Current trends and future perspectives of bone substitute materials – From space holders to innovative biomaterials
Introduction
The breakthrough in the present-day development of bone substitute materials (BSM) was initially achieved by Barth and Ollier who carried out animal experiments in order to study different bone replacement materials for the first time (Barth, 1895). Historically, autogenous bone grafts, allografts, and a variety of biomaterials have been used for the repair of osseous defects and the augmentation of compromised bone. The ideal bone-graft substitute is biocompatible, bioresorbable, osteoconductive, osteoinductive, structurally similar to bone, easy to use, and cost-effective. Approximately 2.2 million bone graft procedures are performed each year worldwide to repair bone defects in orthopaedics, neurosurgery and oral & maxillofacial surgery with a yearly estimated costs of $2.5 billion (Van Heest and Swiontkowski, 1999). Problems related to the availability of graft material, donor-site morbidity, immunogenicity and biomechanical integrity have limited its success. An increasing number of bone graft materials with completely different origins are commercially available for many applications throughout the human body. They are variable in their composition, their mechanism of action and, therefore, their indications.
BSM are generally considered to be a highly important alternative to bone grafting in dental surgery, implantology and periodontology. Donor site morbidity is diminished while simultaneously guaranteeing a nearly unlimited level of material disposition. In this way, a large variety of osseous defects can be repaired using BSM. Due to current developments innovative BSMs with new chemical, structural and subsequent biological properties will embrace a lot of requirements in order to imitate the characteristics of the bone defect. Crucial for the clinical success of BSMs are their interactions with the adjacent tissue structures and cells due to a macroporous interconnecting structure of >100 micron diameter promoting cell infiltration, bone growth and vascularisation. In the context of large osseous augmentations, autogenous bone is still used as the preferred gold standard material. However, in certain clinical settings and appropriate indications a combination of BSM with living tissue/cells or BSM alone may be suitable.
The current functions of BSM are as follows
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space maintenance for bone regeneration
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pre-setting of the desired anatomical form
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supporting functions for the periosteum and associated membranes
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acceleration of bone remodelling
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osteoconductive structural guidance for the regeneration of osseous tissue
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carrier substance for antibiotics, growth factors or approaches by gene therapy (Rupprecht et al., 2007, Fischer et al., 2011, Maus et al., 2008a, Smeets et al., 2009b, Kolk et al., 2011)
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scaffolds for tissue engineering approaches (Handschel et al., 2009a, Naujoks et al., 2011)
The morbidity associated with autogenous bone graft harvest and concerns regarding transmission of live viruses from allografts have been the impetus for research into a variety of bone grafting materials. Current requirements for an ideal BSM are rigorous, as listed below:
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biocompatibility
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osteoinduction and osteopromotion/osteoconduction
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porosity
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stability under stress
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resorbability/degradability
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plasticity
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sterility
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stable and long-term integration of implants
Biocompatibility ensures the absence of toxicity, teratogenity or carcinogenicity. The lack of antigenicity guarantees the avoidance of pro-inflammatory and immunologic reactions. All such requirements serve as a basis for effective long-term tolerance (Horch et al., 2006), and such criteria are mainly fulfilled by available synthetic materials.
In addition BSMs should support osteogenesis conductively, stabilize the coagulum, fill up osseous defects and contribute to mechanical resistance. In this way BSMs serve as an artificial extracellular matrix in order to support and later stabilize the new creation of bone. This so called osteoconductive effect means that the attachment of new osteoblasts and osteoprogenitor cells is supported by the graft, providing an interconnected structure for migration of new cells and formation of new vessels (Kao and Scott, 2007). Moreover, a stimulating effect on the osteogenetic cells called osteogenicity or osteopromotive represents the ability of a graft to induce non differentiated stem and/or osteoprogenitor cells to differentiate into osteoblasts causing new bone formation at locations where it is unexpected. These processes are influenced by cytokines such as bone morphogenetic protein (BMP) that induce differentiation of mesenchymal stem-cells, to result in new bone formation that parallels direct osseous interconnection.
Interconnecting porosity of a BSM is one of the most important requirements for continuous vascular ingrowth (Eggli et al., 1988, Hing et al., 2005). Many pores extend to the surface and can be vascularized with an adequate diameter (>approx. 100 μm) (Cornell, 1999, Klawitter and Weinstein, 1974). Smaller pore diameters are more advantageous in the adhesion and incorporation of mineralized tissues, cell-to-implant contacts and in the absorption of extracellular liquids (Chesnutt et al., 2009, Hertz and Bruce, 2007). An incomplete co-mingling of the material with adjacent vessels can result in particles that are encased by connective tissue. Condensation of the materials can cause a reduction or a loss of their porosities (Maus et al., 2008b). A process that yields biomechanical properties such as those that exist in normal bone is highly desirable (Kao and Scott, 2007). In particular, form stability is of essential importance with regard to larger bony defects. Resorption of the material and replacement by normal bone is either biologically based on the influence of cells or by chemical-physical dissolving processes (Misch and Dietsh, 1993), and should occur simultaneously in the ideal case. If not, the formation of connective tissue may occur resulting in biomechanical inferior structures (Kao and Scott, 2007). The BSM should be easy to use, should withstand sterilization and should come in sufficient quantities. In a time of global economic downturns, costs are an important issue in clinical applications.
