany) was introduced in 1981, and the early clinical results, published in 1984, were clearly superior to those of the polymeric or metallic prostheses used at that time.¹³ In 1982, the use of Bioglass (USBiomaterials, Alachua, FL) to reconstruct the ossicles was reported by Merwin et al.¹⁴ In this study, it was discovered that the bioactive glass bonded not only with the remaining bone stock of the ossicle, but also directly to the typanic membrane via collagen attachment to the surface of the glass. This was the first time any implant material demonstrated direct bonding to the soft tissue of the tympanic membrane. The compositions of the Bioglass and Ceravital materials are shown in Table II.

Table II. Composition and properties of bioactive glasses.

The ability of the bioactive glass prosthesis to bond directly to the eardrum and bone prevented the device from breaking through the tympanic membrane, which had been the main mode of failure of devices made from metals or polymers. An additional advantage of the bioactive glass prosthesis was its ability to be easily shaped for a precise fit in the ear canal, which also enhanced the early success rate.

In a retrospective 10-year follow-up of clinical studies, Lobel found that the overall success rate for the Bioglass and Ceravital implants was significantly greater than for the polymer systems.¹⁵ Extrusion rates for these materials were only 3 and 9%, respectively, compared with rates from 23 to 60% for various polymer systems.

Another early clinical use of bioactive glass compositions was developed by a research team headed by Stanley, using the 45S5 composition of Bioglass (shown in Table II) as a natural tooth-form implant following extraction.^16,17 During the initial phases of these studies, it was found that after splinting the tooth for 3 months, all implants were retained solidly in the sites, evidently bonded to the bony tissue. After 6 months, however, it was discovered that the implants were missing and the sockets healed over. Histologic examination of these implant sites revealed that the root portion of the original implants remained in the dental ridge, directly bonded to bone.

This discovery led to the development of a totally submerged, ridge-maintenance implant to preserve the alveolar ridge following tooth extraction.¹⁸ The bioactive glass cones acted as space fillers after the extraction of natural teeth, and delayed the resorption of the alveolar ridge. The long-term clinical report of a human study of 242 implants showed an overall success rate of 86% with an average postsurgery follow-up of 5 years; some patients were followed for as long as 9 years and 3 months.¹⁹

These results were significantly better than previous clinical trials with similar root-form implants made from dense hydroxyapatite. In the dense-HA trials, the rate of implant loss and dehiscence (gradual migration of the implant through the gingiva) ranged from 10% loss and 13% dehiscence to more than 50% implant loss.^20,21 It has been postulated that the main reason for the higher success rate of the bioactive glass implants is the more rapid and extensive formation of the bioactive HCA layer at the surface of the implants, which acts as a pseudoperiodontal ligament.

While the initial clinical application of bulk bioactive glass implants was successful, the limiting factor of poor mechanical strength resulted in the development of applications for the material as particulates for fill-in bone voids. In these nonstructural graft sites, load bearing was not a requirement. The first successful use of bioactive glass for filling bony defects was reported by Wilson in a primate model in 1987.¹² It was found that the bioactive glass granules not only allowed bone to fill into the periodontal defects, but also encouraged the proliferation of bone throughout the defect simultaneously—that is, bone growth independent of connection with the bony wall of the defect. This phenomenon was termed "osteoproduction," and clearly distinguished bioactive glass from osteoconductive materials, such as hydroxyapatite.

Since these early animal studies, numerous clinical programs have shown that bioactive glass granules are effective in treating periodontal defects, as well as other bony defects in the oral cavity.^22–26 The results of the various studies have been remarkably similar: they have all shown significantly more bony infill using the bioactive glass than with the standard treatment of open debridement. With follow-up periods from 6 months to 2 years, the various studies show defect fill from 60 to 70% for the bioactive glass versus 30 to 35% for controls. In addition, the soft issue appears to be healthier and to heal more rapidly around the bioactive glass—filled defects. With more than 4 years of general clinical experience in the market, bioactive glass compositions are proving to be the materials of choice for the repair of periodontal defects. The particulate form of Bioglass has also been used to fill fresh extraction sites in the jaw—usually for the placement of dental implants—or to preserve the height of the alveolar ridge. The top photo in Figure 1 shows severe bone loss around a molar. The tooth was extracted, Bioglass placed in the site, and bridgework fitted over the extracted tooth. The lower photo shows the reconstructed site three years postoperatively. Note that the Bioglass has allowed the bone to regenerate; the tissue appears to be normal, healthy bone. This type of application for bioactive glasses has become standard in the clinical setting during the past few years.

