Material Characterization Methods

Abstract

The present invention provides a method for determining a characteristic of a target area (15) of a material (10), the target area (15) being within a range of 100 μm 2 ~100mm 2 and the method comprises an exposure step comprising providing a liquid jet (20) to the target area (15), the liquid jet (20) having a jet speed selected from the range of 2 to 150 m / s, a measurement step comprising detecting deformations (16) of the material in the target area (15) and providing a related signal, and an analysis step comprising determining a characteristic of the target area (15) based on the related signal.

Description

[Technical field]

[0001] The present invention relates to a method for determining a property of a target area of ​​a substance The present invention further relates to an injection method for injecting a fluid into a substance The present invention further relates to a system for determining a property of a target area of ​​a substance. [Background technology]

[0002] Methods for measuring material properties are known in the art. For example, US Patent Application Publication No. 2006 / 052719 describes a method for determining the anisotropy of a subject's skin by measuring the propagation speed of mechanical energy between a mechanical energy generator and a mechanical energy detector along multiple directions of skin extension, each of which is separated from at least one other direction by about 0° to about 10°, and at least two of which are separated from each other by about 30° to about 180°.

[0003] French patent application FR 3 006 448 describes an ultrasonic device and method for measuring, inspecting and classifying the mechanical and / or thermal properties of a medium by means of at least one broadband acoustic source coupled to at least one solid guide with elastic waves of known impedance and permeability, acoustically and thermally contained and damped in an insulating structure and coupled to the medium on a defined surface with a controlled support force, said coupling may result from a first coupling of the solid guide to a liquid guide that is continuously radiated with a constant or variable hydrostatic pressure, said liquid also being intermittently heated and radiated in the form of a collimated jet impinging on the surface of the medium.

[0004] WO 2010 / 150154 describes a device for detecting temporal changes in the optical properties of the subcutaneous layer in vivo, and describes a drug delivery device including an arrangement and method for drug delivery. For optimal control of drug delivery by a transdermal drug delivery device, an optical feedback control is described that makes it possible to detect changes in the optical properties of the subcutaneous layer caused by fluid injected from a fluid jet.

[0005] US Patent Application Publication No. 2011 / 319791, "Systems and Methods for Measuring Mechanical Properties of Deformable Materials" (D3), describes systems that use a probe, such as a mechanical device or a gas / liquid jet, to deform the surface of a material and optically record the three-dimensional (3D) topography of the resulting deformation of the surface. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2006 / 052719 [Patent Document 2] French Patent Application Publication No. 3006448 [Patent Document 3] International Publication No. 2010 / 150154 Brochure [Patent Document 4] US Patent Application Publication No. 2011 / 319791 Summary of the Invention [Problem to be solved by the invention]

[0007] The properties of viscoelastic materials such as skin reported in the literature can vary greatly, both due to the many methods used and due to the heterogeneous and / or multi-layered nature of (some) viscoelastic materials such as skin. For example, skin fissures can depend on parameters such as relative humidity, temperature, age, and how the force or load is applied (static or dynamic). The resulting skin critical stress value σ crit can be found in a wide range, from 500 kPa to 20 MPa for static loads. Besides the critical stress, the measurement of other mechanical properties can be strongly influenced by the type of probe used. For example, an indentometer can give different values ​​depending on the size of the indenter and the dynamics of the applied load. In particular, it can be difficult to measure skin properties under realistic conditions, ex vivo or in vivo.

[0008] For example, accurate measurement of skin properties may facilitate needle-free jet injection into the skin, as the needle-free jet injection properties can be adjusted accordingly. This allows a desired dose of drug to be delivered precisely to the desired injection depth. For example, insulin may typically be tailored for delivery within subcutaneous fat with consistent perfusion, but its uptake may be better within the dermis. Similarly, vaccines targeting antigen-presenting cells may be advantageously delivered within the dermis, but it may be difficult to target this thin layer consistently. Similarly, nucleic acid (DNA) or ribonucleic acid (RNA) vaccines produced to treat Covid-19 may benefit from delivery within the dermis.

[0009] In contrast, when jet injection is performed with inappropriate energy settings, such as by inaccurate measurement or assumption of in situ skin properties, the injected liquid may be injected too shallowly or too deeply, i.e., may inadvertently reach unintended skin layers. For example, if the liquid jet is provided with insufficient power, the jet may not penetrate the skin and the unaccepted liquid may splash back, resulting in the delivery of an incorrect dose of medication, risk of contaminating the syringe parts, or accidental contact with the body of the medical professional. Furthermore, if the liquid jet is provided with excessive power, bruising may occur, which may be painful and cosmetically undesirable.

[0010] Furthermore, skin is anisotropic, i.e., the physical properties of skin can vary depending on how it is measured, e.g., locally or on a larger scale. The term "anisotropy" with respect to a material can refer to the material's non-uniform response to a stimulus, i.e., the material responds differently to stimuli in different directions.

[0011] Furthermore, the properties of viscoelastic materials such as skin can be rate dependent, meaning that the material can respond differently depending on the duration and time scale of the stimulus.

[0012] For example, the jet injection may be relatively localized, so it may be desirable to determine relevant skin parameters locally.

[0013] Prior art may describe methods for measuring the properties of a material, such as skin, by statically deforming the material with multiple traction surfaces to determine strain. Contact with the material may cause irreversible deformation, such as bruising or other damage to the skin, and potentially also contamination. Furthermore, the time scale of deformation may not provide a good estimate of material properties at the speed of needleless injection. Furthermore, for skin, such deformation may cause discomfort to the subject.

[0014] The prior art may also describe a method for measuring the properties of a material by vibrating the skin with a mechanical shaker and determining the properties based on the detected surface waves. However, the measurement of the properties may not be done locally, but rather may be averaged over a large portion of the material. This may result in inaccurate local measurements. Also, contact with the material may lead to contamination.

[0015] Prior art methods may also have a relatively low frequency range for skin deformation. However, the determined material properties may not extend to "fast" deformations that give typical rate dependence of viscoelastic material properties, e.g., associated with needleless injection. Furthermore, slow measurement speeds may be susceptible to errors caused by changing material properties as a function of, e.g., humidity and stress.

[0016] Furthermore, prior art methods may require multiple measurements to determine the value of a property of a material such as skin in different directions.

[0017] Furthermore, prior art methods can also cause irreversible changes (locally) such as damaging the material.

[0018] Similarly, it may be desirable to measure the (viscoelastic / mechanical) properties of other viscoelastic materials, such as coatings, in a controlled, localized and / or non-invasive manner. [Means for solving the problem]

[0019] It is therefore an aspect of the present invention to provide an alternative method for determining the properties of a target region of a substance, which preferably also at least partially obviates one or more of the above-mentioned disadvantages. The present invention may have as its object to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0020] Thus, in a first aspect, the present invention provides a method for determining the properties of a target area of ​​a viscoelastic substance. In an embodiment, the target area is 100 μm 2 ~100mm 2 The target area may have a size selected from the range of 0.1 - 1.0 m / s. The method may comprise one or more of an exposing step, a measuring step and an analyzing step. The exposing step may in particular comprise providing a liquid jet to the target area, in particular the liquid jet having a jet speed selected from the range of 2 - 150 m / s. The measuring step may comprise detecting (spatiotemporal) deformations of the material in the target area and in particular providing a related signal. The analyzing step may comprise determining a characteristic of the target area based on the detected deformations, in particular based on the related signal.

[0021] The method of the invention may provide the advantage that a material may be deformed locally, non-invasively, at high frequency, and efficiently in time. For example, by continuously jetting or using a train of droplets, a frequency range of 0.001-50 kHz may be covered. The measurement may be (essentially) continuous, with a spatial resolution of less than 10 μm, for example less than 5 μm. The method may further facilitate determining various properties of the material, such as strain, Young's modulus, viscosity, shear elasticity, and shear viscosity. Furthermore, the method may facilitate determining anisotropy in multiple directions in a single measurement. Furthermore, the method may simultaneously probe the material and provide the material with liquid, especially with additives (see below), for example to prepare the material for subsequent injection.

[0022] For purposes of illustration, the present invention may be described herein primarily in the context of measuring properties of skin, however, it will be apparent to those skilled in the art that the present invention is not limited to such embodiments and may also be applied, for example, to measuring properties of coatings.

[0023] Thus, in certain embodiments, the invention can provide a method for determining a characteristic of a target area of ​​a material, the target area being within 100 μm 2 ~100mm 2 and the method comprises an exposure step comprising providing a liquid jet to a target area, the liquid jet having a jet speed selected from the range of 2 to 150 m / s, a measurement step comprising detecting deformation of the material in the target area and providing a related signal, and an analysis step comprising determining a property of the target area based on the related signal. Thus, the invention can provide a (characterization) method for determining a property of a target area of ​​a material.

