Bioactive-Glass in Oral and Maxillofacial Surgery

Abstract

The use of synthetic materials to repair craniofacial defects is increasing today and will increase further in the future. Because of the complexity of the anatomy in the head and neck region, reconstruction and augmentation of this area pose a challenge to the surgeon. This review discusses key facts and applications of traditional reconstruction bone substitutes, also offering comparative information. It then describes the properties and clinical applications of bioactive-glass (B-G) and its variants in oral and maxillofacial surgery, and provides clinical findings. The discussion of each compound includes a description of its composition and structure, the advantages and shortcomings of the material, and its current uses in the field of osteoplastic and reconstructive surgery. With a better understanding of the available alloplastic implants, the surgeon can make a more informed decision as to which implant would be most suitable in a particular patient.

Successful repair of skull and facial defects, whether arising from trauma, tumor resection, or congenital disorders, continues to be a major challenge to oral and maxillofacial surgeons. Techniques vary, depending on the nature of the defect and quantity of tissue required. Reconstructions with autologous hard tissues have a long history with good clinical outcomes. [1] However, bone autografts have certain disadvantages, such as limited availability when the volume of the defect is sizable, reduced dimensional stability together with an additional surgical site for the bone harvest, which prolongs operation time, convalescence, and donor-site morbidity. [2] Recently, several new alloplastic materials have expanded our arsenal of reconstructive options. Their benefits are not only the avoidance of donor-site morbidity but also the increasing availability and ready usage of biomaterials, three-dimensional stability, their cost effectiveness in reduction of the operating time, known composition and safety. [3] Nevertheless, a limited number of these products approach equivalence to autologous transplants. [4] Failure of most implants originates at the interface between the biomaterial and its host tissue. [5] This means that surface activity of the alloplast is critical in evaluating its suitability for bone replacement, particularly if the area to be reconstructed will be subject to stress loading. Bioactive implants provide a potential solution to the problem of interface failure. [5] A bioactive material is defined as one that elicits a specific biological response and forms a living bond with the host tissues, [5] rather than forming an interfacial layer of scar tissue. This process prevents formation of a fibrous capsule surrounding the implant by the adhesion of repair tissues. Hench et al [5] reported the first bioactive material in 1971. They tested whether a phosphate containing silica-based material could fulfill the criterion of tissue bonding. The major breakthrough was that a degradable glass of the composition SiO₂ 45, Na₂O 24.5, CaO 24.5, and P₂O₅ 6 in weight percent (wt%), later termed 45S5, formed a bond with living bone so strong that it could not be removed without breaking the bone. [5] The selection of the composition was ideal; the low silica content made the glass easy to melt but also gave it the ability to form a surface layer of hydroxyapatite (HA) chemically and structurally similar to the mineral phase of human bone, following the immediate release of ionic species from the bulk material in contact with body fluids. [6] It has been shown that the glass dissolves at a rate equal to that at which new host tissue is remodeled, serving as a biocompatible interface along which bone cells migrate due to its osteogenic properties. [5] Notably, the constituents are physiological chemicals found in the body, typically silicium, sodium, potassium, magnesium, oxygen, calcium, and phosphorus. According to several studies, the concentration of these chemicals never rise to levels that could disturb the adjacent tissues. [6,7] In this respect, biologically active glasses have equally demonstrated considerable antibacterial [8] and angiogenesis-promoting characteristics. [9] The antimicrobial properties exhibited are likely multifactorial involving the creation of a local alkaline environment and the resistance of the material to bacterial adhesion and biofilm formation. [10,11] Integration of mesenchymal stem cells and various growth factors such as vascular endothelial growth factor serve to augment the materials ability to repair tissue defects and stimulate neovascularization. [12] Hench’s 45S5 bioactive-glass (B-G), known also as Bioglass^®, as it was trademarked by the University of Florida, and its variant products have been used in a variety of different shapes such as plates, rods, or rigid devices as well as in the form of particulate in many medical applications (Figure 1). [13,14,15,16,17,18,19,20,21,22] Clinically, these surface-reactive glass–ceramic biomaterials have been thoroughly investigated by oral and maxillofacial surgeons (

Table 1. Prospective randomized clinical studies evaluating the efficacy of B-G and its variants in craniomaxillofacial bone reconstruction and oral surgery.

). This article reviews their use both in craniomaxillofacial trauma and bone reconstructive surgery, as well as in oral surgery, starting with the former.

