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  • Open access
  • 113 Reads
Design and FEM simulation of an asymmetric pinched flow fractionation microfluidic system for high-throughput screening applications

The separation of microscopic encapsulates is an area of increasing importance due to applications in a wide variety of fields ranging from the production of cosmetics and pharmaceuticals to the search for new molecules and genetically-modified microorganisms. Major challenges are related to the proximity in physicochemical properties of the encapsulating material and the suspension media. This is the case for encapsulation into polymeric capsules and lipid-based systems such as liposomes. We are particularly interested in liposomes as they can be useful in model studies of the interaction between molecules and organisms with lipid bilayers, which represent possible interactions with cells. In this regard, we have recently started a research program for the search of translocating peptides by using a surface display system that locates the possible candidate molecules on the surface of yeasts. To determine whether a candidate exhibits translocating abilities, the yeasts with the displayed peptides need to come in contact with liposomes and as a result, they might end up encapsulated. At this point, the encapsulated need to be separated out and collected for further analyses. An attractive route for separation is microfluidics as they permit control over flow rates and interaction times. Here, we explored in silico an asymmetric pinched Flow fractionation (AsPFF) microfluidic system for the separation of particles in the range of 50 and 500 µm. The simulations involved the particle tracing module in COMSOL multiphysics with the aim of mainly separating yeasts of 50 µm and liposomes of 200 µm with the encapsulated yeasts. We investigated flow rate ratios in the range of 1:25 to 1:50 over the 11 different outlets of the system (see Figure below). The results show separation efficiencies above 90%, which are very encouraging and open the opportunity to further explore this microfluidic system experimentally via low-cost manufacturing in the laser cut PMMA devices that we have developed over the past few years in our group. Moreover, this opens the opportunity for improving separation efficiencies in other biological and biomedical applications of interest.

  • Open access
  • 93 Reads
Formulation and characterization of gelatin-based hydrogels for the encapsulation of Kluyveromyces lactis and chitosan nanoparticles: biotech and biomedical applications

A difficulty when orally administering microorganism-based probiotics is the significant loss of their bioactivity as they pass through the gastrointestinal (GI) tract. To overcome these issues, we propose to encapsulate the probiotic yeast Kluyveromyces lactis on chemically crosslinked gelatin hydrogels to protect the bioactive agents in different environments. Moreover, a challenge to obtain favorable results with therapeutic drugs and biomolecules is the inefficient process of cellular administration. For this reason, we considered chitosan and gelatin nanoparticle loading systems to improve therapeutic efficacy . Also, we prepared hydrogels to encapsulate such nanoparticles by the chemical crosslinking of gelatin, an inexpensive and commercially available polymer. This is crucial to ensure scalability and cost-effectiveness. To explore changes in key physicochemical parameters and their impact on cell viability, we varied the concentration of the crosslinking agent (glutaraldehyde) and the gelatin. The synthesized hydrogels were characterized in terms of morphological, physical-chemical, mechanical, thermal, and rheological properties. This comprehensive characterization allowed us to identify critical parameters to facilitate encapsulation and enhance the system performance. Mainly due to pore size in the range of 5–10 µm, sufficient rigidity (breaking forces of about 1 N), low brittleness and structural stability under swelling and relatively high shear conditions, we selected hydrogels with a high concentration of gelatin (7.5% (w/v)) and concentrations of the crosslinking agent of 3.0% and 5.0% (w/w) for cell and nanoparticles encapsulation. Yeasts were encapsulated and subsequently tested in bioreactor operation and GI tract simulated media, thereby leading to cell viability levels that approached 95% and 50%, respectively. After testing, the hydrogels’ firmness was only reduced to half of the initial value and maintained resistance to shear even under extreme pH conditions. These encouraging results indicate that the proposed encapsulates are suitable to overcome most of the major issues of oral administration of drugs and probiotics and open the possibility to explore additional biotech applications further.

