Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/30—Auxiliary operations or equipment
  • B29C64/379—Handling of additively manufactured objects, e.g. using robots
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/30—Auxiliary operations or equipment
  • B29C64/364—Conditioning of environment
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
  • B29C64/205—Means for applying layers
  • B29C64/209—Heads; Nozzles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
  • B29C64/227—Driving means
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
  • B29C64/25—Housings, e.g. machine housings
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
  • B29C64/264—Arrangements for irradiation
  • B29C64/268—Arrangements for irradiation using laser beams; using electron beams [EB]
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/30—Auxiliary operations or equipment
  • B29C64/307—Handling of material to be used in additive manufacturing
  • B29C64/321—Feeding
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/30—Auxiliary operations or equipment
  • B29C64/386—Data acquisition or data processing for additive manufacturing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
  • B29C64/30—Auxiliary operations or equipment
  • B29C64/386—Data acquisition or data processing for additive manufacturing
  • B29C64/393—Data acquisition or data processing for additive manufacturing for controlling or regulating additive manufacturing processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y30/00—Apparatus for additive manufacturing; Details thereof or accessories therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y50/00—Data acquisition or data processing for additive manufacturing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y50/00—Data acquisition or data processing for additive manufacturing
  • B33Y50/02—Data acquisition or data processing for additive manufacturing for controlling or regulating additive manufacturing processes
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
  • C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M37/00—Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C2791/00—Shaping characteristics in general
  • B29C2791/004—Shaping under special conditions
  • B29C2791/005—Using a particular environment, e.g. sterile fluids other than air
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y10/00—Processes of additive manufacturing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B33—ADDITIVE MANUFACTURING TECHNOLOGY
  • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
  • B33Y70/00—Materials specially adapted for additive manufacturing

Definitions

• the present invention relates to the field of regenerative medicine making it possible to artificially produce biological organs and tissues, designated by "tissue engineering".
• tissue engineering The need for tissue and organ transplants has increased dramatically worldwide over the past decade. The main reasons are the increase in life expectancy, the incidence of vital organ dysfunction and degenerative diseases, and the need to offset the consequences of tumor removal. Due to this organ shortage, in the European Union alone, more than 63,000 patients are waiting for an organ transplant (kidney, liver, heart, cornea ...), and 6 new patients are added every hour. waiting lists. In contrast, only about 33,000 donors were identified in 2016. While some countries are taking steps to increase the number of organ donations, many patients awaiting transplants will not receive them in time. Clinicians therefore need tissue and organ replacements that are fully characterized and secure, specific to a given patient and potentially "off the shelf".
• tissue engineering products belong to the Therapeutic Drug category Investment (MTI). They are distinct from conventional pharmaceuticals and therefore present unique challenges. They require quality assurance and complex logistics, and must be transplanted into patients by qualified surgeons, while meeting important regulatory requirements such as the regulation of Medicines for innovative Therapies (ITNs) as well as Good Laboratory Practices ( GLP) and Manufacturing (BPF).
• ITNs Intelligent Therapies
• GLP Good Laboratory Practices
• BPF Manufacturing
• Tissue engineering approaches are traditionally based on the use of biocompatible materials, shaped to form a 3D scaffold (“scaffold”) on which live cells are seeded before their maturation in a bioreactor. So, as cells multiply, they populate the scaffold and synthesize an extracellular matrix to create 3D tissue.
• tissue engineering products Despite substantial investments to meet clinical and commercial expectations, and while scientific achievements at the preclinical research stage have been impressive, these traditional tissue engineering approaches struggle to both deliver clinical results and become profitable . Indeed, a very small number of tissue engineering products have obtained their marketing authorization to date, and even in these cases, the therapeutic benefit did not meet expectations and marketing was not profitable. . This is illustrated by the fact that three of these ITNs have been withdrawn from the market, despite sufficient safety and efficiency: Provenge® (2015), Chondrocelect® (2016) and MACI® (in suspension). To meet clinical and commercial expectations, the manufacture of tissue engineering products is therefore subject to several challenges that must be resolved. These relate to:
• the ability to personalize tissue engineering products in order to offer specific treatments to a patient for example by integrating autologous cells and / or patient anatomical data.
