WO2020211048A1

WO2020211048A1 - Biological 3d printing system and method

Info

Publication number: WO2020211048A1
Application number: PCT/CN2019/083274
Authority: WO
Inventors: 郑海荣; 李飞; 王珊珊; 蔡飞燕; 孟龙; 苏敏; 黄继卿
Original assignee: 深圳先进技术研究院
Priority date: 2019-04-18
Filing date: 2019-04-18
Publication date: 2020-10-22

Abstract

The present invention discloses a biological 3D printing system and method. The system comprises a medical imaging module, a sound field inversion module, an artificial intelligent module, a sound control module and a water tank. The medical imaging module is used for performing imaging on human tissue to obtain a tissue slice image; the sound field inversion module is used for taking the obtained tissue slice image as a target sound field and calculating an ultrasonic pulse sequence corresponding to the compound target sound field; the artificial intelligent module is used for inputting the tissue slice image and the ultrasonic pulse sequence into a preset deep neural network learning model so as to obtain a target three-dimensional structure digital model and a target ultrasonic pulse sequence; and the sound control module is used for emitting the target ultrasonic pulse sequence so as to establish a sound field corresponding to the target three-dimensional structure digital model, and capturing suspension cells in the water tank by utilizing the sound field so as to construct a biological tissue structure corresponding to the human tissue. The present invention can effectively guarantee the biological activity of cells, and avoid damage to cells during cross-linking molding.

Description

Biological 3D printing system and method

Technical field

The invention relates to the technical field of cell printing, in particular to a biological 3D printing system and method.

Background technique

Biological 3D printing is a technology capable of positioning and assembling biological materials or cell units according to the principle of additive manufacturing under the drive of digital three-dimensional models, and manufacturing tissue engineering scaffolds and tissues and organs. It can effectively solve the current problem of limited sources of transplanted organs.

In terms of current biological 3D printing technology, the biggest difficulty lies in cell viability and cross-linking. First of all, in terms of cell activity, for the droplet jet and extrusion printing methods, the common feature of the two is that there are nozzles, while the nozzle printing method has always been a problem with cell activity. The biggest factor causing damage is the shear force caused by the flow of liquid during printing, and the nozzle structure will greatly increase the damage to the cells when the nozzle diameter is small. Therefore, in this printing method with nozzle structure, cell activity and Printing accuracy is difficult to achieve at the same time. Increasing the nozzle diameter will reduce the printing resolution, while reducing the nozzle diameter will reduce cell viability. Secondly, in terms of cross-linking molding, cross-linking molding is to fix and shape the printed bio-ink patterns through temperature control, chemical treatment, ultraviolet irradiation, etc. However, these cross-linking methods may cause cell damage.

technical problem

The present application provides a biological 3D printing system and method, which can solve the technical problem that the biological 3D printing technology in the prior art is difficult to ensure cell viability and is likely to cause damage to the cells during cross-linking.

Technical solutions

Specifically, the first aspect of the present invention provides a biological 3D printing system, which includes a medical imaging module, a sound field inversion module, an artificial intelligence module, a sound control module, and a water tank;

The medical imaging module is used to image human tissues to obtain tissue slice images;

The sound field inversion module is configured to use the obtained tissue slice image as the target sound field, and calculate and synthesize the ultrasound pulse sequence corresponding to the target sound field;

The artificial intelligence module is used to input the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain a target three-dimensional structure digital model and a target ultrasound pulse sequence;

The sound control module is used to transmit the target ultrasonic pulse sequence, establish the sound field corresponding to the digital model of the target three-dimensional structure, and use the sound field to capture the suspended cells in the water tank to construct the corresponding human tissue Biological tissue structure.

Preferably, the sound field inversion module is specifically used for:

Using the tissue slice image as the target sound field, arrange and distribute virtual point sources according to the tissue slice image to form a tissue pattern;

According to the gray level of the tissue pattern, the intensity of the point source at the target space position is set, and the ultrasonic pulse sequence is calculated inversely according to the acoustic wave equation.

