Patent Description:
Serial femtosecond crystallography (SFX) known from the prior art uses intense and short pulses of X-rays from a free-electron laser to record many snapshot diffraction patterns of particles, in particular protein crystals, that flow across the X-ray beam generated by an X-ray source. Serial femtosecond crystallography was developed primarily to overcome the issue of radiation damage that may occur in conventional particle crystallography using X-ray tubes or synchrotron radiation, for example. The exposure to the X-ray beam modifies the structure under investigation, requiring a relatively large structure size of the particles, in particular large crystals, which are often difficult to grow, and cryogenic temperatures, which may also modify the structure from the physiologically relevant one. The short pulses of the X-ray free-electron laser (XFELs) are detected and the resulting structural information gained before destruction of the particle under X-ray exposure takes place, allowing much greater exposures, and hence much smaller particles which do not need to be cryogenically cooled. However, the particle is completely vaporized after the X-ray exposure, so measurements must be carried out repeatedly, each time with a fresh particle. One way to accomplish that is to flow a slurry comprising many distributed particles in a liquid jet across the X-ray beam. However, the duty cycle of the X-ray pulses is low when comparing the duration of pulses to the duration between pulses. Therefore, to increase the chance of the X-ray pulses intercept the randomly arriving particles at the interaction region, a high concentration of particles must be injected, resulting in a low sample delivery efficiency (the fraction of injected particle intercepted by the X-ray pulses). In the contrary, a high concentration of particles distributed in the fluid often leads to clogging of the capillary used to deliver the particles into the X-ray beam. In practice, a low concentration of samples must be injected, resulting a low hit fraction (the fraction of X-ray intercepting a particle). Therefore, measurements must be carried out over a longer period of time to collect enough diffraction patterns from particles.

<CIT> discloses a generic device of the kind described in the preamble of claim <NUM>. <CIT> also refers to a microfluidic device, in particular for acoustic particle separation. <CIT> and <CIT> refer to microfluidic systems for acoustic flow cytometry.

<NPL>, relates to improvement of nanoparticle injection to overcome longitudinal and transversal mismath of particle-stream and x-ray-beam size in single-particle/single-molecule imaging at x-ray free-electron lasers.

The object of the present invention is to provide a device and a system, which allow an efficient examination of particles distributed in a fluid by radiation, in particular X-ray radiation.

According to a first aspect of the present invention, the object is solved by a device according to claim <NUM>. The device comprises a body, being formed as a chip, from a body material being a chip material, a fluid channel extending through the body, an acoustic wave guide embedded in the body, and an acoustic wave condenser embedded in the body. The fluid channel forms a fluid path through the body, such that the fluid channel is configured to guide a flow of a sample fluid, in which sample particles are distributed, through the fluid channel along the fluid path. The wave guide is configured to guide an acoustic reference wave, when transmitted via the body to the wave guide, to an application region of the fluid channel. The wave condenser at least partly forms the application region of the fluid channel. Further, the wave condenser is configured to generate a standing acoustic wave in the application region from the reference wave when the wave guide guides the reference wave into the application region resulting in an acoustic force field in the application region, which pushes sample particles when entering the application region into at least one bunch of sample particles in the application region.

The device offers the advantage that particles distributed in a fluid and carried by a fluid flow through the fluid channel of the device can be concentrated by means of the device into a bunch within the application area. A plurality of particles is arranged in the bunch, such that the concentration of particles within this bunch is significantly higher than the concentration of particles within the fluid upstream of the application area. After the bunch of particles is generated by means of the device, the bunch may be transported downstream with the flow of the fluid to be subsequently examined by means of X-rays. However, it is also possible that the bunch of particles generated in the application area of the fluid channel of the device is examined by means of the X-rays. In this case, the X-rays also penetrate the device.

The particles are preferably formed by crystals, in particular protein crystals, or cells.

Due to the increased concentration of the particles in the bunch by means of the device, a particularly high efficiency in the examination of the particles by means of X-rays is possible. If the X-rays are directed at the application area itself or at an area downstream of the application area rather than at a section of the fluid channel upstream of the application area, and if it is also ensured that the X-rays are directed at the bunch of particles generated by means of the device, then there is a significantly higher probability that the X-rays will encounter at least one of the particles in the bunch. The interaction with the particles modifies the X-radiation so that the resulting modified X-radiation is detectable by means of a detector. Based on the measured, modified X-ray radiation, information about the structural configuration of the particles can be obtained.

To achieve the bunching of the particles in the application area, the device comprises a body, wherein the fluid channel of the device extends through the body. The fluid channel thus serves to carry a fluid, which is also referred to as a sample fluid. Within the fluid, the particles are distributed. The particles may also be referred to as sample particles. The fluid channel forms a fluid path through the body, such that the fluid channel guides the fluid in a transport direction along the fluid path. An initial concentration of sample particles distributed in the sample fluid may exist at an inlet end of the fluid channel, where the sample fluid is introduced into the fluid channel. Preferably, the fluid channel extends from the inlet end to an outlet end. The application region of the fluid channel may be provided between these two ends. Thus, the application region of the fluid channel may be defined by a portion of the fluid channel disposed between the inlet-side end of the fluid channel and the outlet-side end of the fluid channel.

The application region of the fluid channel is at least partially formed by the wave condenser of the device. For example, in the application region of the fluid channel, a channel wall of the fluid channel may be completely or partially formed by the wave condenser. The wave condenser is configured to generate a standing acoustic wave in the application region based on a reference wave when said reference wave enters the application region of the fluid channel. By the wave condenser, the application area of the fluid channel may be shaped, for example, such that a maximum diameter of the application region of the fluid channel corresponds to half the wavelength of the reference wave, so that when the reference wave enters the application region, it is reflected from opposite inner sides of the application region of the fluid channel, thereby creating the standing acoustic wave. Thus, the wave condenser may be configured and/or formed to localize the acoustic force field in the application region. The acoustic force field may be an acoustic pressure field or may be a result of the acoustic pressure field. The standing acoustic wave causes an acoustic force field within the application area, which acts on the particles transported by the fluid into the application area, causing the particles to be compressed and/or concentrated into a bunch within the application area.