• bio-printing To overcome the limits of traditional tissue engineering approaches, different bio-printing approaches have been proposed. According to the works, these printing processes are called bio-printing, micro-printing of elements biological or bioprinting in English. These use the principles of 3D printing, and proceed by layer-by-layer assembly of the constituents of biological tissues (such as cells and the extracellular matrix) according to organizations predefined by digital design. Despite the analogies in principle, it should be pointed out that bio-printing differs from the manufacture of prostheses by 3D printing by the nature of the material deposited (living and not inert) as well as by the technologies used.
• bio-printing concerns the preparation of synthetic living tissues for experimental research, replacing tissues taken from living beings, in order to avoid regulatory and ethical problems.
• bio-printing will make it possible to produce organs for transplantation without the risk of rejection, for example of the epidermis, bone tissues, kidney parts, liver as well as other vital organs, heart valves or hollow structures such as vascular structures.
• the global 3D bioprinting market was estimated at € 450 million in 2014 and is expected to increase significantly over the next decade at an annual growth rate of approximately 16.7%, reaching 8, 2 billion euros by 2025 1. According to analysts 2, the medical segment of the bio-printing market should dominate in 2022 with more than 30.0% thanks to the introduction of manufacturing-compatible bio-printers from MTI.
• the delivery system also includes a sterilizable enclosure and at least one robotic arm assembly and a delivery device within the sterilizable chamber.
• the robotic arm is configured to move the dispensing device comprising a first dispensing member and a second dispensing member, the first dispensing member being removably connectable to the second dispensing member.
• Figures 10 and 11 of this patent mainly relate to the handling of well plates, with a print head and the activation module both housed in the sterile enclosure unlike the invention.
• a material dispenser intended to place said material on the table to form said object
• Patent application US2018290386 describes a process of the prior art with steps for creating pharmaceutical products by a 3D printer.
• a product is printed according to the instructions.
• At least one attribute of the product is measured and compared to the desired attributes of the desired end product. If there is a difference between the product attributes and the desired attributes, changes are made to the instruction set and a new product is printed. When there is a match between product attributes and desired attributes, a safe and precise medical product has been created.
• Patent application US2017320263 describes a process for printing at least one biological ink, said process using at least one laser type print head to deposit at least one droplet of at least one biological ink on a deposition surface of a receiving substrate, characterized in that the printing method uses at least one nozzle printing head to deposit at least one droplet of at least one biological ink on a surface for depositing the same receiving substrate as the head laser type printing.
• Patent application US2016297152 relates to a sterilizable container intended to receive one or more bioactive fluid (s) and / or one or more preparative fluid (s) comprising:
• an area inside the container configured to receive at least one set of sterilizable 3D printer
• a set of sterilizable 3D printer including:
• the presence in the sterile chamber of mechanical equipment leads to the production of microparticles which are transported by the air flow in the bio-printing space, which goes against the intended objective.
• the printing means are directly integrated into the sterilizable area.
• these elements are among the main contributors to particulate pollution in confined spaces.
• the present invention relates to a method and an installation for the production by bioimpression of a biological tissue using three distinct modules:
• An activation module (a laser, a transducer, 7) for the transfer to a target of biological objects via the print head, imperatively placed outside the sterilizable enclosure
• a module for moving the print head relative to the target positioned either inside or outside the sterilizable enclosure.
• the enclosure includes an interaction zone with the activation module.
• the invention particularly relates to a method and an installation for additive printing of biological tissues by unit deposition on a target of elements comprising living cells, as well as other constituents making it possible to reconstitute living biological tissue.
• a bio-printing system according to claim 1, and optionally including technical characteristics of a dependent claim, taken in isolation or in technically feasible combination of other characteristics described below.
• the object of the invention is to transfer from a source to a target objects of biological interest, comprising living cells (for example pluripotent stem cells or any other differentiated cells), sometimes of different types, as well as products biological materials such as collagen and more generally extracellular matrix materials.
• Objects of biological interest can be brought together in a fluid to form a “bio-ink” containing biological particles such as for example living cells. These bio-inks are then prepared and packaged in a sterile form, so that they can be used to print biological tissue when the time comes.
• Bioprinting means, within the meaning of this patent, the spatial structuring of living cells and other biological products, by a process achieving geometric structuring, in particular a stack of layers formed by individualized deposits of objects of biological interest, assisted by computer to develop living tissues and organs for tissue engineering, for regenerative medicine, pharmacokinetics and more generally research in biology.
