• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The subject of the invention is a method for printing at least one ink, said method comprising a step of focusing a laser beam (66) so as to generate a cavity in an ink film (74) a step of forming at least one ink droplet (82) from a free surface (78) of the ink film (74) and a step of depositing said droplet (82) on a surface of depositing (56) a receiver substrate (58) positioned at a given distance (L) from the film (74), characterized in that the laser beam (66) is oriented in the opposite direction to the gravitational force (G), the free surface (78) of the film facing upwards towards the depositing surface (56) placed above the ink film (74).
    公开号:FR3030360A1
    申请号:FR1462568
    申请日:2014-12-17
    公开日:2016-06-24
    发明作者:Fabien Guillemot
    申请人:Institut National de la Sante et de la Recherche Medicale INSERM；Universite de Bordeaux；
    IPC主号:
    专利说明:

    [0001] The present invention relates to a laser printing process and to a device for its implementation. Ink printing is used in many fields to reproduce complex patterns. Thus, the printing of elements can in particular be implemented in areas as diverse as biology, electronics, materials or watchmaking. The problems encountered in these different areas are similar and relate in particular to the need to achieve combinations of elements at very small scales. A pattern reproduction of depositing material at specific locations can be done chemically or physically via the use of masks or via a selective ablation step. To overcome the drawbacks of these methods (risk of contamination, complexity of implementation, difficulty of combining the deposition of several elements), ink printing processes have been developed. They have the advantage of being able to very easily generate element patterns thanks to the computer-assisted design tools with which they are associated. In the field of biology, according to the books, these printing processes are called bio-printing, micro-printing of biological elements or bioprinting in English. According to these methods, the biological tissue is obtained by printing organic ink droplets. To obtain a volume, the droplets are arranged in layers that are superimposed on each other. According to a first variant, the ink is stored in a reservoir and passes through nozzles or capillaries to form droplets which are transferred onto a support. This first so-called nozzle printing variant includes bioextrusion, inkjet printing or microvalve printing.
    [0002] Bioextrusion makes it possible to obtain a large cell density of the order of 100 million cells per milliliter and a resolution of the order of a millimeter.
    [0003] The printing by microvalves makes it possible to obtain a lower cell density of the order of a few million cells per milliliter and a better resolution of the order of 100 μm. The inkjet printing makes it possible to obtain a cell density identical to microvalve printing, less than 10 million cells per milliliter and a better resolution of the order of 10 μm. In the case of bioextrusion, the cells are deposited from a first nozzle and a hydrogel is simultaneously deposited from a second nozzle. Alternatively, the cells and the hydrogel are mixed in a reservoir before extrusion. In the other two cases, the ink is an aqueous medium containing the cells. According to the variants, the bioextrusion makes it possible to deposit the ink continuously in the form of filaments or discontinuously in the form of droplets. According to these nozzle printing modes, the printing resolution being related in particular to the section of the nozzles, only biological inks with given rheological characteristics can be used for high resolutions. Thus, biological inks with high cell density can be difficult to print with high resolution because this printing technique induces at the time of passage through the nozzle significant shear stresses may damage the cells. In addition, with this type of ink, the risk of clogging of the nozzles by the cells is important due in particular to the sedimentation of the cells inside the tanks.
    [0004] To be able to use a wide range of biological inks and achieve a high level of resolution, a method of printing biological elements by laser has been developed. This printing process called laser bio-printing, is also known as "Laser-Assisted Bioprinting" (LAB) in English. The invention relates more specifically to this type of printing process. By way of comparison, laser bio-printing makes it possible to print inks with a high cell density of the order of 100 million cells per milliliter with a resolution of 10 μm. In the same way, laser printing has also been developed in other areas to improve the resolution and expand the range of usable inks. Compared to nozzle printing techniques, laser printing provides greater flexibility of use (possibility of printing on soft, non-planar surfaces, ...), reduces shear stresses, limits the risks of sedimentation. According to another advantage, it is possible to print from a small volume of ink of the order of a few microliters which is interesting for the deposits of expensive materials. Finally, it is possible to use the printing system to view and select the drop zone as described in WO2011 / 107599. As illustrated in FIG. 1, a device for printing biological elements by laser which is based on the so-called Laser-Induced Forward Transfer (LIFT) technique in English, comprises a pulsed laser source 10 emitting a laser beam 12, a system 14 for focusing and orienting the laser beam 12, a donor support 16 which comprises at least one biological ink 18 and a receiving substrate 20 positioned to receive droplets 22 emitted from the donor support 16.
    [0005] According to this printing technique, the laser beam is pulsed and at each pulse a droplet is generated. The biological ink 18 comprises a matrix, for example an aqueous medium, in which there are elements, for example cells, to be deposited on the receiving substrate 20. The donor support 16 comprises a wavelength-transparent plate 24 the laser beam 12 which is coated with an absorbent layer 26 on which is affixed the biological ink 18 in the form of a film. Absorbent layer 26 converts light energy into kinetic energy. Thus, the laser beam 12 produces a spot heating at the absorbent layer 26 which vaporizes a gas bubble 28 which by expansion causes the ejection of a droplet of biological ink. According to a known arrangement, the laser beam 12 impacts the donor support 16 by being oriented in an approximately vertical direction and in a direction from top to bottom, in the same direction as the gravitational force G. Thus, the biological ink 18 is placed under the blade 24 so as to be oriented downwards towards the receiving substrate 20 which is placed under the donor support 16. In view of this arrangement, the biological ink 18 is in the form of a film with a thickness E less than a given threshold to be able to be held on the blade. This threshold varies in particular according to the surface tension, the viscosity and the density of the biological ink.
    [0006] The formation of the droplets 30 from the ink film depends on numerous parameters which are particularly related to the laser beam 12 (wavelength, energy, pulse duration, etc.), to the nature of the biological ink. 18 (surface tension, viscosity, ...), external conditions (temperature, hygrometry, ...). Droplet formation also depends on the thickness of the film E of the biological ink. The droplets will not form if the thickness E of the biological ink film is not within a thickness range delimited by a lower bound and an upper bound. If the thickness E has a value greater than the upper limit, no droplet will form because the expansion of the gas bubble 28 is too low to reach the free surface of the film. If the thickness E has a value lower than the lower limit, the gas bubble 28 will burst at the free surface causing the uncontrolled projection of a plurality of microdroplets to the receiving substrate. Therefore, the thickness of the film E must be substantially constant over the entire surface of the donor support 16 to obtain a reproducibility of the droplet formation irrespective of the zone of the donor support 16 impacted by the laser beam 12. in Figure 1, this thickness E is not constant.
