High strength, biodegradable and cytocompatible alpha tricalcium phosphate-iron composites for temporal reduction of bone fractures

Publication date: Available online 9 February 2018
Source:Acta Biomaterialia
Author(s): E.B. Montufar, M. Casas-Luna, M. Horynová, S. Tkachenko, Z. Fohlerová, S. Diaz-de-la-Torre, K. Dvorak, L. Celko, J. Kaiser
In this work alpha tricalcium phosphate (α-TCP)/ iron (Fe) composites were developed as a new family of biodegradable, load-bearing and cytocompatible materials. The composites with composition from pure ceramic to pure metallic samples were consolidated by pulsed electric current assisted sintering to minimise processing time and temperature while improving their mechanical performance. The mechanical strength of the composites was increased and controlled with the Fe content, passing from brittle to ductile failure. In particular, the addition of 25 vol.% of Fe produced a ceramic matrix composite with elastic modulus much closer to cortical bone than that of titanium or biodegradable magnesium alloys and specific compressive strength above that of stainless steel, chromium-cobalt alloys and pure titanium, currently used in clinic for internal fracture fixation. All the composites studied exhibited higher degradation rate than their individual components, presenting values around 200 μm/year, but also their compressive strength did not show a significant reduction in the period required for bone fracture consolidation. Composites showed preferential degradation of α-TCP areas rather than β-TCP areas, suggesting that α-TCP can produce composites with higher degradation rate. The composites were cytocompatible both in indirect and direct contact with bone cells. Osteoblast-like cells attached and spread on the surface of the composites, presenting proliferation rate similar to cells on tissue culture-grade polystyrene and they showed alkaline phosphatase activity. Therefore, this new family of composites is a potential alternative to produce implants for temporal reduction of bone fractures.Statement of SignificanceBiodegradable alpha-tricalcium phosphate/iron (α-TCP/Fe) composites are promising candidates for the fabrication of temporal osteosynthesis devices. Similar to biodegradable metals, these composites can avoid implant removal after bone fracture healing, particularly in young patients. In this work, α-TCP/Fe composites are studied for the first time in a wide range of compositions, showing not only higher degradation rate in vitro than pure components, but also good cytocompatibility and mechanical properties controllable with the Fe content. Ceramic matrix composites show high specific strength and low elastic modulus, thus better fulfilling the requirements for bone fractures fixation. A significant advance over previous works on the topic is the use of pulsed electric current assisted sintering together with α-TCP, convenient to improve the mechanical performance and degradation rate, respectively.

Graphical abstract

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A Continuum of Mineralization from Human Renal Pyramid to Stones on Stems

Publication date: Available online 9 February 2018
Source:Acta Biomaterialia
Author(s): Benjamin A Sherer, Ling Chen, Misun Kang, Alex R. Shimotake, Scott V Wiener, Tom Chi, Marshall L Stoller, Sunita P. Ho
The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralization within the renal pyramid to larger interstitial plaques that ultimately lead to the formation of clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed.Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall's plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones.Statement of SignificanceNephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall's plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall's plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention.

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In vitro methods for the evaluation of antimicrobial surface designs

Publication date: Available online 10 February 2018
Source:Acta Biomaterialia
Author(s): Jelmer Sjollema, Sebastian A.J. Zaat, Veronique Fontaine, Madeleine Ramstedt, Reto Luginbuehl, Karin Thevissen, Jiuyi Li, Henny C. van der Mei, Henk J. Busscher
Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term "antimicrobial" can encompass different mechanisms of action (here termed "antimicrobial surface designs"), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized.Statement of SignificanceEuropean COST-action TD1305, IPROMEDAI aims to provide better understanding of mechanisms of antimicrobial surface designs of biomaterial implants and devices. Current industrial evaluation standard tests do not sufficiently account for different, advanced antimicrobial surface designs, yet are urgently needed to obtain convincing in vitro data for approval of animal experiments and clinical trials. This review aims to provide an innovative and clear guide to choose appropriate evaluation methods for three distinctly different mechanisms of antimicrobial design: (1) antimicrobial-releasing, (2) contact-killing and (3) non-adhesivity. Use of antimicrobial evaluation methods and definition of industrial standard tests, tailored toward the antimicrobial mechanism of the design, as identified here, fulfill a missing link in the translation of novel antimicrobial surface designs to clinical use.