• Bioprinting involves simultaneously depositing living cells and biomaterials layer by layer to make living tissue such as artificial structures of the skin, heart valves, cartilage, heart tissue, kidneys, liver and on other vital organs or hollow structures such as the bladder as well as vascular structures.
• the invention also relates to a cassette for a bioprinting system mentioned above, characterized in that it is constituted by a closed sterilizable enclosure constituting the envelope of a printing module.
• the invention also relates to a bioprinting process for the manufacture of a structured biological material, from materials at least part of which consists of biological particles (cells and cellular derivatives) consisting in controlling the movement of at least one target by means of a robot in three dimensions opposite at least one printhead placed in a closed and sterile enclosure, said printhead being supplied and controlled from outside of said enclosure in order to guarantee the safety of the fabric produced with regard to the regulatory requirements of the clinical area.
• FIG. 1 shows a schematic view of a first variant of a bio-printer according to the invention
• FIG. 2 shows a schematic view of a second variant of a bio-printer according to the invention
• FIG. 3 shows a schematic view of a third variant of a bioprinter according to the invention.
• FIG. 4 shows a schematic view of a fourth variant of a bioprinter according to the invention.
• FIG. 5 shows a schematic view of a fifth variant of a bioprinter according to the invention.
• FIG. 6 shows a perspective view from the front of an embodiment of the invention
• FIG. 7 shows a perspective view, from the side of an embodiment of the invention.
• FIG. 8 shows a schematic view of an alternative embodiment in the form of a rigid cassette
• FIG. 9 shows a schematic view of an alternative embodiment in the form of a flexible cassette
• FIG. 10 shows a view of an installation according to the invention with a sterile glove box
• FIG. 11 shows a view of an installation according to the invention with a sterile glove box
• FIG. 12 shows a view of an installation according to the invention with an alpha transfer system with secure interlocking with a beta type container.
• FIGS. 1 to 5 show views of alternative embodiments of the hardware architecture of a bioprinter according to the invention. It is composed of several essential organs:
• An additive printing head (1) whose configuration depends on the technology used, comprising a bio-ink transfer zone made up of objects of biological interest and a target (6).
• One or more sources (2) for supplying the additive printing head (1) with bio-ink consisting of objects of biological interest •
• bio-printing head means the part of the bio-printing system formed by the support receiving the bio-still or more generally objects of biological interest to transfer to the target, and presenting the exit zone of the objects of biological interest towards the target, but not including the activation means, for example:
• the bioprinting head does not include the laser and the optical components for pulsed laser bioprinting
• the bioprinting head does not include the means of electrical generation which activate the actuator (valve / piezo)
• the bio-printing head does not include syringe pumps
• print head (1) constituted by the terminal part of the equipment, receiving the bio-ink and / or the objects of biological interest to be transferred as well as the interfaces for transfer activation organs
• activation means (5) physically separable from the print head (1), and mechanically, electrically, acoustically or optically couplable with the bio-print head (1) , comprising all of the means making it possible to control the physical transfer of an object of biological interest present in the bioprinting head to the target.
• the invention aims to optimize the sterile area, and for this: a) the print head (1) is imperatively placed in a sterilizable enclosure (10),
• a sealed interaction zone (20) allows the activation of the print head (1) by the printing means (5).
• the other components of the bio-printer can be placed in the sterilizable enclosure (10) or outside this enclosure (10).
• the power source (2) can be associated with the print head (1) in the sterilizable enclosure (10), which then forms a cassette which can be introduced into a bio-printer, then removed for the maturation of the printed fabric.
• the mechatronic assembly (3) for moving the target (6) relative to the source can also be associated with the print head (1) inside the sterilizable enclosure (10), with or without the power source (2).
• the maturation chamber (4) can also be associated with the print head (1) inside the enclosure (10), with or without the power source (2) and / or the mechatronic assembly. (3) displacement.
• the invention can be implemented in different ways.
• FIG. 1 represents a generic view where the sterilizable enclosure (10) contains:
• the supply source (2) for example the bio-ink tank and the supply system, which, according to the invention can also be arranged in a non-sterile area, with a connector for the sterile transfer of objects of biological interest in the sterilizable enclosure (10) -
• the displacement means (3) of the print head (1) which, according to the invention can also be arranged in a non-sterile area, with a sterile mechanical connector.