    [0007] This problem of reproducibility is not limited to the case of biological inks. It is present in any field of use when laser printing an ink film. To remedy this problem, a publication entitled "Microdroplet deposition through a film-free laser forward technique" published on October 1, 2011 on the site www.elsevier.com proposes a device as described in Figure 2. As previously, this device comprises a laser source 32 emitting a laser beam 34, a system 36 for focusing and orienting the laser beam 34, a donor support 38 which contains at least one biological ink 40 and a receiving substrate 42 positioned to receive droplets 44 emitted from the donor support 38. According to this publication, the donor support 38 comprises a reservoir 46 without an upper wall so that the free surface 48 of the biological ink 40 contained in the reservoir faces the receiving substrate 42. To obtain a surface free 48 regular and substantially flat, the biological ink is not in the form of a thin film but a volume having a depth of the order of 3 mm. In this way, the bottom of the reservoir has no influence on the shape of the free surface 48 of the biological ink and the side walls of the reservoir have an effect limited to the periphery of the free surface 48 because of the Surface tension.
    [0008] Given the depth of the biological ink volume, the free surface 48 is necessarily upward to remain in the reservoir and the receiving substrate 42 is positioned above the biological ink 40. According to this document, to obtain the ejection of a droplet, the laser beam 34 is focused just below the free surface 48 to a depth of the order of 40 to 80 microns. Thus, the droplets emitted from the free surface 48 are projected towards the receiving substrate 42 in a sense of displacement contrary to the direction of the gravitational force G. Even if the solution proposed by this publication makes it possible to obtain a free surface 48 for flat ink, it is not necessarily suitable for inks that are in the form of suspensions, such as biological inks. Indeed, as indicated above, these biological inks contain elements to be printed, such as cells, embedded in a matrix, which tend to sedimentation down tank bottom. Since the concentration of printing elements is low close to the free surface, the printed droplets have in fact low concentrations of cells, which is generally detrimental to the printed biological tissue. Moreover, according to this method, it is very difficult to control the number of cells and the concentration of the deposited cells. This sedimentation problem is not limited to biological inks. Thus, it is found during the laser printing of inks in the form of suspensions, such as suspensions of particles or nanoparticles in a liquid matrix, whatever the field of application of these inks. According to another disadvantage of the method of publication, the ink must be able to absorb the laser beam which can limit the range of inks that can be printed according to this technique.
    [0009] Also, the present invention aims to overcome the drawbacks of the prior art by providing a printing process that can print with great precision a wide range of elements. In particular, this method makes it possible to print a wide range of biological elements, in particular so as to obtain complex biological tissues. For this purpose, the subject of the invention is a method for printing at least one ink, said method comprising a step of focusing a laser beam so as to generate a cavity in an ink film, a step of forming at least one ink droplet from a free surface of the ink film and a step of depositing said droplet on a delivery surface of a receiving substrate, characterized in that the laser beam is oriented in contrast to the gravitational force, the free surface of the film facing upwards towards the depositing surface placed above the ink film. This configuration makes it possible in particular to obtain a thickness E for the substantially constant ink film, while limiting the appearance of the phenomena of sedimentation. In addition, it allows the use of a wide range of inks. The ink printed by the method according to the invention can be any liquid ink and can be in the form of a solution or in the form of a suspension. Among the usable inks, there may be mentioned in particular biological inks, inks used in electronics or watchmaking. According to one application, the ink is a biological ink. Preferably, the distance separating the ink film from the deposition surface and / or the energy of the laser beam are adjusted so that the kinetic energy of the droplet is almost zero when the droplet touches the deposition surface. This feature limits the risk of damage to the elements (cells or other) contained in the droplet. According to one embodiment, the distance separating the ink film and the dispensing surface is fixed and between 1 and 2 mm and the energy of the laser beam is adjusted so that the kinetic energy of the droplet is almost zero when the droplet touches the dispensing surface.
    [0010] According to another characteristic, the printing method comprises a preliminary phase of calibration of the energy of the laser beam. This calibration phase comprises a step of measuring a peak angle of a deformation of the free surface of the ink film at a fixed moment after the impact of the laser beam and a step of adjusting the energy of the laser beam as a function of the measured value of the peak angle.
    [0011] Preferably, the energy of the laser beam is adjusted so that the tip angle is less than or equal to 105 °. In this case, the energy of the laser beam is sufficient to cause the formation of a droplet. Advantageously, the energy of the laser beam is adjusted so that the tip angle is greater than or equal to a second threshold to obtain a kinetic energy that is almost zero at the moment when the droplet formed reaches the deposition surface.
    [0012] For an ink film, preferably a biological film, of the order of 40 and 50 μm, the moment for measuring the tip angle is preferably of the order of 4 to 5 μm. count the impact of the laser beam. Advantageously, the ink film has a thickness greater than 20 μm.
