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Biomedical subjects

Mattias Karlsson

Publications and source records attributed to Mattias Karlsson.

12 recordsLinked to original sources
PubMed2005

Microfluidic technologies in drug discovery.

Microfluidic systems are increasingly used as tools in various stages of the drug discovery process. Microscale systems offer several obvious advantages, such as low sample consumption and significantly reduced analysis or experiment time. These technologies raise the possibility of massive parallelization and concomitant reduction in cost per acquired data point. In addition, fluids in confined spaces display unique behaviors that can be used to acquire information not accessible using macroscopic systems. This article will focus on the implementation of microfluidic systems and technologies in the process of drug discovery.

Chemistry, Pharmaceutical↗
PubMed2005

Microfluidic gradient-generating device for pharmacological profiling.

We describe an on-chip microfluidic gradient-generating device that generates concentration gradients spanning nearly 5 orders of magnitude starting from a single concentration. The exiting stream of drugs held at different concentrations remains laminar in a recording chamber and can be presented as 24 discrete solutions to a cell-based sensor. The high-performance characteristics of the device are demonstrated by pharmacological screening of voltage-gated K+ channels (hERG) and ligand-gated GABA(A) receptors using scanning-probe patch-clamp measurements. Multiple data point dose-response curves and IC50 and EC50 values were rapidly obtained, typically in less than 30 min, through its combined functionality of gradient generation and open-volume laminar flow. The device facilitates rapid pharmacological profiling of ion channel and GPCR effectors and enables the acquisition of large numbers of data points with minute sample consumption and handling.

Animals↗
PubMed2005

Fluid mixing in growing microscale vesicles conjugated by surfactant nanotubes.

This work addresses novel means for controlled mixing and reaction initiation in biomimetic confined compartments having volume elements in the range of 10(-12) to 10(-15) L. The method is based on mixing fluids using a two-site injection scheme into growing surfactant vesicles. A solid-state injection needle is inserted into a micrometer-sized vesicle (radius 5-25 microm), and by pulling on the needle, we create a nanoscale surfactant channel connecting injection needle and the vesicle. Injection of a solvent A from the needle into the nanotube results in the formation of a growing daughter vesicle at the tip of the needle in which mixing takes place. The growth of the daughter vesicle requires a flow of surfactants in the nanotube that generates a flow of solvent B inside the nanotube which is counterdirectional to the pressure-injected solvent. The volume ratio psi between solvent A and B inside the mixing vesicle was analyzed and found to depend only on geometrical quantities. The majority of fluid injected to the growing daughter vesicle comes from the pressure-based injection, and for a micrometer-sized vesicle it dominates. For the formation of one daughter vesicle (conjugated with a 100-nm radius tube) expanded from 1 to 200 microm in radius, the mixing ratios cover almost 3 orders of magnitude. We show that the system can be expanded to linear strings of nanotube-conjugated vesicles that display exponential dilution. Mixing ratios spanning 6 orders of magnitude were obtained in strings of three nanotube-conjugated micrometer-sized daughter vesicles.

Fluorescent Dyes↗
PubMed2004

A microfluidics approach to the problem of creating separate solution environments accessible from macroscopic volumes.

We report on a microfluidic device that generates separate solution environments in macroscopic volumes. Spatially distinct patterns are created by emitting fluids from 16 different sources (closely spaced microchannels) into a solution-filled macroscopic chamber. The fluid in neighboring microchannels couples viscously in the macroscopic container, generating one single interdigitated stream. Scanning nanoelectrode amperometry was used for characterizing the concentration landscape and the diffusion zones between solutions running in parallel at different coordinates in the stream. These experiments were complemented by finite element simulations of the Navier-Stokes and mass transport equations to describe the velocity distributions and the diffusion behavior. For in channel flow velocities of 50 mm.s(-1), patterns could persist on the order of millimeters to centimeters in the open volume. The most narrow diffusion zones with widths less than 10 microm (5-95% concentration change) were found some tens of micrometers out in the macroscopic container. We demonstrate that a 14-microm-diameter nearly spherical object (biological cell) attached to a micropipet can be moved from one solution environment to another by a lateral displacement of only 8 microm. The device is suitable for applications where the solution environment around a microscopic or nanoscopic sensor needs to be changed multiple times, i.e., in order to build layered structures, for obtaining binding isotherms, and kinetic information, for example, on ion channels, enzymes, and receptors as well as in applications where different loci on an object need to be exposed to different environments or where complex solution environments need to be created for studies of interfacial chemistry between two streaming layers.

Journal Article↗
PubMed2004

Mechanical tweezer action by self-tightening knots in surfactant nanotubes.

Entanglements and trefoil knots on surfactant nanotubes in the liquid phase were produced by a combination of network self-organization and micromanipulation. The resulting knots are self-tightening, and the tightening is driven by minimization of surface free energy of the surfactant membrane material. The formation of the knot and the steady-state knot at quasi-equilibrium can be directly followed and localized by using fluorescence microscopy. Knots on nanotubes can be used as nanoscale mechanical tweezers for trapping and manipulation of single nano- and micrometer-sized high-aspect ratio objects. Furthermore, we demonstrate that by controlling the surface tension, objects captured by a knot can be transported along given trajectories defined by the nanotube axes.

Fluorescence↗
PubMed2004

Biomimetic nanoscale reactors and networks.