[0024] In an embodiment, the property may in particular comprise a dynamic property. In a further embodiment, the property may in particular comprise a mechanical property (or "viscoelastic property"). In a further embodiment, the property may be selected from the group comprising Young's modulus, viscous modulus, shear elasticity, and shear viscosity. The term "property" may refer herein to multiple (different) properties, such as, for example, both Young's modulus and viscous modulus.

[0025] The material may in particular be a viscoelastic material, i.e. a material that exhibits both elastic and viscous behavior when deformed. For example, in an embodiment, the material may comprise a polymer. In a further embodiment, the material may comprise a (ex vivo) soft tissue, such as (ex vivo) skin or (ex vivo) eye. In a further embodiment, the material may comprise a hydrogel, such as, for example, one or more of gelatin, agarose, and polyacrylamide. Gelatin and agarose are commonly used to provide texture to food and can also be used as skin substitutes. Polyacrylamide may be used, for example, for studies on cell durotaxis (the ability of cells to migrate in a substrate with a stiffness gradient). In a further embodiment, the material may comprise an artificially produced tissue or biomaterial, such as a dermal equivalent, or a cell cultured tissue for implantation, such as 3D printed tissues and organs.

[0026] The term "target area" may in this specification refer in particular to the area of ​​the material for which the properties are to be determined, i.e. the properties may be determined specifically for the target area. In particular, (a part of) the target area may be exposed to a liquid jet (see below). In an embodiment, the target area is within a range of 50 μm 2 ~150mm 2 In the range of 100 μm 2 ~100mm 2 range, e.g. 200μm 2 ~30mm 2 In a further embodiment, the target area may have a size selected from the range of 300 μm 2 ~3mm2 range, e.g. 500μm 2 ~1mm 2 In a further embodiment, the target area may have a size selected from the range of 100 μm 2 ~1mm 2 The size can be selected from the range of

[0027] The method may specifically include one or more of an exposing step, a measuring step, and an analyzing step. In particular, in an embodiment, the method includes an exposing step, a measuring step, and an analyzing step.

[0028] In an embodiment, the method may include an exposing step. The exposing step may include providing a liquid jet (or "jet") to the target area. In particular, the exposing step may include ejecting the liquid jet towards the target area, for example using a jet ejection system, such that the liquid jet impacts the target area.

[0029] In general, the term "jet" may refer to a natural or artificial collimated stream of a substance. For example, it may be possible to generate a jet (or "jet") from a small orifice or nozzle. In this specification, the term "jet" refers to a high-velocity and small-diameter stream of liquid extruding from a (small) opening. The jet may have a velocity of at least 1 m / s. In an embodiment, the jet may have high stability. That is, the jet may essentially comprise a substantially continuous, in particular uninterrupted, stream of liquid. In a further embodiment, the jet may comprise a continuous stream of individual droplets. The jet may have a (jet) diameter selected from the range of 10 to 3000 μm, such as from the range of 15 to 500 μm, in particular from the range of 25 to 300 μm, such as from the range of 50 to 150 μm. Thus, in an embodiment, the individual droplets (of the continuous stream of individual droplets) may (each) have a diameter selected from the range of 10 to 3000 μm, such as the range of 15 to 500 μm, in particular the range of 25 to 300 μm, such as the range of 50 to 150 μm.

[0030] Jetting systems and methods are known in the art. For example, the method of the present invention can be carried out by ejecting a liquid jet onto a target area using the system described in WO 2020 / 182665, which is incorporated herein by reference.

[0031] In an embodiment, the exposing step may comprise providing the liquid jet with a jet velocity selected in the range of 1-250 m / s, for example in the range of 2-150 m / s, in particular in the range of 5-70 m / s. The jet velocity may be selected in particular taking into account the substance, for example taking into account the (typical) properties of such a substance. In particular, the jet velocity may be selected to be high enough to provide a (observable) deformation in the substance (by a sensor system). Furthermore, the jet velocity may be selected to be low enough so as not to damage the substance, such as by bursting. It will be clear to the skilled person that a jet velocity suitable for providing a (observable) deformation without (substantially) damaging the substance depends not only on the substance but also on other jet properties of the liquid jet, such as the jet diameter, the jet volume and / or the jet angle (with respect to the target area). The jet velocity may be selected in particular, for example based on the substance, to be sufficient to provide a deformation in the target area. The jet velocity may further be selected to be below an (estimated) threshold for injection into the substance. In general, the jet velocity of the liquid jet may be (relatively) stable from the moment of ejection to the moment of impact on the target site. However, the jet velocity referred to herein may specifically refer to the jet velocity of the liquid jet immediately prior to the impact of the liquid jet on the target area. Thus, in an embodiment, the jet velocity may be the jet velocity at (or "immediately prior to") the impact of the liquid jet on the target area. In a further embodiment, the jet velocity may be the jet velocity at the time of the generation of the jet, such as the jet velocity of the liquid jet as it exits the microfluidic device.

[0032] In a further embodiment, the exposing step may comprise providing the liquid jet to the target area from a distance of 50 cm or less, such as 20 cm or less, in particular 10 cm or less. In a further embodiment, the exposing step may comprise providing the liquid jet to the target area from a distance (relative to the location in the microfluidic device where the liquid jet exits the microfluidic device) of 5 cm or less, in particular 3 cm or less, such as 2 cm or less. In a further embodiment, the exposing step may comprise providing the liquid jet to the target area from a distance of 1 cm or more, such as 3 cm or more, in particular 5 cm or more.

[0033] In a further embodiment, the exposing step can include providing the liquid jet with a jet volume selected from the range of 500 μL or less, such as 200 μL or less, in particular 100 μL or less. In a further embodiment, the exposing step can include providing the liquid jet with a jet volume selected from the range of 10 μL or less, such as 5 μL or less, in particular 1 μL or less. In a further embodiment, the exposing step can include providing the liquid jet with a jet volume selected from the range of 500 nL or less, such as 300 nL or less, in particular 100 nL or less.

[0034] In a further embodiment, the exposure step can include providing the liquid jet with a jet volume selected from the range of 2-50 nL, for example from the range of 5-25 nL, in particular from the range of 8-13 nL. In particular, a (relatively) small jet volume can be selected to avoid pooling of liquid on the target area that may obscure the measurement of the deformation. Thus, in a further embodiment, the exposure step can include providing the liquid jet with a jet volume selected from the range of 75 nL or less, for example from 50 nL or less, in particular from 40 nL or less. In a further embodiment, the exposure step can include providing the liquid jet with a jet volume selected from the range of 30 nL or less, for example from 20 nL or less, in particular from 15 nL or less.

[0035] In further embodiments, the jet volume may be selected from the range of 1 nL or more, such as 2 nL or more, in particular 5 nL or more. In further embodiments, the jet volume may be selected from the range of 10 nL or more, in particular 20 nL or more, such as 50 nL or more, in particular 100 nL or more. In further embodiments, the jet volume may be 1 μL or more, such as 5 μL or more, in particular 10 μL or more, such as 100 μL.

[0036] In a further embodiment, the exposing step may comprise providing a liquid jet with a circular equivalent (jet) diameter selected from the range of 20 μm to 5 mm, such as the range of 30 μm to 3 mm, in particular the range of 50 μm to 1 mm. In particular, a small circular equivalent diameter may facilitate a more localized detection of the property. Thus, in an embodiment, the circular equivalent diameter may in particular be 3 mm or less, such as 1 mm or less, in particular 500 μm or less, for example 100 μm or less.

[0037] The equivalent circular diameter (ECD) (or "circular equivalent diameter") of a (irregularly shaped) two-dimensional shape is the diameter of a circle of equivalent area. For example, the equivalent circular diameter of a square with side a is 2*a*SQRT(1 / π). For a circle, the diameter is the same as the equivalent circular diameter. If a circle in the xy plane with diameter D is warped (in the xy plane) into any other shape without changing the area size, the equivalent circular diameter of that shape will be D. In particular, the equivalent circular diameter of a liquid jet can be determined in a plane perpendicular to the path of travel of the liquid jet (towards the target area).

[0038] In a further embodiment, the liquid jet may have a circular equivalent (jet) diameter D2 and the target area may have a circular equivalent (target) diameter D3, where D3 is selected from the range 3*D2 to 30*D2, for example from the range 5*D2 to 20*D2, in particular from the range 7*D2 to 15*D2.

[0039] In a further embodiment, the exposing step can include providing a liquid jet with an equivalent sphere (jet) diameter selected from the range of 30 μm to 3 mm.

[0040] The equivalent spherical diameter (ESD) (or "spherical equivalent diameter") of a (irregularly shaped) three-dimensional shape is the diameter of a sphere of equivalent volume. For a sphere, the diameter is the same as the equivalent spherical diameter. If a sphere in the xyz plane with diameter D is distorted (in the xyz plane) into any other shape without changing the volume, the equivalent spherical diameter of that shape will be D.