Preferably, the sound control module includes an array ultrasonic transducer, a signal generator and a power amplifier;

The array ultrasonic transducer is an ultrasonic transducer based on a surface array or an ultrasonic transducer based on a ring array, the signal generator is used to generate an electrical signal for exciting the array ultrasonic transducer, and the power amplifier is used for To amplify the electrical signal.

Preferably, the sound control module further includes a beam synthesizer;

Each element on the array ultrasonic transducer corresponds to one transmit/receive channel of the beam combiner, the signal generator, and the power amplifier.

Preferably, the array ultrasonic transducer is located in the water tank.

Preferably, the water tank contains biological ink containing suspended cells and growth factors.

Preferably, the biological 3D printing system further includes a flow control module, and the flow control module is used to uniformly distribute the suspended cells in the water tank in a silent space.

Preferably, the flow control module includes a water pump and a control circuit, the water pump is located at the bottom of the water tank, and the control circuit controls the water pump to control the suspended cells in the water tank to be uniformly distributed in a silent space.

The second aspect of the present invention provides a biological 3D printing method, which includes:

Image human tissues to obtain tissue slice images;

Taking the obtained tissue slice image as the target sound field, and calculating and synthesizing the ultrasound pulse sequence corresponding to the target sound field;

Inputting the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain a digital model of the target three-dimensional structure and the target ultrasound pulse sequence;

Transmit the target ultrasonic pulse sequence, establish a sound field corresponding to the digital model of the target three-dimensional structure, and use the sound field to capture suspended cells in the water tank to construct a biological tissue structure corresponding to the human tissue.

Preferably, the calculating and synthesizing the ultrasonic pulse sequence corresponding to the target sound field includes:

Beneficial effect

The biological 3D printing system provided by the present invention includes a medical imaging module, a sound field inversion module, an artificial intelligence module, a sound control module, and a water tank. Compared with the prior art, there is no nozzle in the traditional method in the present invention. Instead, it adopts acoustic control technology. Because acoustic control technology has the advantages of non-contact and non-damage, it will not cause damage to cells, can effectively ensure the biological activity of cells, and can also control cells in parallel. Therefore, in addition to traditional Dot-based printing can also achieve surface-based or three-dimensional-based printing, so it has a higher printing speed; at the same time, because the sound field will produce stress and deformation on the cells, the present invention can also provide a certain mechanical environment for the cells , To promote cell growth and fusion, to fix and shape the three-dimensional complex structure assembled by discrete cells, thereby avoiding cell damage during cross-linking and molding.

Description of the drawings

Fig. 1 is a schematic structural diagram of a biological 3D printing system in an embodiment of the present invention;

2 is another schematic diagram of the structure of the biological 3D printing system in the embodiment of the present invention;

3 is a schematic diagram of the steps of the biological 3D printing method in an embodiment of the present invention;

FIG. 4 is a schematic flowchart of sub-steps of a biological 3D printing method in an embodiment of the present invention.

The best mode of the invention

In order to make the objectives, features, and advantages of the present invention more obvious and understandable, the technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the description The embodiments are only a part of the embodiments of the present invention, but not all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work shall fall within the protection scope of the present invention.

Please refer to Figure 1. Figure 1 is a schematic structural diagram of a biological 3D printing system in an embodiment of the present invention. In an embodiment of the present invention, the biological 3D printing system 100 includes a medical imaging module 101, a sound field inversion module 102, an artificial intelligence module 103, and a sound field. The control module 104 and the water tank 105.

Among them, the medical imaging module 101 is used to image human tissues to obtain tissue slice images, that is, large data of biological tissue structure. The imaging method can be MRI (Magnetic Resonance Imaging, magnetic resonance imaging) or ultrasound imaging.

The sound field inversion module 102 is used to use the obtained tissue slice image as a target sound field, and calculate and synthesize an ultrasound pulse sequence corresponding to the target sound field. Among them, the ultrasonic pulse sequence is the ultrasonic pulse sequence emitted by the array ultrasonic transducer of the target sound field.

The artificial intelligence module 103 is used to input the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain the target three-dimensional structure digital model and the target ultrasound pulse sequence.

