GB2545476A - Non-invasive agitation device - Google Patents

Abstract

A non-invasive agitation device for multi-field treatment of a liquid sample comprises a piezoelectric material layer source 12, a platform to displace a specific beam trajectory, an acoustic cavity to reflect the acoustic beam and a sensor arranged to probe the acoustic wave front. An electrode pair and a magnet also create movement within the device via a magnetic field. Acoustic forces involve launching acoustic beams from a piezoelectric source 12, affixed to a moving platform 13. This in turn agitates standing acoustic wave nodes across a sample and cavity, resulting in agitating nodes that spin. This agitation capability, resulting from combined acoustic and magnetic force fields, provides a quasi-solid-state form for production scale operations.

Description

Backfiround of this invention

The present invention describes an agitation device to perform multi-field sample treatment by combining non-contact acoustic and magnetic fields.

Historically, traditional methods to agitate samples in the liquid phase, comprised low-frequency mixing methods that used direct mechanical action to extend manual hand movements by creating a mechanical repeat action. The evolution of the agitation process has progressed from basic blenders and stirrers to additional methods for sample compression and shaking at relatively low frequencies. These actions use a variety of mechanical forces to accelerate chemical reactions, liberate materials held within sample structures, or induce other favourable changes. In general, optimising product yield and process rate, depends on empirical parameters such as when, where and how much mechanical force is applied. These mechanically invasive methods are used in the food processing industry to refine and concentrate materials for making cheeses, sauces, chocolates and other edible substances. Further, they are used in the chemical processing industry, to accelerate reaction kinetics. Though they enable favourable testing and quality control through inducing sample homogeneity, the disadvantage of these traditional mechanical methods is the need for cleaning, high risk of fouling and contamination, catastrophic failure due to wear or disruptive materials, and difficulty in reducing to the microscale .

More recently, there have been suggestions to use components based on piezoelectric transducers to produce smaller, faster mechanical vibrations within liquid samples. These high-frequency devices can excite metal, ceramic or polymer containers such that their inside faces generate longitudinal compression waves at powers and frequencies that beneficially agitate the contained material. This method is often termed sonochemistry; it accelerates reactions by associating its reactants quickly, initiates new chemical transformations such as transesterification, or on the other hand, can rapidly clean surfaces. To intensify the process, transducers with curved surfaces have been used. These concentrate sound to a focal point, which although useful for greater efficiency, also reduces the sample process volume.

The outstanding limitations of these acoustic approaches are numerous, and include poor reproducibility, lack of uniformity, device contamination, excessive shear forces, sample denaturation, localised heating, or other undesirable changes in the sample. Other processing problems are associated with: drifting and detuning as the acoustic device action is perturbed by mechanical changes in the sample; the inability of oscillatory movements to induce large scale flow in the sample; and the single longitudinal polarisation of the acoustic device providing a limited agitation spectrum.

Hence this invention presents a multi-field driven non-invasive agitation device that engages node forces via acoustic beams and magnetic force fields. The combined action is uniform, reproducible, controllable and potentially sterile, overcoming many of the limitations found in the prior art.

The proposed approach posits a multi-field agitation device based on acoustic and magnetic forces. It comprises: A piezoelectric material layer source, formed in a manner whereby applying a sinusoidal electrical signal transmits a longitudinal acoustic wave beam into a proximal liquid sample.

An acoustic cavity which is arranged to reflect the acoustic beam and support an array of standing wave nodes. A platform transducer to which the piezoelectric material layer source is fixed, arranged to move in any combination of XYZ directions, to displace a specific beam trajectory and its associated nodes. A sensor which is arranged to probe the acoustic wavefront and provide a feedback signal to reduce motional noise of the node.

An electrode pair arranged in a manner whereby the region in-between acts as a source of liquid flow. A magnetic field, preferably perpendicular to the electrode pair region and sourced from a permanent magnetic material such as a neodymium iron boron magnet (NdFeB) or similar. A controller which is arranged to drive the piezoelectric material layer source, the electrode pair, and receive signals from pressure sensors, and programmatically alter its output.