[0041] Generally, the liquid jet can be provided perpendicular to the target area, i.e., the liquid jet can travel along a path (essentially) perpendicular to the target area before impacting the target area. Providing the liquid jet (essentially) perpendicular to the target area can provide the advantage that an (essentially) uniform force can be provided in an in-plane direction of the target area, which can facilitate the determination of properties in different directions, since the subsequent deformations can be different in different directions from the impact site.

[0042] Thus, in an embodiment, the exposing step may comprise providing the liquid jet to the target area at a (jet) angle of 45° to 90° (relative to the target area), such as an angle of 60° to 90°, particularly an angle of 75° to 90°, for example an angle of 85° to 90°, particularly an angle (essentially) 90°.

[0043] However, in embodiments, the liquid jet can also be provided at an angle (relative to normal) to the target area. Providing the liquid jet at an angle can provide the advantage that the liquid jet is less likely to penetrate the material, and can also result in an asymmetric (radial) response of the material to the impingement of the liquid jet, which can provide additional information. In particular, material properties may be probed in a shear-dependent manner. Furthermore, providing the liquid jet at an angle can facilitate measurements in non-uniform areas.

[0044] Thus, in an embodiment, the exposing step may involve providing the liquid jet to the target area at an angle (relative to the target area) of between 30° and 85°, such as an angle of between 45° and 80°, in particular an angle of between 50° and 75°.

[0045] As mentioned above, the material may be anisotropic, i.e. the (value of) a property of the material may depend on the measurement conditions. Thus, in an embodiment, the exposure step may include varying the measurement conditions (over time). Thereby, the property may be conveniently determined for different measurement conditions, which may also facilitate the interpolation or extrapolation of the (value of) the property to non-measurement conditions.

[0046] Thus, in an embodiment, the exposing step may include varying (over time) jet characteristics of the liquid jet. For example, the exposing step may include varying (circular or spherical equivalent) diameter or jet velocity of the liquid jet over time. In particular, in an embodiment, the exposing step may include varying one or more of the jet velocity, the diameter (circular or spherical equivalent) and the jet angle (relative to the target area) of the liquid jet. For example, varying the jet (impingement) velocity over time may inform the dependence of material properties on the impact force. Furthermore, for example, varying the frequency at which the liquid jet, and in particular the plurality of droplets, is provided may inform the dependence of material properties on the strain rate. Varying the jet diameter may refer in particular to varying one or more of the circular equivalent diameter of the liquid jet and the spherical equivalent diameter of the liquid jet, in particular the circular equivalent diameter of the liquid jet.

[0047] In a further embodiment, the exposing step may comprise varying the jet velocity in the range of 1 to 250 m / s, such as in the range of 2 to 150 m / s, in particular in the range of 5 to 70 m / s.

[0048] In a further embodiment, the exposing step may comprise varying the equivalent jet circle (or sphere) diameter of the liquid jet in the range of 10 μm to 5 mm, in particular in the range of 20 μm to 4 mm, for example in the range of 30 μm to 3 mm.

[0049] In a further embodiment, the exposing step may include varying the jet angle, particularly in the range of 45° to 90° (relative to the target area).

[0050] As mentioned above, the method may further comprise providing a plurality of (sequentially provided) droplets to the target area. In particular, in an embodiment, the exposing step may comprise providing a liquid jet, the liquid jet comprising a plurality of (sequentially provided) droplets. In particular, the (droplets within) the plurality of droplets may be provided at intervals (independently) selected from the range of 0.02-10 ms, such as the range of 0.05-5 ms, in particular the range of 0.1-2 ms.

[0051] Thus, in an embodiment, the exposing step may comprise providing a plurality of droplets at a frequency selected from the range of 0.001 to 50 kHz, such as the range of 0.1 to 50 kHz, particularly the range of 1 to 30 kHz.

[0052] In particular, in embodiments the exposing step may involve varying the properties of two or more of the plurality of droplets, e.g. by varying the properties of the droplets continuously, in particular linearly, or, for example, by varying the properties of the droplets in steps (e.g. five droplets having (essentially) a first set of properties followed by five droplets having a second set of properties).

[0053] Thus, in an embodiment, the exposing step may include varying the jet characteristics of the liquid jet (over time) by varying the jet characteristics along a plurality of (sequentially provided) droplets.

[0054] In further embodiments, the exposing step may include varying the interval between two or more successive droplets of the plurality of droplets, i.e., the two or more successive intervals may differ in duration. In particular, the exposing step may include varying the frequency at which the plurality of droplets are provided (over time). In particular, in embodiments, the exposing step may include varying the frequency in the range of 0.1 to 50 kHz.

[0055] In a further embodiment, the exposure step may include providing a frequency sweep, for example in the range of 0.001-50 kHz, for example in the range of 0.1-50 kHz, particularly in the range of 1-30 kHz. The term "frequency sweep" may particularly refer herein to starting from a first frequency, adjusting the frequency continuously or stepwise to a terminal frequency, and then returning (continuously or stepwise) to the starting frequency. This allows the response of the material to different shock frequencies to be determined in an efficient manner.

[0056] As mentioned above, the change in jet characteristics during the exposure phase may occur in a stepwise manner. In particular, in an embodiment, the exposure phase may include a first phase and a second phase, the first phase and the second phase differing in one or more of jet velocity, jet spacing, jet angle, and jet diameter. In a further embodiment, the first phase and the second phase may differ in (at least) jet velocity. In a further embodiment, the first phase and the second phase may differ in (at least) jet spacing. In a further embodiment, the first phase and the second phase may differ in (at least) jet angle. In a further embodiment, the first phase and the second phase may differ in (at least) jet diameter.

[0057] The method may in an embodiment further comprise a measuring step. The measuring step may comprise detecting (spatiotemporal) deformations of the (viscoelastic) material in the target area and in particular for providing an associated signal. For example, in an embodiment the measuring step may comprise detecting radiation, such as optical radiation or acoustic radiation, from the target area. The detected radiation may be indicative of the deformation, since the target area may be deformed due to the impact of the jet and the deformation may affect the reflection of the radiation.

[0058] The term "related signal" may refer herein to a signal related to the detected deformation. In particular, the related signal may include raw and / or processed data related to the (detected) deformation.

[0059] In an embodiment, the measuring step may comprise projecting a mark onto (at least a part of) the target area, such as by (optical) radiation. For example, the mark may comprise (straight) lines or a pattern, such as a (regular) 2D grid or a planar light, in particular a (regular) 2D grid. Since the deformation of the target area due to the impact of the liquid jet may comprise indentations and / or surface waves, the mark may undergo deformation as a result of the (relative) height of the projected area being changed. For example, the mark may resemble a mesh surface plot, such as when the mark comprises a (regular) 2D grid, which may facilitate the determination and quantification of the deformation.

[0060] In a further embodiment, the measurement step may in particular comprise optically detecting deformations in the target area, for example by detecting optical (measurement) radiation from the target area, including in particular detecting mark deformations in the mark.

[0061] In a further embodiment, the measuring step may include acoustically detecting deformations in the target region, for example by detecting acoustic (measurement) emissions from the target region.

[0062] The (measurement) radiation may be ambient radiation, such as provided by an ambient light source, but may also be specifically intended to facilitate measurement. In particular, by providing (measurement) radiation to a target area and detecting (reflected) radiation, measurement noise and / or measurement uncertainty may be reduced.

[0063] Thus, in an embodiment, the measurement step may comprise (i) providing (measurement) radiation, in particular laser radiation, to the target area, and (ii) detecting reflected (measurement) radiation from the target area, in particular providing a related signal. In an embodiment, the radiation may comprise optical radiation. In a further embodiment, the radiation may comprise acoustic radiation. Thus, in an embodiment, the related signal may be based on the detected reflected radiation, and may for example comprise raw and / or processed data based on the detected reflected radiation.

[0064] As mentioned above, the impact of the liquid jet on a target area of ​​the material may result in surface waves moving along the surface of the material. In particular, the surface waves may provide information regarding the (viscoelastic) properties of the material. Thus, in an embodiment, the measuring step may comprise measuring wave properties of the surface waves (after the liquid jet has impacted on the material) in the target area, in particular the wave properties being selected from the group comprising propagation velocity and amplitude decay, and in particular providing an associated signal.

[0065] In an embodiment, the method may include, inter alia, measuring the deformation using a sensor (array). In a further embodiment, the method may include measuring the deformation using laser profilometry, i.e. directing a laser line at the surface so that it reflects to a (high speed) camera. When the surface deforms, the laser line is deflected and both the wave amplitude and the wave speed can be measured. In laser profilometry, the wave amplitude can be measured with an accuracy of less than 40 μm.