  • Open access
  • 68 Reads
Modelling and simulation of multiphase flow for nanoparticle translocation

Encapsulation of bioactive molecules within liposomes represents a potential approach for
upholding their activity and stability under harsh environments [1]. Indeed, liposomes are
considered one of the most attractive vehicles to deliver therapeutics [2-4]. Magnetite nanoparticles
(MNPs) linked to molecules such as OmpA and Buforin-II are promising to enhance translocation of
those compounds through the lipid bilayer of liposomes and consequently, of cells [5-7]. Besides,
microfluidic devices have shown to be successful at producing homogeneous and stable liposomes
by controlling the interaction of continuous and dispersed phases [8-12]. This work intends to
analyze multiphase behavior under external forces in microfluidic devices for encapsulating
ferrofluidic compounds that model MNPs transported into liposomes to optimize the use of these
devices. In ongoing work, we have developed in silico models, which suggest that by introducing
acoustic fields from ultrasonic baths, the interaction between continuous and dispersed phases
increases. This is mainly due to acoustophoretic forces inducing a multidirectional force vector within
microfluidic channels, which serves to focus fluid streamlines, enhances mixing, and ultimately
allows the transport of nanoparticles [13-14]. Regarding this, to quantify the interaction between
fluid phases, which relates the encapsulation process of the nanoparticles within liposomes, we
propose a reaction model that couples mixture, diluted species, and chemical reactions. This
approach considers Michaelis-Menten equation to model the interaction between the liposomes and
nanoparticles, referring to enzyme and substrate respectively. These models are implemented aided
by COMSOL Multiphysics® software. Correlating both reaction and mixture behavior it is expected
to estimate the efficiency of the proposed method, by quantifying changes in the dispersed phase
fraction and the reaction rate, which represents the active pass through the bilayer.

[1] T. Alkayyali, T. Cameron, B. Haltli, R. G. Kerr, and A. Ahmadi, “Microfluidic and cross-linking
methods for encapsulation of living cells and bacteria - A review,” Anal. Chim. Acta, vol. 1053, pp.
1–21, 2019.
[2] M. Maeki, N. Kimura, Y. Sato, H. Harashima, and M. Tokeshi, “Advances in microfluidics for lipid
nanoparticles and extracellular vesicles and applications in drug delivery systems”, Adv. Drug Deliv.
Rev., vol. 128, pp. 84–100, 2018.
[3] L. Sercombe, T. Veerati, F. Moheimani, S. Y. Wu, A. K. Sood, and S. Hua, “Advances and
challenges of liposome assisted drug delivery,” Front. Pharmacol., vol. 6, no. DEC, pp. 1–13, 2015.
[4] A. Akbarzadeh et al., “Liposome: Classification, preparation, and applications,” Nanoscale Res.
Lett., vol. 8, no. 1, pp. 1–8, 2013.
[5] N. Lopez-Barbosa et al., “Magnetite-OmpA Nanobioconjugates as Cell-Penetrating Vehicles with
Endosomal Escape Abilities,” ACS Biomater. Sci. Eng., vol. 6, no. 1, pp. 415–424, 2020.
[6] M. Cuellar et al., “Novel BUF2-magnetite nanobioconjugates with cell-penetrating abilities,” Int.
J. Nanomedicine, vol. 13, pp. 8087–8094, 2018.
[7] J. Perez, J. Cifuentes, M. Cuellar, A. Suarez-Arnedo, J. C. Cruz, and C. Muñoz-Camargo, “Cellpenetrating and antibacterial BUF-II nanobioconjugates: Enhanced potency via immobilization on
polyetheramine-modified magnetite nanoparticles,” Int. J. Nanomedicine, vol. 14, pp. 8483–8497,
[8] S. Damiati, U. Kompella, S. Damiati, and R. Kodzius, “Microfluidic Devices for Drug Delivery
Systems and Drug Screening,” Genes (Basel)., vol. 9, no. 2, p. 103, 2018.
[9] L. M. Montes-de-Oca et al., “Micro-Encapsulation of Probiotic Metabolites and Magnetic
Nanoparticles Inside Liposomes using Microfluidic Devices,” Microsc. Microanal., vol. 24, no. S1, pp.
1430–1431, 2018.
[10] J. Gubernator, “Active methods of drug loading into liposomes: Recent strategies for stable drug
entrapment and increased in vivo activity,” Expert Opin. Drug Deliv., vol. 8, no. 5, pp. 565–580, 2011.
[11] M. Guimarães Sá Correia, M. L. Briuglia, F. Niosi, and D. A. Lamprou, “Microfluidic
manufacturing of phospholipid nanoparticles: Stability, encapsulation efficacy, and drug release,”
Int. J. Pharm., vol. 516, no. 1–2, pp. 91–99, 2017.
[12] A. J. Conde et al., “Continuous flow generation of magnetoliposomes in a low-cost portable
microfluidic platform,” Lab Chip, vol. 14, no. 23, pp. 4506–4512, 2014.
[13] D. J. Collins, Z. Ma, J. Han, and Y. Ai, “Continuous micro-vortex-based nanoparticle
manipulation via focused surface acoustic waves,” Lab Chip, vol. 17, no. 1, pp. 91–103, 2017.
[14] G. G. Yaralioglu, I. O. Wygant, T. C. Marentis, and B. T. Khuri-Yakub, “Ultrasonic mixing in
microfluidic channels using integrated transducers,” Anal. Chem., vol. 76, no. 13, pp. 3694–3698,