    [0013] For an ink that is in suspension with a high concentration of elements to be printed, the ink film preferably has a thickness of between 40 and 60 μm. Advantageously, to improve the accuracy of the deposition of the elements to be printed, the ink film 74 has a thickness E of between 1.5D and 2D, D being the diameter of the elements to be printed which have an approximately spherical shape or the diameter of a sphere in which at least one element to be printed is inscribed. The invention also relates to a printing device for implementing the printing method of the invention. It comprises: at least one pulsed laser source configured to emit a laser beam; an optical system for focusing and orienting said laser beam; at least one donor support on which is affixed a film of at least one ink with a surface; free, and - at least one receiving substrate comprising a depositing surface. The printing device is characterized in that the laser beam is oriented in the opposite direction to the gravitational force and in that the free surface of the film is directed upwards towards the depositing surface placed above the film ink. Other features and advantages will become apparent from the following description of the invention, a description given by way of example only, with reference to the accompanying drawings in which: FIG. 1 is a diagrammatic representation of a printing device by FIG. 2 is a schematic representation of a laser printing device which illustrates another variant of the invention. FIG. 3 is a diagrammatic representation of a device of FIG. 4A to 4D are side views illustrating the formation or not of a droplet according to different regimes, FIGS. 5A to 5D are diagrams which illustrate a droplet at different times of the present invention. its formation, the last FIG. 5D illustrating the moment when a droplet reaches a recipient substrate, FIG. 6 is a section of a donor support illustrating the relationship between the tail 7A and 7B are side views illustrating the formation of a protrusion on the free surface of a biological ink film, prior to the formation of a droplet, at the same instant but produced with different energies for the laser beam, FIG. 8 is a schematic representation of a printing device according to one embodiment of the invention combining at least one head of laser-like printing and at least one inkjet-type printing head, FIG. 9 is a perspective view of a printing device according to an embodiment of the invention combining a printing head 10 is a perspective view of a portion of the printing device of FIG. 9 when printing with one of the printing heads of FIG. inkjet type, Figure 11 is a section of a part of the printing device of FIG. 9 when printing with the laser-type printing head; FIG. 12 is a perspective view of a 3-dimensional representation of a part of a biological tissue 13 is a perspective view of a slice of the representation of FIG. 12, FIG. 14 is a top view of the slice of FIG. 13 illustrating the positioning of the droplets of FIG. organic inks. In FIG. 3, there is shown a printing device 50 for producing at least one biological tissue by assembling, layer by layer, according to a predefined arrangement, different constituents, for example an extracellular matrix and various morphogens. Thus, the printing device 50 makes it possible to deposit layer-by-layer droplets 52 of at least one biological ink 54 on a deposition surface 56 which corresponds to the surface of a receiving substrate 58 for the first layer or to the last layer deposited on said receiving substrate 58 for the following layers.
    [0014] In order to simplify the representation, the deposition surface 56 corresponds to the surface of the receiving substrate 58 in FIG. 3. According to one embodiment in FIG. 6, the biological ink 54 comprises a matrix 60, for example a medium in which there are present elements 62, for example cells or aggregates of cells, to be printed on the dispense surface 56. According to the case, a biological ink 54 comprises in the matrix 60 only one kind of elements to be printed. 62 or more kinds of elements to be printed 62. Alternatively, the biological ink 54 may comprise only one component. By biological ink is meant for the present patent application a biological material or biomaterial. By way of example, the biological ink comprises only an extracellular matrix (for example collagen), an extracellular matrix and elements such as cells or aggregates of cells, an aqueous medium containing elements such as cells or aggregates of cells. The biological ink 54 is not more described because it can have different natures and different rheological characteristics from one ink to another. This printing device comprises a laser source 64 configured to emit a laser beam 66 which is characterized inter alia by its wavelength, its frequency, its energy, its diameter, its pulse duration. Preferably, the laser source 64 is parameterizable in order to adjust at least one characteristic of the laser beam, in particular its energy. In order to form droplets dissociated from each other, the laser source 64 is a pulsed source. To give an order of magnitude, it is possible to eject 10,000 droplets per second. By way of example, the laser source 64 is a laser source with a wavelength of 1064 nm. In addition, from the laser source, the printing device 50 comprises an optical system 68 which allows adjustment of the focusing along an axis Z perpendicular to the deposition surface 56. Advantageously, the optical system 68 comprises a lens which enables focusing the laser beam 66 on an impacted area. Preferably, the optical system 68 includes a mirror for changing the position of the impacted area. Thus, the optical system 68 makes it possible to modify the zone impacted by the laser beam in an impact plane referenced Pi in FIG.
    [0015] The laser source 64 and the optical system 68 are not further described because they are known to those skilled in the art and may be identical to those of the prior art. The printing device 50 also comprises at least one donor support 70 which comprises, according to one embodiment, an absorbent layer 72 at the wavelength of the laser beam 66 on which is affixed a film 74 of at least one biological ink. For the remainder of the description, film is understood to mean that the biological ink occupies a volume with a thickness (dimension in a direction perpendicular to the impact plane Pi) of less than 500 μm. Unlike a reservoir, the fact that the biological ink is packaged in the form of a film makes it possible to avoid sedimentation phenomena. The absorbent layer 72 is made of a material adapted to the wavelength of the laser beam 66 to transform the light energy into a spot heating of the absorbent layer 72. Preferably, the donor support 70 is positioned so that the optical system focuses the laser beam at the level of the absorbent layer 72. According to one embodiment, the absorbent layer 72 is made of gold, titanium, or other depending on the wavelength of the laser beam 66. According to another In one embodiment, the donor support 70 does not include an absorbent layer 72. In this case, the energy of the laser beam 66 is absorbed by the ink.
    [0016] Preferably, the donor support 70 comprises a blade 76 of a material transparent to the wavelength of the laser beam 66 which comprises on one of its faces a coating corresponding to the absorbent layer 72. The presence of the blade 76 confers rigidity the donor support 70 for handling and to conserve the ink and / or the absorbent layer 72 substantially flat in the plane of impact Pi.
    [0017] The biological ink film 74 comprises a free surface 78 which is spaced from the absorbent layer 72 by a distance E corresponding to the thickness of the film 74 and which is spaced from the dispense surface 56 a distance L. free surface 78 and the dispense surface 56 face each other. As illustrated in FIG. 3, the laser beam 66 is adapted to produce a cavity 80 at the interface between the absorbent layer and the biological ink film 74 which generates a droplet 82 which detaches from the free surface 78 to move towards the dispense surface 56.
    [0018] For the rest of the description, a vertical direction is parallel to the gravitational force G and the up-down direction corresponds to the direction of the gravitational force G. The direction of the laser beam 66 and the direction of the movement of the droplet are parallel to the vertical direction.
    [0019] Pull up: According to one characteristic of the invention, the laser beam 66 and therefore the movement of the droplet 82 are oriented in the opposite direction to the gravitational force G. Thus, the free surface 78 of the film 74 of biological ink is facing up. During its movement of the film 74 of biological ink to the dispense surface 56, the droplet 82 moves upwards, in the low-high direction. This configuration provides the following advantages: It limits the appearance of sedimentation phenomena, the biological ink being in the form of a film, It makes it possible to obtain a thickness E for the film 74 of substantially constant biological ink, the influence of the gravitational force G on the shape of the free surface 78 of the film 74 being limited by the fact that the free surface 78 is oriented upwards, It makes it possible to use a wide range of biological ink when an absorbent layer 72 independent of the film 74 of biological ink is used to transform the light energy into a punctual heating. Kinetic energy virtually zero at the time of deposition of a droplet on the receiving substrate: The formation of a droplet 82 from a biological ink film will depend on many parameters, mainly the characteristics of the biological ink, characteristics of the laser beam and the conditions of realization. FIGS. 4A to 4D show the evolution over time of the deformation of the free surface of the biological ink film, resulting or not in the formation of a droplet, for different values of the energy of the beam laser 66, the latter having an energy of 21 μl for FIG. 4A, of FIG. 35 for FIG. 4B, of 40 μJ for FIG. 4C and 43 μ.1 for FIG. 4D.