[0066] In an embodiment, the method may further comprise an analysis step. The analysis step may comprise determining (viscoelastic) properties of the target area based on the (detected) deformation, in particular based on the associated signal. In a further embodiment, the analysis step may comprise determining properties of the target area based on the (detected) reflected (measured) radiation. In a further embodiment, the analysis step may comprise determining properties of the target area based on wave properties.

[0067] For example, the analysis step can include determining (viscoelastic) properties of the target region based on the propagation of surface waves. Properties of the surface waves, such as the propagation velocity and amplitude attenuation on the surface of the material, can be introduced into a model to determine the Young's modulus and viscosity coefficient β of the material. Assuming that the material is isotropic and viscoelastic along a single radial direction, the surface wave velocity c s The relationship between and the Young's modulus E of the skin is:

number

[0068] The rate of viscous wave attenuation can be calculated from the wave amplitudes obtained at two different locations on the skin using the following relationship:

number

number

number

[0069] Similarly, the shear viscosity μ can be related to the Young's modulus E, so that the shear viscosity μ can also be determined using the methods of the invention, for example, based on a predefined relationship between the shear viscosity μ and the Young's modulus E. For example, for an agarose gel, the shear viscosity can be determined (approximately) according to: μ = 6.005 * 10 -5 E + 0.00834

[0070] In further embodiments, the properties may include the break point, yield point, toughness, and Poisson's ratio of the target region.

[0071] In particular, the break point (or "fracture point") may be defined as the point at which a material breaks when stress is applied. The break point may be measured by observing the penetration of a target area by a liquid jet.

[0072] The yield point can be measured by gradually increasing the impact velocity up to the point where the material is permanently deformed. Specifically, the jet (impingement) velocity (representing stress) can be gradually increased to find the yield point. At each jet velocity, the depth z(r_n) at several locations can be measured before impact. The yield point is reached at an impact velocity where at least one z(r_n) does not return to its original position.

[0073] The toughness of a material may be related to the yield point. In particular, the toughness may be the area under the stress-strain curve up to the break point. The strain can be obtained by measuring the displacement at each time of z(r_n) (close to the impact point).

[0074] Poisson's ratio can be measured by measuring the depth and width of the material deformation upon impact. Specifically, Poisson's ratio can be determined based on the aspect ratio of the deformation profile formed during impact, i.e., by taking the ratio between z_max(r_0) and r_max, where r_0 is the center of impact, z_max is the maximum depth of deformation, and r_max is the maximum radius of deformation.

[0075] Furthermore, if multiple droplets are provided to a target area at a given frequency and the jet velocity is increased while maintaining that frequency, at the break point the vibration mode of the material may change, and the change from pre-break (under vibration) and post-break (during vibration) may indicate the break point, i.e., the break (or fracture) of the material may be observed through a change in the wave propagation signal.

[0076] The term "stage" and similar terms as used herein may refer to a period (of time) (also called a "phase") of a method and / or mode of operation. Different stages may (partially) overlap (in time). For example, a measurement stage may generally be initiated before an exposure stage and may extend beyond the exposure stage. However, for example, a measurement stage may typically be completed before an analysis stage. It will be clear to the skilled person how the stages may be advantageously arranged in time. For example, a measurement stage may be initiated before an exposure stage in order to measure the target area before the deformation, so that the deformation can be accurately determined.

[0077] In an embodiment, the method may further include a preparation step. The preparation step may include providing an additive to the target area, in particular the additive comprises one or more of water and oil. For example, the method may include providing a preparation jet to provide the additive to the target area. In a further embodiment, the additive may comprise a liquid or a semi-solid, such as a gel or cream. In particular, the additive may be provided for one or more of: (i) homogenizing the target area; (ii) facilitating measurement; (iii) enhancing penetration by a needleless injection system; (iv) (pre)tensioning the material; and (v) providing more reproducible properties, for example by saturating the material with water. For example, in the case of (relatively) smooth materials, deformations may be relatively difficult to detect. Thus, an additive comprising visible particles may be provided to the target area (or a 2D grid may be projected onto the target area), so that a movement associated with the deformation of the visible particles may be detected for (part of) the measurement of the deformation.

[0078] In embodiments, the additive may include a penetration enhancer, such as to facilitate subsequent injection during the injection phase, In particular, the additive may include a penetration enhancer selected from the group including ethanol, dimethyl sulfoxide, sodium dodecyl sulfate, and propylene glycol.

[0079] Additionally, additives can be provided to target areas of a material to determine the effect of the additive on the (viscoelastic) properties of the additive on the material, e.g., to determine the effect of a moisturizing cream on the properties of skin.

[0080] In a further embodiment, the preparation step can include ablation of (at least a portion of) the target area. Similarly, to provide an additive, ablation can facilitate homogenization of the target area prior to measurement.

[0081] In a further embodiment, during the exposing step, the liquid jet may include an additive, in particular the additive includes a penetration enhancer.

[0082] In an embodiment, the method, particularly the exposing step, can include controlling one or more of the temperature, tension, and humidity of the target area. The method can include providing tension to the target area, such as via a contact element (see below). Similarly, as described above for the jet properties, the temperature, tension, and humidity to which the material is exposed can affect the properties of the material. Thus, the method can include measuring the properties under controlled conditions, or can include varying one or more of the temperature, tension, and humidity to determine the properties under different conditions, which can further facilitate, for example, the interpolation and extrapolation of the properties to other temperatures.

[0083] In an embodiment, the material may comprise (animal) skin, particularly ex vivo skin, or particularly in vivo skin. In a further embodiment, the material may comprise human skin. For example, the method may comprise determining properties of the skin, for example to facilitate future jet injection (see below).

[0084] In a further embodiment, the method may be a non-medical method, in particular a non-diagnostic method.

[0085] In further embodiments, the substance may include an inanimate object. For example, in embodiments, the substance may include a coating.

[0086] In a second aspect, the present invention may provide an injection method for injecting a fluid into a substance. The injection method may in particular comprise one or more of a characterization step, a parameterization step and an injection step. The characterization step may in particular comprise determining a (viscoelastic) property of a target area of ​​the substance in the (characterization) method of the present invention. The parameterization step may comprise selecting (a value of) a second jet property for injecting the fluid into the substance based on the (determined) property (of the substance), the second jet property being selected from the group comprising jet speed, jet volume, jet rate and jet angle. The injection step may comprise ejecting a second liquid jet towards the (target area of) the substance based on the (value of) the second jet property, the second liquid jet comprising a fluid, in particular the second liquid jet having the (value of) jet property.

[0087] Thus, the injection method of the present invention may advantageously comprise: (i) determining (viscoelastic) properties of a target region of a substance using a (first) liquid jet based on the (characterization) method of the present invention, (ii) selecting suitable second jet properties for injection into the substance based on the (viscoelastic) properties, and (iii) providing a second liquid jet having the second jet properties to the target region, whereby the injection method may tailor the properties of the second liquid jet to the local properties of the target region of a substance in order to improve jet injection, e.g. by improving the accuracy of the injection volume and / or injection depth.

[0088] Thus, in an embodiment, the preparation step may include selecting second jet characteristics for injecting the fluid into the (target area of) the substance based on the (viscoelastic) properties. The second jet characteristics may be selected from a group including, inter alia, jet velocity (relative to the target area), jet volume, jet rate, e.g. jet frequency, and jet angle. In this specification, the term "second jet characteristics" may also refer to a plurality of second jet characteristics. Thus, in an embodiment, the second jet characteristics may include (at least) the jet velocity. In a further embodiment, the second jet characteristics may include (at least) the jet volume. In a further embodiment, the second jet characteristics may include (at least) the jet rate. In a further embodiment, the second jet characteristics may include (at least) the jet angle.

[0089] In particular, in an embodiment, the parameterization step may include selecting the second jet characteristics based on the (viscoelastic) properties and the target parameters, in particular the target parameters being selected from the group including injection depth and injection volume.

[0090] In a further embodiment, the injection step may comprise ejecting a second liquid jet towards the substance, in particular towards a target area of ​​the substance, based on the second jet characteristics. In particular, the second liquid jet may have second jet characteristics. Furthermore, the second liquid jet may in particular comprise a fluid. For example, the fluid may comprise a compound selected from the group comprising insulin, analgesics, vaccines, and biosensor molecules. In a further embodiment, the fluid may be selected from the group comprising surfactants, solvents, binders, fillers, aromatic amines, in particular primary aromatic amines (PAA), and polycyclic aromatic hydrocarbons (PAH). Thus, the fluid may comprise one or more functional ingredients (active ingredients). For example, the fluid may comprise a (dissolved) pharmaceutical product and / or a (dissolved) functional food product, for example for use in the treatment of a disease. In this specification, the term "pharmaceutical product" may refer to one or more of a drug, a diagnostic marker (such as for MRI), etc. The term "functional food product" may refer to, among others, a nutritional agent, a dietary supplement, an herbal product, etc. The term functional food may specifically refer to foods that also have medicinal functions.

