Medical applications of organic-inorganic hybrid materials within the field of silica-based bioceramics

Research on bioceramics has evolved from the use of inert materials for mere substitution of living tissues towards the development of third-generation bioceramics aimed at inducing bone tissue regeneration. Within this context hybrid bioceramics have remarkable features resulting from the synergistic combination of both inorganic and organic components that make them suitable for a wide range of medical applications. Certain bioceramics, such as ordered mesoporous silicas, can exhibit different kind of interaction with organic molecules to develop different functions. The weak interaction of these host matrixes with drug molecules confined in the mesoporous channels allows these hybrid systems to be used as controlled delivery devices. Moreover, mesoporous silicas can be used to fabricate three (3D)-dimensional scaffolds for bone tissue engineering. In this last case, different osteoinductive agents (peptides, hormones and growth factors) can be strongly grafted to the bioceramic matrix to act as attracting signals for bone cells to promote bone regeneration process. Finally, recent research examples of organic-inorganic hybrid bioceramics, such as stimuli-responsive drug delivery systems and nanosystems for targeting of cancer cells and gene transfection, are also tackled in this tutorial review (64 references).     

Controlling E. coli adhesion on high-k dielectric bioceramics films using poly(amino acid) multilayers

The influence of high-k dielectric bioceramics with poly(amino acid) multilayer coatings on the adhesion behavior of Escherichia coli (E. coli) was studied by evaluating the density of bacteria coverage on the surfaces of these materials. A biofilm forming K-12 strain (PHL628), a wild-type strain (JM109), and an engineered strain (XL1-Blue) of E. coli were examined for their adherence to zirconium oxide (ZrO(2)) and tantalum oxide (Ta(2)O(5)) surfaces functionalized with single and multiple layers of poly(amino acid) polyelectrolytes made by the layer-by-layer (LBL) deposition. Two poly(amino acids), poly(l-arginine) (PARG) and poly(l-aspartic acid) (PASP), were chosen for the functionalization schemes. All three strains were found to grow and preferentially adhere to bare bioceramic film surfaces over bare glass slides. The bioceramic and glass surfaces functionalized with positively charged poly(amino acid) top layers were observed to enhance the adhesion of these bacteria by up to 4-fold in terms of bacteria surface coverage. Minimal bacteria coverage was detected on surfaces functionalized with negatively charged poly(amino acid) top layers. The effect of different poly(amino acid) coatings to promote or minimize bacterial adhesion was observed to be drastically enhanced with the bioceramic substrates than with glass. Such observed enhancements were postulated to be attributed to the formation of higher density of poly(amino acids) coatings enabled by the high dielectric strength (k) of these bioceramics. The multilayer poly(amino acid) functionalization scheme was successfully applied to utilize this finding for micropatterning E. coli on bioceramic thin films.     

Nano-crystalline aluminum-containing hydroxyapatite based bioceramics: synthesis and characterization

The hydroxyapatite and hydroxyapatite-based bioceramics with high Al contents were synthesized using sol–gel method, and their characterization was carried out by X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy. With the increase of Al content, the crystallinity is dramatically decreased, and the phase structure belonging to hydroxyapatite was transformed into the new phases, including aluminum calcium phosphate and/or aluminum phosphate. The average crystallite size of the bioceramic samples was found to be in the range of 10–50 nm. FTIR spectroscopy results verified the presence of various $ {\text{PO}}_{4}^{3 - } $ and $ {\text{OH}}^{ - } $ groups in the samples. The density value of the samples significantly increased with the addition of Al. It is evaluated that hydroxyapatite bioceramic can be converted to new bioceramics with high Al contents.     

The investigation of some physical properties and microstructure of Zn-doped hydroxyapatite bioceramics prepared by sol–gel method

In this study, the effect of Zn-dopant on the physical properties and microstructure of hydroxyapatite (HAP) bioceramics was investigated. The average crystallite size, phase composition and degree of crystallization of the pure hydroxyapatite and Zn-doped hydroxyapatite bioceramic samples prepared by sol–gel method were determined by X-ray diffraction method. It was seen that all the bioceramic samples were composed of the nanoparticles (29–46 nm). Fourier transform infrared spectroscopy was used to determine the functional groups in the samples. The dielectric properties of the bioceramics were investigated by dielectric impedance spectroscopy method, and the surface morphologies of them were analyzed using scanning electron microscopy technique. When the densities of the samples were measured by Archimedes method, it was seen that the densities of the samples increased with the increase of the molar ratio of Zn. The crystallization degree for all the samples dramatically decreased with the increasing content of the Zn dopant. With the increase of Zn to HAP, a change was observed in the degree of the crystallization, phase compositions, dielectric properties and microstructures of the samples.     