    [0020] For the same biological ink and under the same conditions of realization, it is noted that there are several regimes depending on the energy of the laser beam. As illustrated in FIG. 4A, if the energy of the laser beam is lower than a lower threshold, the droplet does not come off the film 74 of biological ink. The maximum height of the deformation 84 generated at the free surface 78 of the film 74 of the ink being less than the distance L separating the film 74 and the deposition surface 56, no element is printed. According to the example chosen, the lower threshold is between 21 and 35 pJ. As illustrated in FIG. 4D, if the energy of the laser beam is greater than an upper threshold, the gas bubble 80 produced inside the film bursts at the free surface causing the uncontrolled projection of microdroplets. According to the example chosen, the upper threshold is between 40 and 43 pl. Between the lower and upper thresholds, as illustrated in FIGS. 4B and 4C, there is in the presence of a regime allowing the formation of a jet. If the distance L between the film 74 and the deposition surface 56 is sufficient, this regime allows the formation of a droplet.
    [0021] Preferably, the distance L is of the order of 1 to 2 mm to allow the formation of a droplet and not a continuous stream that stretches from the film to the dispensing surface. This configuration limits the risks of contamination of the biological tissue produced by the biological ink. According to another characteristic of the invention, for the same biological ink and under the same conditions of realization, the distance L separating the film 74 from biological ink and the deposition surface 56 and / or the energy of the laser beam 66 are adjusted so that the kinetic energy of the droplet is almost zero when the droplet 82 touches the dispense surface 56, as shown in Figure 5D. This configuration limits the risk of damage to the print elements that are cells.
    [0022] By almost zero, it is meant that the kinetic energy is zero or very slightly positive to allow the droplet to be fixed on the drop surface 56. This circumstance is made possible by the fact that the droplet 82 moves in the opposite direction to the droplet. gravitational force G. Preferably, the distance L between the film 74 of biological ink and the dispense surface 56 is fixed. Consequently, the energy of the laser beam 66 is adjusted so that the kinetic energy of the droplet is almost zero when the droplet 82 touches the deposition surface 56.
    [0023] Whatever the application, printing with a regime that leads to a deposit at zero speed reduces the risk of splashing in English of the droplet at the time of contact with the dispensing surface. Calibration Technique: As previously stated, the formation of the droplet is not solely related to the energy of the laser beam. It is also related to the nature of the biological ink, in particular its viscosity, its surface tension and the conditions of production. FIGS. 5A to 5D, 7A to 7D illustrate a calibration method for determining the energy of the laser beam to obtain an optimum regime for the formation and deposition of the droplets, in particular a regime which leads to a deposition at zero velocity at a given distance L. FIGS. 5A to 5D show some of the steps of forming a droplet 82 between the moment of the impact of the laser beam illustrated in FIG. 5A and the deposition of the droplet 82 on the deposition surface 56.
    [0024] According to one characteristic of the invention, the calibration method for adjusting the energy of the laser comprises the steps of measuring a peak angle θ of a deformation 86 of the free surface 78 of the film 74 of the biological ink. at a fixed instant Ti after the impact of the laser beam 66 and to adjust the energy of the laser beam 66 as a function of the measured value of the tip angle O.
    [0025] As illustrated in FIGS. 5B, 7A and 7B, the deformation 86 has a symmetrical shape with respect to a median axis Am parallel to the vertical direction. This deformation 86 comprises a vertex S centered with respect to the median axis Am. This vertex S corresponds to the zone of the deformation 86 farthest from the remainder of the free surface 78 of the film 74. In a plane containing the median axis Am, the vertex S is extended by a first sidewall 88 on one side of the median axis Am and by a second sidewall 88 'on the other side of the central axis Am, the two sidewalls 88, 88' being symmetrical relative to the medial axis Am. Each flank 88, 88 'comprises a point of inflection. The first flank 88 comprises at its point of inflection a first tangent Tgl and the second flank 88 'comprises at its inflection point a second tangent Tg2, the two tangents Tgl and Tg2 being intersecting at a point of the median axis Am.
    [0026] The point angle θ corresponds to the angle formed by the tangents Tg1 and Tg2 and oriented towards the film 74 (ie downwards). To obtain the formation of a droplet, the tip angle θ must be less than or equal to a first threshold θ1.
    [0027] Thus, as illustrated in FIG. 7A, if the tip angle θ is greater than the first threshold θ1, the energy of the laser beam is not sufficient to generate a droplet. On the contrary, as illustrated in FIG. 7B, if the tip angle θ is smaller than the first threshold θ1, the energy of the laser beam is sufficient to generate a droplet. To obtain a quasi-zero kinetic energy at the moment when the droplet formed reaches the deposition surface 56 placed at a distance L from the free surface 78 of the film 74, the tip angle θ must be greater than or equal to a second threshold O 2. Preferably, the value of the tip angle θ is determined by taking a picture at the instant T1 of the deformation 86. According to one embodiment, the shooting is carried out by means of a camera whose axis aiming line is perpendicular to the vertical direction.
    [0028] The instant T1 is a function of the thickness of the film and varies very little from one ink to another. Advantageously, the instant T1 is of the order of 4 to 5 us since the impact of the laser beam for a film thickness E of the order of 40 to 50 μm. This moment T1 corresponds to FIG. 5B. The first threshold 01 is approximately equal to 1050. Thus, if at the instant T1 the point angle θ is less than or equal to 1050, the energy of the laser beam is sufficient to generate a droplet 82. The second threshold 02 is function of the distance L between the dispensing surface 56 and the free surface 78 of the film 74 of the ink. The second threshold 02 is inversely proportional to the distance L.
