AU2018201765A1 - 3D Printing and Bioprinting Process Using High Intensity Focused Ultrasound (HIFU) Technology - Google Patents

Abstract

To address the limitations of existing 3D printing processes restricted to two dimensional layer by layer and surface printing methods, it is proposed to provide a 3D printing process using high intensity focused ultrasound (HIFU) technology to produce deep three dimensional formations within a medium using a three dimensional toolpath motion. Ultrasound waves penetrate plurality of mediums with matching acoustic impedance with the HIFU transducer concentrating energy into a focal point to stimulate temperate increase at desired location. Thermoresponsive material is contained within the liquid medium whereby a phase transition occurs from liquid to gel or solid upon heating above its transition temperature. The proposed process is able to be utilized in bioprinting to produce tissue and organ cell formations using biocompatible materials and whereby the formations are able to be produced in-vivo within the patient. \0 Figure 2

Description

3D Printing and Bioprinting Process Using High Intensity Focused

Ultrasound (HIFU) Technology

This invention relates to processes, methods and apparatus of 3D printing and bioprinting and their applications in additive manufacturing and medical technologies

Background to the invention [0001] There are several additive processes known that are used for both 3D printing and bio-printing. The main differences between processes are in the way layers are deposited to create 3D shapes, the materials used in those layers and the energy form that is applied to form, bind or cure the parts. Each process and method has its advantages and drawbacks.

[0002] Standard ISO/ASTM52900-15 defines seven categories of Additive Manufacturing (AM) processes within its meaning: binder jetting, directed energy deposition, material extrusion, material jetting, powder bed fusion, sheet lamination and vat photopolymerization.

[0003] Each prior 3D printing process has a common constraint in which the addition of material and its forming can only be applied on the surface of the current layer being formed and must be clear from obstructions in between the produced part and the energy source. Unidirectional layer by layer 3D printers operate as 2.5 axis machines, where only two axes move simultaneously along each layer and the third axis increments the layer level. This most often results in limitations on the part shapes that can be produced and the applications these 3D printing and bioprinting processes can be used in.

[0004] Fused Deposition Modeling (FDM) produces parts by heating and extrusion of material from a nozzle which hardens rapidly after being placed on the part surface of the current layer and repeated until all layers are completed.

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The parts manufactured using FDM process are limited in their shape complexity, particularly portions of the part that have minimal supporting layers underneath that either cannot be produced or require a temporary support member that has to be produced and later removed.

[0005] Selective laser sintering (SLS), direct metal laser sintering and electron beam melting (EBM) all use a powder based material that are either metals or polymers, in which the powder is spread on the current layer and is then melted and formed together by using a high energy laser or electron beam in a gaseous or vacuum environment. As previously the parts are produced layer by layer in a single direction and the addition of material and its forming is constrained to the surface of the current layer.

[0006] Inkjet 3D printing also uses a plaster or resin like powder material that is spread across the current layer. However in this case it applies a binder in the cross-section of the part using an inkjet-like process. As previously the parts are produced layer by layer in a single direction and the addition of material and its forming is constrained to the surface of the current layer.

[0007] Laminated object manufacturing is whereby thin layers are cut to shape and joined together, layer by layer.

[0008] Other processes cure liquid materials using technologies such as stereolithography (SLA). Photopolymerization is primarily used in SLA to produce a solid part from a liquid state. SLA printing systems can spray photopolymer materials onto the part surface in desired shape and cure each photopolymer layer with a broad UV light source. SLA printing systems can also compromise of a tank with a transparent bottom filled partially with a photopolymerizing resin, in which the part base is raised and a targeted light emitting device solidifies and cures the resin layer by layer in the desired shape. As previously the parts are produced layer by layer in a single direction and the

2018201765 12 Mar 2018 addition of material and its forming is constrained to the surface of the current layer.

[0009] 3D bioprinting is a developing medical technology that fabricates artificial tissues and organs. The material commonly used in bioprinting is a liquid mixture of cells, matrix and nutrients knows as Bioinks. The bioprinting process involves dispensing cells onto a biocompatible scaffold using a successive layer by layer approach to generate 3D structures. The tissues are then placed to an incubator to mature.

[0010] Photolithography, stereolithography and direct cell extrusion are common bioprinting processes that have similar limitations and constraints as with conventional 3D printing process described above. In medical applications the layer by layer bioprinting processes in which the cells must be applied and formed on the surface of the biocompatible structures limits the fabrication of tissues and organs in-vitro, in which invasive surgery would often be required on the patient.