Figure 1. Preoperative radiograph (top) of a lower-right first molar with advanced alveolar bone loss caused by periodontal disease. Follow-up radiograph (bottom) taken approximately three years after placement of Bioglass and a three-unit bridge. Virtually all of the graft material has been replaced by dense, normal bone.

The use of bioactive glasses for orthopedic applications has been somewhat limited because of the poor mechanical properties of the materials. One method of improving a material's strength—thereby increasing its suitability for load-bearing applications—is to heat-treat the glass to form a glass-ceramic. Japanese researchers have used a calcium-phosphate-silicate formulation to create a high-strength, bioactive system.²⁷ These materials have been shown to bond with bone, yielding failure loads comparable to those for dense hydroxyapatite, and 70% of that for bone.²⁸ The success of these long-term animal experiments has led to a number of clinical applications in orthopedics.²⁹ These include clinical studies of A-W glass-ceramic vertebral spacers and of glass-ceramic structural prostheses used to fill-in the iliac crest following the harvesting of autogenous bone.

In the case of vertebral spacers, several clinical indications were studied in 70 patients, including vertebral replacement resulting from metastatic tumor resection, burst fractures, compression fractures, and lumbar instabilities. The results have shown excellent compatibility, with good fixation of the devices.

Figure 2. Bioglass reaction stages.

The iliac-crest spacer has been used for pain relief and to prevent distortion of the normal anatomy or possible fracture following graft harvesting. In a study of 113 patients spanning 3 years, the authors report a success rate of more than 90%, with no rejection or complications during the duration of the study.

CONCLUSION

The technology of bioactive glasses for medical use is relatively new. Over a 13-year clinical history, there have only been a few uses of the materials, but these applications have been extremely successful. Perhaps most telling is the absence of any reports of adverse responses to these materials in the body.

It has been postulated by Hench that the release of soluble silica from the surface reactions of these glasses, combined with the formation of HCA layers, actually stimulates and accelerates bone healing.¹¹ The research to prove or disprove this hypothesis is being conducted at numerous university and corporate laboratories throughout the world. The continued growth of clinical applications for these glass compositions will result in better solutions for the repair and regeneration of natural tissues.

REFERENCES

1. LL Hench and EC Ethridge, Biomaterials, an Interfacial Approach (New York: Academic Press, 1982).

2. GE Levitt et al., "Forming Methods for Apatite Prosthesis," Journal of Biomedical Materials Research 3 (1969): 683–685.

3. JJ Klawitter and SF Hulbert, "Application of Porous Ceramics for the Attachment of Load-Bearing Orthopaedic Applications," Journal of Biomedical Materials Research Symposium 2 (1971): 161–168.

4. LL Hench et al., "Bonding Mechanisms at the Interface of Ceramic Prosthetic Materials," Journal of Biomedical Materials Research 2, no. 1 (1972): 117–141.

5. LL Hench and HA Paschall, "Histochemical Responses at a Biomaterials Interface," Journal of Biomedical Materials Research 5, no. 1 (1974): 49–54.

6. LL Hench and J Wilson, eds., An Introduction to Bioceramics (Singapore: World Scientific Publishing, 1993).

7. JE Davies, ed., The Bone-Biomaterial Interface (Toronto: University of Toronto Press, 1993).

8. OH Anderson et al., "Evaluation of the Acceptance of Glass in Bone," Journal of Materials in Medicine 3 (1992): 326–328.

9. T Kokubo et al., "Apatite Formations in Ceramics, Metals, and Polymers Induced by a CaO, SiO₂-Based Glass in a Simulated Body Fluid," in Bioceramics, vol. 4, eds. W Bonfield, GW Hastings, and KE Tunner (Guilford, CT: Butterworth-Heinemann, 1991).