The particles distributed in the sample fluid will move in the presence of an acoustic force field when the acoustic properties of particles and sample fluid are different, which is preferably assumed. Such a difference may relate to an acoustic contrast factor, density of the particles and the fluid, compressibility of the particles and fluid, as well as sound speed of the particles and the fluid. The magnitude of the acoustic force of the acoustic force field on particles depends on several factors such as particle size, acoustic energy density, acoustic wave frequency, and acoustic contrast factor. The direction of movement of the particles in an acoustic field may depend on the acoustic contrast factor so that particles may move from a region of high to low or low to high pressure, but in either case, a concentration of the particles will take place. The high- and low-pressure regions are effectively produced by the acoustic standing wave. Preferably, a primary axial (PA) acoustic radiation force of the standing acoustic wave moves particles in the application region to the nodal plane of the standing acoustic wave. It can be for example used for lining up the particles to the middle of the application region of the fluid channel. A gradient of the acoustic force field from high pressure antinodes to the low-pressure nodes may also generate a primary lateral (PL) acoustic radiation force for the bunching of the particles within the application region of the fluid channel. The primary lateral (PL) acoustic radiation force may also cause a tapping of the particles, such that the particles can be held against the flow of the fluid in the application area. The wave condenser may be configured to create localized acoustic pressure zone with a high-pressure gradient. In the high-pressure gradient, the PL acoustic radiation force may hold particles within the application region against drag force of the fluid flow in transport direction and/or the PA acoustic radiation force may push particles to the middle of the channel, which supports and/or causes the particle bunching.

The wave condenser may form a resonance cavity for the acoustic reference wave in the application of the fluid channel. This resonance cavity may localize the acoustic force field in the application region. The wave condenser may be coupled to wave guide in the boundary of the fluid channel.

It has been found to be challenging to direct the acoustic reference wave into the application region. Therefore, in addition to the wave condenser, the device includes a wave guide configured to guide the acoustic reference wave. The wave guide and the wave condenser are both embedded in the body of the device, respectively. Further, the wave guide is preferably embedded in the body of the device such that when the acoustic reference wave encounters the body of the device, it is at least partially captured by the wave guide and directed into the application region of the fluid channel. Therefore, in order to generate the standing acoustic wave in the application region of the fluid channel, the wave guide and the wave condenser cooperate. In particular, due to the energetic effect of this interaction, the desired acoustic wave can be generated by means of the device in the application region with an intensity that allows the particles to be concentrated by means of the resulting acoustic force field.

In principle, the wave guide can be designed in very different ways. For example, the wave guide may be single-piece or multi-piece. The wave guide may also be formed as an integral part of the body of the device. In this case, the wave guide may be formed by one or more portions of the body of the device. It had been found to be advantageous if the wave guide forms at least two mutually spaced edges at which the acoustic reference wave is at least partially reflected. The edges are not necessarily formed by physical structural edges. The at least two mutually spaced edges may be disposed within the body of the device such that they guide the acoustic reference wave to the fluid channel application region. Each of the edges may be formed by a transition from one material to another material. Additionally or alternatively, each of the edges may be formed by a junction of an acoustic impedance within the body of the device. Each edge may therefore be created by a cavity within the body of the device.

The wave guide may be configured to cause a higher acoustic intensity to the application region. As a result, the acoustic reference wave can be generated by normal size transducers instead of small ones to transfer the acoustic power of a large area to small area in microfluidic chip. The small (micron) size transducers have challenges in fabrication, soldering, and implementation in microfluidic device for such application The power of the small size acoustic transducer may be deliberately concentrated by the wave guide to the application region of the fluid channel instead of attenuating it because of actuating the entire body or device.

The body of the device is formed as a chip. The body material of the body is chip material. The chip may be a glass chip. However, the chip may also be formed at least partly by different material.

The fluid channel is formed by the body. The fluid channel may be formed as an integral part of the body. This integration may prevent further acoustic impedance step or acoustic impedance mismatch in the transition from the body to the fluid channel. The wave condenser forms at least part of the application region of the fluid channel. It is therefore preferred that the wave condenser is also formed as an integral part of the body of the device. In other words, the wave condenser is formed by the body of the device. It is also possible that the body of the device is formed in one piece. In this case, it is preferred that both the fluid channel and the condenser are integrally formed by the body of the device. The wave guide is formed by the body. Preferably, the wave guide is an integral part of the body of the device. The integral design of the wave guide allows particularly precise guiding of the acoustic reference wave into the application region of the fluid channel.

Additionally, the wave guide is formed by at least one cavity in the body. Preferably, the wave guide is formed by at least two cavities in the body of the device. Preferably, the wave guide is formed by exactly two separated cavities in the body. With at least two cavities, the cavities may be spaced apart such that the wave guide is formed to direct the acoustic reference wave in the region of the body between the cavities to the application region of the fluid channel. Each cavity may be formed as a closed cavity. Each cavity may create a reflective boundary for the acoustic reference wave. Preferably, each cavity has an acoustic impedance different to the acoustic impedance of the body material of the body. Due to the different acoustic impedance, the acoustic reference wave can be reflected at each of the cavities, and thus be guided into the application area of the fluid channel.

According to a further preferred embodiment of the device, each cavity is a gas filled cavity or a vacuum cavity. Preferably, each cavity of the wave guide is filled with air. Air is considered an embodiment of the broad term gas. The body material of the body of the device is preferably not gaseous, but preferably of a solid material. Therefore, the body of solid material may have the at least one resting cavity placed in it. The wave guide formed by the at least one cavity can be arranged in a particularly compact manner in the body of the device. Thus, a particularly compact device can be achieved.

According to a further preferred embodiment of the device, the wave guide is formed by at least two cavities and a guiding section, which is formed by body material of the body, wherein the guiding section is arranged in between the cavities and configured to transmit the acoustic reference wave into the application region. As an effect, the acoustic wave will be reflected on each transition from body material to air, so that the acoustic wave remains in the guiding section formed by body material until it reaches the application region of the fluid channel. An acoustic reference wave entering the body material of the body of the device may thus be guided to the fluid channel application area with little attenuation loss. Preferably, a width of the guiding section is larger than the wavelength of the acoustic reference wave, such that the acoustic reference wave can be transmitted by the guiding section.