[0011] The underlying reason for why the prior additive processes are constrained to printing on part surface of the current layer is due to the process in which energy or material is applied. FDM printing inhibits physical access of the nozzle head with the extruded material towards the internal layers after the layers are already produced. SLS, SLA and other additive processes with light emitting energy sources are mostly unable to penetrate the surface layer of the parts and in which cases they can such as UV light through a translucent material, it has adverse effects through the layers it is passing to reach its destination.

[0012] It is an object of this invention to provide a means of a 3D printing process with a penetrating energy source deep into a target location with minimal adverse effects to surrounding layers, and hence eliminating constraint of

2018201765 12 Mar 2018 unidirectional layer by layer printing, allowing for formation of complex geometrical parts and its use for in-vivo bioprinting of tissues and organs with minimally invasive surgery and eliminating need for transplant operations required for in-vitro bio-printed tissues and organs.

[0013] High intensity focused ultrasound (HIFU) is a developing technology that has been used as an early stage medical technology to treat a variety of disorders. Its function is to concentrate ultrasound waves at a single target and thereby generate intense vibration, heat and pressure. In medical applications it is commonly used for occupational therapy, physical therapy, cancer treatment by ablation of tissue, breaking up of kidney stones by lithotripsy, cataract treatment by phacoemulsification and body contouring cosmetic operations.

Brief description of the invention [0014] The present invention provides a 3D printing process which includes

a) a 3D printer device with a high intensity focused ultrasound (HIFU) transducer located at its printing head and supporting electronic equipment

b) a liquid medium used to produce formations by 3D printers with HIFU technology containing temperature responsive materials in which phase transition occurs from liquid to gel or solid upon heating past the transition temperature and if desired a thermochromic coloring additive with a similar transition temperature

c) a 3D toolpath and omnidirectional layer printing method for 3D printers with HIFU technology

d) a method of in-vivo bioprinting with HIFU technology to produce three dimensional cell formations of tissues and organs within a patient [0015] To address the limitations of prior 3D printing processes utilizing a unidirectional layer by layer printing process on the part surface, it is proposed to provide a 3D printing process that applies high intensity focused ultrasound

2018201765 12 Mar 2018 (HIFU) energy through a liquid medium to produce gel or solid three dimensional structures.

[0016] Ultrasound energy is able to penetrate through a medium with stable acoustic impedance without being absorbed or reflected at the boundaries of formations that are either inherent in the medium or have occurred through 3D printing. In application of ultrasound in 3D printing and bioprinting, energy is able to penetrate previously formed three dimensional structures or natural organic bodies.

[0017] The proposed 3D printing process incorporates a high intensity focused ultrasound (HIFU) transducer to concentrate the ultrasound energy into a single focal point. The shape and location of the focal point is derived by the physical properties of the transducer and the supplied signal frequency. The ultrasound energy is also transferred at a significantly less strength into a cone shaped region of the medium in between the transducer face and the focal point as well as the cone shaped region past the focal point. The application of concentrated ultrasound energy at the focal point results in a temperature increase of the medium.

[0018] The proposed 3D printer would move the HIFU transducer and its focal point with respect to the medium at the desired omnidirectional toolpath and speed to produce three dimensional formations. The layer slices are generated along the localized member lengths of the formation in three dimensional plane surfaces to produce structurally strong formations for complex geometries. The medium used for the proposed process of 3D printing contains temperature responsive materials that are able to phase transition from a liquid to gel or solid and if desired change in color due to thermochromic additives after the liquid medium is heated above its transition temperature. The rate at which medium temperature increases along the toolpath is derived by the power supplied to the transducer, the focal intensity and focal shape of the transducer design, the heat

2018201765 12 Mar 2018 capacity of the medium and the speed of the focal point movement in the medium.

[0019] In another aspect, this invention provides the ability for in-vivo bioprinting in which three dimensional cell structure formations of tissues and organs is produced within the patient. Bioprinting process using HIFU technology is achieved by utilization of existing imaging technology to accurately guide the transducer along its toolpath inside the patient and injection of temperature responsive liquid medium containing cells and other biocompatible materials into the patient by minimally invasive surgery. Phase transition from liquid to gel or solid will occur upon heating the medium above the body temperature in the desired formation and location within the body, whilst the rest of the liquid medium removed from the body after the bioprinting process. The cells within the formation will be allowed to mature in a stable environment, allowed to bond with natural body tissue and any unwanted materials used in the medium to be biodegradable and be removed from the body over time.