    [0029] The second threshold 02 is high and equal to approximately 80 ° for a low distance L of the order of 1 mm. The choice of a relatively small distance L will be preferred to reduce the stresses in the jet and at the moment of contact of the droplets with the dispensing surface. The second threshold 02 is low and equal to approximately 500 for a significant distance L of the order of 10 mm. The choice of a relatively large distance L will be preferred if it is desired to print at long distance, for example if the donor support 70 has larger dimensions than those of the well at the bottom of which the dispensing surface 56 is positioned.
    [0030] This technique of calibrating the energy of the laser beam makes it possible to optimize the speed of the jet by reducing it to limit the risk of damage to the elements contained in the ink, especially at the time of deposition on the deposition surface 56. Thickness of the Ink film: Preferably, the biological ink comprises a high concentration of printing elements 62 to obtain a biological tissue with a high concentration of cells. In this case, as illustrated in FIG. 3, the droplet 82 comprises a high volume fraction of elements to be printed 62. For high concentration biological inks, the thickness E of the film 74 is of the order of 40 to 60 μm. Advantageously, to improve the accuracy of the deposition of the elements to be printed, the film 74 of biological ink has a thickness E between 1.5D and 2D, where D is the diameter of the elements to be printed 62 which have an approximately spherical shape or the diameter a sphere in which a print element 62 is inscribed.
    [0031] According to one embodiment, the film 74 of biological ink has a thickness E greater than or equal to 20 μm for the smallest elements to be printed which have a diameter of the order of 10 to 15 μm. The thickness E of the film may be of the order of 400 μm when the elements to be printed 62 are aggregates of cells. Generally, the thickness E of the film is less than 100 μm when the elements to be printed 62 are unit cells. A printing technique combining a laser-type print head and a nozzle-type print head: According to another characteristic of the invention, the printing method uses at least one laser-type print head for at least a first biological ink and at least one nozzle print head for at least one second biological ink. This combination makes it possible to increase the production rate. By nozzle print head is meant a print head which includes an orifice through which the second biological ink passes. Thus, a nozzle-type print head may be an inkjet-type print head, a microvalve print head, a bioextrusion-type print head.
    [0032] Preferably, each laser-type print head is identical to that described in FIG. 3. However, the invention is not limited to this laser-type printing head. Thus, it is conceivable to use the laser-type printing heads described in FIGS. 1 and 2 or others.
    [0033] The nozzle-type print heads are no longer described because they are preferably identical to those of the prior art. In the case of a biological tissue comprising disjunct cells separated by extracellular materials, the extracellular materials are preferably deposited by the nozzle printing head (s) and the cells are preferably deposited by the head (s). (s) Laser type printing. Since extracellular materials are less sensitive to shear effects, it is possible to deposit them with a nozzle print head. The biological ink cartridges for nozzle-type printheads having a volume very much greater than the volume of ink (of the order of 400) supported by a donor support 70 for a laser-type printing head, it is possible to deposit the materials of the extracellular matrix with a high flow rate. Even if a nozzle-type print head is capable of depositing the inks with a high flow rate, each donor support intended for a laser-type printing head supporting a very small volume of ink, it is necessary to change them frequently. which tends to increase the time of removal compared to a nozzle print head. Printing device comprising a donor support storage chamber: In FIGS. 8 to 11, a printing device is shown according to one embodiment of the invention. This printing device comprises a frame 100 supporting a laser-type printing head 102 and a plurality of inkjet-type printing heads 104, 104 ', 104 ", which frame 100 comprises an X, Y, Z mark. , the Z axis being oriented in the vertical direction, the X, Y plane corresponding to a horizontal plane, the printing heads 102, 104, 104 ', 104 "are fixed with respect to the frame 100 and positioned in such a way that that the droplets are emitted vertically, upwards.
    [0034] The printheads 102, 104, 104 ', 104 "are offset in a first direction parallel to the Y axis. According to one embodiment, the jet-type printheads 104, 104', 104" ink are placed side by side. The laser-like print head 102 is spaced apart from the jet type printheads 104, 104 ', 104 "The printing device also comprises a movable frame 106, a moving frame guiding and moving system 106 relative to the frame 100 in three directions parallel to the axes X, Y, Z and a control system for controlling the movements of the moving frame 106. The guidance and displacement system and the control system are chosen so as to achieve a micrometric precision concerning the displacements of the mobile frame 106 with respect to the frame As illustrated in FIG. 10, the mobile frame 106 comprises a frame 108 for detachably fixing at least one receiving substrate 58. When it is secured to the frame mobile, the displacements of the receiving substrate 58 are controlled with a micrometric precision The laser-type printing head 102 comprises a cylindrical hollow body 11 0, fixed relative to the frame, which contains a portion of an optical system and which is surmounted by a tubular portion 112 which comprises an upper end 114 placed which opens in a horizontal plane. These elements are configured so that a laser beam guided by the optical system scans the section of the upper end 114. Each donor support 70 has the shape of a disk positioned on a base 116. According to one embodiment illustrated in Figure 11, each base 116 has the shape of a tube which comprises at its upper edge a recess 118 which has a diameter identical to that of a donor support 70 and a height sufficient to maintain it. Thus, this recess 118 makes it possible to position a donor support 70 with respect to the pedestal that receives it. The upper end 114 and the base 116 have shapes that cooperate with each other so that the base 116 is immobilized at a given position with respect to the upper end 114 and therefore relative to the X, Y, Z mark of the frame. According to one embodiment, the base 116 comprises an outer collar 120 which bears against the upper end 114 and makes it possible to position the base along the axis Z. Below the collar 120, the base 116 comprises a frustoconical surface 122 which cooperates with a frustoconical portion provided inside the tubular portion 112. These forms make it possible to center the base 116 relative to the tubular portion 112 and to position it in an XY plane. Preferably, it is possible to use magnetic materials to improve the positioning of the base 116 relative to the tubular portion 112. Advantageously, the printing device comprises an enclosure 124 configured to store at least one base 116. This enclosure 124 comprises at least one opening 125 for entering and leaving the base (s) 116 stored. According to one embodiment, this enclosure 124 has a parallelepipedal shape. Preferably, the enclosure 124 has dimensions adapted to be able to store several bases. Thus, the printing device can successively print several biological inks with the same laser-type printing head 102.