The wave guide may be configured, in particular by means of the at least two cavities and body material in between, to operate according to the principle of reflection and transmission of the acoustic wave. The cavities may each create a reflective boundary due to the difference between the acoustic impedance of the body material and the cavity. Such boundaries may reflect the acoustic reference wave and guide it to the application region of the fluid channel. The thickness of the guiding section between the cavities may be adjusted so that the acoustic reference wave can be transmitted.

According to a further preferred embodiment of the device, the guiding section comprises a conical shape tapering in direction of the application region of the fluid channel. This allows the intensity of the acoustic reference wave in the application area to be particularly high. Preferably, a diameter of the guiding section or a distance between the cavities is tapering in direction of the application region. The conical or tapered shape allows the acoustic reference wave to be collected from a wide area and directed into the application area in a concentrated manner. Thus, the conical shape of the guiding section may be formed to direct the acoustic wave into the application region. Preferably, the guiding section is formed as a guiding horn, in particular a micro-horn. Preferably, the guiding section is configured to collect the acoustic reference wave when entering the body or the body material of the body.

The wave guide and/or the wave condenser may be integrally formed in the body by femtosecond laser induced chemical etching (FLICE) or two-photon polymerization (2PP).

The ability of the FLICE techniques in creating complicated 3D structures in glass allows fabrication of the wave guide as 3D wave guide or the wave condenser as 3D wave condenser. Such an acoustic wave guide may be configured to guide the acoustic reference wave in any 3D directions towards the application region of the fluid channel.

Furthermore, the wave guide may be configured to guide the acoustic reference wave along a predefined path in the body of the device. The predefined path may be linear, curved or along a predefined arbitrary shaped trajectory. Thus, the acoustic reference wave entering the body material of the body may be guided in curved path by the wave guide to the application region of the fluid channel.

According to a preferred embodiment of the device, the wave guide may be formed as multifunctional microstructures. This may be achieved by structural modifications inside the wave guide, preferably without deteriorating the travelling guiding ability of the acoustic reference wave. This may introduce different energy domains. In an example, the wave guide may comprise narrow fluid channels inside (preferably formed via FLICE or 2PP techniques), wherein the inside channels allow introduction of further fluid to the application region. This further fluid could be of interest for applications such as drug delivery or cancer therapy investigations. It is also possible to integrate optical sub-wave guides inside the wave guide of the device. The sub-wave guides may be created by FLICE technique.

According to a further preferred embodiment of the device, the wave condenser is formed by at least one concave-shaped wall section of a channel wall for the fluid channel, wherein the at least one wall section at least partly forms the application region of the fluid channel. Each concave-shaped wall section increases the width of the fluid channel. The concave-shape of the wave condenser may support the technical effect of localizing the standing acoustic wave in the application region of the fluid channel. Each concave-shaped wall section is preferably configured to reflect at least a part of the acoustic reference wave entering the application region. Each concave-shaped wall section has an acoustical impedance to reflect the acoustic reference wave. Thus, the acoustic reference wave guided to the wave condenser via the wave guide may be at least partly transmitted through the channel wall into the application region of the fluid channel, where the transmitted acoustic reference wave is at least partly reflected on the inside surface of the concave-shaped wall section resulting in the standing acoustic wave. As a result, the wave condenser is preferably configured to localize the acoustic force field in the application region of the fluid channel. In an example, each concave-shaped wall section may be formed as a bowl. Each concave-shaped wall section may be of micro-size. At least two concave-shaped wall sections may be arranged opposite each other in the radial direction of the fluid channel, in particular in the application region of the fluid channel. The body material of the body of the device surrounding the wave condenser may be configured not to resonate with the acoustic reference wave.

According to a further preferred embodiment of the device, at least one edge is formed in a transition area from a linear wall section of the channel wall to the at least one concave-shaped wall section of the channel wall. Preferably, an edge is formed at each transition from a linear section of the channel wall to a concave shaped wall section of the channel wall. Each, concave shaped wall section projects outwardly rather than inwardly into the fluid channel such that the application region of the fluid channel is enlarged by each concave shaped wall section of the channel wall. Preferably, the fluid channel is formed upstream from the application region by a linear wall section of the channel wall. This linear wall section may be circular-cylindrical. Furthermore, it is preferably provided that the fluid channel downstream from the application region is formed by a further linear wall section of the channel wall. This linear wall section may also be circularly cylindrical. Each edge may cause a streaming in the application region of the fluid channel. The streaming may also refer to as circular streaming or spiral streaming. The streaming may be formed by fluid in the application region set into circulatory motion by the edge. As a result, the fluid may circulate in within the application region right next to the edge. The streams and/or the circulating fluid may cause (further) force pushing particles entering the application region towards the center of the application region. This further supports the bunching of the particles. As a result, both, the streaming and the standing acoustic wave support and/or cause the bunching of particles in the application region.

According to a further preferred embodiment of the device, the wave condenser is formed by two opposite arranged wall sections of the channel wall or a single ring-shaped wall section of the channel wall. For example, the wave condenser may be formed by two opposite arranged concave-shaped wall sections. Each concave-shaped wall section may have the form of a bowl. For example, the ring-shaped wall section can be formed by the radially outer half of a torus.

According to a further preferred embodiment of the device, the application region of the fluid channel is at least partly formed by the wave condenser such that a reference width of the application region perpendicular to a transport direction of the fluid channel matches a half wavelength of the reference wave with a tolerance of less than <NUM>% of the half wavelength of the reference wave. The width of the application region is preferably the maximum width of the channel in the application region. Preferably, the reference width is measured in a direction perpendicular to the transport direction in the application region. When an acoustic reference wave enters the application region of the fluid channel, it is reflected from the opposite inner sides of the wave condenser. To generate the standing acoustic wave, it is advantageous if the reference width between the opposite inner sides of the wave condenser corresponds to half the wavelength of the acoustic reference wave. Often, the acoustic reference wave does not have exactly a single wavelength, but the acoustic reference wave has a predetermined wavelength spectrum. When the wavelength of the acoustic reference wave is referred to, this preferably means an average wavelength of the predetermined wavelength spectrum. Against this background, a standing acoustic wave can be achieved within the application region even if the reference width of the application region or the wave condenser does not exactly correspond to half the wavelength of the acoustic reference wave, but has a certain deviation. This deviation is preferably called tolerance and is preferably smaller than <NUM>% or <NUM>% of the half wavelength of the acoustic reference wave.

According to a further preferred embodiment of the device, the body is a monolithic body. Preferably, the body is made as a single piece. This allows a particularly compact design of the device.