Detailed description of the invention [0020] Preferred embodiments of the invention will be described with reference to the drawings in which:

Figure 1 is a schematic view of a 3D printer frame and components with a HIFU transducer at its printing head and a thermoresponsive liquid medium of which the transducer is submerged in;

Figure 2 is a schematic view of the HIFU transducer and supporting bracket submerged in a thermoresponsive liquid medium whilst being driven to produce a focused ultrasound wave propagation on an intended formation of figure 1;

Figure 3 is a detail view of the focused ultrasound wave propagation on an intended formation, toolpath travel and the region already formed of figure 2;

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Figure 4 is a schematic view of the focal point and focal shape of focused ultrasound wave propagation in a thermoresponsive liquid medium of figure 1 and figure 2;

Figure 5 is a schematic view of in-vivo bioprinting operation using a 3D printing process with HIFU transducer as the focused wave propagation penetrates the skin, fat and other tissue layers to rebuild tissue for an organ by heating an injected biocompatible material;

[0021] As shown in figure 1 the components required for a 3D printing process using high intensity focused ultrasound (HIFU) of this invention are a conventional 3D printer base 1, a HIFU transducer 7 and a container 9 of a liquid medium 10.

[0022] The 3D printer base 1 has the conventional structure of 3D printer frame 2, conventional axial driving motors 4 in three axis, conventional sliding mechanisms 5 and conventional shaft screw mechanism 6 for allowing motion of the printing head in relation to the container 9 in both horizontal and vertical directions respectively.

[0023] The proposed 3D printing process using HIFU is operated by the control enclosure 3 in which contains the conventional type power supply, control output to the three axial motors 4 and communication interface with a computer except for the addition of proposed power signal transmitted to the HIFU transducer 7 using HIFU transducer cabling 11. Thereby the control enclosure 3 contains a signal generator module of which produces an oscillating signal in frequency matching the design requirement of the HIFU transducer 7 and pulse width modulation matching the requirements of the duty cycle of the HIFU transducer 7. Additionally the control enclosure 3 contains a power amplifier module and an impedance matching module that meets the requirements of the power output and impedance matching required for efficient operation of the HIFU transducer 7. The duty cycle and power output to the HIFU transducer 7 is determined by

2018201765 12 Mar 2018 the instructions received by the control enclosure 3 from the computer and is controlled by adjusting pulse width modulation on the signal generator and voltage input to the power amplifier.

[0024] The container 9 is placed on platform 13 in which can be controlled to move in directions as designated by the arrangement of the axial motors 4, 3D printer frame 2 and the sliding mechanisms 5 and shaft screw mechanism 6. A liquid medium 10 is placed within container 9 in which the 3D printing process using HIFU technology is applied.

[0025] The HIFU transducer 7 is mounted on a support bracket 12 which allows motion of the HIFU transducer 7 in directions as designated by the arrangement of the axial motors 4, 3D printer frame 2 and the sliding mechanisms 5.

[0026] The HIFU transducer 7 is either partially or completely submerged in liquid medium 10 throughout the operational lifecycle of the proposed 3D printing process.

[0027] As shown in figure 2 schematic the HIFU transducer 7 is operational whilst partially submerged in liquid medium 10. The conventional type HIFU transducer 7 contains a curved face 19 from which the ultrasound wave propagates. The curved face 19 must always be submerged in liquid medium 10 whilst in operation and hence determines the minimum depth the HIFU transducer 7 must be partially submerged. The curved face 19 produces a focused ultrasound wave propagation that is concentrated at a focal point 16 at high intensity and has a characteristic near zone 15 and divergence zone 17 in which low intensity power is transmitted onto the liquid medium 10.

[0028] Desired three dimensional formation 18 is produced by the toolpath of focal point 16 in which most of the ultrasound power output is concentrated as determined by the design and efficiency of the HIFU transducer 7.

2018201765 12 Mar 2018 [0029] As shown in figure 3 the focused ultrasound wave propagation is penetrating through desired three dimensional formation 18 in the liquid medium whilst the focal point 16 is in motion after having completed the toolpath 25 that shows the formation already produced.