Among them, the above-mentioned deep neural network learning model can use a conventional deep neural network (Deep Neural Networks, DNN) model. The neural network layer inside the DNN model can be divided into three categories, input layer, hidden layer and output layer. Generally speaking, the first One layer is the input layer, the last layer is the output layer, and the number of layers in the middle are all hidden layers.

The acoustic control module 104 is used to transmit a target ultrasonic pulse sequence, establish a sound field corresponding to a digital model of the target three-dimensional structure, and use the sound field to capture suspended cells in the water tank 105 to construct a biological tissue structure corresponding to the aforementioned human tissue.

Specifically, the acoustic force generated by the sound field established in the space is used to capture the suspended cells, and the biological tissue structure corresponding to the accurate three-dimensional structure digital model is constructed in two-dimensional layer by layer or three-dimensional overall, and then through the natural growth method, the dispersed suspended cells are The three-dimensional structure assembled by acoustic control is fixed and formed.

Among them, the water tank 105 is an area for 3D printing. The water tank 105 is filled with biological ink containing suspended cells and growth factors. The sound field can be used to synthesize and assemble suspended cells in the water tank 105 to form a specific biological tissue structure. Specifically, the water tank 105 is made of biocompatible medical stainless steel, quartz glass and other materials.

Specifically, the sound field inversion module 102 is specifically used for:

Taking the above-mentioned tissue slice image as the target sound field, arrange and distribute the virtual point sources according to the tissue slice image to form a tissue pattern; according to the gray level of the tissue pattern, set the intensity of the point source at the target space position and reverse it according to the acoustic wave equation Calculate the above ultrasonic pulse sequence.

Among them, the acoustic wave equation is derived from the continuum equation and the momentum equation, and is an important partial differential equation describing the propagation of sound waves in the medium.

The biological 3D printing system 100 provided by the embodiment of the present invention includes a medical imaging module 101, a sound field inversion module 102, an artificial intelligence module 103, a sound control module 104 and a water tank 105. Compared with the prior art, the present invention does not There is no nozzle in the traditional method, but the acoustic control technology is used. Because the acoustic control technology has the advantages of non-contact and non-damaging, it will not cause damage to the cells, can effectively ensure the biological activity of the cells, and can also Parallel manipulation, so in addition to traditional dot-based printing, surface-based or stereo-based printing can also be achieved, so it has a higher printing speed; at the same time, because the sound field will produce stress and deformation on the cells, the present invention also It can provide a certain mechanical environment for cells, promote cell growth and fusion, and fix the three-dimensional complex structure assembled by discrete cells, thereby avoiding cell damage during cross-linking and molding.

Further, based on the foregoing embodiment, in the embodiment of the present invention, the sound manipulation module 104 includes an array ultrasonic transducer, a signal generator, and a power amplifier. Among them, the array ultrasonic transducer can be an ultrasonic transducer based on a surface array or an ultrasonic transducer based on a ring array; the signal generator is used to generate electrical signals for exciting the above-mentioned array ultrasonic transducer, and the power amplifier is used To amplify the electrical signal. In addition, the transmission signal of the signal generator may be a continuous sinusoidal signal or may be a pulsed sinusoidal signal.

Among them, the function of the array ultrasonic transducer is to convert the input electrical power into mechanical power (ie ultrasonic wave) and then transmit it out, and consume a small part of the power itself.

In order to better understand the present invention, the embodiments of the present invention provide an array ultrasonic transducer, which may be composed of a housing, a matching layer, a piezoelectric ceramic area array transducer, a backing, and an outgoing cable. The piezoelectric ceramic area array transducer is made of PZT-5 piezoelectric material polarized in the thickness direction. There are 4 piezoelectric ceramic area array transducers, and each area array has 4096 elements. The piezoelectric ceramic area array transducer is used as a basic ultrasonic transducer, which transmits or receives ultrasonic signals. The received ultrasonic signals can perform ultrasound imaging of the printed organs and observe the anatomical structure and growth of the organs in real time. The imaging method can be based on the traditional pulse echo mode to obtain a two-dimensional B mode image, or through a transmission method to obtain a two-dimensional ultrasound CT image, and can reconstruct a three-dimensional image from the two-dimensional image, or directly obtain a three-dimensional image from the three-dimensional volume data.