According to a further preferred embodiment of the device, the body material of the body is based on glass, silicon, metal, diamond, sapphire or plastic. Preferably, the body material is glass, silicon, metal, diamond, sapphire, ceramic or plastic.

According to a second aspect of the invention, the problem mentioned at the introduction is solved by a system comprising the features of claim <NUM>. The system comprises a first wave generator, which is configured to generate a first acoustic reference wave, a fluid pump for generating a flow of sample fluid, and a first device. The first device is formed by a device according to the first aspect of the invention and/or one of the related preferred embodiments. The advantageous explanations, preferred features, technical effects and/or advantages as explained in connection with the first aspect of the device and/or the related preferred embodiments are referred to in an analogous manner for the first device of the system. Furthermore, the fluid pump of the system is directly or indirectly coupled to the fluid channel of the first device for pumping the sample fluid through the fluid channel of the first device. The first wave generator is directly or indirectly coupled to the first device such that the first acoustic reference wave, generated by the first wave generator, is transmitted to the wave guide of the first device.

Preferably, the wave generator is connected to the body of the first device such that the first acoustic reference wave generated by the first wave generator is transmitted to the body material of the body of the first device. For transmitting the first acoustic reference wave from the first wave generator to the body material of the body, alternatively, another transmission element may be used that is arranged between the first wave generator and the body of the first device. In this case, the first wave generator is indirectly coupled to the first device. Nevertheless, a transmission of the first acoustic reference wave from the first wave generator to the body of the first device takes place.

According to a preferred example, the first wave generator is configured to generate an acoustic reference wave with a reference frequency of more than <NUM>,<NUM>. Thus, the equivalent half wavelength of the acoustic reference wave is preferably less than <NUM> micrometers. However, the acoustic reference wave is not limited to the aforementioned frequency. In practice, the frequency of the acoustic reference wave may depend on the particular design of the device for the application. In particular, a higher frequency for the acoustic reference wave can be advantageous if particularly small particles, for example sub-micron particles, are to be examined.

Particles may be distributed in an initial concentration in the fluid that is pumped in by the fluid pump at an inlet end of the fluid channel. The pump causes a fluid flow of the fluid through the fluid channel, which transports the particles carried by the fluid into the application region. Particles entering the application region are exposed to the standing acoustic wave and the resulting force field, creating the bunch of particles within the application region. The standing wave is caused by the acoustic reference wave. Initially, the reference acoustic wave is generated by the first wave generator, then transmitted to the body of the first device and guided within the body by the wave guide to the application region. Within the application region, the acoustic reference wave is converted into the acoustic standing wave by the wave condenser.

By regularly switching on and off the first wave generator, a sequence of bunches of particles can be generated, which leave the application region one after the other and are further transported by the fluid flow in the transport direction downstream along the fluid channel.

The bunches of particles generated in the application region can subsequently be exposed to radiation to examine the structural composition of the particles. Due to the high concentration of particles within the bunch, these examinations can be carried out particularly efficiently.

According to a preferred embodiment of the system, the system comprises a second device. The second device is formed by another device according to the first aspect of the invention and/or one of the related preferred embodiments. The advantageous explanations, preferred features, technical effects and/or advantages as explained in connection with the first aspect of the device and/or the related preferred embodiments are referred to in an analogous manner for the second device of the system. Alternatively or additionally, the second device may be configured analogously to the first device. The fluid channel of the first device and the fluid channel of the second device are connected in series, such that the fluid channel of the second device is downstream to the fluid channel of the first device.

The first device and the second device may be formed in an integral manner, so that the two devices are formed as a single device. This single-piece device may thus be formed in a first section by the first device and in a further, second section by the second device.

However, it is also possible, that the first device and the second device are each formed as separate devices. Preferably, the two devices are connected in series such that the fluid channel of the first device and the fluid channel of the second device each form part of an uninterrupted fluid channel. In particular, it is possible for the second device to be coupled directly downstream of the first device such that the uninterrupted fluid channel is formed exclusively by the fluid channel of the first device and the fluid channel of the second device. However, it is also possible that another device is arranged between the two devices with an associated fluid channel connecting the two fluid channels of the first and second devices.

As a result of the direct or indirect series connection of the fluid channels of the first and second devices, the system comprises at least two application regions located along the common channel (that is, in series) so as to successively improve the bunching. This might be of advantage at high flow rates and high bunching rates when there might not be enough time during one cycle to create a narrow bunch. The application regions could be located in a single integrated body forming both devices, or each in its own device (first and second device, respectively) with the fluid channels connected by capillaries, for example. The spacing of the application regions may be determined by the flow speed and the bunching period. Given that the period may be determined by the application, one would need to set the flow speed to ensure synchronization (that the bunching action in the application region of the fluid channel of the second device occurs when the bunch released form the application region of the fluid channel of the first device arrives).

According to a further preferred embodiment of the system, the system comprises a control unit. The control unit is configured to control the first wave generator such that the first wave generator generates the first reference wave in a first pattern with alternating on-periods and off-periods resulting in a new first bunch of sample particles in the application region of the fluid channel of the first device during each on-period of the first pattern. As a result, a new bunch of particles is created in the application region of the fluid channel of the first device.

As will become apparent from the explanation of one of the following preferred embodiments of the system, a newly created bunch of particles may be exposed to radiation while still within the application region to examine the structural constitution of the particles of the bunch. Alternatively, however, it is also possible for a newly created bunch of particles to be released at the end of the corresponding on-period from the application region resulting in a sequence of bunches carried by the flow of fluid downstream of the application region of the first device. The bunches of particles carried downstream by the fluid may be exposed to radiation downstream to perform the appropriate examination of the particles.

Before the bunches created by the first device are exposed to radiation, it is possible that the particles are further concentrated within the respective bunch. For this purpose, the second device already explained may be used, which can be coupled in series with the first device.

According to a further preferred embodiment of the system, the system comprises a second wave generator, which is configured to generate a second acoustic reference wave. The second wave generator is directly or indirectly coupled to the second device such that the second acoustic reference wave, generated by the second wave generator, is transmitted to the wave guide of the second device. The advantageous explanations, preferred features, technical effects and/or advantages as explained in connection with the first wave generator and the first device and/or the related preferred embodiments are referred to in an analogous manner for the second wave generator and the second device, respectively.