[0030] As shown in figure 4 the focal point 16 has a shape at the focal zone that specifies the volumetric region of maximum intensity of ultrasound power applied. The proposed focal zone represents a cylinder used as a close approximation of the actual ellipsoidal focal zone the conventional type HIFU transducer 7 produces. The cylindrical shape approximation is used to derive the toolpath and printing speed of the proposed 3D printing process using HIFU technology that is required to produce desired formation 18. The distance of the focal point 16 from both the HIFU transducer 7 and the curved face 19 is provided by the physical design of the HIFU transducer 7 and the signal frequency. Both the diameter and the length of the cylindrical focal zone at focal point 16 is also provided by the physical design of HIFU transducer 7 and the signal frequency. The approximate volume of the focal zone for the proposed 3D printing process is as specified in equation 1.

Yfocal zone ^— * lengthf_ocai zone Equation 1 [0031] The focal point 16 distance from the HIFU transducer 7 determines the maximum depth in which the toolpath can penetrate through the already produced three dimensional formation in order to avoid collision, as specified in equation 2.

Depth_max = distance_{focal point} - ^Iengthf°^{cal zone} Equation 2 [0032] The liquid medium 10 is composed of a temperature responsive material in which a phase transition occurs from a liquid to a gel or solid when the liquid medium has been heated past its transition temperature. The inclusion of a thermochromic color additive at a similar transition temperature can also be used to represent the boundaries of the phase transition and highlight the three dimensional formations 18 from the liquid medium 10.

2018201765 12 Mar 2018 [0033] An example of a thermoresponsive material that can be used to achieve this phase transformation is Poloxamer 407 that is dissolved in water at concentrations 10% to 25%. Poloxamer 407 is a triblock copolymer consisting of central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol. When a Poloxamer 407 solution is below its transition temperature the viscosity of the solution is low and when the solution has increased above its transition temperature the viscosity of the solution is dramatically increased to create a gel. The concentration of Poloxamer 407 in water determines both the gel viscosity and transition temperature of the thermoresponsive liquid medium 10.

[0034] The proposed 3D printing process using HIFU technology increases temperature of the thermoresponsive liquid medium 10 and is made to produce three dimensional formations 18 at the toolpath of the focal point 16. The rate of increase in temperature can be calculated by the focal intensity produced by the HIFU transducer 7, the diameter of the focal zone, the velocity of the focal point toolpath with respect to the liquid medium 10 and the volumetric heat capacity of the liquid medium as given in equation 3 and equation 4.

ATfpcal zone Intensity _focaI zone t 0p,_v medium

Equation 3

ATtoolpath _α Intensity_{focal zone} * diameter_{focaI zone} Cp,v medium * velocity toolpath

Equation 4 [0035] The conventional type HIFU transducer 7 has a duty cycle rating in which it must be cooled after use. For a continuous and uninterrupted 3D printing

2018201765 12 Mar 2018 process using HIFU technology, pulse width modulation is applied by the signal generator to achieve the required duty cycle. Depending on the speed of motion of the focal point 16 and its focal zone, a maximum recommended length of pulse period is set for an even heat distribution created by the toolpath of the focal point 16 as it travels across the desired formation 18 as given in equation 5. The pulse width is thereby set with respect to the pulse period in order to meet the required duty cycle of the HIFU transducer as given in equation 6.

fr,max diameterf_ocai _zone velocityt_oo]p_ath

Equation 5 fw,max

Pt,max * Duty Cycle

100

Equation 6 [0036] The liquid medium 10 must not be heated above its boiling temperature otherwise cavitation and fountaining effect occurs which can disturb the production of three dimensional formations 18 and lower the power output of the HIFU transducer 7. To lower the temperature increase in the liquid medium whilst maintaining the toolpath speed of focal point 16 and the power supplied to the HIFU transducer 7, the pulse width can be reduced and the HIFU transducer 7 operated below its duty cycle.

[0037] The initial temperature of the liquid medium and the toolpath temperature post HIFU energy application required to produce three dimensional formations with proposed invention is as specified in equation 7 and equation 8 respectively, in which the phase transition temperatures are determined by the medium composition.