Preferably the source and platform are driven using converse piezoelectricity, based on quartz, lithium niobate, PZT, PVDF, zinc oxide materials or other transduction film or process.

Preferably the source and platform are arranged to support a standing acoustic wave with an array of positionable nodes.

Preferably the wave energy is arranged to agitate by compression and expansion.

Preferably the nodes are arranged to agitate by converging the sample .

Preferably the source motion is arranged to agitate by producing nodal spin modes, spanning the range from a circular fundamental to frustrated higher order agitation modes.

Preferably liquid flow is arranged to agitate by passing over the array of nodes .

Preferably agitation is applied by multiple forces comprising three acoustic and one magnetic, i.e. wave compression, nodal convergence, nodal spin and Lorentz liquid flow, respectively.

Preferably the period of the source motion is greater than the period of the acoustic wave.

Preferably the acoustic cavity is made from steel, glass, polymer or ceramic materials.

Preferably the number of acoustic beams arranged exceeds one, and intersects to form an array of nodes.

An example of the present invention will now be described with reference to the figures. In this instance, a multi-field agitation process is performed, by coupling three acoustic forces and a magnetic force to loosen and liberate weakly-bound molecules from a heterogenous sample matrix.

Brief description of the figures

Figure 1: An illustration of an idealised sample, comprising weakly bound protein molecules, subject to multi-field agitation based on three acoustic forces and one magnetic force.

Figure 2: A schematic of the piezoelectric source and platform, used to produce acoustic agitation forces based on wave compression; nodal convergence and nodal spin.

Figure 3: A schematic of a region sourcing liquid flow, based on the presence of an electrode pair and magnetic field.

Figure 4: Examples of nodal spin modes, derived from acoustic forces that microscopically agitate the sample (shown in 2D for illustration purposes).

Figure 5: Example showing agitation via a multiple beam, transducer reflector geometry that anchors the sample, and subjects it to wave compression, convergence and nodal spin, against complementary magnetic flow forces.

Figure 6: A range of cavity shapes for holding the sample, transducer reflector components, electrode pair and magnetic field source .

Figure 7: Electronic waveform generator and programmatic controller to generate acoustic wave energy, position and spin the nodes, reduce their motional noise, and adjust the Lorentz flow velocity.

Description of the invention

Figure 1 is an illustration of a multi-field based agitation process using acoustic forces to release trapped (weakly-bound) molecules [1], combined with magnetic forces [2] to enhance the transport of molecules for subsequent removal.

Much of the agitation occurs around the node centre [3]. Its structure comprises an outer region where compression forces prevail [4], and an inner convergent region [5] formed from a negative energy gradient, all of which is carried collectively by the spin of the node itself [6] through a specific path [7].

Although oscillatory agitation can liberate weakly bound molecules [8] from low diffusivity regions [9], flow forces over a larger scale are needed for reliable transit and exit of the molecules. A complementary non-contact approach to generate that force uses electrical and magnetic fields. These forces result from combining a small ion current [10] between two electrodes [11], with the field (not shown) from a local permanent magnet, helping to pump the smallest of particles and molecules through the sample.

Thus, based on these combined forces, it is possible to remove weakly bound molecules by acoustic agitation, and then use magnetic forces to transfer those molecules to an exit nozzle, all via force fields alone.

Figure 2 is a schematic of the acoustic source [12] mounted on a platform [13] that directs longitudinal standing waves along an axis [14]. Within the beam, a series of nodes will form. These can be circulated by moving the platform, generating a family of nodal spin modes [15 ] .

If the source is displaced by the platform in any combination of XY or Z directions, then the node moves in a circle, or other higher order spin agitation modes. This action works together with other forces. For example, the compression-expansion forces derived from wave energy, and the convergence forces that accompany the node.