Calvarial Defects Reconstruction

Calvarial bone reconstruction is adopted to repair large skull bone defects resulting from the treatment of tumors, infections, trauma, intracranial hemorrhage, or infarction. These defects cause discomfort as well as other functional problems to patients. Reconstructive surgery serves to protect the brain, provides a satisfying aesthetic outcome, and frequently involves the use of preserved allogenous bone grafts, as not enough autologous hard tissues are available. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. [23] Currently, several alloplastic materials, such as metals, plastics, ceramics, and fiber-reinforced composites (FRCs) are used for the reconstruction of skull bone defects under compromised healing conditions. [24] Metallic implants have been used alone [25] or combined with bone dust or HA cement to enhance bone ingrowth and integrity in cranial bone reconstructions. [26] Polymethylmethacrylate (PMMA), polyethylene, and polyether ketone have been used in various formulations. [27] Although acrylic resins are readily available for immediate usage and can be easily shaped either with manual or handpiece instruments during the operation, they do not attach chemically to surrounding bone and, later on, foreign-body reactions have been observed. [27] In cranioplasty, late plate exposure and alloplast displacement, because of lack of incorporation at the donor site, are practical disadvantages associated with the use of these materials, in which case the removal becomes necessary with a technically challenging operation. [27]

Previous studies have reported on 45S5 B-G particles mixed with autologous bone particles harvested from cranial burr holes as an adjunct to cranial vault reconstruction. [28,29] This was done to reconstruct full-thickness defects in two young patients, when minimal spontaneous bone regeneration was expected. On follow-up computer tomography (CT) scans, these patients demonstrated conversion of the majority of the reconstructed defect to bone density within 6 months. At 4-year follow-up, both patients had stable reconstruction, and there was no need for reoperation or biopsy of the biomaterial.

A promising new development was represented by the use of customized porous implants, made of a supporting FRCs [23] or PMMA [30] framework and modified B-G (S53P4), to combine workability of resinous materials with innate bioactive/antimicrobial properties of the latter in calvarial [23] and midface bone [30] reconstructions. Beneficial effects of S53P4 particles with the composition SiO₂ 53, Na₂O 23, CaO 20, and P₂O₅ 4.0 wt% have been demonstrated experimentally10,11 and put to use for various clinical indications. [13,14,16,31,32,33] In the manufacturing process, prototyping models of the defect regions were created with additive manufacturing technology and these templates were used to prepare the patient-specific implants (Figure 2). [23,30] The last mentioned were perforated with holes 1.5 mm in diameter to enhance body fluid perfusion, coated with S53P4 granules of 0.5 to 0.8 mm in size and the application of prostheses (overall average thickness of 3.5 mm) was done with either biodegradable fixation screws or sutures. In longitudinal clinical and radiological examinations, with follow-up times up to 4 years [23] and 5 years, [30] normal progressive wound healing with diminishing postoperative clinical symptoms was observed and the implants retained their original position regardless of the fixation type, providing the expected functional as well as aesthetic outcome at all time points. Furthermore, there were no long-term complications such as implant-induced skull resorption, or later inflammatory reactions and acute toxicities systemically. Readers should also be aware that there was no donor-site morbidity because the custom-made implants did not need any graft operations. The perforated structure of the implants favored tissue ingrowth, yet providing solid flexural modulus and mechanical strength, but the bioactive coating was regarded as the key attribute, especially for those patients with a history of previous reconstruction material removal because of infection. [23] The strong porous structure of the composite implants mimicked surrounding bone, while S53P4 particles on their surface enabled new hard tissue formation by osteoblasts. The growth and maturation of natural bone in the porous inner layers provided firm adhesion, which in turn prevented longterm complications such as alloplast displacement. Finally, the synthetic implants did not evoke artifacts in postoperative imaging modalities for tumor follow-up. The bioactive coating was permeable to X-rays and performed in CT imaging (Figure 2) as well as methacrylate alone. [23,30] The same applies to magnetic resonance imaging (MRI), as S53P4 is nonmagnetic.

Surgical Approaches to Orbit and Facial Skeleton

Today, a remarkable share of clinical challenges regarding the fronto-orbital area that require obliterative and reconstructive surgery can be resolved with biomaterials. Such clinical conditions can be chronic suppurative frontal sinusitis, mucoceles, pyoceles, complicated fractures (especially those involving the frontal sinus drainage pathway), and tumors (such as carcinoma). Frontal bone osteomyelitis with bone necrosis and frontal sinus diseases with orbital or intracranial extension after tumor removal are also presumed to be conditions for reconstruction with biomaterials. Defects after subcranial tumor resection in the anterior skull base often need a reconstruction material, and this is another field for the use of tissue replacement materials.