[0091] The injection of the second liquid jet may affect the properties of the substance. Thus, in an embodiment, the injection method may include a second characterization step, which involves determining the properties of the target area of ​​the substance using the method of the invention. The second characterization step may in particular be placed in time after the injection step.

[0092] The second characterization step may, among other things, facilitate comparing the properties of the material before and after injection. For example, the comparison may facilitate determining the effect of the injection on the material, which may inform future selection of the second jet properties and provide further information on the material. Additionally, the second characterization may facilitate determining that the second jet has indeed penetrated (the target region of) the material.

[0093] In a further aspect, the present invention may provide a system for determining a characteristic of a target area of ​​a substance, the system comprising one or more of a microfluidic device for jetting, a sensor system, and a control system. In particular, the microfluidic device may be configured to provide a liquid jet to the target area with a jet speed selected from the range of 2 to 150 m / s. In an embodiment, the sensor system may be configured to detect deformation of the substance in the target area, in particular to provide an associated signal to the control system. The control system may be configured to determine the characteristic of the target area based on the associated signal.

[0094] Thus, the system may be specifically configured to carry out the methods of the present invention.

[0095] In certain embodiments, the system comprises a microfluidic device for jetting, a sensor system, and a control system, the microfluidic device configured to provide a liquid jet to a target area at a jet speed selected from the range of 2 to 150 m / s, the sensor system configured to detect deformation of a material in the target area and provide an associated signal to the control system, and the control system configured to determine a characteristic of the target area based on the associated signal.

[0096] Thus, the system may comprise one or more of a microfluidic device, a sensor system and a control system. In particular, the control system may be configured to control the microfluidic device and / or the sensor system.

[0097] In this specification, the term "control" and similar terms may refer to, among other things, at least determining an action or supervising the execution of an element. Thus, in this specification, "control" and similar terms may refer to, for example, imposing an action on an element (determining the action or supervising the execution of the element), such as, for example, measuring, indicating, activating, opening, shifting, changing temperature, etc. Moreover, the term "control" and similar terms may further include monitoring. Thus, the term "control" and similar terms may include imposing an action on an element, and also imposing an action on an element and monitoring the element. The control of the element may be performed by a control system. Thus, the control system and the element may be functionally coupled, at least temporarily, or permanently. The element may comprise a control system. In an embodiment, the control system and the element may not be physically coupled. The control may be performed via wired and / or wireless control. The term "control system" may also refer to a number of different control systems, particularly those that are functionally linked, where one of them, for example a master control system, may be a control system and one or more of the other systems may be slave control systems.

[0098] Microfluidic devices (also called "microfluidic platforms" or "microfluidic systems") comprise a wide range of devices related to the field of microfluidics, which typically handles the movement, control and manipulation of fluids in small volumes, such as volumes on the order of μL, nL, pL and fL. Microfluidic devices may be capable of precisely controlling and manipulating micrometer-sized fluids down to sub-micrometer-sized scales. The channels or features present on the chip are obtained through processes including lithography, dry etching, wet etching, soft lithography and / or bonding, but can also be provided by other (new) techniques such as laser ablation. With respect to the inventive system, the microfluidic device may be configured in particular for (liquid) jetting.

[0099] In an embodiment, the microfluidic device may be configured to provide a liquid jet to a target area, in particular with a jet velocity selected from the range of 1 to 250 m / s, such as the range of 2 to 150 m / s, in particular the range of 5 to 70 m / s.

[0100] In a further embodiment, the microfluidic device can be configured to provide a liquid jet with an equivalent circular diameter selected from the range of 30 μm to 3 mm.

[0101] In a further embodiment, the microfluidic device can be configured to provide a liquid jet with an equivalent sphere diameter selected from the range of 30 μm to 3 mm.

[0102] In further embodiments, the microfluidic device may be configured to provide a liquid jet to the target area at an angle (with respect to the target area) of between 45° and 90°, such as an angle of between 60° and 90°, in particular an angle of between 75° and 90°, such as an angle of between 85° and 90°, in particular an angle of (essentially) 90°. Similarly, in embodiments, the microfluidic device may be configured to provide a liquid jet to the target area at an angle (with respect to the target area) of between 30° and 85°, such as an angle of between 45° and 80°, in particular an angle of between 50° and 75°.

[0103] The sensor system may be configured to sense (or "detect") a signal, such as an optical or acoustic signal, among others. In an embodiment, the sensor system may comprise one or more sensors configured to receive one or more signals. For example, in an embodiment, the sensor system may comprise a (high speed) camera configured to detect an optical signal. In a further embodiment, the sensor system may comprise a microphone configured to detect an acoustic signal. Thus, in an embodiment, the sensor system may be configured to detect optical and / or acoustic radiation, in particular optical radiation, or in particular acoustic radiation.

[0104] In an embodiment, the sensor system may be configured to detect deformations, such as surface waves, of a material in a target area and, among other things, provide an associated signal to a control system.

[0105] In an embodiment, the control system may be configured to determine a characteristic of the target region based on the associated signal, for example based on the (detected) deformation or based on wave characteristics.

[0106] A system, in particular a control system, may have an operational mode. The term "operational mode" may be indicated as "control mode". A system, or an apparatus, or a device (see also further below) may perform an operation in a "mode" or "operational mode" or "mode of operation". Similarly, in a method, an operation, phase, or step may be performed in a "mode" or "operational mode" or "mode of operation". This does not exclude that a system, or an apparatus, or a device may also be adapted to provide another operational mode or a number of other operational modes. Similarly, this does not exclude that before and / or after performing a mode, one or more other modes may be performed. However, in an embodiment, a control system (see also further below) may be available that is adapted to provide at least the operational mode. If other modes are available, the selection of such a mode may in particular be performed via a user interface, although other options may also be possible, such as performing a mode depending on a sensor signal or a (time) scheme. An operational mode may also refer, in embodiments, to a system, or apparatus, or device that can only operate in a single operational mode (ie, "on" and without further tunability).

[0107] In an embodiment, the mode of operation may include one or more of an exposure phase, a measurement phase, and an analysis phase.

[0108] In the exposing step, the microfluidic device may be (configured to) provide a liquid jet to the target area.

[0109] In the measurement phase, the sensor system may be (configured to) detect deformations at the target area and in particular provide a related signal to the control system. In a further embodiment, the sensor system may be (configured to) detect radiation, such as optical and / or acoustic radiation, from the target area and in particular provide a related signal to the control system.

[0110] In the analysis stage, the control system may be (configured to) determine characteristics of the target region based on the associated signals.

[0111] In an embodiment, the system may further comprise a contact element. The contact element may in particular be configured to contact the substance at a predetermined distance from the target area. In a further embodiment, the predetermined distance may be selected in the range of 0-10 mm, for example in the range of 1-7 mm, in particular in the range of 2-5 mm.

[0112] In a further embodiment, the contact element may be configured to position the microfluidic device at a distance of 50 cm or less, such as 20 cm or less, in particular 10 cm or less (relative to the position in the microfluidic device where the liquid jet exits the microfluidic device) from the target area. In a further embodiment, the contact element may be configured to position the microfluidic device at a distance of 5 cm or less, in particular 3 cm or less, such as 2 cm or less, from the target area. In a further embodiment, the contact element may be configured to position the microfluidic device at a distance of 1 cm or more, such as 3 cm or more, in particular 5 cm or more, from the target area.

[0113] In an embodiment, the contact element may in particular be removable. Thus, the system may be configured to operatively couple to a removable contact element. Such an embodiment may be particularly suitable for situations where contact with the substance is subject to hygiene considerations. In a further embodiment, the contact element may be a disposable contact element.

[0114] The contact elements can further facilitate access to target areas of the measurement object that are limited by geometric constraints.

[0115] As mentioned above, in embodiments, the substance may include skin, and thus, in embodiments, the contact element may be specifically configured to contact the skin of the subject.

[0116] In further embodiments, the substance may include an eye. Thus, in embodiments, the contact element may be specifically configured to contact the eye of the subject.

[0117] Furthermore, the contact element may be configured to define a chamber together with the substance, i.e. the contact element and the substance together may define a chamber. In an embodiment, when the contact element is placed on the substance, the substance may thus define at least a portion of the chamber wall. In particular, the target area may define at least a portion of the chamber wall. Providing a chamber may particularly facilitate providing a controlled situation in the target area, such as by limiting the influence of the surroundings. Thus, in a further embodiment, the system, in particular the control system, may be configured to control one or more of the temperature, (pre)tension, and humidity in the chamber. The term "pre-tension" may in particular refer herein to providing tension to the substance, in particular to the target area, before the exposure step.

[0118] Thus, in an embodiment, the system may include one or more of a temperature control element, a tension providing element, and a humidity control element, such as a humidifier or dehumidifier.

[0119] The contact element may in particular comprise a tension providing element, i.e. the contact element may be configured, for example, to stretch the material when placed on the material.