• the activation means (5) for example the laser and the associated optical components, is arranged below this sterilizable enclosure (10), a transparent window (20) forming the interface allowing the passage of the light beams.
• the activation means (5) is not disposed in a sterile area.
• FIG. 2 represents a variant in which all the constituents, with the exception of the activation means (5), are placed in the sterilizable enclosure (10).
• FIG. 3 represents a variant in which all the constituents, with the exception of the activation means (5) and the displacement means (3) of the print head (1), are placed in the sterilizable enclosure (10 ).
• the coupling between the print head (3) and the displacement means (3) is carried out for example by a magnetic transmission or by a sterile articulation crossing the wall of the sterilizable enclosure (10).
• FIG. 4 shows a variant in which only the print head (1) and a maturing zone (4) are placed in the sterilizable enclosure (10). All the other constituents, in particular the activation means (5) and the displacement means (3) as well as the power source (2) are outside the sterilizable enclosure.
• FIG. 4 represents a variant in which only the print head (1) and a maturation zone (4) are placed in the sterilizable enclosure (10), as well as the displacement means (3). All the other constituents, in particular the activation means (5) and as well as the power source (2) are outside the sterilizable enclosure.
• FIG. 5 represents a variant in which the print head (1), a maturation zone (4) and the robotic arm (3) ensuring the relative movement of the print head (1) relative to the target, are placed in the sterilizable enclosure (10. Only the activation means (5) and the power source (2) are outside the sterilizable enclosure.
• the bio-printer consists of a chassis, the lower part (11) of which cannot be sterilized, contains the activation means (5), for example the optical head, the laser and the imaging systems for a laser printer.
• This frame is surmounted by a sterilizable enclosure (10) constituted by a positive pressure chamber supplied by a blower (15) via a filter cartridge (16).
• a robotic arm (3) placed in this sterilizable enclosure (10) ensures the movement of a target (6) relative to a print head (1).
• a sealed window (20) allows the transmission of the laser beam and of the imaging beams between the sterilizable enclosure (10) and the printing means (5) placed in a non-sterilizable area.
• the enclosure (10) is closed by a glass wall (22) crossed by interfaces (21) for sterile handling gloves.
• GMP Good Manufacturing Practices
• the sterilizable enclosure (10) has, according to a variant not illustrated, a control mechanism for a sealed device making it possible to perform these tasks in an aseptic or dust-free atmosphere, inside this enclosure, for manual handling of objects or products.
• the wall of the enclosure (10) has for example a flange whose outer periphery is equipped with ears intended to cooperate with an imprint of the flange of the glove box.
• the enclosure flange (10) is inserted into the glove box flange.
• the sterilizable enclosure (10) can also include a hatch mounted in a flange for communication with another sterilizable enclosure, for example for maturation after printing.
• the bioprint isolation system is based on a sterilizable cassette containing the target (6) and the print head. It consists of sterile / sealed interfaces (DPTE door, beta- bag, optical window, injector) allowing it to be connected to at least one supply source for objects of biological interest transferable for printing, to one or more activation means, to a mechanical coupling means for moving the target (6) in relation to the head and to the elements necessary for maturation (culture media, C02, 02, ).
• the cassette can be used for maturation. It is transportable between the printing system and an incubator.
• the power source for transferable objects of biological interest for the printing process can be connected to a cell culture machine constituted by a dedicated tank.
• the cassette is coupled to means for characterizing the tissue or the organ (online characterization of the tissue during manufacture or after its manufacture (imaging, Raman spectroscopy, OCT, physico-chemical analysis).
• the cassette can provide a single window, several windows, windows on both sides (front and rear sides) etc.
• the system optionally includes, for the maturation phase (bioreactor), means of control and regulation of the following elements:
• the cassette optionally includes an identifier of the fabric to be printed and associated printing parameters (sequence, sources, CAD model, etc.) linked to databases (connected cassette).
• the identifier can be of graphic type (for example barcode or QRcode matrix code) or digital, for example in the form of a digital sequence recorded in a memory of an RFT type radio frequency label.
