Basic Principles and Recent Advances in Magnetic Cell Separation

Magnetic cell separation has become a key methodology for the isolation of target cell populations from biological suspensions, covering a wide spectrum of applications from diagnosis and therapy in biomedicine to environmental applications or fundamental research in biology. There now exists a great variety of commercially available separation instruments and reagents, which has permitted rapid dissemination of the technology. However, there is still an increasing demand for new tools and protocols which provide improved selectivity, yield and sensitivity of the separation process while reducing cost and providing a faster response. This review aims to introduce basic principles of magnetic cell separation for the neophyte, while giving an overview of recent research in the field, from the development of new cell labeling strategies to the design of integrated microfluidic cell sorters and of point-of-care platforms combining cell selection, capture, and downstream detection. Finally, we focus on clinical, industrial and environmental applications where magnetic cell separation strategies are amongst the most promising techniques to address the challenges of isolating rare cells.

The Origins and the Current Applications of Microfluidics-Based Magnetic Cell Separation Technologies

The magnetic separation of cells based on certain traits has a wide range of applications in microbiology, immunology, oncology, and hematology. Compared to bulk separation, performing magnetophoresis at micro scale presents advantages such as precise control of the environment, larger magnetic gradients in miniaturized dimensions, operational simplicity, system portability, high-throughput analysis, and lower costs. Since the first integration of magnetophoresis and microfluidics, many different approaches have been proposed to magnetically separate cells from suspensions at the micro scale. This review paper aims to provide an overview of the origins of microfluidic devices for magnetic cell separation and the recent technologies and applications grouped by the targeted cell types. For each application, exemplary experimental methods and results are discussed.

Origin of Perovskite Multiferroicity and Magnetoelectric-Multiferroic Effects—The Role of Electronic Spin in Spontaneous Polarization of Crystals

In this semi-review paper, we show that the multiferroic properties of perovskite ABO3 crystals with B(dn), n > 0, centers are fully controlled by the influence of the electronic spin on the local dipolar instability that triggers the spontaneous polarization of the crystal. Contrary to the widespread statements, the multiferroicity of these crystals does not emerge due to the addition of unpaired electrons (carrying magnetic moments) to the spontaneously polarizing crystal; the spin states themselves are an important part of the local electronic structure that determines the very possibility of the spontaneous polarization. This conclusion emerges from vibronic theory, in which the ferroelectricity is due to the cooperative interaction of the local dipolar distortions induced by the pseudo-Jahn-Teller effect (PJTE). The latter requires sufficiently strong vibronic coupling between ground and excited electronic states with opposite parity but the same spin multiplicity. The detailed electronic structure of the octahedral [B(dn)O6] center in the molecular orbital presentation shows how this requirement plays into the dependence of the possible perovskite magnetic, ferroelectric, and multiferroic properties on the number of d electrons, provided the criterion of the PJTE is obeyed. Revealed in detail, the role of the electronic spin in all these properties and their combination opens novel possibilities for their manipulation by means of external perturbations and exploration. In particular, it is shown that by employing the well-known spin-crossover phenomenon, a series of novel effects become possible, including magnetic-ferroelectric (multiferroic) crossover with electric-multiferroic, magnetic-ferroelectric, and magneto-electric effects, some of which have already been observed experimentally.

Steric Quenching of Mn(III) Thermal Spin Crossover: Dilution of Spin Centers in Immobilized Solutions

Structural and magnetic properties of a new spin crossover complex [Mn(4,6-diOMe-sal2323)]+ in lattices with ClO4−, (1), NO3−, (2), BF4−, (3), CF3SO3−, (4), and Cl− (5) counterions are reported. Comparison with the magnetostructural properties of the C6, C12, C18 and C22 alkylated analogues of the ClO4− salt of [Mn(4,6-diOMe-sal2323)]+ demonstrates that alkylation effectively switches off the thermal spin crossover pathway and the amphiphilic complexes are all high spin. The spin crossover quenching in the amphiphiles is further probed by magnetic, structural and Raman spectroscopic studies of the PF6− salts of the C6, C12 and C18 complexes of a related complex [Mn(3-OMe-sal2323)]+ which confirm a preference for the high spin state in all cases. Structural analysis is used to rationalize the choice of the spin quintet form in the seven amphiphilic complexes and to highlight the non-accessibility of the smaller spin triplet form of the ion more generally in dilute environments. We suggest that lattice pressure is a requirement to stabilize the spin triplet form of Mn3+ as the low spin form is not known to exist in solution.

The Microscopic Mechanisms Involved in Superexchange

In earlier work, we previously established a formalism that allows to express the exchange energy J vs. fundamental molecular integrals without crystal field, for a fragment A–X–B, where A and B are 3d1 ions and X is a closed-shell diamagnetic ligand. In this article, we recall this formalism and give a physical interpretation: we may rigorously predict the ferromagnetic (J < 0) or antiferromagnetic (J > 0) character of the isotropic (Heisenberg) spin-spin exchange coupling. We generalize our results to ndm ions (3 £ n £ 5, 1 £ m £ 10). By introducing a crystal field we show that, starting from an isotropic (Heisenberg) exchange coupling when there is no crystal field, the appearance of a crystal field induces an anisotropy of exchange coupling, thus leading to a z-z (Ising-like) coupling or a x-y one. Finally, we discuss the effects of a weak crystal field magnitude (3d ions) compared to a stronger (4d ions) and even stronger one (5d ions). In the last step, we are then able to write the corresponding Hamiltonian exchange as a spin-spin one.