10. T Kokubo and S Ito, "Ca, P-Rich Layer Formed on High-Strength Bioactive Glass Ceramic A-W," Journal of Biomedical Materials Research 24 (1987): 331–343.

11. LL Hench and JK West, in Life Chemistry Reports (Amsterdam, The Netherlands, Harwood Academic Publishers, 1996).

12. J Wilson et al., "Bioactive Materials for Periodontal Treatment: A Comparative Study in Biomaterials and Clinical Applications," ed. A Pizzofarrato and PG Marchetti (Amsterdam, The Netherlands, Elsevier, 1987).

13. R Reck, "Bioactive Glass-Ceramics in Ear Surgery: Animal Studies and Clinical Results," Laryngoscope 94, no. 2 (1984): 1–54.

14. GE Merwin et al. "Comparison of Ossicular Replacement Materials in a Mouse Ear Model," Otolaryngology Head Neck Surgery 90 (1982): 461–469.

15. K Lobel, "Ossicular Replacement Prosthesis," in Clinical Performance of Skeletal Prostheses, eds. LL Hench and J Wilson (New York: Chapman and Hall, 1986).

16. HR Stanley et al., "The Implantation of Natural Tooth from Bioglasses in Baboons," Oral Surgery 42 (1976): 29–47.

17. HR Stanley et al., "The Implantation of Natural Tooth from Bioglass in Baboons–Long Term Results," Journal of Oral Implantology 2 (1981): 26–36.

18. HR Stanley et al., "Residual Alveolar Ridge Maintenance with a New Endosseous Implant Material," Journal of Prosthetic Dentistry 58 (1987): 607–613.

19. HR Stanley et al., "Using 45S5 Bioglass Cones as Endosseous Ridge Maintenance Implants to Prevent Alveolar Ridge Resorption: A 5-Year Evaluation," International Journal of Oral and Maxillofacial Implants 12 (1997): 95–105.

20. P Kagvonkit et al, "Clinical Evaluation of Durapatite Submerged-Root Implants for Alveolar Bone Preservation." International Journal of Oral and Maxillofacial Surgery 15 (1986).

21. AN Cranin and R Shpuntoff, "Hydroxyapatite (HA) Cone Implants for Alveolar Ridge Maintenance–One-Year Follow-Up," Journal of Dental Research 63 (Special Issue) (1984).

22. SJ Froum et al., "Comparison of Bioglass Synthetic Bone Graft Particles and Open Debridement in the Treatment of Human Periodontal Defects: A Clinical Study," Journal of Periodontology 69 (1998): 698–709.

23. G Fox, "The Effectiveness of Bioactive Glass in the Repair of Human Periodontal Osseous Defects" (paper presented at the 80th meeting of the American Academy of Periodontology, New Orleans, October 8–11, 1996).

24. JS Zamet et al., "Particulate Bioglass as a Grafting Material in the Treatment of Periodontal Intrabony Defects," Journal of Clinical Periodontics 24 (1997): 410–418.

25. CA Shapoff, DC Alexander, and AE Clark, "Clinical Use of a Bioactive Glass Particulate in the Treatment of Human Osseous Defects," Compendium 18 (1997): 352–363.

26. SB Low, CJ King, and J Krieger, "An Evaluation of Bioactive Ceramic in the Treatment of Periodontal Osseous Defects," International Journal of Periodontics and Restorative Dentistry 17 (1997): 359–367.

27. T Kokubo et al., "Apatite and Wollasonite–Containing Glass-Ceramics for Prosthetic Applications," Bulletin of Institutional Chemical Research (Kyoto University, Japan) 60 (1982): 260–268.

28. T Nakamura et al., "A New Glass Ceramic for Bone Replacement. An Evaluation of Its Bonding to Bone Tissue," Journal of Biomedical Materials Research 19 (1985): 685–698.

29. T Yamamuro, "A-W Glass-Ceramic: Clinical Applications," in An Introduction to Bioceramics, eds. LL Hench and J Wilson, (Singapore: World Scientific Publishing, 1993).

David C. Greenspan, PhD, is vice president and chief technology officer at USBiomaterials Corp. (Alachua, FL).