• a network interface card such as an Ethernet port, for controlling the manufacturing and data acquisition process, for managing alarms, for saving the experience on local hard disk, for informing the user in real time by SMS, e-mail ...
• FIGS 10 and 11 illustrate examples of installation with glove boxes (25).
• the laser printing module (1) consists of at least one laser head and one target (6).
• the laser head consists of a transparent flat surface (also called donor) on which an ink film is deposited.
• the ink supply source (2) of said head is constituted either by a reservoir which has been placed in the sterile enclosure thanks to the use of a SAS (manual spreading of ink on the surface of the donor thanks to the waterproof glove or thanks to the robot associated with a pipettor) either by a tank and a pump (working in pressure or in flow) located outside of the enclosure (automatic spreading of the ink by fluidic means).
• the activation means (5) for transferring the ink to the target (6) consists of a laser located outside the enclosure.
• the sealed interaction means (20) is in this case a sealed optical window transparent to the wavelength of the laser.
• the means (3) for relative movement of the print head relative to the target (6) consists of a 6-axis robotic arm.
• the printing module by microvalve (1) consists of a target and one or more valves fitted with a needle that can have different shapes, lengths and opening diameters (6).
• the ink supply source (2) for said valve consists of a reservoir and a pressurization pump located outside the enclosure.
• the activation means (5) for transferring the ink to the target (6) consists of a shutter, of the piezoelectric type or a solenoid.
• the sealed interaction means (20) can in this case be a connector, a perforable cover (septum) or a sealed joint.
• the means (3) for relative movement of the print head relative to the target (6) consists of a 6-axis robotic arm.
• the extrusion printing module (1) consists of a target and a final reservoir equipped with a needle that can have different shapes, lengths and opening diameters (6).
• the ink supply source (2) of said extruder is constituted by an initial reservoir and a pressurizing pump located outside the enclosure.
• the activation means (5) for the transfer of said biological objects to the target (6) consists of the pressurization system.
• the sealed interaction means (20) can in this case be a connector, a perforable cover (septum) or a sealed joint.
• the means (3) for relative movement of the print head relative to the target (6) consists of a 6-axis robotic arm.
• a dermis consisting of an alternation of layers of biomaterials (collagen type) printed either by microvalve or by extrusion and of cellular layers (fibroblast type) printed by laser.
• the precision of the cellular patterns makes it possible to ensure a structure and a function of the dermis close to that of a native skin after maturation.
• An epidermis consisting of a layer at the confluence of cells (keratinocyte type) printed by laser.
• This dermis is carried out in an incubator either inside or outside the sterile enclosure depending on the layout of said incubator. At the end of this stage, the skin has reached maturity and can be implanted in a patient.
• the cassette configuration is particularly suitable for the manufacture of one or more tissues or biological organs, intended for example for the manufacture of autologous tissues.
• a tissue or an organ can be based on the use of several cassettes for reasons of differentiated maturation, of compatibility of the printing module with a single type cellular,...
• Another advantage of the cassette lies in the fact that it can be introduced into the operating room after a final sterilization step and opened as close as possible to the patient.
• the substrate could be encapsulated in a module removable from the cassette in order to be placed in a dedicated bioreactor.
• the cassette can be all or part for single use.
• the cassette can be reused after internal and external sterilization.
• the casing of the cassette can be rigid or flexible (ethylene vinyl acetate, PVC, thermoplastics of the PU type, low density polyethylene, of the transfusion materials type, silicone, metallic (stainless steel 304L, 316L) or plastic (polycarbonate for example).
• rigid or flexible ethylene vinyl acetate, PVC, thermoplastics of the PU type, low density polyethylene, of the transfusion materials type, silicone, metallic (stainless steel 304L, 316L) or plastic (polycarbonate for example).
• FIG. 4 represents an exemplary embodiment of the invention in the form of a rigid cassette. It allows the use of main equipment consisting of complex and costly parts, namely the activation means with one or more printheads, for example laser, a means (3) for relative movement of the printhead by relative to the target (6) and all of the computer and optical means.
• the cassette consists of a sterilizable closed enclosure (10) configured to allow its positioning on this equipment for a specific operation.
• the cassette contains in the closed and sterilizable enclosure
• connecting rods 131, 132, 133 ensuring the coupling with the relative displacement means and passing through the enclosure (10) by watertight seals (134, 135, 136).