Further, the sound control module 104 also includes a beam combiner. Wherein, each array element on the above-mentioned array ultrasonic transducer corresponds to one transmitting/receiving channel of the above-mentioned beam combiner, signal generator and power amplifier. The beam combiner is used to control the amplitude and phase of the pulse signal emitted by the array ultrasonic transducer, and its control method can be realized by software or hardware.

Wherein, the above-mentioned array ultrasonic transducer is located in the water tank 105, so that the acoustic field can be used to capture the suspended cells in the water tank 105.

In the biological 3D printing system 100 provided by the embodiment of the present invention, the sound manipulation module 104 includes an array ultrasonic transducer, a signal generator, and a power amplifier. The array ultrasonic transducer may be an ultrasonic transducer based on a surface array or It is an ultrasonic transducer based on a ring array, so that the acoustic manipulation module 104 can be used to assemble cells into a two-dimensional or three-dimensional complex structure.

Further, based on the above embodiment, please refer to FIG. 2. FIG. 2 is another structural diagram of the biological 3D printing system in an embodiment of the present invention. In the embodiment of the present invention, the biological 3D printing system 100 includes a medical imaging module 101 and a sound field reflection. Performance module 102, artificial intelligence module 103, sound control module 104, water tank 105 and flow control module 106.

Among them, the flow control module 106 is used to make the suspended cells in the water tank 105 evenly distributed in the silent field space.

It is understandable that when using the sound field to capture suspended cells in the water tank 105, if the suspended cells in the water tank 105 are not uniformly distributed, the cells cannot be captured in the area where the cells were originally captured, resulting in inaccurate capture results, which cannot meet the requirements of 3D printing. Claim. Therefore, in the embodiment of the present invention, in order to improve the accuracy of 3D printing, the flow control module 106 is used to uniformly distribute the suspended cells in the water tank 105 in the silent space.

Specifically, the flow control module 106 includes a water pump and a control circuit, where the water pump is located at the bottom of the water tank 105, and the control circuit controls the water pump to control the suspended cells in the water tank 105 to be uniformly distributed in the silent field space. It should be noted that the number of the above-mentioned water pumps is at least one. When the number of the water pumps is more than one, the control circuit controls each water pump at the same time so as to form a linkage between the water pumps.

The biological 3D printing system 100 provided by the embodiment of the present invention further includes a flow control module 106, which can effectively improve the accuracy of 3D printing by maintaining the suspended cells in the water tank 105 to be uniformly distributed in the silent space.

The main advantages of the biological 3D printing system 100 provided in this embodiment include:

(1) Instead of nozzles in traditional methods, acoustic control technology is used. Because acoustic control technology has the advantages of non-contact and non-damage, it will not cause damage to cells and can effectively ensure the biological activity of cells.

(2) Since the sound field pattern can be flexibly controlled by the ultrasonic pulse sequence, the present invention can print relatively complex biological tissue structures.

(3). Cells can be controlled in parallel. In addition to traditional dot-based printing, surface-based or volume-based printing can also be achieved, so it has a higher printing speed.

(4) Since the sound field will cause stress and deformation to the cells, the present invention can also provide a certain mechanical environment for the cells, promote the growth and fusion of the cells, and fix the three-dimensional complex structure assembled by discrete cells, thereby avoiding Damage to cells during cross-linking.

(5) The use of artificial intelligence modules to learn biological structure big data (tissue slice images) and acoustic manipulation big data (ultrasound pulse sequence) can improve the spatial resolution of tissue slice images in the three dimensions of in-plane and inter-layer, and improve The synthesis accuracy of the target sound field will finally establish a precise three-dimensional digital structure model and the corresponding ultrasonic emission pulse sequence.

(6) The sound control module can be used to assemble cells into a two-dimensional or three-dimensional complex structure.