Manipulation of Time- and Frequency-Domain Dynamics by Magnon-Magnon Coupling in Synthetic Antiferromagnets

Magnons (the quanta of spin waves) could be used to encode information in beyond Moore computing applications. In this study, the magnon coupling between acoustic mode and optic mode in synthetic antiferromagnets (SAFs) is investigated by micromagnetic simulations. For a symmetrical SAF system, the time-evolution magnetizations of the two ferromagnetic layers oscillate in-phase at the acoustic mode and out-of-phase at the optic mode, showing an obvious crossing point in their antiferromagnetic resonance spectra. However, the symmetry breaking in an asymmetrical SAF system by the thickness difference, can induce an anti-crossing gap between the two frequency branches of resonance modes and thereby a strong magnon-magnon coupling appears between the resonance modes. The magnon coupling induced a hybridized resonance mode and its phase difference varies with the coupling strength. The maximum coupling occurs at the bias magnetic field at which the two ferromagnetic layers oscillate with a 90° phase difference. Besides, we show how the resonance modes in SAFs change from the in-phase state to the out-of-phase state by slightly tuning the magnon-magnon coupling strength. Our work provides a clear physical picture for the understanding of magnon-magnon coupling in a SAF system and may provide an opportunity to handle the magnon interaction in synthetic antiferromagnetic spintronics.

Continuous Flow Labeling and In-Line Magnetic Separation of Cells

There is an identified need for point-of-care diagnostic systems for detecting and counting specific rare types of circulating cells in blood. By adequately labeling such cells with immunomagnetic beads and quantum dots, they can be efficiently collected magnetically for quantification using fluorescence methods. Automation of this process requires adequate mixing of the labeling materials with blood samples. A static mixing device can be employed to improve cell labeling efficiency and eliminate error-prone laboratory operations. Computational fluid dynamics (CFD) were utilized to simulate the flow of a labeling-materials/blood mixture through a 20-stage in-line static mixer of the interfacial-surface-generator type. Optimal fluid mixing conditions were identified and tested in a magnetic bead/tumor cell model, and it was found that labeled cells could be produced at 1.0 mL/min flow rate and fed directly into an in-line magnetic trap. The trap design consists of a dual flow channel with three bends and a permanent magnet positioned at the outer curve of each bend. The capture of labeled cells in the device was simulated using CFD, finite-element analysis and magnetophoretic mobility distributions of labeled cells. Testing with cultured CRL14777 human melanoma cells labeled with anti-CD146 1.5 μm diameter beads indicated that 90 ± 10% are captured at the first stage, and these cells can be captured when present in whole blood. Both in-line devices were demonstrated to function separately and together as predicted.

Tailoring Magnetic and Transport Anisotropies in Co100−x–Cux Thin Films through Obliquely Grown Nano-Sheets

The magnetic and transport properties of pulsed laser-deposited Co100−x–Cux thin films were tailored through their nano-morphology and composition by controlling for the deposition geometry, namely normal or oblique deposition, and their Cu content. All films were composed of an amorphous Co matrix and a textured growth of Cu nanocrystals, whose presence and size d increased as x increased. For x = 50, all films were superparamagnetic, regardless of deposition geometry. The normally deposited films showed no in-plane magnetic anisotropy. On the contrary, controllable in-plane uniaxial magnetic anisotropy in both direction and magnitude was generated in the obliquely deposited films. The magnetic anisotropy field Hk remained constant for x = 0, 5 and 10, Hk ≈ 35 kAm−1, and decreased to 28 and 26 kAm−1 for x = 20 and 30, respectively. This anisotropy had a magnetostatic origin due to a tilted nano-sheet morphology. In the normally deposited films, the coercive field Hc increased when x increased, from 200 (x = 0) to 1100 Am−1 (x = 30). In contrast, in obliquely deposited films, Hc decreased from 1500 (x = 0) to 100 Am−1 (x = 30) as x increased. Activation energy spectra corresponding to structural relaxation phenomena in obliquely deposited films were obtained from transport property measurements. They revealed two peaks, which also depended on their nano-morphology and composition.

The Advantages of EPR Spectroscopy in Exploring Diamagnetic Metal Ion Binding and Transfer Mechanisms in Biological Systems

Electron paramagnetic resonance (EPR) spectroscopy has emerged as an ideal biophysical tool to study complex biological processes. EPR spectroscopy can follow minor conformational changes in various proteins as a function of ligand or protein binding or interactions with high resolution and sensitivity. Resolving cellular mechanisms, involving small ligand binding or metal ion transfer, is not trivial and cannot be studied using conventional biophysical tools. In recent years, our group has been using EPR spectroscopy to study the mechanism underlying copper ion transfer in eukaryotic and prokaryotic systems. This mini-review focuses on our achievements following copper metal coordination in the diamagnetic oxidation state, Cu(I), between biomolecules. We discuss the conformational changes induced in proteins upon Cu(I) binding, as well as the conformational changes induced in two proteins involved in Cu(I) transfer. We also consider how EPR spectroscopy, together with other biophysical and computational tools, can identify the Cu(I)-binding sites. This work describes the advantages of EPR spectroscopy for studying biological processes that involve small ligand binding and transfer between intracellular proteins.

An Uneven Chain-like Ferromagnetic Copper(II) Coordination Polymer Displaying Metamagnetic Behavior and Long-Range Magnetic Ordering

Ferromagnetic coupling exists in an uneven chain-like copper(II) complex with both end-on azido and syn-syn carboxylato bridges, (Cu3(L)2(N3)4(H2O)3)n (1, HL = 6-hydroxynicotinic acid). It is the first example of one-dimensional (1D) chain-like copper(II) coordination polymer showing both metamagnetic behavior and long-range magnetic ordering (Tc = 6.7 K), thanks to the interchain hydrogen bonds, which make a three-dimensional (3D) supramolecular array of the entire molecular structure and mediate the interchain antiferromagnetic interaction.