• These connecting rods (131, 132, 133) are intended to transmit the movements of the relative displacement members of the target (6) relative to the source along the three axes X, Y, Z,
• the printing module (1) which is constituted by a medium for the flow of a fluid carrying the transferable objects of biological interest with a supply conduit (141) and an outlet conduit (142), connected to tanks (143, 144) outside the enclosure (10).
• Said activation means (5) is located outside of said sterilizable closed enclosure (10) and interacts with the printing module (1) via a window (140).
• This cassette makes it possible to prepare a tissue by positioning it on the main equipment, then ensuring the maturation of the bio-printed tissues in another site, for example in a maturation enclosure.
• FIG. 5 represents an exemplary embodiment of the invention in the form of a flexible cassette. It differs from the rigid cassette in that the sterilizable enclosure has flexible walls (200) connecting an upper rigid face (210) and a rigid lower face (220), presenting the window (140).
• the upper face has two claws (211, 212) located inside the sterilizable enclosure, to receive the target (6) on which are deposited the biological elements transferred from the bio-ink consisting of transferable objects of biological interest (148).
• bio-printer is traditionally composed of several essential organs:
• one or more printheads comprising a bio-ink transfer zone made up of objects of biological interest
• the biological ink is stored in a reservoir and passes through nozzles or capillaries to form droplets which are transferred to a target (6).
• This first so-called nozzle printing variant includes bioextrusion, inkjet printing or microvalve printing.
• a method for printing biological elements without a nozzle has been developed.
• This printing process called bio-printing by laser is also known as "Laser-Assisted Bioprinting” (LAB) in English.
• bioextrusion different means of activating printing have been implemented: a worm, a piston or a pneumatic system. It allows you to work with a high cell density of around 100 million cells per milliliter and a resolution of around a millimeter.
• Bioextrusion consists in mechanically pushing biological elements placed in a micro-syringe through a nozzle or a needle of a few hundred micrometers in diameter.
• the advantage of this technology is based on its low cost and its simplicity of implementation. On the other hand, it suffers from limits associated with coarse resolution and a non-negligible cell mortality linked to the shearing imposed on the cells during their passage through the nozzle.
• inkjet bioprinting it consists in projecting micro-droplets of a liquid containing cells or a biomaterial on a substrate.
• the projection is caused by a thermal or piezoelectric process.
• Thermal inkjet printing works via the transient activation of an electrical resistance (with a strong thermal effect) which produces a vapor bubble which propels a droplet through an orifice of 30 to 200 mpi in diameter.
• Piezoelectric inkjet printers use an electrical pulse that generates a shape change in a piezoelectric crystal that contracts the ink tank. The relaxation of the crystal causes the drop to be ejected. This technique has the advantage of being fast, whether in terms of preparation time or printing speed.
• the means of activation of the printing is the pressurization of the liquid by compressed air.
• the liquid to be printed is released by actuation of a solenoid valve.
• Bioprinting by micro-valve is close to inkjet technologies but differs in that the inkjet is formed by the pressurization of the ink and then the rapid opening of a solenoid valve. Having the same constraints as inkjet bio-printing, this technology has the advantage of being able to print more viscous solutions than inkjet systems.
• the pressure is from a few hundred mbar to a few bars and makes it possible to obtain a lower cell density of the order of a few million cells per milliliter and a resolution of the order of a few tens of miki.
• a device for printing biological elements by laser which is based on the technique called “Laser-Induced Forward Transfer” (LIFT) in English, comprises a pulsed laser source emitting a laser beam, a system for focusing and orienting the laser beam, a donor support which comprises at least one biological ink and a recipient substrate positioned so as to receive droplets emitted from the donor support.
• the laser beam is pulsed and at each pulse a droplet is generated.
• the biological ink comprises a matrix, for example an aqueous medium, in which elements, for example cells, are present, to be deposited on the receiving substrate.
• the donor support includes a transparent slide at the wavelength of the laser beam which can be coated with an absorbent layer (metallic, polymer, etc.) or not (“sacrificial layer free LIFT” in English) depending on the configurations on which is affixed the biological ink in the form of a film.
• an absorbent layer metallic, polymer, etc.