Graphical abstract

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Cyclic RGD functionalized liposomes encapsulating urokinase for thrombolysis

Publication date: Available online 9 February 2018
Source:Acta Biomaterialia
Author(s): Nengpan Zhang, Chunlin Li, Dayong Zhou, Chen Ding, Yaqing Jin, Qingmei Tian, Xiangzhou Meng, Kefeng Pu, Yimin Zhu
Thrombosis, a critical event in blood vessels, not only is associated with myocardial infarction and stroke, but also accounts for considerable morbidity and mortality. Thrombolytic drugs are usually applied to the treatment of acute myocardial infarction, acute cerebral infarction and pulmonary embolism. However, thrombolytic drugs show limited efficacy in clinical practice because of the short half-life in plasma and systemic side effects. In this study, the cyclic RGD (cRGD) functionalized liposomes were prepared to encapsulate urokinase, a cheap and widely used thrombolytic drug in clinic and better thrombolysis efficacy was achieved. The flow cytometry analysis showed that the cRGD liposomes could bind to the activated platelets while not to the resting platelets. In vitro release study revealed that the release percentage reached plateau in about 5 h with 60% urokinase being released from liposomes. Results from the in vitro thrombolysis experiments demonstrated a good thrombolysis potential of the cRGD urokinase liposomes. The in vivo thrombolysis study demonstrated that the cRGD liposomes could significantly reduce the dose of urokinase by 75% while achieving the equivalent thrombolysis effect as the free urokinase in mouse mesenteric thrombosis model. In conclusion, the cRGD liposomes encapsulating urokinase hold great promise in clinic for better thrombolytic efficacy.Statement of SignificanceIn this paper, the cRGD liposomes were prepared to encapsulate urokinase for targeted thrombolysis therapy. The cRGD liposomes could specifically bind to the activated platelets and could stably and continuously release its loaded urokinase. The mouse mesenteric thrombosis model was established to evaluate the thrombolysis effect of the cRGD urokinase liposomes. The results demonstrated that the cRGD liposomes could improve the thrombolytic efficacy by almost 4-fold over free urokinase. In conclusion, the cRGD liposomes encapsulating urokinase had great potential for the clinical treatment of thrombosis.

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Improvement studies on emission and combustion characteristics of DICI engine fuelled with colloidal emulsion of diesel distillate of plastic oil, TiO 2 nanoparticles and water

Abstract

Experimentation was conducted on a single cylinder CI engine using processed colloidal emulsions of TiO₂ nanoparticle-water-diesel distillate of crude plastic diesel oil as test fuel. The test fuel was prepared with plastic diesel oil as the principal constituent by a novel blending technique with an aim to improve the working characteristics. The results obtained by the test fuel from the experiments were compared with that of commercial petro-diesel (CPD) fuel for same engine operating parameters. Plastic oil produced from high density polyethylene plastic waste by pyrolysis was subjected to fractional distillation for separating plastic diesel oil (PDO) that contains diesel range hydrocarbons. The blending process showed a little improvement in the field of fuel oil-water-nanometal oxide colloidal emulsion preparation due to the influence of surfactant in electrostatic stabilization, dielectric potential, and pH of the colloidal medium on the absolute value of zeta potential, a measure of colloidal stability. The engine tests with nano-emulsions of PDO showed an increase in ignition delay (23.43%), and decrease in EGT (6.05%), BSNO_x (7.13%), and BSCO (28.96%) relative to PDO at rated load. Combustion curve profiles, percentage distribution of compounds, and physical and chemical properties of test fuels ascertains these results. The combustion acceleration at diffused combustion phase was evidenced in TiO₂ emulsion fuels under study.