The earlier widely used autogenic tissues are associated with donor-site morbidity, whereas allogenic, animal-derived graft materials and bank tissues have a risk of biohazard infections. [34] Microvascular free flaps can have aesthetic limitations. Endoscopic Lothrop-type procedures have been recommended to resolve the problems with chronic frontal sinusitis and, recently, even to avoid chronic frontal sinusitis after osteoplastic flap failure. [34] Despite these advances in frontal sinus surgery, there are still problematic cases where the osteoplastic procedure with obliteration is preferable.

In bone reconstruction with alloplasts, the most important practical factors are an adequate knowledge of their composition along with awareness of specific advantages and disadvantages. Synthetic materials are available in any time and amount, whereas large reconstructions and reoperations may limit the use of autogenic grafts. They are manufactured under controlled conditions, and thus the exact compositions are well known. Another obvious advantage is avoidance of having to harvest autogenic tissues. This decreases the total time needed for surgery, and also the length of wounds is reduced. In experimental studies comparing synthetic biomaterials, B-Gs produced more new bone over the same period than materials such as HA and tricalcium phosphate, [35] and the bone produced by the first was shown to be more similar to natural frontal bone. HA cement was associated with unsatisfactory long-term results due to exposure of the material, delayed inflammatory reactions, and infections originating in the frontal sinus area. [36,37] Other distinctive qualities of B-Gs are ability to remain where placed even with adjacent suctioning, hemostasis, and incorporation into host bone without the fibrous encapsulation encountered with most other synthetic materials. [38]

Accurate filling with saline liquid-moistened B-G granules (S53P4 formula, 0.5–0.8 and 0.8–1.0 mm in size) was used successfully for contour restoration of the facial skeleton and frontal bone reconstruction, [39,40,41,42,43] with uneventful outcomes or any evidence of resorption. Indeed, the B-G granule remnants seemed to maintain perdurable and uniform bony reconstruction. [34] When using biologically active materials, it is advisable to know their resorption behavior, and this should closely match the bone formation rate at the reconstruction or implant sites. The slower degradation rate and lack of resorption presented by S53P4 may be due to glass composition, which has higher silica content than the parent 45S5 B-G.

Separate similar studies were performed with tailor-made, rigid B-G plates which were fitted into place for the repair of orbital floor fractures, with good maintenance of globe position during follow-up periods of 5 years, [44] as well as after fronto-orbital tumor resections, with the only difference that in this case, implants were manufactured casting glass of the S53P4 composition. [34,42,43,45] Without exception, the biomaterials used were well tolerated, with good functional and aesthetic outcomes (Figure 3and Figure 4). The B-G plate met most of the criteria for a beneficial orbital wall reconstruction material. Besides, it represented the only orbital reconstruction reconstruction material with antibacterial properties, which may be the reason why acute or late infections were not reported. [45] This is a very important aspect in orbital wall reconstructions, where a connection between the orbit and the maxillary sinus is common. In fact, infections originating from the maxillary sinus can lead to the need to remove the reconstruction material. [45] In histologic studies, special attention was paid to new bone formation and conversion of B-G. [34] The results were in agreement with the findings of other studies, [7] in which bonding between the glass implant surface and host tissues was formed by attachment of collagen fibers to newly formed silica-rich containing layers. Although B-G is a slowly biodegradable material, the plates were firmly attached to orbital bone structures when histological samples were harvested, indicating immobilization and incorporation to the orbital bone even without specific screw fixation. [45]

Paranasal Sinuses Surgery

The maxillofacial area is a unique challenge to the surgeon because it is related to infection-sensitive structures such as the paranasal sinuses, upper respiratory tract, and oral cavity. Notably, frequent infections, inflammatory disorders, posttraumatic conditions, and tumors affect the frontal sinus and present unique requirements for successful surgical treatment. Indications for frontal sinus obliteration include problematic conditions that cannot be resolved with functional endoscopic sinus surgery techniques due to irreversibly damaged natural drainage. Such indications can include chronic suppurative frontal sinusitis, mucoceles, pyoceles, complex fractures (especially those involving the drainage pathway), and tumors, such as osteomas. [46]

Finding a reliable, biocompatible, and safe material for frontal sinus obliteration has proven difficult. Abdominal fat is well established as a versatile and reliable material in frontal sinus obliteration. [46] In addition, pericranial flaps are interesting alternatives in frontal sinus obliteration. [46] Compared with HA cement, frontal sinus obliteration with autogenic fat is more cost effective but requires a longer operation time. [46] However, a risk of donor-site morbidity is related to abdominal fat and autogenic bone transplantation.