• sacrificial layer free LIFT in English
• optical / laser processes can be implemented as a substitution or as a complement to laser bio-printing (imaging of the donor surface / target-shoot system / photo-polymerization, texturing, cavitation, cutting, etc.). ) combined with laser scanning using galvanometric mirrors in order to produce patterns on the receiving substrate.
• CAD Computer Aided Design
• bio-inks containing cells and / or biomaterials
• tomographic reconstructions can be carried out, for example, using microscopic, histological or medical imagery; downstream, the bio-printed biological tissues are conditioned before being sent to the user.
• the last three steps of the above manufacturing sequence, as well as the packaging step, must be carried out in a perfectly sterile environment, free of any particles likely to contaminate the bioprinted tissue, which could alter its growth during maturation and its functionality, and / or infecting the patient after implantation of the tissue.
• the printing assembly (1) consists of one or more laser heads and a target (6).
• the laser head (s) consist of a transparent flat surface on which an ink film is deposited either manually by means of a glove box, or by the robot, or by fluidic means linked to the source of power supply (2).
• the power source (2) of said head is constituted by a reservoir and a pressurizing pump or working in flow.
• the means for activating (5) the transfer of said biological objects to the target (6) consists of a laser located outside the enclosure.
• the sealed interaction means (20) is in this case a sealed optical window transparent to the wavelength of the laser.
• the means (3) for relative movement of the print head relative to the target (6) consists of a robotic arm or a mechatronic actuator.
• the sterilizable closed enclosure corresponds to any of the previously described configurations.
• the printing assembly (1) consists of one or more valves and a target (6).
• the power source (2) of said valve consists of a reservoir and a pressurization pump.
• the activation means (5) for the transfer of said biological objects to the target (6) consists of a shutter, of the piezoelectric type or a solenoid.
• the sealed interaction means (20) is in this case a perforable cover or a sealed joint.
• the means (3) for relative movement of the print head relative to the target (6) consists of a robotic arm or a mechatronic actuator.
• the sterilizable closed enclosure corresponds to any of the previously described configurations.
• the printing assembly (1) consists of one or more extrusion nozzles, and a target (6).
• the power source (2) of said nozzle consists of a reservoir and a pressurizing pump.
• the activation means (5) for the transfer of said objects biological towards the target (6) is a nozzle feed control, for example a mechanical control by a worm, or a piston, or a direct pneumatic control.
• the sealed interaction means (20) is in this case a perforable cover or a sealed joint.
• the means (3) for relative movement of the print head relative to the target (6) consists of a robotic arm or a mechatronic actuator.
• the sterilizable closed enclosure corresponds to any of the previously described configurations.
• the printing assembly (1) consists of one or more ink jet printing heads, and a target (6).
• the power source (2) of said ink jet print head is constituted by a reservoir and a feed pump.
• the activation means (5) for the transfer of said biological objects to the target (6) is a piezoelectric, acoustic, thermal, laser, etc. control.
• the sealed interaction means (20) is in this case a perforable cover or a sealed joint.
• the means (3) for relative movement of the print head relative to the target (6) consists of a robotic arm or a mechatronic actuator.
• the sterilizable closed enclosure corresponds to any of the previously described configurations.
• the printing assembly (1) consists of one or more several acoustic printheads, and a target (6).
• the power source (2) of said acoustic printhead consists of a reservoir and a feed pump.
• the activation means (5) for the transfer of said biological objects to the target (6) is a transducer, a laser, etc.
• the means (3) for relative movement of the print head relative to the target (6) consists of a robotic arm or a mechatronic actuator.
• the sterilizable closed enclosure corresponds to any of the previously described configurations.

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• 2018
  • 2018-10-25 FR FR1859889A patent/FR3087702B1/fr active Active
• 2019
  • 2019-10-24 JP JP2021522454A patent/JP2022511646A/ja active Pending
  • 2019-10-24 WO PCT/FR2019/052541 patent/WO2020084262A1/fr unknown
  • 2019-10-24 KR KR1020217015699A patent/KR20210081405A/ko unknown
  • 2019-10-24 EP EP19813109.6A patent/EP3870446A1/de active Pending
  • 2019-10-24 US US17/287,873 patent/US20210394444A1/en active Pending
  • 2019-10-24 CN CN201980068570.5A patent/CN115943051A/zh active Pending

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