Ordered mesoporous materials in the context of drug delivery systems and bone tissue engineering

Chemistry, materials science and medicine are research areas that converge in the field of drug delivery systems and tissue engineering. This paper tries to introduce an example of such an interaction, aimed at solving health issues within the world of biomaterials. Ordered mesoporous materials can be loaded with different organic molecules that would be released afterwards, in a controlled fashion, inside a living body. These materials can also react with the body fluids giving rise to carbonated nanoapatite particles as the products of such a chemical interaction; these particles, equivalent to biological apatites, enable the regeneration of bone tissue.     

Calcium phosphate bioceramics and bioceramic composites

This paper reviews selected aspects of research work carried out in bioceramics and bioceramic composites at the Ceramics Laboratory IIT, Bombay, India. The focus here is in understanding and developing calcium hydroxyapatite (HA) bioceramics and biocomposites, including calcium hydroxyapatite-titanium (HA-Ti) and calcium hydroxyapatite-polymethylmethacrylate (HA-PMMA). Research involving apatite-wollastonite (AW) bioglass ceramics and bioceramic composites of AW with titanium as well as with polymethylmethacrylate will be presented in a future article. HA powders were precipitated from solutions with varying Ca/P ratios and calcined at a range of temperatures to investigate their structural evolution. HA-Ti composites were prepared by powder metallurgical processes using HA powders calcined at 400 °C, followed by compaction at 600 MPa and subsequent sintering at 1,000–1,200 °C. HA-PMMA composites containing up to 40 wt% PMMA were prepared by hot pressing at 150 °C and 150 MPa pressure. The phases present in the various materials were identified by X-ray diffraction (XRD) and functional groups by FTIR, while the sample morphologies were investigated by SEM. The bioactivity of the composites was evaluated by soaking them in simulated body fluid (SBF) for 7 days, to evaluate their apatite-forming ability (a key indicator of bioactivity). The results obtained are interpreted to aid in the development of “design rules” for the use of such biocomposite materials in specific biomedical application.     

医用生物陶瓷及临床应用

生物陶瓷是用于修复和重建外伤和疾病患者骨骼的陶瓷。它们可以是惰性, 可吸收和生物活性的。临床应用于髋、膝、牙、腱和韧带, 治疗牙周病和颌面重建, 牙嵴增高与加固颌骨, 脊柱融合及肿瘤切除后骨的填充, 碳涂层用作心脏瓣膜。新开发的模拟生物过程和离子注入的新技术, 在聚合物表面形成类骨磷灰石层, 具有良好的生物活性和延展性, 不仅可替代硬组织, 而且可替代软组织。生物活性铁磁微晶玻璃和耐化学腐蚀的放射性玻璃可用于癌症治疗。     

Structure‐Directing Agents for the Synthesis of TiO2‐Based Drug‐Delivery Systems

A series of titanium oxides was prepared by using a surfactant‐template method (STM) and used as a carrier for the sustained release of ibuprofen, which was chosen as a model drug. This STM provides an efficient route to TiO₂ matrices with both high surface area (when compared with those that were obtained by using traditional synthetic approaches) and well‐defined mesoporous textures. Some parameters of the synthetic procedure were varied: pH value, surfactant, and thermal treatment. The physicochemical nature of the surface carriers were investigated by means of N₂‐physisorption measurements and FTIR spectroscopy. The effect of the amount of drug on the release kinetics was also investigated. The drug delivery was evaluated in vitro in four different physiological solutions (that simulated the gastrointestinal tract) to analyze the behavior of the TiO₂‐based systems if they were to be formulated as oral DDSs. Our optimized approach is a good alternative to the classical methods that are used to prepare efficient TiO₂‐based drug‐delivery systems.     

Synthesis of bioceramic scaffolds for bone tissue engineering by rapid prototyping technique

This study presents a novel rapid prototyping process to fabricate silicate/hydroxyapatite (HA) bone scaffolds for tissue engineering applications. The HA particles are embedded in the gelled silica matrix to form a green part of bioceramic bone scaffold after processing by selective laser sintering. The composition of the bioceramic scaffold is in the series of SiO₂·P₂O₅·CaO. Results indicate that the proposed process could fabricate a multilayer hollow shell structure with brittle property but sufficient integrity for handling prior to post-processing. The fabricated bone scaffold models had a surface finish of 25 μm, a dimensional shrinkage of 16 %, a maximum bending strength of 4.7 MPa, and an apparent porosity of 28 % under the laser energy density of 1.5 J/mm². In vitro bioactivity evaluation by optical density value using a microculture tetrazolium test assay revealed that the bioceramic bone scaffolds were suitable for cell culture, demonstrating their application in tissue engineering.     