The platform is a composite transducer comprising a stack of piezoelectric crystals (or other electromechanical transducer). The first has a poled axis to produce a shear horizontal movement [16], i.e. sideways movement. The second is made of the same material, but rotated through 90° in the crystal plane [17]. The third is a different crystal cut, for example X-cut Quartz, leading to expansion and contraction along the thickness direction [18]. This combination, driven by voltages from the controller, supports localised movement of the source in all directions.

The reflector [19] is part of the wall of the cavity, or an inserted element. It supports standing wave nodes well known in the prior art, that are comprised of stationary low-pressure points that act so material converges towards them.

In contrast, motion of the platform creates moving low pressure points. Hence through these nodal modes, the sample gets a wider spectrum of agitation. Also high powers that denature the sample are avoided.

Figure 3 is a schematic of a region sourcing liquid flow for distribution across nodes.

This setup uses two electrodes [11] in a partially conductive fluid medium [21] containing a dispersion of molecular elements [22] whose joining line [20] is perpendicular to flow. For this mechanism to operate, two conditions must be met. First, a small flow of ions between the electrodes must be present. Second, the line through the electrode pair must sit in a magnetised region [23], which is easily achieved with a proximal NdFeB magnet or similar.

This electrical geometry deviates the ion trajectory, leading to coherent Lorentz forces, that create flow [24], supplementing the character acoustic wave.

Figure 4 show examples of nodal spin modes that can be induced in the sample. These patterns, in some cases are similar to the familar Lissajous figures viewable on oscilloscopes. They relate to a wide spectrum of movement. Agitation ranges from a circular fundamental mode [25], to the frustrated vortices of higher order modes [26,27].

Samples that will benefit include mixed material phases, often biologically derived. These may have several layers of differing mechanical properties, such as porosity, hydrophilicity, and texture. Pores may be variable in width extent and connectivity. There may be particulate phases of random shape, size distribution, that are anisotropic and non-linear in constitution.

The consistency of the agitation effect, and reduction of any noise, is maintained by feedback from the controller. This is either by phase adjustment of the source transducer motion, or phase adjustment of the active surface of the reflector.

To produce nodal spin modes of choice, corresponding sinusoidal voltages are applied to the composite launch transducer. This moves the beam and the nodes in unison. The frequency of the launch transducer motion is preferred to be lower than the acoustic standing wave frequency. In practical terms, the spin mode will need an empirical optimisation step.

The overarching benefit is that the agitation is progressive, and active over the whole volume on a microscopic scale.

Figure 5 is an example of a cylindrical cavity from above [28] showing stronger agitation of the sample. It combines two or more acoustic beams (three are shown in this example) from multiple sources [29] and reflectors [30] to form a nodal array [31].

Here the beam paths [32] overlap to reduce the size of the node, which enhances the strength of the nodal spin modes. This action will hold a portion of the sample suspended in the nodal array.

Here, the larger components will be held in place, whereas smaller molecules will be free to move, according to their local diffusivity and the magnetic force applied.

The benefit is that raising the frequency of the beams will anchor in place different fractions of the sample. This in turn, alters the agitation action. Other variables that can be optimised include respective beam angles, beam numbers, and power levels.

Position control and the magnetic forces also work together. Here the magnetic forces drive the smaller components not anchored in the acoustic field, through the held fraction of the sample. Ultimately, this combination strategically applies forces to achieve the optimum sample miscibility, avoiding brute force agitation and expediting the process.

Figure 6 shows a range of cavities for holding the sample, transducer reflector components, electrode pair and magnetic field source .

The cavity helps to support concentrated acoustic wave energy. The spherical [33] , cylindrical [34] or hexagonal cavities (shown from above) [35] are preferred, although cubical cavities [36] and others with opposing faces exist. Optimum coupling prefers plane and parallel surfaces. Also dense construction materials such as steel are preferred. Refinements for cavity mounting transducers, tuning reflectors and producing standing waves are well established in the prior-art.