According to a further preferred embodiment of the system, the control unit is configured to control the second wave generator such that the second wave generator generates the second reference wave in a second pattern with alternating on-periods and off-periods. Preferably, the control unit is configured to control the first and second wave generators, such that the second pattern is synchronized with the first pattern and/or such that the particles are further concentrated in the bunches that sequentially enter the application region of the fluid channel of the second device.

According to a further preferred embodiment of the system, the system comprises a radiation generator and a radiation detector. The radiation generator is arranged such that the application region of the fluid channel of the first or second device is exposed to radiation generated by the radiation generator resulting in modified radiation, and wherein the radiation detector is arranged to detect the modified radiation. The radiation preferably refers to X-ray radiation or IR radiation. The radiation may also refer to visible light or to UV light. Similar configurations apply for the generator and the detector. For instance, the radiation generator is preferably configured as an X-ray generator and the radiation detector is preferably configured as an X-ray detector.

As explained in connection with the device, the wave guide of the first and/or second device may be configured to guide the acoustic reference wave along a predefined path in the body of the respective device. The predefined path may be linear, curved or along a predefined arbitrary shaped trajectory. Thus, the acoustic reference wave entering the body material of the body of the respective device may be guided in curved path by the wave guide to the application region of the fluid channel of the respective device. As an effect, the first and/or second wave generator may be arranged at a side region of the body of the respective device, wherein the radiation generator is arranged below the application region of the fluid channel of the respective device and the detector may be arranged above this application region, such that the application region is exposed to the radiation generated by the radiation generator. The preferred arrangement of the radiation generator below the application region and of the radiation detector above the application region offers the advantage that the radiation generated by the radiation generator is directed to the bunch within the application region where the particles within the bunch have the highest concentration. This is especially valid if the radiation generator is located below the application region of the fluid channel of the second device and the radiation detector is located above said application region.

Further features, advantages and application possibilities of the present invention may be derived from the following description of exemplary embodiments and/or the figures.

Furthermore, in the figures, same reference signs may indicate same or similar objects.

<FIG> schematically illustrates a preferred embodiment of the device <NUM>. The device <NUM> is preferably a part of the system <NUM> also schematically shown in <FIG>. The following explanations in connection with the device <NUM> may therefore refer to the system <NUM> with the device <NUM> or to the device <NUM> alone.

The device <NUM> is used to bunch particles <NUM> within an application region <NUM>, such that the bunched particles <NUM> form a bunch <NUM> of particles <NUM>. The bunch <NUM> may also be referred to as the first bunch <NUM>. Bunching the particles <NUM> in a bunch <NUM> provides the advantage that this bunch <NUM> can be exposed to radiation, in particular X-rays, to examine the structural constitution of the particles <NUM> of the bunch <NUM>. Due to the increased concentration of particles <NUM> within the bunch <NUM>, there is a high probability that a large portion of the radiation will be modified upon impingement on the particles <NUM> of the bunch <NUM>, such that the resulting modified radiation represents the information regarding the structural composition of the particles <NUM> of the bunch <NUM>.

To achieve the bunching of particles <NUM>, the device <NUM> includes a body <NUM>, a fluid channel <NUM>, an acoustic wave guide <NUM>, and an acoustic wave condenser <NUM>.

The body <NUM> of the device <NUM> may also be referred to as the base body <NUM>. The body <NUM> may be formed in one part or in multiple parts. Preferably, the body <NUM> is made of glass, silicon, metal, diamond, sapphire, ceramic or plastic. Accordingly, the same applies to the body material <NUM> of the body <NUM>. Where the body <NUM> is formed of multiple parts, the parts may be formed of different materials, preferably each based on a material from the aforementioned selection of materials.

The fluid channel <NUM> of the device <NUM> extends through the body <NUM>, and it can therefore also be referred to that the fluid channel <NUM> is embedded in the body <NUM> of the device <NUM>. It has been found to be particularly advantageous if the fluid channel <NUM> is integrally formed by the body <NUM>. As schematically shown in <FIG>, it may preferably be provided that a channel wall of the fluid channel <NUM> is integrally formed by the body <NUM> and/or the body material <NUM> of the body <NUM>.

The fluid channel <NUM> defines a fluid path <NUM> along which a fluid <NUM> is routed through the fluid channel <NUM> in the transport direction <NUM>. The system <NUM> shown in <FIG> further includes a fluid pump <NUM> indirectly coupled to the fluid channel <NUM> of the device <NUM>. The fluid pump <NUM> is configured to pump the fluid <NUM>, in which the particles <NUM> are distributed, into the fluid channel <NUM> of the device <NUM> at an input end thereof. The fluid <NUM>, which enters the fluid channel <NUM> by means of the pump <NUM>, has an initial concentration of particles <NUM>. In principle, the particles <NUM> distributed in the fluid <NUM> could already be exposed to radiation, in particular X-rays, in a section upstream of the device <NUM> in order to examine the structural composition of the particles <NUM>. However, this gives rise to the disadvantages mentioned in the introduction, such as low efficiency. Obtaining knowledge about the structural composition of the particles <NUM> can be made much more efficient by means of radiation if the particles <NUM> are arranged in a higher concentration, as in the bunch <NUM> of particles <NUM>.

Therefore, the device <NUM> is based on the idea of significantly increasing the concentration of particles <NUM> in the fluid <NUM> in an application region <NUM> within the device <NUM> to create bunches <NUM> of particles <NUM> in the fluid <NUM>, such that more efficient investigation of the structural composition of the particles <NUM> is enabled. To achieve the increased concentration of particles <NUM> in a bunch <NUM>, the device <NUM> includes the acoustic wave guide <NUM> and the acoustic wave condenser <NUM>.

The acoustic wave guide <NUM> may also be referred to as the wave guide <NUM>. The acoustic wave guide <NUM> is configured to direct an acoustic reference wave within the body <NUM>, which acoustic reference wave is preferably generated by the first wave generator <NUM> of the system <NUM>. For this purpose, the wave generator <NUM> may be directly or indirectly connected to the body <NUM> such that the reference acoustic wave generated by the wave generator <NUM> is transported by the body material <NUM> of the body <NUM>. The wave guide <NUM> directs the reference acoustic wave within the body <NUM> to the application region <NUM> of the fluid channel <NUM>, such that the reference acoustic wave enters the application region <NUM> of the fluid channel <NUM>.