To date, no BSM is available that is equal to autogenous bone (Horch et al., 2006, Smeets et al., 2009a, Aebi et al., 1991), and current BSMs serve primarily as filling and frame building materials, mostly providing osteoconductivity for the bone healing process (Horch et al., 2006, Spector, 1992, Buser et al., 1998). In addition, every current allograft and xenograft product carries histocompatibility antigens different from those of the host with an increased risk of potential graft versus host reaction.
Ideally, the healing processes of the defects should result in regenerated and vital bone without residual foreign bodies.
Section snippets
Variety of bone replacement materials
Currently the most important biomaterials for routine clinical use in the head and neck region are divided in five subcategories according to their origin (Laurencin et al., 2006).
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BSMs of natural origin
Materials are subdivided into harvested bone grafts and graft substitutes: autogen (from same individual) (Gerressen et al., 2009, Kirmeier et al., 2007, Nkenke et al., 2004, Schlegel et al., 2003a, Springer et al., 2004) allogen (from same species) (Kubler et al., 1994), xenogen (from a
BSMs of natural origin
In principle, biologic materials, with the exception of autogenous transplants, generally have a minimal risk of transmission of infectious disease and antigenicity resulting in graft versus host reaction. Worldwide either autograft or allograft tissue is used in 90% of all bone replacement procedures.
Synthetic (alloplastic) materials
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ceramics: biological glasses, TCP, HA and glass ionomer cements
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metal: titanium
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polymers: polymethylmethacrylate, polylactides/polyglycolides and copolymers
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cements: calcium phosphate (CP) cements
Composite materials
In ideal cases composite biosynthetic materials have osteoconductive osteogenic and osteoinductive activities (Den Boer et al., 2003, Smeets et al., 2009a). Because of the countless combinations of inorganic and organic components no subdivision of the composites is possible in practice (Schnurer et al., 2003). Although new composites have become widely available, the search for a suitable composite that can supplant autogenic bone grafts continues (Vaccaro et al., 2002, Smeets et al., 2009a).
BSM combined with growth factors
Among the bone growth factors tested in heterotopic and orthotopic locations, bone morphogenic proteins (BMPs), either in native (BMP) or recombinant forms (rhBMPs), appear to be the most effective and therefore the most promising (Schmidmaier et al., 2007, Cook et al., 1994, Fischer et al., 2011). BMPs enable skeletal tissue formation during embryogenesis, growth, and healing, as well as throughout adulthood (Reddi, 1992, Ripamonti and Reddi, 1994, Kirker-Head, 2000, Fischer et al., 2011).
BMPs
BSM with living cells
Composite biosynthetic transplants consist of a carrier as an osteoconductive scaffold combined with osteogenic cells and/or growth factors (Lane et al., 1999, Vaccaro et al., 2002). A ‘‘combined graft’’ contains osteogenic cells and cytokines along with a BSM as a synthetic osteoconductive matrix. Composite materials being tested in preclinical and clinical trials may exhibit functionality comparable to autografts and allografts. Composite synthetic grafts offer an alternative that can
Final evaluation of the indications for BSM
BSM can create adequate bone formation for clinical use, depending on the indication. BSM can be used successfully in sinus floor elevation as well as in augmentation of three-dimensional defects up to a certain volume. Larger defect situations require more permeable BSMs, with a minimum interconnecting pore channel diameter of 250–300 μm for better neovascularization and osteoconduction. In absolute vertical or horizontal alveolar ridge augmentation procedures under compromised bone layer
Summary and future outlook
For different bone augmentation (e.g. the creation of a sufficient peri-implant bone bedding for successful long-term implantation), (I) autologous bone alone, (II) autologous bone in combination with BSM and (III) and BSM alone are all established materials.
Human allogenic materials with good biocompatibility are accompanied by a small risk of HIV- or HCV- infection and prion transmission. The available osteoconductive materials of HA and TCP origin have comparably good biocompatibilities but
Acknowledgement
The authors thank the following companies for providing samples of the respective imaging materials: ARTOSS GmbH, Rostock, Germany; Botiss Dental GmbH, Berlin, Germany; Degradable Solutions, Schlieren, Switzerland; DENTSPLY Friadent, Mannheim, Germany; Geistlich AG, Wolhusen, Switzerland; RIEMSER Arzneimittel AG, Greifswald - Insel Riems, Germany; Synthes GmbH, Solothurn, Switzerland; Zimmer Dental GmbH, Freiburg, Germany.
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