[0120] In an embodiment, the system may further comprise a radiation source. The radiation source may be configured to provide radiation to the sensor system via the target area, in particular during the measurement phase. In particular, the radiation source may be configured to provide radiation to the target area, for example when the contact element is placed on the material, such that reflected radiation is provided from the target area to the sensor system.

[0121] However, it may also be desirable to keep the material from contacting the contact elements, particularly in the case of sensitive materials, for example, and therefore in an embodiment the system may be configured to be positioned away from the material during operation.

[0122] In a further embodiment, the radiation source may be configured to provide optical and / or acoustic radiation, in particular optical radiation, or in particular acoustic radiation.

[0123] The system may further comprise a mark projector configured to project a mark, such as a 2D grid, onto the target area, particularly during the measurement phase.

[0124] In an embodiment, the control system may be specifically configured to control one or more of a temperature control element, a tension providing element, a humidity control element, a radiation source, and a mark projector.

[0125] The system may be part of or applied in, for example, a (handheld) medical device, a (handheld) cosmetic device, an assembly line, a (3D) printer, a robot, sensing applications where a jet is sprayed against a surface such as the skin to obtain a reproducible spray against the sensor surface, modification of coatings or films in an industrial environment.

[0126] Thus, in an embodiment, the system may be specifically integrated into a handheld device.

[0127] The embodiments described herein are not limited to a single aspect of the invention. For example, an embodiment describing a method may further relate to, for example, a system, in particular an operation mode of the system, or in particular a control system. Similarly, a system embodiment describing the operation of the system may further relate to a method embodiment. In particular, a method embodiment describing the operation (of a system) may indicate that the system, in an embodiment, is configured for and / or suitable for the operation. Similarly, a system embodiment describing the operation of (a stage within) an operation mode may indicate that a method, in an embodiment, may include those operations. [Brief description of the drawings]

[0128] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding reference symbols indicate corresponding parts, in which: [Figure 1] 1 illustrates a schematic representation of an embodiment of the method of the present invention. [Diagram 2] 1 illustrates a schematic representation of an embodiment of the method of the present invention. [Figure 3A] 4 shows measurement results obtained with an embodiment of the method of the present invention. [Figure 3B] 4 shows measurement results obtained with an embodiment of the method of the present invention. [Figure 3C] 4 shows measurement results obtained with an embodiment of the method of the present invention. [Figure 3D] 4 shows measurement results obtained with an embodiment of the method of the present invention. [Figure 4] 4 shows measurement results obtained with an embodiment of the method of the present invention. [Diagram 5] 1 illustrates a schematic diagram of an embodiment of a system of the present invention; [Figure 6] The experimental results are shown diagrammatically. [Figure 7]1 shows schematic diagrams of experimental results. The schematic diagrams are not necessarily to scale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0129] 1 shows a schematic representation of one embodiment of a method for determining the properties of a target area 15 of a substance 10, in particular a property selected from the group comprising Young's modulus, viscous modulus, shear elasticity, and shear viscosity. The target area 15 is a 100 μm 2 ~100mm 2 In an embodiment, the method may comprise an exposing step, a measuring step and an analyzing step. The exposing step may comprise providing a liquid jet 20 to the target area 15, in particular the liquid jet 20 having a jet speed selected in the range of 2-150 m / s, for example in the range of 5-70 m / s. The measuring step may comprise detecting (spatiotemporal) deformations 16 of the material in the target area 15 and in particular providing a related signal. The analyzing step may comprise determining a characteristic of the target area 15 based on the deformations 16, in particular based on the related signal.

[0130] Specifically, FIG. 1 shows a schematic of an experimental setup where thermocavitation is obtained by focusing a continuous wave laser on the bottom of a microfluidic device with a microscope objective. The thermocavitation bubbles expand and generate a liquid jet, which is directed at a material 10, which deforms upon impact. The process is recorded with a high-speed camera with illumination coming from a light source reflected at the material surface. The high-speed jet results from the thermal cavitation process and can be directed to impinge on a pendant droplet of different liquids with various properties. Thermal cavitation can refer to the phenomenon where a liquid is locally vaporized by a focused laser, leading to the nucleation of a bubble. The expansion of the nucleated bubble can be controlled on the microfluidic chip to give rise to a jet by a flow focusing effect. Furthermore, the system can be tuned to fire several successive jets, and the successive jets can be used to perform frequency sweeps. Jet characteristics such as jet speed and jet diameter can be controlled by varying the laser spot size, power, and chip geometry.

[0131] Thus, in the illustrated embodiment, the liquid jet 20 may be provided by a microfluidic device 110. The microfluidic device may comprise a heating source 111, such as, for example, a continuous wave laser source, an objective lens 112, and a microfluidic chip 113. For example, in an embodiment, a liquid in the microfluidic chip 113 may be boiled using the heating source 111 such that the liquid jet 20 is ejected from the microfluidic chip 113. During operation of the microfluidic device 110, laser radiation may be applied to the microfluidic chip (liquid therein) such that the liquid boils, resulting in the generation of a rapidly expanding gas bubble. The expansion of the gas bubble converts at least a portion of the laser radiation energy into kinetic energy, which is transferred to the liquid in motion. In particular, the microfluidic device may be configured such that the rapidly expanding gas bubble moves towards an opening directed towards the target area 15, thereby transferring kinetic energy to the liquid, resulting in the formation of the liquid jet 20 that is ejected from the opening.

[0132] In the illustrated embodiment, the liquid jet can be provided at an angle of about 90° to the target area, i.e., the liquid jet can be provided (essentially) perpendicular to the target area. In a further embodiment, the exposing step can include providing the liquid jet 20 to the target area 15 at an angle selected from the range of 45° to 90°, such as from the range of 50° to 80°.

[0133] In an embodiment, the exposure step may include varying the jet characteristics of the liquid jet 20, for example, by varying the jet velocity in the range of 5 to 70 m / s or by varying the diameter (spherical or circular equivalent) of the liquid jet 20 in the range of 30 μm to 3 mm.

[0134] In the illustrated embodiment, the liquid jet 20 includes a plurality of (sequentially provided) droplets 25. The exposure phase may include providing the plurality of droplets 25 at intervals (independently) selected from the range of 0.02-10 ms, among others. For example, in an embodiment, the plurality of liquid jets 20 may be provided at a frequency selected from the range of 0.001-50 kHz, e.g., 0.1-50 kHz.

[0135] In further embodiments, the exposing step may include varying jet characteristics of the liquid jet 20 between the (successively provided) droplets 25. In particular, in embodiments, the exposing step may include a first phase and a second phase, the first phase (of droplets 25) and the second phase (of droplets 25) differing in one or more of jet velocity, jet spacing, and jet diameter.

[0136] In a further embodiment, the exposing step can include varying the spacing between two or more successive droplets 25 of the plurality of droplets 25. In particular, the exposing step can include varying the spacing between the plurality of droplets to provide a frequency sweep in the range of 0.1 to 50 kHz.

[0137] In the illustrated embodiment, the method, and in particular the measuring step, may comprise detecting the deformation 16 after impact with the liquid jet 20, using a sensor system 120, for example a (high speed) optical camera or for example a microphone. In particular, in an embodiment, the measuring step may comprise acoustically detecting the deformation 16 in the target area 15, i.e. the measuring step may comprise detecting acoustic emissions from the target area 15 and in particular providing an associated signal.

[0138] In an embodiment, the method may further include a preparation step. The preparation step may include providing an additive 30 to the target area 15, in particular, the additive 30 including one or more of water and oil. For example, in an embodiment, the preparation step may include spraying the additive onto (on) the target area 15.

[0139] Fig. 2 shows diagrammatically the deformation 16 of a target area 15 of a material 10 after the impact of a liquid jet 20. In particular, Fig. 2 shows diagrammatically a material 10 comprising visible particles 11, the impact of the liquid jet 20 resulting in a (visible) displacement of the particles 11 and the generation of surface waves 17 in the target area 15 of the material 10. In particular, both the (degree of) displacement of the particles 11 and the properties of the surface waves 17, such as the amplitude and the damping rate, may depend on the (viscoelastic) properties of the material 10. Thus, the displacement of the particles 11 and the properties of the surface waves may exhibit (viscoelastic) properties.

[0140] Fig. 2 further shows in a schematic way an embodiment of an injection method for injecting a fluid 41 into a material 10. In particular, the injection method can comprise a characterization step, a parameterization step and an injection step. The characterization step (top three panels) can comprise determining the (viscoelastic) properties of a target area 15 of the material 10 using the (characterization) method according to the invention. The parameterization step can comprise selecting second jet properties for injecting the fluid 41 into the material 10 based on the properties (of the material 10), in particular the jet properties being selected from the group comprising jet speed, jet volume, jet rate and jet angle. The injection step can comprise ejecting a second liquid jet 40 towards the (target area 15 of the material 10) based on the jet properties, in particular the second liquid jet 40 having jet properties and in particular the second liquid jet 40 comprising the fluid 41.