It had been found to be particularly advantageous if the wave guide <NUM> is integrated into the body <NUM> and/or formed by the body <NUM>. As can be seen schematically from <FIG>, it is preferably provided that the wave guide <NUM> comprises, for example, two cavities <NUM> within the body <NUM>. Preferably, the two cavities <NUM> of the wave guide <NUM> are spaced apart from each other such that a guiding section <NUM> is formed between the two cavities <NUM>. The guiding section <NUM> may also be referred to as the guide section <NUM>. This guiding section <NUM> may be formed by the body material <NUM> of the body <NUM>. The two cavities <NUM> may each be formed as vacuum cavities <NUM>. However, it is also possible that each cavity <NUM> is filled with a gas, in particular air. At the transition from the body material <NUM> of the body <NUM> to each of the two cavities <NUM>, a step in the acoustic impedance occurs. If the acoustic reference wave is preferably transmitted to the body <NUM> by means of the first wave generator <NUM> of the system <NUM>, the acoustic reference wave is further transmitted by the body material <NUM> of the body <NUM> and/or at least partially reflected at the aforementioned cavities <NUM> due to the step in the acoustic impedance. As a result, the acoustic reference wave is at least partially held in the guiding section <NUM> between the cavities <NUM> and thereby directed into the application region <NUM> of the fluid channel <NUM>. Preferably, the guiding section <NUM> of the wave guide <NUM> is aligned with the application region <NUM> along a direction perpendicular to the transport direction <NUM>.

Preferably, the wave condenser <NUM> of the device <NUM> is formed by the body <NUM> and/or is formed as an integral part of the body <NUM>. As can be seen schematically from <FIG>, the wave condenser <NUM> is formed, for example, by two oppositely disposed concave channel wall sections <NUM> of a channel wall of the fluid channel <NUM>. The channel wall of the fluid channel is preferably integrally formed by the body <NUM>. Thus, each of the two concave channel wall sections <NUM> may also be integrally formed through the body <NUM>. A maximum distance and/or channel diameter between the two oppositely disposed concave channel wall sections <NUM> is also referred to as a reference width <NUM>. The two oppositely disposed concave channel wall sections <NUM> expand the channel diameter in the application region <NUM>. Preferably, the reference width <NUM> is larger than the diameter of the fluid channel <NUM> in a linear wall section <NUM> upstream and/or downstream of the application region <NUM> of the fluid channel <NUM>. Preferably, the wave condenser <NUM> and/or the associated concave channel wall sections <NUM> are formed such that the reference width <NUM> corresponds to a half wavelength of the acoustic reference wave. Preferably, the reference width <NUM> can deviate from half the wavelength of the acoustic reference wave by a maximum of <NUM>% or a maximum of <NUM>%. By having the reference width <NUM> at least substantially equal to half the wavelength of the reference acoustic wave, a standing acoustic wave in the application region <NUM> is generated from the reference acoustic wave by means of the wave condenser <NUM>. This standing acoustic wave in the application region <NUM> causes an acoustic force field in the application region <NUM> that acts on particles <NUM> as they enter the application region <NUM>, pushing and/or concentrating these particles <NUM> into a bunch <NUM> of particles <NUM> within the application region <NUM>. In other words, the wave condenser <NUM> is adapted to cause a standing acoustic wave based on the reference acoustic wave as it enters the application region <NUM>, which in turn causes a force field to push the particles <NUM> together into a bunch <NUM> within the application region <NUM>. The force field also causes the particles <NUM> entering the application region <NUM> to be held in the application region <NUM> against the flow of the fluid <NUM>.

The shape of the acoustic wave condenser <NUM> is preferably configured such that the standing acoustic wave generated in the application region <NUM> remains localized and/or retained in the application region <NUM>. This ensures a particularly effective bunching of the particles <NUM> in the application region <NUM>.

The bunching of the particles <NUM> in the application region <NUM> can be intensified and/or improved by an additional effect. To achieve this effect, an edge <NUM> is preferably formed in at least one transition region from a linear wall section <NUM> of the channel wall to the at least one concave shaped wall section <NUM> of the channel wall. As can be seen schematically from <FIG>, such an edge <NUM> is formed, for example, in the transition region from the linear wall section <NUM> of the channel wall located upstream of the application region <NUM> to each concave shaped wall section <NUM>. When fluid <NUM> flows in the transport direction <NUM> through the fluid channel <NUM> from a region that is upstream of the application region <NUM> into the application region <NUM>, the fluid is directed past each edge <NUM>, resulting in a spiral and/or circular motion of the fluid <NUM> in the application region <NUM> in the transport direction <NUM> immediately downstream of the edge <NUM>. A similar effect may be created at the at least one edge <NUM>, which may be formed in the transition region from the at least one concave-shaped wall section <NUM> to the downstream linear wall section <NUM> of the channel wall. Preferably, each of the aforementioned edges <NUM> may cause a spiral or circular motion of the fluid <NUM> within the application region <NUM>, said motion forcing particles <NUM> into the center of the application region <NUM>. Said movement thus helps to concentrate particles <NUM> into the bunch <NUM> within application region <NUM>. This technical effect may exist superimposed on the bunching effect of particles <NUM> by the standing acoustic wave. Thus, both the spiral or circular motion of the fluid <NUM> within the application region <NUM> and the standing acoustic wave may result in the creation of a bunch <NUM> of particles <NUM> within the application region <NUM>.

A further preferred embodiment of the device <NUM> is schematically shown in <FIG>. As can be seen from <FIG>, it may be provided that the reference width <NUM> in the application region <NUM> is smaller than the average diameter of the fluid channel <NUM> upstream and/or downstream of the application region <NUM>. Preferably, the reference width <NUM> is configured such that an acoustic reference wave, for example generated by the first wave generator <NUM> and transmitted to the body <NUM> of the device <NUM>, results in a standing acoustic wave within the application region <NUM>. For example, the larger or smaller diameter of the fluid channel <NUM> upstream and/or downstream of the application region <NUM> may be adapted to prevent a standing acoustic wave from being generated in these regions of the fluid channel <NUM>, even if a portion of the reference acoustic wave enters one of said regions of the fluid channel <NUM> (downstream and/or upstream of the application region <NUM>).