For magnetic stirring, the cylindrical shape is preferred. The permanent magnet can be positioned on one, or both of the circular faces. The mounting of electrodes, is preferably along the central axis and inner surface of the cylinder, so the resulting electric field is perpendicular to the magnetic pole.

For practical operation, sample inlets and outlets will be positioned and adapted according to the application. In some instances a sample will be injected and processed for a period of time. In others, an external pump may replace or augment magnetic stirring. The net result may a portable device. These devices could be connected in series or parallel, as part of a larger batch or continuous industrial process .

Figure 7 is a wiring schematic of the controller and electronic waveform synthesiser which generates AC and DC signals to drive components related to the acoustic and magnetic sources (positions are arbitrary).

Controlling the acoustic nodes relies on generating three categories of controller output [37]. First is the piezoelectric material layer source [12] for creating the beam. This is fed a sinusoidal voltage where amplitude, frequency and phase can be controlled. Second is XYZ platform transducer [13] for beam positioning. This device receives three outputs of amplitude, frequency and phase. Third is the reflector [19], whose surface has a grid of periodic electrodes [38], that receive a voltage array output from the controller. This allows the reflector shape to be adaptive so wavefront distortions can be corrected. The feedback to the controller input [39] is from an array of pressure sensors [40] positioned in the acoustic field, adjacent or attached to the inner surface of the cavity. To control the acoustic field, an algorithm [41] processes this data. It 'writes' corrections back to the controller output [37], to reduce noise i.e. unwanted distortions in the node positions. This feedback is overlaid with manual settings such as the frequency or power of the acoustic compression field.

In contrast, controlling the magnet stirrer is much simpler. A manually set voltage is proportional to the magnetic force and stirring velocity. Therefore the controller simply feeds this voltage to the electrode pair. However, this is a limited voltage in order to avoid electrolysis.

This invention provides high reproducibility, very low risk of contamination, tempered shear forces, minimises denaturation, and no localised heating. The process is efficient, scalable and uniform.

It is applicable to microfluidic processes handling heterogeneous fluids, where good mixing, limited shear and sterile conditions are required. This is important for sensitive fluids containing e.g. liposomes and for cell processing. Further the approach offers unique and custom made mixing patterns, which may offer new process opportunities .

Patent Citations 1. Lauer, Carl G., and Barbara Alving. Plasminogen Activating Factor, Ultrasound. Google Patents, 1995. https://www.google.com/patents/US5399158. 2. Rosenschein, Uri. Ablation of Blood Thrombi by Means of Acoustic Energy. Google Patents, 1996. https://www.google.com/patents/US5524620. 3. Klinman, Dennis M., Ae-Kyung Yi, Serge L. Beaucage, Jacqueline Conover, and Arthur M. Krieg. "CpG Motifs Present in Bacteria DNA Rapidly Induce Lymphocytes to Secrete Interleukin 6, Interleukin 12, and Interferon Gamma." Proceedings of the National Academy of Sciences 93, no. 7 (1996): 2879-83. 4. Miles, Robin R., Phillip Belgrader, and Shanavaz L. Nasarabadi. Container with Cavity for Retaining Spore or Cell Sample in Ultrasonic Transmission Medium, Membrane Cover with Piezoelectric Material Attached, and Means for Membrane to Flex and Vibrate Causing Ultrasonic Excitation of Medium. Google Patents, 2000. https://www.google.com/patents/US6100084. 5. Chu, Wei-Sing. Fixing Tissue Samples Using Ultrasound Radiation at a Frequency of at Least lOOkhz, Produced by a Ultrasound Transducer; Accurate and Optimum Fixation without over Fixing or Tissue Damage. Google Patents, 2001. https://www.google.com/patents/US6291180. 6. Alexandrov, Andrei V., Jaroslaw A. Aronowski, and Anne W. Wojner. Therapeutic Methods and Apparatus for Use of Sonication to Enhance Perfusion of Tissue. Google Patents, 2004. https://www.google.com/patents/US6733450. 7. Desilets, Charles S., and Jens U. Quistgaard. Vortex Transducer. Google Patents, 2007. https://www.google.com/patents/US7273459. 8. Warner, Cynthia L., Cynthia J. Bruckner-Lea, Jay W. Grate, Timothy Straub, Gerald J. Posakony, Nancy Valentine, Richard Ozanich, Leonard J. Bond, Melissa M. Matzke, and Brian Dockendorff. "A Flow-Through Ultrasonic Lysis Module for the Disruption of Bacterial Spores." Journal of the Association for Laboratory Automation 14, no. 5 (October 2009): 277-84. doi:10.1016/j.jala.2009.04.007. 9. Kim, Sung-Chun. Method and Apparatus for Producing Cells and Fat Soluble Materials by Cell Culture. Google Patents, 2011. https://www.google.com/patents/US20130309757. 10. Rybyanets, Andrey. Single Element Ultrasound Transducer with Multiple Driving Circuits. Google Patents, 2013. https://www.google.com/patents/US8568339.

