Bio-printing intervertebral disc tissue engineering scaffold based on organoid

Abstract

The invention provides an organoid-based bio-printing intervertebral disc tissue engineering scaffold, and belongs to the technical field of intervertebral disc tissue engineering scaffolds. Comprising a shell, the shell is filled with intervertebral disc organoid microspheres, the upper end of the shell is connected with a mounting block and an artificial bionic fiber ring, and the artificial bionic fiber ring is arranged on the outer side of the shell; the artificial bionic annulus fibrosus comprises L-polylactic acid, hyaluronic acid HA, vascular endothelial growth factors, type I collagen, polycaprolactone PCL, collagen and nano-hydroxyapatite, wherein the vascular endothelial growth factors are wrapped in biodegradable nanoparticles and are uniformly dispersed in the annulus fibrosus material. The inner surface area of the micro-channel is increased through the micro-channel of the multi-layer grid structure with different diameters and directions, more contact points are provided for exchange of nutrient substances, oxygen and metabolic waste, the micro-channel is monitored through the intelligent response system, and the blocking possibility is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of intervertebral disc tissue engineering scaffolds, and more specifically, to an organoid-based bioprinted intervertebral disc tissue engineering scaffold. Background Art

[0002] Degenerative disc disease is a common and frequently occurring disease in modern society. Among them, herniated disc is the most common and is a common cause of low back and leg pain, which seriously affects the quality of life of patients. When the intervertebral disc degenerates, its height will decrease and its normal mechanical conduction function will be impaired.

[0003] With the continuous advancement of medical technology, tissue engineering scaffolds using organoids for bioprinting have also become a hot topic. They are mainly based on the structure and function of natural intervertebral discs. Through bioprinting technology, a similar three-dimensional scaffold structure is constructed to provide cells with a growth environment similar to that in the body, inducing cells to grow and differentiate according to normal physiological patterns, thereby achieving the regeneration of intervertebral disc tissue. In addition, bioprinting technology can accurately control the distribution of cells and materials, and construct tissue engineering scaffolds with complex structures and functions, providing a new strategy for the treatment of intervertebral disc diseases.

[0004] However, when constructing organoids, there are significant differences between individuals in the same batch of organoids, as well as between samples of organoids in different batches, and the controllability of organoid formation is poor. Based on the above technical problems, the prior art also provides some solutions. For example, the Chinese patent with the authorization announcement number CN115154674B discloses a 3D bioprinted bone tissue engineering scaffold based on bone organoids. By setting microchannels, end 3 and filling cavities, the graft can be vascularized, and endothelial cells can migrate and proliferate on the scaffold, thereby stably transmitting oxygen, nutrients and growth factors to promote bone tissue growth;

[0005] However, in actual use, the microchannel may be just a simple tubular structure that does not take into account the complex environment in the body. After implantation into the human body, fragments produced by cell metabolism, deposition of extracellular matrix components, and possible inflammatory response products are easily accumulated in the microchannel, and nutrients and signal molecules cannot be evenly transported to various areas in the filling cavity. For example, organoids close to the microchannel can obtain sufficient nutrients and stimulation, and grow and differentiate faster, while organoids far away from the microchannel will grow slowly due to lack of sufficient support, and even suffer necrosis, which ultimately leads to uneven organoid growth. Summary of the invention

[0006] In view of the problem in the prior art that the microchannels of the tissue scaffold cannot evenly transport nutrients, resulting in slow organoid production or even necrosis, the purpose of the present invention is to provide a bio-printed intervertebral disc tissue engineering scaffold based on organoids.

[0007] To solve the above problems, the present invention adopts the following technical solutions:

[0008] An organoid-based bioprinted intervertebral disc tissue engineering scaffold, comprising;

[0009] A shell, wherein the shell is filled with intervertebral disc organoid microspheres, and the upper end of the shell is connected to a mounting block;

[0010] An artificial bionic fiber ring, which is arranged on the outside of the shell, and comprises poly(L-lactic acid), hyaluronic acid (HA), vascular endothelial growth factor, type I collagen, poly(caprolactone) PCL, collagen and nano-hydroxyapatite, wherein the vascular endothelial growth factor is encapsulated in biodegradable nanoparticles and uniformly dispersed in the fiber ring material, and the artificial bionic fiber ring also comprises elastin-derived peptides to give it better elasticity and flexibility;

[0011] The ends are located at two ends of the shell, and the opposite ends of the two ends are connected to an intervertebral disc organoid filling cavity, the intervertebral disc organoid filling cavity is filled with in vitro cultured intervertebral organoid microspheres with a diameter of 500 to 1000 microns, and the inner wall of the intervertebral disc organoid filling cavity is coated with a cell adhesion peptide or a specific growth factor fixing layer;

[0012] A microchannel unit, wherein the microchannel unit is connected between two intervertebral disc organoid filling cavities, and the microchannel unit is composed of a plurality of microchannels forming a multi-level grid structure, and the inner wall of the microchannel unit has a self-cleaning coating to prevent the microchannel from being blocked;

[0013] It also includes an intelligent response system based on sensor feedback data, wherein the sensor is a micro biosensor installed inside the shell, and the micro biosensor is used to detect physical and chemical parameter data inside the shell.