  • Open access
  • 91 Reads
In silico analysis of microfluidic systems for the purification of magneto-liposomes

Magnetite nanoparticles (MNPs) have been considered for a number of applications in drug delivery. However, the main challenge is to assure high cell-penetration levels, especially when dealing with cargoes that show limited membrane passing. A strategy is to encapsulate the MNPs into liposomes to form magnetoliposomes (MLs) capable of fusing with membranes to achieve high delivery rates. Magnetoliposomes have therefore been used as carriers in the biomedical field due to their ability to release active molecules that can be used in treatments of diverse diseases. There are several techniques to produce such encapsulates, however, the main challenge is that the process often leads to an important fraction of non-encapsulated MNPs. Purification of such a fraction is challenging because of the small size difference between the particles and the MLs and the reduced magnetic responsiveness. Seeking to obtain pure MLs with potential use in the medical field, the following study presents finite element simulations using COMSOL Multiphysics of two purification methods. Accordingly, we implemented magnetic separation and asymmetric pinched flow fractionation separation to evaluate their purification efficiencies in light of operation parameters such as the Flow Rate Ratio (FRR) and Total Velocity Ratio (TVR). Additionally, a mixture interaction approach was used to model the MNPs as a dispersed ferrofluid phase. This was compared with a particle tracing approach where MNPs are considered individual entities subjected to hydrodynamic forces. The results show efficiencies between 60% and 90% for both separation methods, which confirms their feasibility to improve and optimize the purification of MLs in a high throughput manner.

  • Open access
  • 73 Reads
Design and Simulation of a Microfluidic Platform for the Encapsulation and Separation of Yeasts Expressing Translocating Peptides

The encapsulation of biomolecules and microorganisms into liposomes is useful for a number of biological and biomedical applications. For instance, it is possible to encapsulate pharmacological compounds to increase properties such as therapeutic effectiveness, circulation times, and biocompatibility. Here, we are interested in encapsulating yeast cells expressing translocating peptide molecules on their surfaces. This is with the final intention of separating out yeasts with translocating activity from those with other types of membrane activities. To accomplish this, we designed a microfluidic system for the synthesis of giant liposomes (100-150 µm in diameter) based on the droplet generation of double emulsions (water-in-oil-in-water) as templates. Giant liposomes were selected here due to their size, lipid structure (unilamellar), and the ability to control the internal content that closely mimic, albeit in a more simplified manner, the structural organization of living cells. The microfluidic device comprises a W/O/W-junction equipped with three sets of inlets, a main channel, and an output channel at an angle of 30°. The performance of the system was evaluated in silico by implementing a Two-Phase flow, Level set model where the flow rate ratios of the continuous and dispersed phases were altered until the droplet was formed. Next, interaction with yeasts was achieved by a Y-junction geometry with two 0.5 mm-length inlets at 45°. The interaction was simulated with the aid of a Mixture model. Maximum velocity was obtained at the center of the channel and a complete mixing at the outlet, which indicates high interaction levels. Finally, we implemented an inertial geometry for the separation of the liposomes with encapsulated yeasts, which is currently under simulation via Euler-Euler and Particle Tracing models.