Claims (16)

1. Claims 1) A processor using multiple fields to agitate a sample comprising; a piezoelectric material layer source; a platform to displace a specific beam trajectory; an acoustic cavity arranged to reflect the acoustic beam(s) and support positionable nodes; a sensor arranged to probe the acoustic wavefront, an electrode pair and magnet, arranged to create flow.
2. 2) A processor in accordance with claim 1 where different nodal spin modes, from a circular fundamental to frustrated higher order agitation modes, optimise the nodal processing action.
3. 3) A processor in accordance with claims 1 and 2 that uses any combination of nodal spin modes, nodal convergence, and general compression and expansion from wave energy.
4. 4) A processor in accordance with claims 1-3 that uses multiple beams to define a physical treatment volume, composed of an array of positionable nodes.
5. 5) A processor in accordance with claims 1-4, that controls average nodal position using feedback from measured wavefront pressure, to calculate transducer displacements and phase of the reflector surface .
6. 6) A processor in accordance with claims 1-5 that adds a continuous flow solid-state pump driven by field-based Lorentz forces.
7. 7) A processor in accordance with claim 1 that uses the inner cavity volume, shape and topology to enhance acoustic resonance and treatment performance.
8. 8) A processor in accordance with claim 1, that 'writes' nodes to spatial coordinates in order to reproduce the flow characteristics of different agitator geometries.
9. 9) A processor in accordance with claims 1-8 that creates vortical flow.
10. 10) A processor in accordance with claims 1-9, that preferentially modulates (pulse included) the source, and/or platform transducer and/or magnetic forces.
11. 11) A processor in accordance with claims 1-10 that uses optimised processor settings for low shear mixing including variables such as source transducer power, nodal spin mode, nodal density, nodal displacement, wave compression and Lorentz flow forces.
12. 12) A non-invasive processor in accordance with claims 1-11 that houses a disposable vessel for sterile physical treatments.
13. 13) A processor in accordance with claims 1-12 for cell processing, tissue engineering, and related bioprocess applications.
14. 14) A processor in accordance with claims 1-12, tailored to extracting both biological and chemical analytes (e.g. nucleic acids, proteins, toxins, cellular fragments) from environmental and clinical samples (e.g. blood, sputum, saliva, stool, soil, vegetation, aqueous media) for diagnostic and analytical applications .
15. 15) A processor in accordance with claims 1-12 tailored to mixing and extraction operations in chemical processing applications (including fine chemicals, pharmaceuticals, biopharmaceuticals, plastics and renewable materials).
16. 16) A processor in accordance with claims 1-15 tailored to macro, micro and nano processing based on chosen operating frequencies and other force field variables.