Further, the embodiment of the present invention also provides a biological 3D printing method. See FIG. 3, which is a schematic diagram of the steps of the biological 3D printing method in the embodiment of the present invention. In the embodiment of the present invention, the above method includes:

Step 301, imaging the human tissue to obtain a tissue slice image;

Step 302: Use the obtained tissue slice image as a target sound field, and calculate and synthesize an ultrasound pulse sequence corresponding to the target sound field;

Step 303: Input the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain a digital model of the target three-dimensional structure and the target ultrasound pulse sequence;

Step 304: Transmit the target ultrasonic pulse sequence, establish a sound field corresponding to the digital model of the target three-dimensional structure, and use the sound field to capture suspended cells in the water tank to construct a biological tissue structure corresponding to the human tissue.

Further, please refer to FIG. 4, which is a schematic flowchart of sub-steps of the biological 3D printing method in an embodiment of the present invention. In the embodiment of the present invention, the ultrasonic pulse corresponding to the target sound field is calculated and synthesized as described in step 301 The sequence includes:

Step 401: Using the tissue slice image as a target sound field, arrange and distribute virtual point sources according to the tissue slice image to form a tissue pattern;

Step 402: Set the intensity of the point source at the target spatial position according to the gray level of the tissue pattern, and calculate the ultrasound pulse sequence in reverse according to the acoustic wave equation.

Wherein, the principle of the method adopted by the above-mentioned biological 3D printing method is consistent with the principle adopted by the biological 3D printing system 100 in the above-mentioned embodiment. For details, please refer to the description of the biological 3D printing system 100 in the above-mentioned embodiment, which will not be repeated here.

Compared with the prior art, the biological 3D printing method provided by the present invention does not have the nozzle in the traditional method, but uses the acoustic control technology, because the acoustic control technology has the advantages of non-contact and no damage Therefore, it will not cause damage to the cells, can effectively ensure the biological activity of the cells, and can also control the cells in parallel. Therefore, in addition to the traditional dot-based printing, it can also achieve surface-based or three-dimensional printing, so it has a higher At the same time, because the sound field will produce stress and deformation to the cells, the present invention can also provide a certain mechanical environment for the cells, promote the growth and fusion of the cells, and fix the three-dimensional complex structure assembled by discrete cells, thereby It avoids the problem of cell damage during cross-linking and forming.

In the several embodiments provided in this application, it should be understood that the disclosed system and method may be implemented in other ways. For example, the system embodiment described above is only illustrative. For example, the division of the modules is only a logical function division, and there may be other divisions in actual implementation, for example, multiple modules or components may be combined or It can be integrated into another system, or some features can be ignored or not implemented. In addition, the displayed or discussed mutual coupling or direct coupling or communication connection may be indirect coupling or communication connection through some interfaces, systems or modules, and may be in electrical, mechanical or other forms.

The modules described as separate components may or may not be physically separated, and the components displayed as modules may or may not be physical modules, that is, they may be located in one place, or they may be distributed to multiple network modules. Some or all of the modules may be selected according to actual needs to achieve the objectives of the solutions of the embodiments.

In addition, the functional modules in each embodiment of the present invention may be integrated into one processing module, or each module may exist alone physically, or two or more modules may be integrated into one module. The above-mentioned integrated modules can be implemented in the form of hardware or software functional modules.

If the integrated module is implemented in the form of a software function module and sold or used as an independent product, it can be stored in a computer readable storage medium. Based on this understanding, the technical solution of the present invention essentially or the part that contributes to the prior art or all or part of the technical solution can be embodied in the form of a software product, and the computer software product is stored in a storage medium , Including several instructions to make a computer device (which can be a personal computer, a server, or a network device, etc.) execute all or part of the steps of the method described in each embodiment of the present invention. The aforementioned storage media include: U disk, mobile hard disk, read-only memory (ROM, Read-Only Memory), random access memory (RAM, Random Access Memory), magnetic disks or optical disks and other media that can store program codes.