Methods based on self-assembly, self-organization, and forced shape transformations to form synthetic or semisynthetic enclosed lipid bilayer structures with several properties similar to biological nanocompartments are reviewed. The procedures offer unconventional micro- and nanofabrication routes to yield complex soft-matter devices for a variety of applications for example, in physical chemistry and nanotechnology. In particular, we describe novel micromanipulation methods for producing fluid-state lipid bilayer networks of nanotubes and surface-immobilized vesicles with controlled geometry, topology, membrane composition, and interior contents. Mass transport in nanotubes and materials exchange, for example, between conjugated containers, can be controlled by creating a surface tension gradient that gives rise to a moving boundary or by induced shape transformations. The network devices can operate with extremely small volume elements and low mass, to the limit of single molecules and particles at a length scale where a continuum mechanics approximation may break down. Thus, we also describe some concepts of anomalous fluctuation-dominated kinetics and anomalous diffusive behaviours, including hindered transport, as they might become important in studying chemistry and transport phenomena in these confined systems. The networks are suitable for initiating and controlling chemical reactions in confined biomimetic compartments for rationalizing, for example, enzyme behaviors, as well as for applications in nanofluidics, bioanalytical devices, and to construct computational and complex sensor systems with operations building on chemical kinetics, coupled reactions and controlled mass transport.

Biological Transport↗
PubMed2003

Nanofluidic networks based on surfactant membrane technology.

We explore possibilities to construct nanoscale analytical devices based on lipid membrane technology. As a step toward this goal, we present nanotube-vesicle networks with fluidic control, where the nanotube segments reside at, or very close (<2 microm) to optically transparent surfaces. These nanofluidic systems allow controlled transport as well as LIF detection of single nanoparticles. In the weak-adhesion regime, immobilized vesicles can be approximated as perfect spheres with nanotubes attached at half the height of the vesicle in the axial (z) dimension. In the strong-adhesion regime (relative contact area, Sr* approximately 0.3), nanotubes can be adsorbed to the surface with a distance to the interior of the nanotubes defined by the membrane thickness of approximately 5 nm. Strong surface adsorption restricts nanotube self-organization, enabling networks of nanotubes with arbitrary geometries. We demonstrate LIF detection of single nanoparticles (30-nm-diameter fluorescent beads) inside single nanotubes. Transport of nanoparticles was induced by a surface tension differential applied across nanotubes using a hydrodynamic injection protocol. Controlled transport in nanotubes together with LIF detection enables construction of nanoscale fluidic devices with potential to operate with single molecules. This opens up possibilities to construct analytical platforms with characteristic length scales and volume orders of magnitudes smaller than employed in traditional microfluidic devices.

Liposomes↗
PubMed2003

Nanotube-vesicle networks with functionalized membranes and interiors.

We describe nanotube-vesicle networks with reconstituted membrane protein from cells and with interior activity defined by an injection of microparticles or molecular probes. The functionality of a membrane protein after reconstitution was verified by single-channel ion conductance measurements in excised inside-out patches from the vesicle membranes. The distribution of protein, determined by fluorescence detection, in the network membrane was homogeneous and could diffuse via a nanotube connecting two vesicles. We also show how injecting small unilamellar protein-containing vesicles can differentiate the contents of individual containers in a network. The combination of membrane activity and interior activity was demonstrated by ionophore-assisted accumulation, and internal Calcium Green-mediated detection, of Ca2+ within a single network container. This system can model a variety of biological functions and complex biological multicompartment structures and might serve as a platform for constructing complex sensor and computational devices.

Biomimetic Materials↗
PubMed2003

Artificial cells: unique insights into exocytosis using liposomes and lipid nanotubes.

Exocytosis is the fundamental process underlying neuronal communication. This process involves fusion of a small neurotransmitter-containing vesicle with the plasma membrane of a cell to release minute amounts of transmitter molecules. Exocytosis is thought to go through an intermediate step involving formation of a small lipid nanotube or fusion pore, followed by expansion of the pore to the final stage of exocytosis. The process of exocytosis has been studied by various methods; however, when living cells are used it is difficult to discriminate between the molecular effects of membrane proteins relative to the mechanics of lipid-membrane-driven processes and to manipulate system parameters (e.g., membrane composition, pH, ion concentration, temperature, etc.). We describe the use of liposome-lipid nanotube networks to create an artificial cell model that undergoes the later stages of exocytosis. This model shows that membrane mechanics, without protein intervention, can drive expansion of the fusion pore to the final stage of exocytosis and can affect the rate of transmitter release through the fusion pore.

Animals↗
PubMed2002

A cell-based bar code reader for high-throughput screening of ion channel-ligand interactions.

This paper presents a microfluidics-patch clamp platform for performing high-throughput screening and rapid characterization of weak-affinity ion channel-ligand interactions. This platform integrates a microfluidic chip consisting of multiple channels entering an open volume with standard patch clamp equipment. The microfluidic chip is placed on a motorized scanning stage and the method relies on the ability to scan rapidly, on the order of milliseconds, a patch-clamped cell across discrete zones of different solutions created in the open volume. Under ideal conditions, this method has the capacity to obtain kinetically resolved patch clamp measurements and dose-response curves of up to 10(3) ligand solutions in a single day.

Animals↗
PubMed2002

Formation of geometrically complex lipid nanotube-vesicle networks of higher-order topologies.

We present a microelectrofusion method for construction of fluid-state lipid bilayer networks of high geometrical complexity up to fully connected networks with genus = 3 topology. Within networks, self-organizing branching nanotube architectures could be produced where intersections spontaneously arrange themselves into three-way junctions with an angle of 120 degrees between each nanotube. Formation of branching nanotube networks appears to follow a minimum-bending energy algorithm that solves for pathway minimization. It is also demonstrated that materials can be injected into specific containers within a network by nanotube-mediated transport of satellite vesicles having defined contents. Using a combination of microelectrofusion, spontaneous nanotube pattern formation, and satellite-vesicle injection, complex networks of containers and nanotubes can be produced for a range of applications in, for example, nanofluidics and artificial cell design. In addition, this electrofusion method allows integration of biological cells into lipid nanotube-vesicle networks.

Lipids↗