In the preferred embodiment of the device <NUM>, as exemplified schematically in <FIG>, the body <NUM> of the device <NUM> is formed in multiple parts. The body <NUM> comprises a bottom part <NUM> and a top part <NUM> arranged on the bottom part <NUM>. The fluid channel <NUM> is formed, at least partly, between the bottom part <NUM> and the top part <NUM>. Thus, it is preferably provided that the application region <NUM> of the fluid channel <NUM> is formed exclusively in a region directly between the bottom part <NUM> and the top part <NUM>. The remaining region of the fluid channel <NUM> may, for example, be exclusively integrated and/or embedded in the bottom part <NUM> of the body <NUM>. The material of the top part <NUM> may be different from the material of the bottom part <NUM>. In principle, however, it is also possible that the bottom part <NUM> and the top part <NUM> are formed of the same material. Preferably, the wave guide <NUM> is exclusively embedded and/or integrated in the bottom part <NUM> of the body <NUM>. As a result, the structural design of the top part <NUM> may be particularly simple. For example, the top part <NUM> may be formed by a glass plate. For example, the bottom part <NUM> may be formed of glass, silicone, metal, diamond, sapphire, ceramic or plastic. Preferably, the bottom part <NUM> is formed in one piece. The top part <NUM> may also be formed in one piece. In this case, the body <NUM> consists of exactly two parts.

As can be seen schematically from <FIG>, it is preferred if the wave guide <NUM> has two cavities <NUM> which are arranged at a distance from one another and are each rectangular in cross-section. Each of the two cavities <NUM> may be formed as a closed cavity <NUM>. However, it is also possible that each of the two cavities <NUM> is formed to be open to the surroundings. Preferably, the distance between the two cavities <NUM> is configured such that no standing acoustic wave can be formed between the two cavities <NUM>. Preferably, the distance between the two cavities <NUM> is greater than half the wavelength of the acoustic reference wave or greater than the entire wavelength of the acoustic reference wave.

In <FIG>, the bottom part <NUM> of the device <NUM> of <FIG> is shown schematically.

<FIG> shows a further preferred embodiment of the device <NUM>. This device <NUM> corresponds at least substantially to the device as shown in <FIG>. The associated advantageous explanations, preferred features, effects and/or advantages as explained in connection with <FIG> are therefore referred to in an analogous manner for the device <NUM> of <FIG>.

The device <NUM> of <FIG> differs from the device <NUM> of <FIG> in particular by the geometric shape of the cavities <NUM>. As can be seen from <FIG>, it is preferably provided that the cavities <NUM> are shaped in cross-section such that the guide section <NUM> between the cavities <NUM> is chronically convergent towards the application region <NUM>. In other words, the cross-section of the cavities <NUM> may be shaped such that the guide section <NUM> reduces in size in the direction of the application region <NUM>. Thus, an at least substantially conical shape for the guiding section <NUM> can be achieved. The conical shape of the guiding section <NUM> ensures that the intensity of the acoustic reference wave when it enters the application region <NUM> is particularly high.

As has been previously explained in connection with <FIG>, the device <NUM> may form a part of the system <NUM>, such as is also illustrated in <FIG>. In addition, the system <NUM> preferably includes the pump <NUM> and the first wave generator <NUM>. Preferably, the first wave generator <NUM> is directly connected to the body <NUM> of the device <NUM> such that a reference acoustic wave generated by the first wave generator <NUM> is transmitted directly to the body <NUM> such that the reference acoustic wave propagates within the body material <NUM> of the body <NUM>. When the acoustic reference wave reaches the region of the wave guide <NUM>, at least a portion of this acoustic reference wave is directed into the application region <NUM> by the wave guide <NUM>. The pump <NUM> may be coupled to the fluid channel <NUM> of the device <NUM> by means of a connector <NUM>, such that the pump <NUM> may pump the fluid <NUM> into the fluid channel <NUM> in the transport direction <NUM> via the connector <NUM>. The connector <NUM> may be formed by a hose or a tube, for example. However, it is also possible for the pump <NUM> to be directly coupled to the fluid channel <NUM> of the device (not shown in <FIG>).

It was found to be particularly advantageous if the system <NUM> further comprises a control unit <NUM> configured to control the first wave generator <NUM>. For example, the control unit <NUM> may be configured to control the first wave generator <NUM> such that the first wave generator <NUM> generates the acoustic reference wave in a first pattern of alternating on-periods and off-periods. During each new on-period, a new bunch of particles <NUM> is generated in the application region <NUM> of the fluid channel <NUM> of the device <NUM>. During each subsequent off-period, the generated bunch <NUM> of particles <NUM> is released, captured by the flow of fluid <NUM>, and transported in the transport direction <NUM>.

In addition, it has been found to be particularly advantageous if the system <NUM> further comprises a radiation generator <NUM> and a radiation detector <NUM>. The radiation generator <NUM> is configured to generate radiation. The radiation may be, for example, X-rays or infrared radiation. The radiation may also be visible light or UV light. Accordingly, it is preferred if the radiation generator <NUM> is configured as an X-ray radiation generator <NUM> or an infrared radiation generator <NUM>. In the foregoing embodiment of the system <NUM> as schematically shown in <FIG>, the radiation generator <NUM> is arranged such that the flow of fluid <NUM> arrives downstream to an application area <NUM>, and that the radiation generator <NUM> is arranged such that the application area <NUM> is exposed to radiation generated by the radiation generator <NUM>. When a bunch <NUM> of particles <NUM> enters the application area <NUM>, the radiation generated by the radiation generator <NUM> is modified when it impinges on the particles <NUM> of the bunch <NUM>, thus resulting in modified radiation. Furthermore, the radiation detector <NUM> is preferably arranged such that the radiation detector <NUM> can detect the modified radiation. Thus, the radiation generator <NUM> and the radiation detector <NUM> may be arranged on opposite sides to the application area <NUM>.