[0014] Optionally, the microchannels of the multi-level grid structure have different diameters and directions, and the design of the microchannels includes but is not limited to spiral, grid or radial shapes to promote uniform distribution and interaction of the intervertebral disc organ-like microspheres in the entire shell.

[0015] Optionally, the self-cleaning coating comprises a biocompatible polymer having anti-fouling and lubricating properties.

[0016] Optionally, the intelligent response system includes:

[0017] A data receiving module, which is used to receive detection data of the micro-biosensor;

[0018] A data analysis module, which is configured to process and analyze the data receiving module to determine whether the parameter deviates from a preset normal range;

[0019] A trigger module, which can initiate a corresponding response action when the data analysis module determines that the key parameters deviate from the normal range;

[0020] The response execution module includes but is not limited to a sustained-release unit activation unit, which is used to trigger the sustained-release unit pre-embedded in the shell to release the corresponding bioactive substance to improve the material exchange efficiency.

[0021] Optionally, the sustained-release unit comprises a plurality of sustained-release modules containing different bioactive substances and distributed in different areas within the shell, wherein at least one sustained-release module contains a pro-angiogenic factor, at least one sustained-release module contains a nutritional supplement, and at least one sustained-release module contains an anti-inflammatory factor.

[0022] Optionally, the inner surface of the shell is also provided with a micro-nano structure capable of promoting cell adhesion and proliferation.

[0023] Optionally, the intervertebral disc organoid microspheres are pre-treated before filling to improve their survival rate, proliferation ability and differentiation potential.

[0024] Optionally, a degradable metal wire reinforcement skeleton is provided inside the mounting block to enhance the mechanical strength of the mounting block. A fiber structure is also provided inside the shell, and the fiber structure is annularly wound around the outside of the plurality of microchannel units.

[0025] Optionally, the shell is integrally printed by a multi-nozzle bioprinter, and the gradient distribution of different materials in space is precisely controlled during the printing process.

[0026] Optionally, the manufacturing process of the shell further includes post-processing the printed shell, such as heat treatment, chemical treatment or bioactivation treatment, to further improve its biocompatibility and mechanical properties.

[0027] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects:

[0028] In the above scheme, the internal surface area of ​​the microchannel is increased by using microchannels with a multi-level grid structure of different diameters and directions, providing more contact points for the exchange of nutrients, oxygen and metabolic waste, and forming more diffusion paths, which helps to evenly distribute and quickly exchange substances in the microchannel, so that the intervertebral disc organoid microspheres can more effectively obtain the required nutrients and oxygen. At the same time, the self-cleaning coating inside the microchannel can reduce the possibility of microchannel blockage, ensure the continuous and effective transmission of nutrients and signal molecules, and facilitate the excretion of metabolic waste.

[0029] Through the intelligent response system, when abnormal parameter changes related to the appearance of microchannels are monitored, the data analysis module in the intelligent response system quickly processes and analyzes these data. Once it is determined that the microchannel is blocked, the trigger module of the intelligent response system is immediately activated, instructing the sustained-release unit near or at a specific position of the microchannel to release bioactive substances. The assimilated and released bioactive substances can stimulate local angiogenesis or cell activity, promote the remodeling or repair of tissues around the microchannels, provide better growth conditions for intervertebral disc organoid microspheres and surrounding tissue cells, and reduce the occurrence of local inflammation caused by microchannel blockage.

[0030] Tonghua encapsulates vascular endothelial growth factor in biodegradable nanoparticles and evenly disperses it in the annulus fibrosus material, which can achieve accurate and sustained release of vascular endothelial growth factor at different stages of intervertebral disc repair, effectively promote angiogenesis, provide more adequate nutrient supply for intervertebral disc organoids, promote their growth and tissue regeneration. At the same time, by adding elastin-derived peptides to the artificial bionic annulus fibrosus, it can provide the artificial bionic annulus fibrosus with better elasticity and flexibility, making its mechanical properties closer to those of the natural intervertebral disc annulus fibrosus and enhancing its adaptability to the complex mechanical environment in the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The accompanying drawings, which are incorporated herein and constitute a part of the specification, illustrate embodiments of the invention and, together with the description, further serve to explain the principles of the invention and to enable those skilled in the relevant art to make and use the invention.

[0032] Figure 1 It is a schematic diagram of the three-dimensional structure of the present invention;

[0033] Figure 2 For the present invention Figure 1 The cross-sectional structure of Figure 1 ;

[0034] Figure 3 This is a schematic diagram of the connection structure between the intervertebral disc organoid filling cavity and the microchannel unit in the present invention;

[0035] Figure 4 For the present invention Figure 3 Schematic diagram of the cross-section structure in ;

[0036] Figure 5 A schematic diagram of the internal structure of the housing provided by the present invention;

[0037] Figure 6 For the present invention Figure 1 The cross-sectional structure of Figure 2 ;

[0038] Figure 7A schematic diagram of the structure of the housing provided by the present invention when it is installed between two vertebral bodies;

[0039] Figure 8 The system framework provided by the present invention Figure 1 ;

[0040] Fig. 9 The system framework provided by the present invention Figure 2 .