The Influence of Temperature and Drug Concentrations Prednisolone in NIPAAm Copolymer

Controlled delivery systems would be more beneficial and ideal if the drug could be delivered with respond to external environmental change. It could be used to overcome the shortcomings of conventional dosage forms. Therefore, the correct amount of drug would be released upon the stimulation of such a temperature and concentration change. The purpose of study is to investigate the influence of temperature and drug concentration from poly(2-hydroxyethyl methacrylate and N-isopropylacrylamide)/poly(HEMA-NIPAAm). The macroporous structure 5HEMA15NIPAAm was showed the most rapid responsiveness in swelling ratio, polymer volume fraction, swelling and deswelling kinetics. The high drug loading capacity was achieved at or below ambient temperature, whilst the release profile was revealed sustain release of conventional anti-inflammatory drug; prednisolone 21 hemisuccinate sodium salt. In general, drug loading capacity and drug diffusion kinetics are influence by the porosity of hydrogels, temperature, and drug concentration.     

两步电化学沉积技术制备功能陶瓷/金属复合镀层

通过两步电化学沉积技术,在医用金属表面得到羟基磷灰石生物活性陶瓷/金属复合镀层.从含有硝酸钙和磷酸二氢氨的溶液中,首先通过恒流模式电化学沉积钙磷生物陶瓷;然后采用恒压模式,在多孔的生物陶瓷沉积层中嵌入金属骨架,从而得到具有良好结合力的羟基磷灰石/金属复合镀层.实验结果表明在复合镀层中作为骨架的金属镍含量约为31%时,复合镀层与基底合金之间的结合力达到21.2MPa.     

Structure-Directing Agents for the Synthesis of TiO(2) -Based Drug-Delivery Systems

A series of titanium oxides was prepared by using a surfactant-template method (STM) and used as a carrier for the sustained release of ibuprofen, which was chosen as a model drug. This STM provides an efficient route to TiO(2) matrices with both high surface area (when compared with those that were obtained by using traditional synthetic approaches) and well-defined mesoporous textures. Some parameters of the synthetic procedure were varied: pH value, surfactant, and thermal treatment. The physicochemical nature of the surface carriers were investigated by means of N(2) -physisorption measurements and FTIR spectroscopy. The effect of the amount of drug on the release kinetics was also investigated. The drug delivery was evaluated in vitro in four different physiological solutions (that simulated the gastrointestinal tract) to analyze the behavior of the TiO(2) -based systems if they were to be formulated as oral DDSs. Our optimized approach is a good alternative to the classical methods that are used to prepare efficient TiO(2) -based drug-delivery systems.     

Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal‐catalyzed carbene transfer has provided an attractive route to afford C3‐functionalized indoles, these protocols are viable only in the presence of N‐protected indoles, owing to competition from the more facile N−H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C−H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α‐diazoacetate to give the corresponding C3‐functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti‐inflammatory drug indomethacin.     

The Development of Novel Nanodiamond Based MALDI Matrices for the Analysis of Small Organic Pharmaceuticals

The utility of novel functionalized nanodiamonds (NDs) as matrices for matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) is described herein. MALDI-MS analysis of small organic compounds (<1000 Da) is typically complex because of interferences from numerous cluster ions formed when using conventional matrices. To expand the use of MALDI for the analysis of small molecules, novel matrices were designed by covalently linking conventional matrices (or a lysine moiety) to detonated NDs. Four new functionalized NDs were evaluated for their ionization capabilities using five pharmaceuticals with varying molecular structures. Two ND matrices were able to ionize all tested pharmaceuticals in the negative ion mode, producing the deprotonated ions [M – H]^–. Ion intensity for target analytes was generally strong with enhanced signal-to-noise ratios compared with conventional matrices. The negative ion mode is of great importance for biological samples as interference from endogenous compounds is inherently minimized in the negative ion mode. Since the molecular structures of the tested pharmaceuticals did not suggest that negative ion mode would be preferable, this result magnifies the importance of these findings. On the other hand, conventional matrices primarily facilitated the ionization as expected in the positive ion mode, producing either the protonated molecules [M + H]⁺ or cationic adducts (typically producing complex spectra with numerous adduct peaks). The data presented in this study suggests that these matrices may offer advantages for the analysis of low molecular weight pharmaceuticals/metabolites.