As can be seen schematically from <FIG>, it is possible for the application area <NUM> to be arranged outside the fluid channel <NUM> of the device <NUM>. However, it is also possible that the application area <NUM> is formed by a portion of the fluid channel <NUM>. For example, the application area <NUM> may be formed in a section of the fluid channel <NUM> downstream of the application region <NUM>. Further, it is possible that the application area <NUM> is disposed in and/or coincides with the application region <NUM>. In this case, it is possible that the particles <NUM> of a bunch <NUM> generated in the application region <NUM> are exposed to the radiation generated by the radiation generator <NUM>, resulting in the modified radiation that can be detected by the radiation detector <NUM>. In this case, the radiation generator <NUM> and the radiation detector <NUM> may be arranged on opposite outer sides in a direction perpendicular to the transport direction <NUM> in alignment with the application region <NUM>.

Another preliminary embodiment of the system <NUM> is shown schematically in <FIG>. For the system <NUM> of <FIG>, reference is made in an analogous manner to the previous advantageous explanations, preferred features, effects and or advantages as discussed in connection with the system <NUM> of <FIG>. In the embodiment of the system <NUM> of <FIG>, the device <NUM> of the system <NUM> of <FIG> forms the first device <NUM> of the system <NUM>. The system <NUM> of <FIG> further comprises a second device <NUM>. Both devices <NUM>, <NUM> may be at least substantially the same. For each of the two devices <NUM>, <NUM>, reference is therefore made to the advantageous explanations, preferred features, effects and or advantages as previously explained for the device <NUM> in connection with <FIG>.

Preferably, the first device <NUM> and the second device <NUM> are connected in series such that the fluid channel <NUM> of the first device <NUM> is coupled downstream to the fluid channel <NUM> of the second device <NUM>. In principle, however, it is also possible that the fluid channel <NUM> of the first device <NUM> is connected to the fluid channel <NUM> of the second device <NUM> by a (further) connector. This is shown purely by way of example in <FIG>.

However, if the first device <NUM> is directly coupled to the second device <NUM>, a particularly compact design of the system <NUM> can be achieved. A further advantageous embodiment (not shown) is characterized in that the first device <NUM> and the second device <NUM> are at least partially integrally formed with each other or are formed by two portions of a common device.

By arranging the second device <NUM> downstream of the first device <NUM>, the flow of the fluid <NUM> is directed through two application regions <NUM> arranged one behind the other, namely first through the application region <NUM> of the first device <NUM> and then through the application region <NUM> of the second device <NUM>. Therefore, it can also be referred to that the fluid channel <NUM> of the first device <NUM> and the fluid channel <NUM> of the second device <NUM> form a common fluid channel of the system <NUM>. In the application region <NUM> of the first device <NUM>, the particles <NUM> are concentrated into a bunch <NUM>. When this bunch <NUM> of particles <NUM> is released in the out-period and caught by the flow of fluid <NUM>, the fluid <NUM> carries the bunch <NUM> of particles <NUM> into the application region <NUM> of the second device <NUM>. A standing wave is also created in this application region <NUM> of the second device <NUM> during the associated on-period, such that the resulting force field further concentrates the particles <NUM> of the bunch <NUM> when this bunch <NUM> has previously entered the application region <NUM> of the second device <NUM>.

<FIG> further illustrates a preferred arrangement of the radiation generator <NUM> in which the application area <NUM> overlaps with the application region <NUM> of the second device <NUM>, or the application area <NUM> is formed by the application region <NUM> of the second device <NUM>. Therefore, the radiation generator <NUM> is arranged such that the application area <NUM> or the application region <NUM> of the second device <NUM> is exposed to radiation generated by the radiation generator <NUM>. Thus, the bunch <NUM> of particles <NUM> further concentrated by the second device <NUM> is also exposed to the radiation generated by the radiation generator <NUM>, resulting in modified radiation that is detected by the radiation detector <NUM>.

The body <NUM> of the second device <NUM> may include a neck section <NUM>, wherein a second wave generator <NUM> is disposed at the end of the neck section <NUM>. The second wave generator <NUM> may form part of the system <NUM>. The neck section <NUM> may direct the reference acoustic wave generated by the second wave generator <NUM> to the wave guide <NUM> of the second device <NUM>, such that the wave guide <NUM> of the second device <NUM> directs the reference acoustic wave into the application region <NUM> of the fluid channel <NUM> of the second device <NUM>. The wave condenser <NUM> of the second device <NUM> then generates a standing acoustic wave in the application region <NUM> of the second device <NUM> based on the reference acoustic wave. The neck section <NUM> further provides the advantage that the radiation generator <NUM> and the radiation detector <NUM> may be disposed on opposite sides of the application region <NUM> of the second device <NUM>, without the radiation generated by the radiation generator <NUM> being disturbed by the second wave generator <NUM>.

By further concentrating the particles <NUM> of the bunch <NUM> in the application region <NUM> of the second device <NUM>, an even more efficient examination of the structural composition of the particles <NUM> can be performed using the modified radiation detected by the radiation detector <NUM>.

Claim 1:
Device (<NUM>) for bunching sample particles (<NUM>), the device (<NUM>) comprising
a body (<NUM>), being formed as a chip, from a body material (<NUM>) being a chip material,
a fluid channel (<NUM>) extending through the body (<NUM>), wherein the fluid channel (<NUM>) is formed by the body (<NUM>),
an acoustic wave guide (<NUM>) embedded in the body (<NUM>), and
an acoustic wave condenser (<NUM>) embedded in the body (<NUM>),
wherein the fluid channel (<NUM>) forms a fluid path (<NUM>) through the body (<NUM>), such that the fluid channel (<NUM>) is configured to guide a flow of a sample fluid (<NUM>), in which sample particles (<NUM>) are distributed, through the fluid channel (<NUM>) along the fluid path (<NUM>),
wherein the wave guide (<NUM>) is configured to guide an acoustic reference wave, when transmitted via the body (<NUM>) to the wave guide (<NUM>), to an application region (<NUM>) of the fluid channel (<NUM>),
wherein the wave condenser (<NUM>) at least partly forms the application region (<NUM>) of the fluid channel (<NUM>), and
wherein the wave condenser (<NUM>) is configured to generate a standing acoustic wave in the application region (<NUM>) from the reference wave when the wave guide (<NUM>) guides the reference wave into the application region (<NUM>) resulting in an acoustic force field in the application region (<NUM>), which pushes sample particles (<NUM>) when entering the application region (<NUM>) into at least one bunch of sample particles (<NUM>) in the application region (<NUM>);
characterized in that the wave guide (<NUM>) is formed by the body (<NUM>) and at least one cavity (<NUM>) in the body (<NUM>).