    [0035] The bases 116 are stored on a base 126 which comprises housings 128, a housing for each base 116. The base 126 has an elongate shape and comprises along its length notches 128 in U. According to a first variant illustrated in FIG. 9 , the length of the base 126 is oriented along the Y axis. According to a second preferred variant, the length of the base 126 is oriented along the X axis and the notches 128 are open in the direction of the printing heads. Advantageously, the enclosure 124 comprises, on a first face facing the printheads, a first opening 125 making it possible to extend the pedestals 116 and on another face a second opening 125 'making it possible to introduce the pedestals 116. According to one embodiment embodiment, the enclosure 124 comprises a guide system for positioning the base 126, for example a rail, the base 126 comprising in the lower part a groove whose section cooperates with that of the rail. This rail opens at the second opening 125 '. It is preferably oriented along the X axis. The enclosure 124 comprises confinement means for keeping inside the enclosure an atmosphere adapted to biological inks, in particular at temperature and / or hygrometry. These confinement means are provided in particular at each opening 125, 125 '. They can take the form of a barrier or an air curtain. In addition to the enclosure, the printing device comprises a mobile clamp 130 for moving the bases between the enclosure 124 and the laser-type printing head 102. In a first variant, the mobile clamp 130 is secured to a movable carriage 132, independent of the movable frame 106, which is configured to move in the directions X, Y, Z.
    [0036] According to another variant, the mobile clamp 130 is secured to the mobile frame 106. According to one embodiment, the printing device comprises a camera (not shown) whose line of sight is perpendicular to the vertical direction. and oriented at the upper surface of the donor support. This apparatus can be used to calibrate the energy of the laser beam of the laser-type print head 102. Process for producing a biological tissue by bio-printing: The first step of said method consists in generating a three-dimensional digital representation of the biological tissue to be printed. In FIG. 12, there is shown at 140 a part of such a representation in the form of a cube which comprises a first volume zone 142 placed inside a second volume zone 144 itself disposed in a third volume zone 146. For the purposes of the description, the representation 140 is greatly simplified. Each volume zone 142, 144, 146 is colored or textured differently, each color or texture corresponding to a set of characteristics among the following characteristics (not limited) material, means of manufacture, trajectory, ... Preferably, each color or texture corresponds to a biological ink. All volume zones 142, 144, and 146 are closed. Advantageously, the representation comprises a plurality of small elementary volumes that have different colors or textures depending on the volume zone to which they belong. According to one embodiment, the representation 140 is derived from a PLY type computer file. The second step of the method consists in slicing the representation 140 in a succession of superimposed layers along an axis Z. In FIG. 13, a layer 148 of the representation 140 is isolated.
    [0037] When slicing the representation 140, to the right of a volume zone change, each layer comprises an edge that corresponds to a zone change. As illustrated in FIG. 13, the layer 148 comprises a first zone 142 'which corresponds to the first volume zone 142, a second zone 144' which corresponds to the second volume zone 144 and a third zone 146 'which corresponds to the third zone For each layer, the zones 142 ', 144', 146 'are colored or textured according to the color or texture of the volume zones 142, 144, 146.
    [0038] Each layer has a thickness E which is determined according to the height of the printed droplets. If the layer comprises only one material to be printed, the layer has a thickness substantially equal to the height of a droplet.
    [0039] When the layer comprises several printing materials, according to a first variant, the layer has a thickness equal to the least common multiple of the droplet heights associated with each material. This variant has the advantage of minimizing the offset in the entire height of the object to be printed and resulting in a fast printing. According to a second variant, the layer has a thickness equal to the greatest common divider of the heights of the droplets associated with each material. This variant has the advantage of increasing the resolution and the number of layers. By way of example, if the first material is printed by laser bio-printing, the printed droplets have a height of the order of 10 μm. If the second material is printed by bio-printing microvannes, the printed droplets have a height of the order of 100 microns. According to the first variant, the layers have a thickness of the order of 100 μm. According to the second variant, the layers have a thickness of the order of 10 μm. Preferably, each layer comprises a plurality of small elementary polygons, for example triangular, which have different colors depending on the zone to which they belong.
    [0040] Thus, the object to be printed corresponds to a set of layers each comprising a set of polygons each having an associated color or texture. A third step of the method consists in determining for each layer the position of the droplets to be printed of each biological ink as a function of the zones 142 ', 144', 146 'which are colored or textured and the expected volume of each of the droplets. For this purpose, each zone 142 ', 144', 146 'of each layer is filled with ellipses 142 ", 144", 146 "whose dimensions are a function of the droplet size of the biological ink to be printed in said zone, as illustrated in Figure 14. For each zone, the ellipses have the same dimensions All ellipses have parallel focal axes.
    [0041] The elliptical shape makes it possible to adapt the distances between the droplets in two directions (a first direction parallel to the focal axes and a second direction perpendicular to the first direction).
    [0042] The center of each ellipse corresponds to the position of the center of a droplet. The positioning of the ellipses is zone by zone, in decreasing order of size. Thus, the largest ellipses arranged in the zone 146 'are positioned first and the smallest ellipses arranged in the zone 142' are positioned last.
    [0043] Preferably, at the level of a zone change, optimization of the positioning is done according to two criteria: maximum ratio of elementary polygons having the right color or texture within an ellipse, of the order of 75% for example , Minimum ratio of elementary polygons having the wrong color or texture within an ellipse, of the order of 5% for example. Overlaps between ellipses can be tolerated. A fourth step of the method is to synchronize the displacement of the dispense surface 56 on which the organic ink droplets are printed and the different print heads.
    [0044] For laser bio-printing, the focus area of the laser is the center of each laser-printed ellipse, and each ellipse is laser pulsed. In this case, the removal surface is fixed, it is the laser that sweeps the entire removal surface. For a larger dispensing surface than the donor support, it is possible to also move the substrate (on which the dispensing surfaces are reported) synchronously with the scanning of the laser. For a nozzle bio-printing, the center of each ellipse corresponds to the supposed point of impact of a droplet on the dispense surface 56. In this case, the printing nozzle is fixed, it is the substrate which is moves. However, the print nozzle could be mobile. Applications: The bio-printing according to the invention can be used to produce: implantable tissues for regenerative medicine, individualized tissues, made from the patient's cells, for selecting in vitro treatments and developing personalized therapeutic solutions Predictive models that reproduce the physiology of healthy human tissues or pathologically-affected tissues to predictively test the efficacy or toxicity of drug molecules, ingredients, and candidates. By way of example and without limitation, the biological tissue is bone tissue.