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Comparison of Hydroxyapatite/Poly(lactide-co-glycolide) and Hydroxyapatite/Polyethyleneimine Composite Scaffolds in Bone Regeneration of Swine Mandibular Critical Size Defects: In Vivo Study

Reconstruction of jaw bone defects present a significant problem because of specific aesthetic and functional requirements. Although widely used, the transplantation of standard autograft and allograft materials is still associated with significant constraints. Composite scaffolds, combining advantages of biodegradable polymers with bioceramics, have potential to overcome limitations of standard grafts. Polyethyleneimine could be an interesting novel biocompatible polymer for scaffold construction due to its biocompatibility and chemical structure. To date, there have been no in vivo studies assessing biological properties of hydroxyapatite bioceramics scaffold modified with polyethyleneimine. The aim of this study was to evaluate in vivo effects of composite scaffolds of hydroxyapatite ceramics and poly(lactide-co-glycolide) and novel polyethyleneimine on bone repair in swine’s mandibular defects, and to compare them to conventional bone allograft (BioOss). Scaffolds were prepared using the method of polymer foam template in three steps. Pigs, 3 months old, were used and defects were made in the canine, premolar, and molar area of their mandibles. Four months following the surgical procedure, the bone was analyzed using radiological, histological, and gene expression techniques. Hydroxyapatite ceramics/polyethyleneimine composite scaffold demonstrated improved biological behavior compared to conventional allograft in treatment of swine’s mandibular defects, in terms of bone density and bone tissue histological characteristics.     

Antibiotics-loaded nanofibers fabricated by electrospinning for the treatment of bone infections

Electrospinning is one of the most promising fabrication techniques of nanostructured membranes for guided bone regeneration. In association with antibiotics, membranes consisting of fibers with sub-micrometric and nanometric dimensions have been tested to prevent and treat bone infections. Electrospinning was recently applied to produce metallic implant coatings for biofilm inhibition. Despite the numerous in vitro and in vivo studies conducted with nanofibers from several polymeric matrices and fabrication methods, there is no consensus on the best conditions to optimize their antimicrobial activity. This study analyzed recent advances in nanofiber fabrication by the electrospinning technique for clinical applications in the treatment of bone infections. An integrative review from MEDLINE/PubMed, Web of Science, and Scielo databases selected 16 works focused on nanofibers' in vitro and in vivo evaluations. It was found that manufacturing methods significantly influence fiber composition, structure, morphology, pore size, and biodegradability. Thus, standardizing these parameters in the production of nanofibers at an industrial scale is one of the challenges in improving drug loading control on the fiber network and its release profiles. Further in vivo studies need to be conducted to optimize the dose effect of antibiotic-loaded membranes in inhibiting the proliferation of pathogens and inflammatory processes without promoting toxicity and reducing bone regenerating capacity.     

Evolution of bioceramics within the field of biomaterials

This review article, dedicated to Prof. Jacques Livage, is focused on current trends in bioceramics. The first generation of inert ceramics aimed to substitute natural bone, hence the research was only focused on inert materials; the second one was aimed at mimicking some biomineralization-related functions and sol-gel chemistry plays a paramount role in their synthesis and properties. Finally, the purpose with third generation bioceramics is basically to provide an adequate scaffolding system which helps the bone cells to perform their natural processes. Tissue engineering attempts to develop artificial materials able to replace biological tissues in situations where the human body cannot perform said replacement by itself. One attempt consists on designing biomimetic materials that combine synthetic materials with cellular recognizing positions. These ceramics must exhibit an adequate degree of porosity. All these ideas shall be discussed in the present work.     

The effects of irradiation on controlled drug delivery/controlled drug release systems

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.     

WhichP450: a multi-class categorical model to predict the major metabolising CYP450 isoform for a compound

In the development of novel pharmaceuticals, the knowledge of how many, and which, Cytochrome P450 isoforms are involved in the phase I metabolism of a compound is important. Potential problems can arise if a compound is metabolised predominantly by a single isoform in terms of drug–drug interactions or genetic polymorphisms that would lead to variations in exposure in the general population. Combined with models of regioselectivities of metabolism by each isoform, such a model would also aid in the prediction of the metabolites likely to be formed by P450-mediated metabolism. We describe the generation of a multi-class random forest model to predict which, out of a list of the seven leading Cytochrome P450 isoforms, would be the major metabolising isoforms for a novel compound. The model has a 76% success rate with a top-1 criterion and an 88% success rate for a top-2 criterion and shows significant enrichment over randomised models.     

Mesoporous materials for drug delivery

Research on mesoporous materials for biomedical purposes has experienced an outstanding increase during recent years. Since 2001, when MCM-41 was first proposed as drug-delivery system, silica-based materials, such as SBA-15 or MCM-48, and some metal-organic frameworks have been discussed as drug carriers and controlled-release systems. Mesoporous materials are intended for both systemic-delivery systems and implantable local-delivery devices. The latter application provides very promising possibilities in the field of bone-tissue repair because of the excellent behavior of these materials as bioceramics. This Minireview deals with the advances in this field by the control of the textural parameters, surface functionalization, and the synthesis of sophisticated stimuli-response systems.