Promising trends of bioceramics in the biomaterials field
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- Arcos, D., Izquierdo-Barba, I. & Vallet-Regí, M. J Mater Sci: Mater Med (2009) 20: 447. doi:10.1007/s10856-008-3616-x
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Biomedical scientific community is currently demanding new advances in the designing of 3rd generation bioceramics, which promote bone tissue regeneration. In the last years, the development of supramolecular chemistry and the application of organic-inorganic hybrid materials in the biomedical field have resulted in a new generation of advanced bioceramics, which exhibit fascinating properties for regenerative purposes together with the possibility of being used as carriers of biologically active molecules. This communication overviews the evolution occurred from the first silica based bioceramics to the last advances in the synthesis of bioceramics for bone tissue regeneration. A critical review concerning the first bioactive glasses as well as the newest hybrid bioactive materials and templated mesoporous bioactive systems, will be performed from the point of view of their potential applications as replacement materials in bone repair and regeneration.
The progress regarding bioceramics for bone and dental tissue has experienced an outstanding development from the very first inert ceramics to the regenerative compounds currently developed. This progress responds to the scientific efforts for improving the tissue-material response after implantation, evolving from inert to bioactive behaviour and, finally to regenerative functions [1–4].
The first generation of bioceramics, named inert ceramics and represented by alumina (Al2O3) and zirconia (ZrO2) played an important role for substitution purposes due to their low reactivity. By that time, the main goal was substitution with the lowest tissue response, perhaps because the only expected tissue response was inflammation and material rejection. However, the discovery of Bioglass by Prof. Hench in 1969 led to a shift in the perspectives regarding the reactivity at the tissue implant interface .
The scientific efforts made so far have resulted in a deep knowledge about silica derived bioactive materials, especially those synthesised through soft-chemistry routes such as the sol-gel process[6, 7] in ternary (SiO2–CaO–P2O5) and binary (SiO2–CaO) systems .
Finally we must highlight the topics concerning mechanical properties, the actual Achille’s heel of bioactive glasses. In this sense, important advances have been made by means of the synthesis of organic–inorganic hybrids .
All these advances and experience contributed to the achievement of 3rd generation bioactive materials for regenerative purposes, as well as to their shaping into scaffolds for tissue engineering. At present, the scaffolds fabrication with appropriate meso and macroporosity, the control on the ionic exchange with the environment, the achievement of suitable mechanical resistance for surgery handling and, of course, the osteogenesis induction are attainable aims, thanks to the efforts made in past decades. This manuscript is an overview of some of the achievements in this field that contributed to this aim.
2 Bioactive glasses: The ionic exchange significance
The ionic exchange was postulated as the first stage of the bioactive process. The dissolution of Ca2+ and Na+ cations from the glass to the surrounding fluid results in the H+ incorporation and the silanol formation at the glass surface. In 2000, Xynos [10, 11] proposed the ionic products of Bioglass dissolution as agents that increased the expression of an osteoblast mitogenic growth factor (IGF-II), suggesting that the ionic products leached during Bioglass dissolution exhibited a stimulatory effect on the osteoblast proliferation mediated by IGF-II. Thereafter, the same research group carried out a larger-scale genomic screening revealing that 45S5 dissolution increased the levels of 60 transcripts, many of them related with the bone tissue formation .
Whereas the significance of Ca and P in the process of bone mineralization was well established, a cellular receptor for Si had not been identified. However, these results agreed with those previously reported by Carlisle [13, 14] regarding the role of silicon during the first stages of bone maturation, as well as the bioactive enhancement of calcium phosphate bioceramics when Si is incorporated into the crystalline structure [15–18]. Therefore, the significance of ion exchange achieves another dimension beyond the initial stage of the bioactive process. The Bioglass ionic product promotes the gene up-regulation that results in an osteoblast proliferation, differentiation and, consequently leading to bone regenerative properties.
The silicon release as silicic acid (Si(OH)4) involves not only the implant degradation but also an osteoproductive stimulus, and calculations of the activation energy for silica dissolution and its relationship with the bioactivity were considered [19, 20].