^freezing ^initial < Fiq-gel/sol Equation 7

Tfiq-gel/sol <· ^initial + ^Ttoolpath < ^boiling Equation 8

2018201765 12 Mar 2018 [0038] As shown in figure 5 the proposed 3D printing process using HIFU technology is used in a medical application for proposed in-vivo bioprinting, in which a cell formation 25 is produced within the patient using HIFU technology. The HIFU transducer 7 is mounted on support bracket 12 to guide the focal point 16 along the required toolpath. A liquid or gel ultrasound coupling agent 20 of the conventional type is placed around the patient body in which the coupling agent 20 has matching acoustic impedance and density of the human body. The HIFU transducer 7 is submerged in the coupling agent 20 at a minimum depth of which curved face 19 is fully submerged during operation. The focused ultrasound wave propagation penetrates the skin tissue 21 and the internal fat and muscle tissue 22 to reach the desired tissue or organ 23 which requires treatment. The tissue or organ 23 is shown to have a hole or split 24 from a previous operation, injury or medical condition and which requires to be regenerated by a cell formation. The focal point 16 is guided along a toolpath to form the cell formation 25 by an increase of temperature above that of the human body. A liquid thermoresponsive and biocompatible cell material 27 is injected into the human body by conventional minimally invasive surgical methods. The liquid thermoresponsive biocompatible material 27 is heated past its transition temperature to produce gel or solid cell formations in which provides a stable environment for the cells to mature and bond with natural body tissue. The thermoresponsive biocompatible material 27 can contain cells, nutrients and biodegradable materials.

[0039] An example of a thermoresponsive and biocompatible material is a polymer called Poly(N-isopropylacrylamide) or PNIPA that is commonly used in medical applications for microgels, membranes, biosensors, thin films, tissue engineering and drug delivery. This material undergoes a phase transition from a swollen hydrated state to a shrunken dehydrated state when heated above 32 degrees Celsius, in which its liquid contents are expelled from the cell formation 25.

2018201765 12 Mar 2018 [0040] The unused thermoresponsive and biocompatible material 27 and the remnant material produced from bioprinting process using HIFU technology is removed at the end of the process by conventional minimally invasive surgical methods.

The benefits of this invention include:

[0041] Those skilled in the art will appreciate that the process of this invention has the advantage where three dimensional formations can be produced by 3D printing internally within an already produced formation or surrounding medium rather than being limited in prior surface 3D printing processes.

[0042] Those skilled in the art will appreciate that the process of this invention allows for three dimensional 3D printing toolpaths to generate complex geometries rather than being limited in prior two dimensional layer by layer 3D printing.

[0043] Those skilled in the art will realize that the invention may be put into practice in bioprinting where complex geometry tissue and organs can be produced with complex internal structures common to human anatomy.

[0044] Those skilled in the art will realize that the invention may be put into practice in in-vivo bioprinting where tissue and organ formations can be produced within the patient and thereby minimizing surgical complications rather than prior externally produced tissue and organ bioprinting processes which require a further surgical transplant operation.

[0045] Those skilled in the art will also realize that the invention may be put into practice in other embodiments but utilizing the essential elements as defined herein.

Claims (6)

1. A 3D printing process which includes

a) a 3D printer device with a high intensity focused ultrasound (HIFU) transducer at its printing head

b) a control enclosure that incorporates supporting electrical modules and methods to power the HIFU transducer

c) a thermoresponsive liquid medium in which three dimensional formations are produced as a phase transition occurs from liquid to gel or solid when heated past its transition temperature

2. A 3D printing process as claimed in claim 1 in which the 3D printer device can control, maneuver and power the HIFU transducer within a liquid medium to produce three dimensional formations.

3. A 3D printing process as claimed in claim 2 in which a three dimensional printing toolpath motion and printing of deep internal geometries is made possible by HIFU wave propagation penetrating through a plurality of mediums with matching acoustic impedance and density.

4. A 3D printing process as claimed in claim 2 in which HIFU energy is transferred into the thermoresponsive liquid medium at the focal point of the HIFU transducer whilst in motion to produce an increase in temperature of the liquid medium and thereby a phase transformation.

5. A bioprinting process as claimed in claim 2 in which a thermoresponsive and biocompatible liquid medium is heated by HIFU energy to produce three dimensional tissue and organ formations.

6. A 3D printing process as claimed in claim 4 in which pulse width modulation is applied to the HIFU transducer to achieve sufficient temperature increase of thermoresponsive liquid medium required for phase