[0141] In general, the injection method may include detecting a property of the target area 15 by exposing the target area 15 to a liquid jet 20 and then providing a second liquid jet 40 to inject a fluid 41 at the target area 15. However, for example in the case of a (relatively) homogeneous material, the injection method may include determining a property of the material 10 at a first target area during a characterization phase and injecting a second liquid jet into the material 10 at a second target area located away from the first target area.

[0142] 3A-3D show schematic experimental observations obtained by the embodiment of the method of the invention shown in FIG. 1. In particular, the processes of bubble generation, jet ejection and droplet impingement were recorded using a sensor system 120, in particular a Photron Fastcam SAX coupled with a 2x microscope objective. A typical experiment duration was about 5 ms and the camera resolution was set to 768x328 pixels with a sample rate of 50k frames per second with an exposure time of 2.5 μs. Typical images obtained from the experiment are shown in FIGS. 3A-3D, in which it is observed how an agarose gel (0.25 wt% agarose) reacts to the impingement of a liquid jet 20. As can be seen in FIG. 1, the sensor system 120 is placed at an angle with respect to the target area 15.

[0143] Impingement of the liquid jet 20 on a target area 15 of the substance 10 may result in a surface wave 17 that travels along the target area (see also Figures 2 and 3A-3D). In an embodiment, the measuring step may include measuring wave properties of the surface wave 17 in the target area 15 (after impingement of the liquid jet 20 on the substance 10), the wave properties being selected from the group including propagation speed and amplitude attenuation, and the analyzing step includes determining the (viscoelastic) properties based on the wave properties.

[0144] Specifically, Figures 3A to 3D correspond to a time series, with Figure 3A corresponding to t = 0 (the moment of impact), Figure 3B corresponding to t = 1.04 ms, Figure 3C corresponding to t = 1.68 ms, and Figure 3D corresponding to t = 3.68 ms.

[0145] In particular, FIGS. 3A-3D show that a surface wave 17 is generated (and observed) following the impact of a liquid jet 20 on a material 10. In FIG.

[0146] 4A-4F show, in a schematic way, experimental observations for the same experiment as in FIGS. 3A-3D, but with the sensor system 120 arranged perpendicular to the (axis of) impingement of the liquid jet 20. The substance 10, here in particular an agarose gel, contains visible particles 11, whose displacements and thus the displacement of the substance 10 can be observed. In particular, FIGS. 4A-4C show the observed horizontal displacements (for 0.5 wt. % agarose), i.e. left-right displacements in the plane of the image. FIGS. 4D-4F show the observed vertical displacements (for 0.5 wt. % agarose), i.e. up-down displacements in the plane of the image. Furthermore, FIGS. 4A, 4D correspond to t=0.06 ms, FIGS. 4B, 4E correspond to t=0.2 ms and FIGS. 4C, 4F correspond to t=0.4 ms. From the displacements the stress in the gel at each point can be calculated.

[0147] Table 1 shows the observed and measured properties of aqueous agarose gels (see formula above), including the determined surface wave velocities in triplicate. [Table 1]

[0148] Fig. 5 shows a schematic representation of an embodiment of a system for determining a characteristic of a target area 15 of a substance 10. In the illustrated embodiment, the system 100 comprises a microfluidic device 110 for jetting, a sensor system 120 and a control system 300. The microfluidic device 110 can be configured to provide a liquid jet 20 to the target area 15, in particular with a jet speed selected from the range of 2 to 150 m / s, for example from the range of 5 to 70 m / s. The sensor system 120 can be configured to detect deformations 16 (see Fig. 4) of the substance 10 in the target area 15 and provide an associated signal to the control system 300. The control system 300 can be configured to determine a characteristic of the target area 15 based on the associated signal.

[0149] In the illustrated embodiment, the system 100 further comprises a contact element 140 configured to contact the substance 10 at a predetermined distance d1 from the target area, in particular, the predetermined distance d1 is selected from the range of 0 to 10 mm.

[0150] In certain embodiments, the contact element 140 can be configured to contact the skin of the subject.

[0151] In particular, the contact element 140 may be configured to define a chamber 145 with the substance 10, and in particular the target area 15 defines at least a portion of the chamber walls 146. Providing the chamber 145 around the target area 15 may facilitate providing controlled conditions at the target area, which may reduce measurement noise, reduce liquid splashing, and facilitate determining properties at different ambient conditions. Thus, in an embodiment, the system 100 may be configured to control one or more of the temperature, (pre)tension, and humidity within the chamber 145.

[0152] Thus, in an embodiment, the system 100 may include, among other things, a temperature control element configured to control the temperature within the chamber 145 .

[0153] In further embodiments, the system 100 can comprise a tension-providing element configured to provide tension to the target area 15. In particular, the contact element 140 can comprise a tension-providing element.

[0154] In further embodiments, the system 100 may include a humidity control element, such as a humidifier and / or dehumidifier, configured to control humidity within the chamber 145 .

[0155] In the embodiment shown, the system 100 further comprises a radiation source 130. The radiation source 130 may be configured to provide (measurement) radiation 131, in particular optical radiation, or in particular acoustic radiation, to the sensor system 120 via the target area 15. The radiation source 130 may thus be configured to provide the radiation 131 to the target area 15 such that reflected radiation 131, 132 reaches the sensor system 120.

[0156] Thus, the sensor system 120 may in particular be configured to detect (measurement) radiation 131, for example reflected radiation 132. In particular, in an embodiment, the sensor system 120 may be configured to detect optical radiation. In a further embodiment, the sensor system 120 may be configured to detect acoustic radiation.

[0157] In further embodiments, the sensor system 120 may be configured to detect ambient radiation reflected off of the target area. Thus, in embodiments, the system 100 may lack the radiation source 130.

[0158] In an embodiment, the system 100, in particular the control system 300, may have operation modes. The operation modes may include, in particular, an exposure phase, a measurement phase, and an analysis phase. In the exposure phase, the microfluidic device may be (configured to) provide a liquid jet 20 to the target area 15. In the measurement phase, the sensor system 120 may be (configured to) detect radiation from the target area 15 and in particular may be (configured to) provide an associated signal to the control system 300. In the analysis phase, the control system 300 may determine a characteristic of the target area 15 based on the associated signal.

[0159] In the illustrated embodiment, the system 100 may be integrated into a handheld device 105, among other things.

[0160] 5 further shows, in schematic form, an embodiment of the method, where the measurement step comprises (i) providing (measurement) radiation 131, in particular laser (measurement) radiation 131, to the target area 15, and (ii) detecting reflected (measurement) radiation 131 from the target area 15 and in particular providing a related signal. In such an embodiment, the analysis step may comprise, in particular, determining a characteristic of the target area 15 based on the reflected radiation 131, for example based on the related signal.

[0161] 6-7 show schematic diagrams of experimental results obtained using the system and method of the present invention. In particular, a liquid jet 20 is projected onto a target area 15 of a material 10, specifically an agarose matrix, resulting in deformation of the material 10.

[0162] Figure 6 shows a schematic representation of the deformation D (μm) of the agarose substrate as a function of time T (ms) and position P (μm). The vertical axis shown in the figure indicates the deformation in the agarose substrate (also shown by the greyscale color bar). From the shown 3D plots, the deformation at a specific time or location can be determined for further analysis (see also Figure 7). In particular, the deformation of each position in the agarose can be tracked in time from impacts on different substrates.

[0163] FIG. 7 shows the deformation at the impact centre of different agarose substrates, especially when impacted by a droplet jet 20 with a jet speed of 33 m / s. The vertical axis shows the deformation D (pixels) of the substrate, while the horizontal axis shows the time T (frames). The deformation of three different agarose substrates is shown, corresponding to agarose concentrations of 0.25 wt%, 0.5 wt% and 1 wt%. In the figure, the difference in reaction time between the different agarose concentrations can be observed. The lower the concentration of agarose, the higher the maximum deformation. Moreover, the substrate undergoes (and recovers from) the maximum deformation sooner with a higher agarose concentration. The deformation can therefore provide information about the properties of the material in the target area.

[0164] The term "plurality" refers to two or more than two. Furthermore, the terms "plurality" and "several" can be used interchangeably.

[0165] The terms "substantially" or "essentially" and similar terms herein will be understood by those skilled in the art. The terms "substantially" or "essentially" may also include embodiments with "entirely", "completely", "all", etc. Thus, in embodiments, the adjectives "substantially" or "essentially" may also be deleted. Where appropriate, the terms "substantially" or "essentially" may also relate to 90% or more, such as 95% or more, particularly 99% or more, more particularly 99.5% or more, including 100%. Furthermore, the terms "about" and "approximately" may also relate to 90% or more, such as 95% or more, particularly 99% or more, more particularly 99.5% or more, including 100%. It is to be understood that with respect to numerical values, the terms "substantially", "essentially", "about" and "approximately" may also relate to a range of 90% to 110%, such as 95% to 105%, particularly 99% to 101% of the value to which they refer.