  • Open access
  • 83 Reads
Synthesis and Resistive Switching of Nanocrystalline Vanadium Oxide Films

The work is devoted to the study of the modes of synthesis of films of nanocrystalline vanadium oxide for the manufacture of resistive memory elements (ReRAM) of neuromorphic systems. The regularities of the influence of pulsed laser deposition modes on the morphology and electrophysical properties of vanadium oxide films were experimentally established taking into account the technological parameters of the substrate temperature, oxygen pressure, the number of pulses, as well as the temperature and duration of postgrowth annealing. It is shown that the change in the number of pulses in the range from 10,000 to 50,000 pulses, substrate temperature from 25 to 650 °C, oxygen pressure from 10-4 to 10-1 Torr, temperature and duration of annealing in the range from 300 to 500 °C and from 30 to 180 minutes, respectively, makes it possible to obtain nanocrystalline films of vanadium oxide with grain size in the range from 231.3±45.3 to 721.8±123.2 nm, surface roughness in the range from 4.3±1.4 to 25.2±5.4 nm, resistivity from 2×10-1 to 12×103 Ω∙cm, and the coefficient of thermal resistance in the range from 0.14 to 0.48. Fabrication modes of nanocrystalline vanadium oxide films were determined with the high-resistance state RHRS = 8 kΩ, the ratio of resistances in the high-resistance state to the resistance in the low-resistance state RHRS/RLRS=1427, as well as the minimum thermal resistance coefficient 0.21, for the creation of elements of resistive memory with low power consumption, a wide range of accepted possible resistance values, and a weak dependence on temperature. The obtained results can be used in the development of technological processes for the formation of nanocrystalline films of vanadium oxides for resistive memory elements in neuromorphic systems. The reported study was funded by RFBR, according to the research project N_ 19-29-03041_mk.

  • Open access
  • 71 Reads
Synthesis and characterization of Gefitinib and Paclitaxel dual drug loaded Cockle shell (Anadara granosa) derived Calcium carbonate nanoparticles

Calcium carbonate nanoparticles have salient properties, such as biocompatibility, pH responsiveness, and the ability to alkalinize a tumor, hence reducing metastasis. A combination therapy regimen is normative for breast cancer, where, besides its side effects, toxic vehicles are required for certain drugs. This study is aimed at transforming the readily available Blood cockle shells (Anadara granosa) to calcium carbonate nanoparticles (CSCaCO3NP), loading them with Gefitinib (GEF) and Paclitaxel (PTXL). Facile top-down synthesis of CSCaCO3NP is comprised of grinding, sieving, and stirring with Tween 80, followed by filtration and finally dry milling for 100 hours. A ratio of 1+0.5:25 of GEF+PTXL: CSCaCO3NP in an equal admixture of DMSO and 0.05%Tween 80 buffer was used for drug loading. Loading content (%) and encapsulation efficiency (%) for GEF and PTXL in dual drug-loaded NP (GEF-PTXL-CSCaCO3NP) was 1.98 ± 0.11, 50.01 ± 2.18 and 0.92 ± 0.01, 45.60 ± 0.32. Field emission Scanning electron micrographs revealed that the nanoparticles were almost spherical with the average diameter (nm) measuring 63.96 ± 22.3 and 87.20 ± 26.66 for CSCaCO3NP and GEF-PTXL-CSCaCO3NP. The Dynamic Light Scattering data gives the average diameter of CSCaCO3NP and GEF-PTXL-CSCaCO3NP as 179 ± 10.9 (nm) and 274 ± 23.22 (nm), respectively, and polydispersive index of 0.3. Zeta potential was -17 ± 1.15 (mV) and 10.30 ± 1.7 (mV), respectively. Fourier-transform Infrared spectroscopy proves that CSCaCO3NP has encapsulated the drugs. X-Ray Diffraction data indicates that the aragonite phase is unaltered. N2 adsorption-desorption isotherms reveal that CSCaCO3NP are mesoporous and that the surface area had reduced from 10.68 ± 0.22 to 9.88 ± 0.24 m2/g after drug loading. For the first time, this work will describe the process to synthesize CSCaCO3NP which was used as a carrier to load GEF and PTXL and its salient characteristics.

  • Open access
  • 44 Reads
Molibdenum Disulfide Field Effect Transistor under Electron Beam Irradiation and External Electric Field

In this work, monolayer molybdenum disulfide (MoS2) nanosheets, obtained via chemical vapor deposition onto SiO2/Si substrates, are exploited to fabricate field-effect transistors with n-type conduction, high on/off ratio, steep subthreshold slope and good mobility. We study their electric characteristics from 10-6 Torr to atmospheric air pressure. We show that the threshold voltage of the transistor increases with the growing pressure.