3 Bioglass monoliths and scaffolds
Bioactive glasses have limited applications due to their brittleness, which reduce their clinical use within non-bearing sites such as periodontal defects, middle ear surgery and small bone filling in general. This fact results in a loss of their potential as bone regeneration material, since their implantation is not appropriate in those locations where a high amount of bone has been lost.
Some efforts have been aimed to obtain sol-gel bioactive glasses (with high surface area and porosity) with monolithic structure but suitable to be degraded under physiological conditions. Zhong and Greenspan [21, 22] reported on the use of high relative-humidity during the drying stage of sol-gel glasses to obtain crack-free structures. The moisture of the near-equilibrium drying step facilitates the reaction among the gel particles, resulting in strengthened gel structures.
Scaffolds for tissue engineering should exhibit an interconnected macroporous structure (with pore sizes above 100 μm). Moreover, the presence of mesopores within the bioceramic skeleton is highly desirable since it facilitates the nutrients permeability and improves the surface area, thus facilitating the subsequent bioresorption. Jones and Hench [40, 41] have proposed a foaming mechanism to fabricate highly macroporous sol-gel glasses with monolithic structures. This strategy relies on the foaming of the gel by means of a surfactant addition and vigorous stirring. Once the sol is foamed, the viscosity is rapidly increased by catalyzing the polycondensation process with HF. The results are SiO2–CaO–P2O5 and SiO2–Ca foams with hierarchical structure, with interconnected macropores ranging in size between 10 and 500 μm and mesopores of several nanometres.
4 Silica mesoporous materials
The discovery of highly ordered mesoporous silica was quickly recognized as a breakthrough that could lead to a variety of important applications in host-guest systems [42, 43]. Silica-based mesoporous materials have unique structural characteristics, since that an amorphous silica network constitutes the wall of well-ordered arrangement of pore system and cavities .
5 Templated bioglasses
The real challenge has been to obtain bioactive multi-component sol-gel glasses, with the textural properties and porous arrangement of the silica based ordered mesoporous materials. The research group of Prof. Zhao carried out the synthesis of SiO2–CaO–P2O5 ordered mesoporous glasses through the evaporation-induced self-assembly (EISA) method in the presence of a non-ionic triblock copolymer (EO20PO70EO20), resulting in 2D-hexagonal pore arrangement after calcinations at 700°C . Such materials as consequence of presence of CaO and P2O5 in their composition together with extraordinary textural properties showed an enhanced bioactive behaviour with faster apatite phase formation than conventional bioactive sol-gel glasses.
6 Biomimetism in templated bioglasses
Another new property derived from the textural and structural characteristics of “templated bioglasses” is their biomimetic mechanism where a sequential transition from amorphous calcium phosphate (ACP)–octacalcium phosphate (OCP)–calcium deficient carbonatehydroxyapatite (CDHA) maturation, similarly to the in vivo biomineralization process, has been for the first time observed .
Usually, all bioceramics obtained so far develop a CHDA phase through the direct crystallization of previously precipitated ACP , without previously formation of OCP phase which is formed in natural bone biomineralization process [53–55]. OCP is a metastable phase and will appear only if the pH in the crystallization system is below 7.
“Templated bioglasses” with 2D-hexagonal mesoporous arrangement and high CaO content (37% in mol) allow an intense Ca2+–H3O+ exchange as a consequence of the open channel array, the high textural parameters and the relatively high CaO content. The resulting surface silanol groups eventually condense into and acid hydrated silica layer with local pH values of 6.5 during the first stage, which favour the OCP formation. On the contrary, this local acid pH does not occur in the surface of conventional bioglasses, whose surface exhibit the same basic media (pH 7.4 or higher) than the surrounding fluid from the beginning of the bioactive process and it can explain the reason OCP has never been observed.
7 Nanostructured materials: New trends in controlled delivery of biologically active molecules for bone tissue regeneration
The characteristics of silica-based ordered mesoporous materials such as: (i) biocompatibility, (ii) large surface area and pore volume, (iii) tunable pore size and distribution and (iv) suitability to be functionalized with organic molecules, make them excellent candidates to be employed as delivery systems of biologically active molecules. Especially interesting is the synergic effect of their properties as bone regenerative bioceramics, together with the capacity to host and release osteogenic agents for bone regenerative purposes. It was in 2001, our research group demonstrated for the first time such capability . Ibuprofen, a common anti-inflammatory drug, was confined inside of MCM-41 type mesoporous materials with different pore size and was subsequently released from such matrices in a simulated body fluid. Since then, the interest in this field has exponentially growth as reflected by the number of research works concerning mesoporous materials as drug delivery systems. Revision articles on this topic can be found in references [58–63].