[0166] The term "comprising" also includes embodiments in which the term "comprising" means "consisting of."

[0167] The term "and / or" specifically relates to one or more of the items listed before and after "and / or." For example, the phrase "item 1 and / or item 2" and similar phrases may relate to one or more of item 1 and item 2. The term "comprising" may, in one embodiment, refer to "consisting of," but in another embodiment, may refer to "including at least the defined species, and may include one or more other species."

[0168] Moreover, terms such as first, second, third, etc. in the specification and claims are used to distinguish between like elements and are not necessarily intended to describe an order or chronology. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operating in orders other than those described or illustrated herein.

[0169] A device, apparatus, or system may be described herein, inter alia, in operation. As will be apparent to one skilled in the art, the present invention is not limited to methods of operation or to devices, apparatus, or systems in operation.

[0170] The term "further embodiment" and similar terms may refer to an embodiment that includes features of the previous embodiment, but may also refer to an alternative embodiment.

[0171] It should be noted that the above-described embodiments are illustrative rather than limiting of the invention, and that those skilled in the art can design many alternative embodiments without departing from the scope of the appended claims.

[0172] In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim.

[0173] The use of the verb "to comprise" and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. Unless the context clearly indicates otherwise, throughout the specification and claims, the words "comprise," "comprising," "include," "including," "contain," "containing," and the like, are to be construed in their inclusive sense, i.e., "including, but not limited to," as opposed to their exclusive or exhaustive sense.

[0174] The article "a" or "an" preceding an element does not exclude the presence of a plurality of such elements.

[0175] The invention can be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In a device, apparatus or system claim enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0176] The present invention also provides a control system capable of controlling a device, apparatus or system or capable of carrying out the methods or processes described herein. Additionally, the present invention also provides a computer program product, which when executed on a computer operatively coupled to or included in a device, apparatus or system, controls one or more controllable elements of such a device, apparatus or system.

[0177] The present invention further applies to a device, apparatus or system comprising one or more of the characteristic features described in the specification and / or shown in the accompanying drawings. The present invention further relates to a method or process comprising one or more of the characteristic features described in the specification and / or shown in the accompanying drawings. Furthermore, when a method or method embodiment is described as being performed in a device, apparatus or system, it will be understood that the device, apparatus or system is suitable for or configured for (performing) the method or method embodiment, respectively.

[0178] Various aspects discussed in this patent may be combined to provide additional advantages. Moreover, those skilled in the art will appreciate that embodiments may be combined, and that more than two embodiments may be combined. Furthermore, some of the features may form the basis of one or more divisional applications.

Claims

1. A method for determining the properties of a target area (15) of a substance (10), said target area (15) being 100 μm ２ ~100mm ２ and wherein the method comprises: an exposing step comprising providing a liquid jet (20) to the target area (15), said liquid jet (20) having a jet volume selected from the range of 500 nL or less, said liquid jet (20) having a jet velocity selected from the range of 2 to 150 m / s, said jet velocity being selected so as to be sufficient to impart a deformation (16) in said material (10), said deformation (16) comprising a surface wave, said jet velocity being selected so as to be below a threshold for injection into said material (10); a measuring step comprising detecting radiation from said target area (15) and measuring wave properties of said surface waves in said target area (15) to provide a related signal, said wave properties being selected from the group comprising propagation velocity and amplitude attenuation; - an analysis step comprising determining said characteristics of said target area (15) based on said wave characteristics; The method comprising:

2. 2. The method of claim 1, wherein the liquid jet (20) has a jet velocity selected from the range of 5 to 70 m / s, the liquid jet (20) has an equivalent circle diameter selected from the range of 30 μm to 3 mm, and the exposing step comprises providing the liquid jet (20) at the target area (15) at an angle of 45° to 90°.

3. The method of claim 2, wherein the exposing step comprises varying the jet velocity in the range of 5 to 70 m / s.

4. The method of claim 2 or 3, wherein the exposing step comprises varying the equivalent circular diameter of the liquid jet (20) in the range of 30 μm to 3 mm.

5. The method of claim 1, wherein the liquid jet (20) has a jet diameter selected from the range of 25 to 300 μm.

6. 6. The method according to any one of claims 1 to 3 and 5, wherein the liquid jet (20) comprises a plurality of droplets (25), the plurality of droplets (25) being provided at intervals selected from the range of 0.02 to 10 ms.

7. 7. The method of claim 6, wherein the exposing step comprises varying the spacing between two or more consecutive droplets (25) of the plurality of droplets (25).

8. The target area (15) is 300 μm ２ ~3mm ２ and the measuring step comprises projecting a mark onto at least a portion of the target area (15), and the measuring step comprises optically detecting the deformation (16) within the target area (15).

9. The method according to any one of claims 1 to 3 and 5, wherein the measuring step comprises acoustically detecting the deformation (16) in the target area (15).

10. 6. The method of claim 1, wherein the measuring step comprises (i) providing radiation (131) to the target area (15) and (ii) detecting reflected radiation (131) from the target area (15), and the analyzing step comprises determining the characteristic of the target area (15) based on the reflected radiation (131).

11. 6. The method of claim 1, wherein the measuring step comprises measuring wave properties of surface waves (17) in the target area (15), the wave properties being selected from the group comprising propagation velocity and amplitude attenuation, and the analyzing step comprises determining the property based on the wave properties.

12. 6. The method of any one of claims 1 to 3 and 5, further comprising a preparation step, said preparation step comprising providing an additive (30) to said target area (15), said additive (30) comprising one or more of water and oil.

13. The method of any of claims 1 to 3 and 5, wherein the property is selected from the group comprising Young's modulus, viscous modulus, shear elasticity, and shear viscosity.

14. The method of any of claims 1 to 3 and 5, wherein the material (10) comprises ex vivo skin or ex vivo eye.

15. The method of any of claims 1 to 3 and 5, wherein the substance (10) comprises a coating.

16. 1. An injection method for injecting a fluid (41) into a substance (10), comprising: a characterization step comprising determining the properties of the target area (15) of said material (10) using a method according to any one of claims 1 to 3 and 5; a parameterization step comprising selecting, based on said characteristics, second jet characteristics for injecting said fluid (21) into said substance (10), said second jet characteristics being selected from the group comprising jet velocity, jet volume, jet rate and jet angle; an injection step comprising injecting a second liquid jet (40) towards said substance (10) based on said second jet characteristics, said second liquid jet (40) comprising said fluid (41); The injection method comprising:

17. 17. The method of claim 16, wherein the parameterizing step includes selecting the second jet characteristic based on the characteristic and a target parameter, the target parameter being selected from the group consisting of an injection depth and an injection volume.

18. A system (100) for determining a characteristic of a target area (15) of a substance (10), comprising a microfluidic device (110) for jetting, a sensor system (120), and a control system (300); - the microfluidic device (110) is configured to provide a liquid jet (20) to the target area (15) at a jet velocity selected from the range of 2 to 150 m / s, the liquid jet (20) having a jet volume selected from the range of 500 nL or less, the jet velocity being selected to be sufficient to impart a deformation (16) in the substance (10), the deformation (16) comprising a surface wave, and the jet velocity being selected to be below a threshold for injection into the substance (10); - said sensor system (120) is configured to detect radiation from said target area, measure wave properties of said surface waves in said target area (15) and provide a related signal, said wave properties being selected from the group comprising propagation velocity and amplitude attenuation; - said control system (300) is configured to determine said characteristics of said target area (15) based on said wave characteristics; The system (100).

19. The sensor system (120) is configured to detect optical and / or acoustic radiation (131), and the system (100) comprises: an exposing step comprising said microfluidic device providing said liquid jet (20) to said target area (15); a measurement stage comprising said sensor system (120) detecting said optical and / or acoustic radiation (131) from said target area (15) and providing said related signal to said control system (300); an analysis stage including said control system (300) determining said characteristics of said target area (15) based on said related signals; 20. The system (100) of claim 18, having modes of operation including:

20. 20. The system (100) of claim 18 or 19, wherein the system (100) is integrated into a handheld device (105).

21. 20. The system (100) of claim 18 or 19, comprising a contact element (140), the contact element (140) configured to contact the substance (10) at a predetermined distance from the target area, the predetermined distance being selected from the range of 0 to 10 mm.

22. 22. The system (100) of claim 21, wherein the contact element (140) is configured to define a chamber (145) together with the substance (10), the system (100) is configured to control one or more of temperature, (pre)tension, and humidity within the chamber (145), and the contact element (140) is configured to contact the skin of a subject.

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