It should be noted that for the foregoing method embodiments, for simplicity of description, they are all expressed as a series of action combinations, but those skilled in the art should know that the present invention is not limited by the described sequence of actions. Because according to the present invention, certain steps can be performed in other order or simultaneously. Secondly, those skilled in the art should also know that the embodiments described in the specification are all preferred embodiments, and the involved actions and modules are not necessarily all required by the present invention.

In the above-mentioned embodiments, the description of each embodiment has its own emphasis. For parts that are not described in detail in an embodiment, reference may be made to related descriptions of other embodiments.

The above is a description of a biological 3D printing system and method provided by the present invention. For those skilled in the art, according to the idea of the embodiments of the present invention, there will be changes in the specific implementation and the scope of application. In summary The content of this specification should not be construed as a limitation of the present invention.

Claims

A biological 3D printing system, characterized in that the system includes a medical imaging module, a sound field inversion module, an artificial intelligence module, a sound control module, and a water tank;

The medical imaging module is used to image human tissues to obtain tissue slice images;

The sound field inversion module is configured to use the obtained tissue slice image as the target sound field, and calculate and synthesize the ultrasound pulse sequence corresponding to the target sound field;

The artificial intelligence module is used to input the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain a target three-dimensional structure digital model and a target ultrasound pulse sequence;

The sound control module is used to transmit the target ultrasonic pulse sequence, establish the sound field corresponding to the digital model of the target three-dimensional structure, and use the sound field to capture the suspended cells in the water tank to construct the corresponding human tissue Biological tissue structure.
The biological 3D printing system according to claim 1, wherein the sound field inversion module is specifically used for:

Using the tissue slice image as the target sound field, arrange and distribute virtual point sources according to the tissue slice image to form a tissue pattern;

According to the gray level of the tissue pattern, the intensity of the point source at the target space position is set, and the ultrasonic pulse sequence is calculated inversely according to the acoustic wave equation.
3. The biological 3D printing system according to claim 1, wherein the sound manipulation module comprises an array ultrasonic transducer, a signal generator and a power amplifier;

The array ultrasonic transducer is an ultrasonic transducer based on a surface array or an ultrasonic transducer based on a ring array, the signal generator is used to generate an electrical signal for exciting the array ultrasonic transducer, and the power amplifier is used for To amplify the electrical signal.
The biological 3D printing system according to claim 3, wherein the sound control module further comprises a beam synthesizer;

Each element on the array ultrasonic transducer corresponds to one transmit/receive channel of the beam combiner, the signal generator, and the power amplifier.
8. The biological 3D printing system of claim 4, wherein the array ultrasonic transducer is located in the water tank.
The biological 3D printing system according to any one of claims 1 to 5, wherein the water tank contains biological ink containing suspended cells and growth factors.
The biological 3D printing system according to claim 6, characterized in that the biological 3D printing system further comprises a flow control module, the flow control module is used to make the suspended cells in the water tank evenly distributed in the silent space .
The biological 3D printing system of claim 7, wherein the flow control module comprises a water pump and a control circuit, the water pump is located at the bottom of the water tank, and the control circuit controls the water pump by controlling the water pump. The suspended cells in the water tank are evenly distributed in the silent space.
A biological 3D printing method, characterized in that the method includes:

Image human tissues to obtain tissue slice images;

Taking the obtained tissue slice image as the target sound field, and calculating and synthesizing the ultrasound pulse sequence corresponding to the target sound field;

Inputting the tissue slice image and the ultrasound pulse sequence into a preset deep neural network learning model to obtain a digital model of the target three-dimensional structure and the target ultrasound pulse sequence;

Transmit the target ultrasonic pulse sequence, establish a sound field corresponding to the digital model of the target three-dimensional structure, and use the sound field to capture suspended cells in the water tank to construct a biological tissue structure corresponding to the human tissue.
9. The biological 3D printing method according to claim 9, wherein the calculating and synthesizing the ultrasonic pulse sequence corresponding to the target sound field comprises:

Using the tissue slice image as the target sound field, arrange and distribute virtual point sources according to the tissue slice image to form a tissue pattern;

According to the gray level of the tissue pattern, the intensity of the point source at the target space position is set, and the ultrasonic pulse sequence is calculated inversely according to the acoustic wave equation.