The drug incorporation is commonly carried out by soaking the matrix into a highly concentrated drug solution and subsequent drying. Therefore, the process is mainly based on the adsorptive properties of mesoporous materials and the surface area has been demonstrated as the main factor, which determines the amount of drug molecules adsorbed, i.e., the greater the surface area the higher amount of drug can be incorporated within the mesoporous matrix [70, 71].
Finally, it must be highlighted that the keystone in the development of silica mesoporous materials as DDSs has been the organic modification of the surface or functionalization. Functionalization of the surface through organic groups provides numerous possibilities to control drug adsorption and release [71–73]. Silica based mesoporous materials show a high density of silanol groups, which can be used to obtain functionalized surfaces by grafting organic silanes ((RO)3SiR’) [74, 75]. The drug loading and release can be effectively controlled by increasing the drug-surface interaction . For this purpose the surface is functionalized with chemical groups that are able to link to the drug molecules through ionic bonds or through ester groups and thus, to enhance the loading and rate release properties via increasing the guest-matrices affinity.
8 Summary and outlook
The advances in bioceramics field have been closely linked to search materials that promoted optimum implant-tissue interactions. Up to 70s, this interaction was considered to be the inert behaviour at the interface, and bioceramics were synthesised aimed to substitute the bone tissue. This concept changed when bioactive bioceramics came out in 1969. The goal of an inert response shifted towards the synthesis of reactive surfaces able to induce specific responses with the living tissues that, in the case of bioceramics, resulted in a strong chemical link with the bones through the so-called bioactive bond, thus ensuring the implant-tissue integration. The bioactive bond is formed through the nucleation and growth of an apatite like phase on the implant surface. This apatite is quite similar to the mineral part of the bone and sometimes has been referred as biomimetic apatites. In fact, the crystal–chemical features and microstructure closely resemble to those of biological ones and the crystallization process mimics the natural formation, in the sense that apatite nanocrystals are formed from their ions in solution. Finally, the 3rd generation bioceramics came up with a new conceptual shift from osteointegration toward osteoregeneration. As explained in this article, some processes such as ions dissolution acquired a new significance concerning the osteogenic function through gene up-regulation. Since bone must colonize the implant, the porosity has become a fundamental factor. Furthermore, the development of tissue engineering has encourage the materials science researchers to develop meso and macroporous ceramics suitable to be used as scaffolds for bone tissue engineering, as well as carriers of osteogenic agents.
By over-viewing the research on bioceramics along time, we can realize that their development and advances are, in some way, related to the decreasing of our pretensions as materials researchers. The 1st generation of inert ceramics was aimed to substitute natural bone; the 2nd one was aimed just to mimic some biomineralization related-function; finally, with the 3rd generation of bioceramics we only pretend to help the bone cells to make their work, by means of supplying appropriated scaffolding. Insofar we develop more sophisticated systems by controlling the implant-tissue interface, we are moving back in our artificial purposes to give way at the natural agents.
The current aims in bioceramic research must be framed in this field. The development of osteoregenerative ceramics through the control of their chemical composition, meso and macroporosity, or by means of osteogenic agents incorporation should play a main role in biomaterials science. Finally, the tailoring of scaffolds with hierarchical porosity (with different pore size level) and precise architectures to fit into specific bone defects also will have a deep impact in near future. In this sense, rapid prototyping techniques are excellent tools for this purpose and are called to be fundamental instruments for the development of the 3rd bioceramics generation.
The authors would like to thank all members of our research team who have contributed with the results described in this work, and whose names are collected in the reference sections. We also thank the Spanish National Science and technology commission (grant MAT-2005-01486) and Autonomous Government of Madrid (grant S-0505/MAT/0324) for financial support.