Moreover, Schottky metal contacts in monolayer MoS2 field-effect transistors (FETs) are investigated under electron beam irradiation. It is shown that the exposure of Ti/Au source/drain electrodes to an electron beam reduces the contact resistance and improves the transistor performance. The electron beam conditioning of contacts is permanent, while the irradiation of the channel can produce transient effects. It is shown that e-beam irradiation lowers the Schottky barrier at the contacts due to thermally induced atom diffusion and interfacial reactions. The study demonstrates that electron beam irradiation can be effectively used for contact improvement though local annealing.

It is also demonstrated that the application of an external field by a metallic nanotip induces a field emission current, which can be modulated by the voltage applied to the Si substrate back-gate. Such a finding, that we attribute to gate-bias lowering of the MoS2 electron affinity, enables a new field-effect transistor based on field emission.

  • Open access
  • 70 Reads
Temperature dependence of Germanium Arsenide field-effect transistors electrical properties

In this work, we report the fabrication of germanium arsenide (GeAs) field-effect transistors with ultrathin channel and their electrical characterizations in a wide temperature range, from 20 K to 280 K. We show that the p-type electrical conductivity and the field effect mobility of GeAs transistors increase with the temperature and that at lower temperatures the electrical conduction of the GeAs channel is dominated by the 3D variable range hopping but becomes band-type at higher temperatures, after the formation of a highly conducting two-dimensional (2D) channel. The presence of this 2D channel, limited to few interfacial GeAs layers, is confirmed by the observation of an unexpected peak in the temperature dependence of the carrier density per area at about 75 K. Such a feature is explained considering a model based on a temperature-dependent channel thickness. Indeed, at higher temperatures, the carrier injection from the contacts increase and the ionization of defects is favoured enabling the formation of a 2D highly conductive channel close to the dielectric interface, which screens the electric field from the gate and confine it to the first few layers of the material. The formation of the 2D channel is corroborated by numerical simulations, that show excellent agreement with the experimental data, and by the estimation of 0.4 nm Debye screening length at room temperature.

  • Open access
  • 49 Reads
Synthesis of size monodisperse water-soluble metal nanoclusters for protein quantification by elemental mass spectrometry

The use of metal immunoprobes, defined as recognition molecules (e.g. antibodies) labelled with metal tags, constitutes an interesting strategy for the analysis of proteins in biological samples. Detection of such immunoprobes by elemental mass spectrometry (MS) allows not only the qualitative analysis of the proteins but also their absolute quantification [1].

In this context, fluorescent and biocompatible metal nanoclusters (MNCs) have been recently established as an alternative not only to conventional fluorophores but also to commercial elemental tags (e.g MAXPAR) or larger metal nanoparticles for elemental detection. MNCs, composed by hundreds of metal atoms, allow achieving high signal enhancement of low abundant proteins (pM range), meanwhile the small nucleus size (< 3 nm) of MNCs avoids the blocking of the antibody recognition sites. We have achieved the synthesis of thiolated AuNCs, AgNCs and PtNCs and they have been successfully employed as labels for specific proteins determination in biological fluids. Moreover, the combination of MNCs labelled immunoprobes with laser ablation (LA) coupled to elemental MS, allowed the quantitative imaging of proteins along tissue structures [2].

The proteins concentration is given by the average of MNCs measured per acquisition point by elemental MS. Therefore, the deviation associated to the MNCs polydispersity will limit the analytical precision, particularly in those samples were the concentrations of the sought protein is very low, such as in the case of single cell analysis. Thus, in this presentation it will be described our efforts to synthesise size monodisperse MNCs aiming to obtain accurate and precise quantification of specific proteins in single cells.

[1] A. Lores-Padín, P. Menero-Valdés, B. Fernández, R. Pereiro, Anal. Chim. Acta, 1128 (2020) 251-268

[2] A. Lores-Padín, B. Fernández, L. Álvarez, H. González-Iglesias, I. Lengyel, R. Pereiro, Talanta 221 (2021) 121489