Promising results have been described with the use of B-G in chronically infected nasal septum perforations [19] and after canal wall down mastoidectomy. [47] B-G-ceramic middle ear implants in ossicular chain reconstructions also showed good tolerance after 8 years. [18] The material appeared to have a broader antimicrobial effect than HA, inhibiting their growth, [48] and S53P4 glass granules (0.5–0.8 and 0.8– 1.0 mm in diameter) moistened in sterile physiologic saline were subsequently used to obliterate the frontal sinuses with favorable results (Figure 3). [31,34,40,46] Moistened small granules of B-G are adherent and easy to handle for filling the cavity completely. Hence, a second operation needed for harvesting of autogenous material can be avoided. Repeated CT or MRI scans of frontal sinuses are the only way to accurately monitor the degree of obliteration and identify the patient at risk for recurrent disease after an osteoplastic procedure. A 5-year clinical follow-up study revealed uneventful outcomes, [40] and bone formation with no loss of volume was reported in the obliterated frontal sinuses over a 10-year period. [31] Peltola et al [46] characterized the long-term histological healing process in B-G obliterated frontal sinuses. Special attention was given to osteogenesis, occurrence of connective tissue, and possible long-term structural changes in the remaining obliteration materials. The authors demonstrated formation of histologically normal bone without connective tissue in direct contact with the biomaterial particles, in the absence of inflammatory changes or foreign-body reactions. The antibacterial properties of B-G provide extraordinarily favorable conditions and are important factors in obliteration material, that is, in chronic infected frontal sinuses, with a relative risk of reinfection. The predictable healing process and the occlusion of the sinuses decrease the risk of relapse. Laboratory studies showed no abnormal changes in inflammatory parameters or in liver and kidney functions, confirming that B-G is a safe, stable material for permanent clinical frontal sinus obliteration. [31]

B-G particles have also been used to modify the maxillary sinuses. Maxilla grafting for elevation of the maxillary sinus floor with composite grafts of granules of S53P4 glass (80–90 wt%) and autologous bone (10–20 wt%) was shown to be as good as the treatment with autogenous bone alone, yielding the same quality and volume of mineralized tissue when a reasonable healing period is allowed. [33,49,50,51,52,53] The use of autogenous bone was dictated by its osteogenic potential related to the number of surviving osteoblasts and osteoin-ductive effect brought about by the release of bone morphogenic proteins and other growth factors, which have the capacity to accelerate deposition of new bone along the graft material. [52] Notwithstanding, the amount of bone needed was considerably decreased and donor-site morbidity alleviated. Using histomorphometric analysis, Tadjoedin et al [53] found that the composite B-G mixture accelerated healing time for bone regeneration to 6 months, compared with 12 months for bone graft alone. Both treatment regimens resulted in stable bone at the reconstructed site. Accelerated bone healing for elevation of the maxillary sinus floor can allow for simultaneous bone augmentation of the sinus floor and placement of titanium implants for dental restoration in patients who would otherwise have insufficient maxillary bone for implant placement. Finally, this combination of findings provides further support for the conceptual premise that the antimicrobial activity of B-G against sinus pathogens [31,48] might contribute to the resolution of inflammatory responses and provide extraordinarily favorable conditions for an uneventful healing process. [49,53]

Conclusion

Acting as a resorbable framework in which bone cells can grow, [54,55] biologically active glasses are an important consideration when choosing the optimal biomaterial to be used as a bone substitute in craniomaxillofacial applications. Their bioactive properties allow for an osteoproductive environment in which the bone–biomaterial interface is uniquely stronger than it would be with other forms of alloplastic materials.

A review of the present literature supports clinical applications of prefabricated implants made of B-G ceramics, as has been used in calvarial and midface bone reconstructions as well as for the repair of orbital floor fractures. Also, present experience with B-G in particulate form, preferably mixed with small amount of autogenous bone, support the convenience of this biomaterial over alternate forms of synthetic graft materials. This protocol has been highly successful for elevation of the maxillary sinus floor in preparation for titanium implant placement in the atrophic maxilla. A similar protocol may prove useful in reconstruction of other areas of the head and neck.