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In vitro assessment of the interactions of dopamine β-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein

Publication date: 30 May 2018
Source:European Journal of Pharmaceutical Sciences, Volume 117
Author(s): Joana Bicker, Gilberto Alves, Ana Fortuna, Patrício Soares-da-Silva, Amílcar Falcão
Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine β-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects. A limited brain exposure results from the combination of several factors, such as a reduced passive permeability or affinity for efflux transporters, but efflux liabilities may also lead to unwanted drug-drug interactions (DDIs) in the presence of co-administered substrates or inhibitors.Thus, the purpose of the study herein presented was to explore the interaction of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), the two major efflux transporters of the BBB that hamper the entry of several drugs to the brain, with the DBH inhibitors, etamicastat, nepicastat and zamicastat. Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes were used as a BBB surrogate model. P-gp and BCRP substrates and/or inhibitors were identified through intracellular accumulation and bidirectional permeability assays. The obtained data revealed that zamicastat is a concentration-dependent dual P-gp and BCRP inhibitor with IC50 values of 73.8 ± 7.2 μM and 17.0 ± 2.7 μM, while etamicastat and nepicastat inhibited BCRP to greater extent than P-gp, with IC50 values of 47.7 ± 1.8 μM and 59.2 ± 9.4 μM, respectively. Additionally, etamicastat was identified as P-gp and BCRP dual substrate, as demonstrated by net flux ratios of 5.84 and 3.87 and decreased >50% by verapamil and Ko143. Conversely, nepicastat revealed to be a P-gp-only substrate, with a net flux ratio of 2.01, reduced to 0.92 in the presence of verapamil. Furthermore, nepicastat displayed a consistently higher apparent permeability (>8.49 × 10⁻⁶ cm s⁻¹) than etamicastat (<0.58 × 10⁻⁶ cm s⁻¹).The identification of etamicastat as a dual efflux substrate suggests that P-gp and BCRP may be partially responsible for the limited central exposure of this compound, in association with its low passive permeability. Moreover, the weak efflux inhibitory potencies of etamicastat and nepicastat revealed a low DDI risk, while the dual P-gp/BCRP inhibition of zamicastat could be studied in the future with synergically effluxed compounds, for which BBB penetration is severely impaired.

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Catalytic oxidation of trichloroethylene from gas streams by perovskite-type catalysts

Abstract

Three perovskite-type catalysts including LaMnO₃, La_0.8Ce_0.2MnO₃, and La_0.8Ce_0.2 Mn_0.8Ni_0.2O₃ are prepared using citric acid sol-gel method and evaluated as catalyst for the oxidation of trichloroethylene (TCE) in air with temperature ranging from 100 to 600 °C. The physicochemical properties of three perovskite-type catalysts were characterized by SEM, EDS, XRD, BET, and XPS to investigate the relationship with catalytic activities. The results show that the removal efficiency of TCE achieved with La_0.8Ce_0.2Mn_0.8Ni_0.2O₃ (the best one) reaches 100% at 400 °C and the mineralization efficiency reaches 100% at 600 °C. The enhanced activity can be attributed to the addition of Ce and Ni which increases the surface areas, active oxygen species, and the redox ability of the Mn⁴⁺/Mn³⁺ ratio on the catalyst surface. As La_0.8Ce_0.2Mn_0.8Ni_0.2O₃ is applied for TCE oxidation, the main intermediate chlorinated byproduct detected is tetrachloroethylene (C₂Cl₄) which is generated by the reaction of TCE and chlorine (Cl₂). The activation energy for the TCE oxidation with La_0.8Ce_0.2Mn_0.8Ni_0.2O₃ catalyst is 51 kJ/mol using kinetic models of power–law type.

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