    [0045] Although described applied to biological inks, the invention is not limited to this application. Thus, the method and the device according to the invention can be used to print any liquid ink, in the form of solution or suspension. Other inks which may be used include, but are not limited to, inks used in coatings in electronics, materials or watches.
    [0046] By way of example and in a nonlimiting manner, the inks may be composed of: precious metals (in particular gold, silver, platinum, rhodium and palladium) or semi-precious metals (of titanium, zirconium, of copper), functional alloys, organic materials, sol-gel systems, ceramics or microcomposites or nanocomposites. These different materials allow to realize different types of coatings: Anticorrosions, With high chemical resistance, Biofunctional (antibacterial, antimicrobial, biocompatible), For food contact, Modifying the surface energy, Non-stick, Electrotechnical (insulating, antistatic or conductive) , Anti-wear, Modifying the optical properties (anti-reflective, photo-catalytic, IR / UV barrier), Modifying the haptic sense, Allowing to reduce the coefficient of friction, Allowing to increase the durability at high temperature, ..
    权利要求:
    Claims (13)
    [0001]
    REVENDICATIONS1. A method of printing at least one ink, said method comprising a step of focusing a laser beam (66) to generate a cavity in an ink film (74), a step of forming at least one ink a droplet (82) of ink from a free surface (78) of the ink film (74) and a step of depositing said droplet (82) on a depositing surface (56) of a receiving substrate (58) positioned at a given distance (L) from the film (74), characterized in that the laser beam (66) is oriented in the opposite direction to the gravitational force (G), the free surface (78) of the film being facing upwardly toward the dispensing surface (56) positioned above the ink film (74).
    [0002]
    Printing method according to claim 1, characterized in that the distance (L) between the ink film (74) and the application surface (56) and / or the energy of the laser beam (66) is adjusted so that the kinetic energy of the droplet is almost zero when the droplet (82) touches the drop surface (56).
    [0003]
    The printing method according to claim 2, characterized in that the distance (L) between the ink film (74) and the application surface (56) is 1 to 2 mm and that the energy the laser beam (66) is adjusted so that the kinetic energy of the droplet is almost zero when the droplet (82) touches the drop surface (56).
    [0004]
    4. Printing method according to any one of the preceding claims, characterized in that the printing method comprises a preliminary phase of calibration of the energy of the laser beam which comprises a step of measuring a peak angle ( 0) deformation (86) of the free surface (78) of the ink film (74) at a fixed instant (T1) after the impact of the laser beam (66) and a step of adjusting the energy of the laser beam (66) as a function of the measured value of the peak angle (0).
    [0005]
    Printing method according to claim 4, characterized in that the energy of the laser beam is adjusted so that the tip angle (θ) is less than or equal to 105 °.
    [0006]
    Printing method according to claim 4 or 5, characterized in that the energy of the laser beam is adjusted so that the tip angle (0) is greater than or equal to a second threshold to obtain an energy almost zero kinetics at the moment when the droplet formed reaches the depositing surface (56).
    [0007]
    Printing method according to claim 6, characterized in that the second threshold is a function of the distance (L) between the depositing surface (56) and the free surface (78) of the ink film (74). .
    [0008]
    8. Printing method according to claim 7, characterized in that the second threshold is approximately 800 for a distance (L) of the order of 1 mm.
    [0009]
    9. Printing method according to one of claims 4 to 8, characterized in that the instant (T1) of measuring the tip angle (0) is of the order of 4 to 5 lis from the impact of the laser beam (66).
    [0010]
    10. Printing method according to one of the preceding claims, characterized in that the ink film has a thickness greater than 20 iim.
    [0011]
    11. Printing method according to one of the preceding claims, characterized in that the ink film has a thickness between 40 and 60 iim for biological inks with a high concentration of printing elements (62).
    [0012]
    Printing method according to one of claims 1 to 10, characterized in that for a biological ink with a low concentration of printing elements (62), the film (74) of biological ink has a thickness of between 1.5D and 2D, where D is the diameter of the elements to be printed (62) that have an approximately spherical shape or the diameter of a sphere in which a print element (62) is inscribed.
    [0013]
    Printing device for carrying out the printing method according to one of the preceding claims, said printing device comprising: at least one pulsed laser source (64), configured to emit a laser beam (66) ), - an optical system (68) for focusing and orienting said laser beam (66), - at least one donor support (70) on which is affixed a film (74) of at least one ink with a free surface (78) ), and - at least one receiving substrate (58) comprising a depositing surface (56) positioned at a given distance (L) from the film (74), characterized in that the laser beam (66) is oriented in the opposite direction to to the gravitational force (G) and that the free surface (78) of the film is upwardly directed towards the depositing surface (56) placed above the ink film.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP3233499B1|2019-05-22|Laser printing method, and device for implementing said method
    EP3234102B1|2018-06-27|Method for laser printing biological components, and device for implementing said method
    EP3595592B1|2021-11-03|Equipment and method for additive manufacturing
    FR2892962A1|2007-05-11|FEMTOSECOND LASER MICROTOME FOR LASER BEAM CUTTING OF A MATERIAL WAFER, IN PARTICULAR IN A CORNEA
    EP3661754B1|2021-07-07|Print head of a printer, printer and printing method
    EP3393820B1|2021-09-22|Process for producing, by etching through a lenticular grating, images that may be selectively viewed by varying angle of observation
    BE1025341B1|2019-02-04|METHOD FOR STRUCTURING A SUBSTRATE
    FR3093944A1|2020-09-25|CARTRIDGE FOR BIOIMPRESSION
    EP3628034B1|2020-11-25|System for depositing material and associated method
    EP3595904B1|2021-05-05|Apparatus and method for depositing particles on a target
    JP2006103220A|2006-04-20|Nozzle plate of inkjet printer and its production method
    FR3102377A1|2021-04-30|Equipment and process for deposition by projection of particles by laser shock waves
    同族专利:
    公开号 | 公开日
    KR20170102481A|2017-09-11|
    FR3030360B1|2018-07-13|
    JP2018507793A|2018-03-22|
    CN107206788B|2019-03-19|
    EP3233499A1|2017-10-25|
    ES2733372T3|2019-11-28|
    US10112388B2|2018-10-30|
    CN107206788A|2017-09-26|
    EP3233499B1|2019-05-22|
    WO2016097619A1|2016-06-23|
    US20170368822A1|2017-12-28|
    JP6706620B2|2020-06-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE3702643A1|1986-02-10|1987-08-13|Toshiba Kawasaki Kk|INK NIBLE PEN AND WRITING HEAD AND WRITING HEAD CASSETTE DAFUER|
    JPS62191157A|1986-02-17|1987-08-21|Toshiba Corp|Recording apparatus using thermal ink jet system|
    US5521140A|1993-10-22|1996-05-28|Sony Corporation|Recording unit structure and recording device|
    WO2003056320A2|2001-12-28|2003-07-10|Foundation For Research And Technology Hellas |Fabrication of biopolymer patterns by means of laser transfer|
    US20080117255A1|2006-11-20|2008-05-22|Roger Steven Cannon|Radiation Activated Micro-Fluid Ejection Devices and Methods for Ejecting Fluids|
    WO2011107599A1|2010-03-04|2011-09-09|INSERM |Bioprinting station, assembly comprising such bioprinting station and bioprinting method|
    JPS61118273A|1984-11-15|1986-06-05|Erumu:Kk|Laser type ink jet printer|
    JPH02266985A|1989-04-10|1990-10-31|Asahi Chem Ind Co Ltd|Thermal transfer sheet for laser recording and image recording method using the same|
    JP2841674B2|1990-03-30|1998-12-24|凸版印刷株式会社|Laser thermal transfer recorder|
    JP3637629B2|1994-10-21|2005-04-13|ソニー株式会社|Recording method|
    JPH10151860A|1996-03-07|1998-06-09|Konica Corp|Image forming material, its manufacture, and image forming method using the material|
    JP2003191656A|2001-12-26|2003-07-09|Dainippon Printing Co Ltd|Intermediate transfer recording medium and card production method|
    JP4107198B2|2002-11-20|2008-06-25|セイコーエプソン株式会社|Droplet ejection device, droplet ejection method, and electro-optical device|
    FR2881373B1|2005-02-01|2008-08-22|Centre Nat Rech Scient|DETECTION SYSTEM FOR OFFSET PRINTING AND MACHINE USING THE SAME|
    CA2616865C|2005-07-28|2014-07-08|Carnegie Mellon University|Biocompatible polymers and methods of use|
    JP4782626B2|2006-07-07|2011-09-28|静岡県|Laser marking method|
    KR101063040B1|2009-07-28|2011-09-07|포항공과대학교 산학협력단|Micromachining method using laser and its device|
    EP2943205B1|2013-01-14|2018-08-22|Scripps Health|Tissue array printing|
    FR3030361B1|2014-12-17|2017-01-20|Univ Bordeaux|METHOD FOR PRINTING BIOLOGICAL ELEMENTS BY LASER AND DEVICE FOR IMPLEMENTING SAID METHOD|FR3030361B1|2014-12-17|2017-01-20|Univ Bordeaux|METHOD FOR PRINTING BIOLOGICAL ELEMENTS BY LASER AND DEVICE FOR IMPLEMENTING SAID METHOD|
    FR3063931B1|2017-03-15|2019-03-22|Poietis|EQUIPMENT AND METHOD FOR ADDITIVE PRINTING|
    FR3063930B1|2017-03-15|2019-03-22|Poietis|BIOIMPRESSION PROCESS|
    FR3063929B1|2017-03-15|2019-03-22|Poietis|EQUIPMENT FOR BIO-INK TRANSFER|
    FR3063932B1|2017-03-15|2019-03-22|Universite de Bordeaux|EQUIPMENT AND METHOD FOR PARTICLE DEPOSITION ON A TARGET|
    FR3082123B1|2018-06-07|2020-10-16|Urgo Rech Innovation Et Developpement|CELLULARIZED DRESSING AND ITS MANUFACTURING PROCESS|
    FR3087703B1|2018-10-25|2020-12-04|Poietis|ROBOTIZED BIO-PRINTING SYSTEM|
    FR3093944B1|2019-03-22|2021-03-19|Poietis|CARTRIDGE FOR BIOIMPRESSION|
    CN110690300B|2019-10-21|2021-10-22|华南理工大学|Laser-induced transfer printing method for electrode grid line of photovoltaic solar cell|
    US20210370702A1|2020-05-27|2021-12-02|Ricoh Company, Ltd.|Light irradiation method, light absorbing material attaching apparatus, flying body generating method and apparatus, image forming method, and three-dimensional object producing method|
    法律状态:
    2015-12-23| PLFP| Fee payment|Year of fee payment: 2 |
    2016-06-24| PLSC| Publication of the preliminary search report|Effective date: 20160624 |
    2016-12-22| PLFP| Fee payment|Year of fee payment: 3 |
    2017-11-27| PLFP| Fee payment|Year of fee payment: 4 |
    2019-12-16| PLFP| Fee payment|Year of fee payment: 6 |
    2020-12-16| PLFP| Fee payment|Year of fee payment: 7 |
    2021-12-30| PLFP| Fee payment|Year of fee payment: 8 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1462568|2014-12-17|
    FR1462568A|FR3030360B1|2014-12-17|2014-12-17|LASER PRINTING METHOD AND DEVICE FOR IMPLEMENTING SAME|FR1462568A| FR3030360B1|2014-12-17|2014-12-17|LASER PRINTING METHOD AND DEVICE FOR IMPLEMENTING SAME|
    KR1020177018692A| KR20170102481A|2014-12-17|2015-12-17|Laser printing method, and device for implementing said method|
    JP2017531541A| JP6706620B2|2014-12-17|2015-12-17|Laser printing method and apparatus for implementing the method|
    ES15837086T| ES2733372T3|2014-12-17|2015-12-17|Laser printing procedure and device for implementation|
    EP15837086.6A| EP3233499B1|2014-12-17|2015-12-17|Laser printing method, and device for implementing said method|
    PCT/FR2015/053569| WO2016097619A1|2014-12-17|2015-12-17|Laser printing method, and device for implementing said method|
    US15/536,541| US10112388B2|2014-12-17|2015-12-17|Laser printing method and device for implementing said method|
    CN201580073859.8A| CN107206788B|2014-12-17|2015-12-17|Laser printing method and device used to perform the method|
    [返回顶部]