[0041] [reference numerals]

[0042] 1. Shell; 11. Mounting block; 101. Degradable metal wire reinforced skeleton; 12. Micro-nano structure; 13. Fiber structure;

[0043] 2. Artificial bionic fiber ring;

[0044] 3. End; 31. Intervertebral disc organoids fill the cavity;

[0045] 4. Microchannel unit; 41. Self-cleaning coating;

[0046] 5. Intelligent response system; 51. Micro biosensor; 52. Data receiving module; 53. Data analysis module; 54. Trigger module; 55. Response execution module;

[0047] 6. Sustained release unit.

[0048] As shown in the figure, in order to clearly implement the structure of the embodiment of the present invention, specific structures and devices are marked in the figure, but this is only for illustrative purposes and is not intended to limit the present invention to the specific structure, device and environment. According to specific needs, ordinary technicians in this field can adjust or modify these devices and environments. DETAILED DESCRIPTION

[0049] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. At the same time, it is explained here that in order to make the embodiments more detailed, the following embodiments are the best and preferred embodiments, and those skilled in the art may also adopt other alternatives to implement some known technologies; and the accompanying drawings are only for more specific description of the embodiments, and are not intended to specifically limit the present invention.

[0050] It should be noted that the references to "one embodiment", "an embodiment", "an exemplary embodiment", "some embodiments" and the like in the specification indicate that the embodiments described may include specific features, structures or characteristics, but not every embodiment may include the specific features, structures or characteristics. In addition, when a specific feature, structure or characteristic is described in conjunction with an embodiment, it should be within the knowledge of a person skilled in the art to implement such feature, structure or characteristic in conjunction with other embodiments (whether or not explicitly described).

[0051] In general, a term can be understood, at least in part, from its use in context. For example, depending, at least in part, on the context, the term "one or more" as used herein can be used to describe any feature, structure, or characteristic in the singular sense, or can be used to describe a combination of features, structures, or characteristics in the plural sense. Additionally, the term "based on" can be understood as not necessarily intended to convey an exclusive set of factors, but can instead, depending, at least in part, on the context, allow for the presence of other factors that are not necessarily explicitly described.

[0052] It will be understood that the meanings of “on,” “over,” and “above” in the present invention should be interpreted in the broadest manner, so that “on” not only means “directly on” something, but also includes the meaning of being “on” something with intervening features or layers therebetween, and “on” or “over” not only means “on” or “above” something, but also includes the meaning of being “on” or “above” something with no intervening features or layers therebetween.

[0053] Additionally, spatially relative terms such as "under," "beneath," "lower," "above," "upper," and the like may be used herein for descriptive convenience to describe the relationship of one element or feature to another element or features, as shown in the accompanying drawings. Spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the accompanying drawings. The device may be oriented in other ways, and the spatially relative descriptors used herein may be similarly interpreted accordingly.

[0054] like Figures 1 to 9As shown, an embodiment of the present invention provides an organoid-based bioprinted intervertebral disc tissue engineering scaffold, comprising a shell 1, wherein the shell 1 is filled with intervertebral disc organoid microspheres, and the upper end of the shell 1 is connected to a mounting block 11, and an artificial bionic fiber ring 2 is also provided on the outer side of the shell 1, wherein the artificial bionic fiber ring 2 comprises polylactic acid, hyaluronic acid HA, vascular endothelial growth factor, type I collagen, polycaprolactone PCL, collagen and nano-hydroxyapatite, wherein the vascular endothelial growth factor is encapsulated in biodegradable nanoparticles and uniformly dispersed in the fiber ring material, and the artificial bionic fiber ring 2 also comprises elastin-derived peptides to give it better The shell 1 has elasticity and flexibility, and ends 3 are provided at both ends of the shell 1, and the two ends opposite to each other are connected to intervertebral disc organoid filling cavities 31, the intervertebral disc organoid filling cavities 31 are filled with in vitro cultured intervertebral disc organoid filling cavities 31 and have a diameter of 500 to 1000 microns, the inner wall of the intervertebral disc organoid filling cavity is coated with a cell adhesion peptide or a specific growth factor fixing layer, and a microchannel unit 4 is provided between two upper and lower adjacent intervertebral disc organoid filling cavities 31, and the microchannel unit 4 is composed of a plurality of microchannels to form a multi-level grid structure, and the inner wall of the microchannel unit 4 has a self-cleaning coating 41 to prevent microchannel blockage;

[0055] like Figure 2 As shown, the embodiment of the present invention further includes an intelligent response system 5 based on sensor feedback data. The sensor is a micro biosensor 51 installed inside the housing 1 . The micro biosensor 51 is used to detect physical and chemical parameter data inside the housing 1 .

[0056] Vascular endothelial growth factor is a highly specific vascular endothelial cell growth factor that has the effects of promoting increased vascular permeability, extracellular matrix degeneration, and vascular endothelial cell migration, and can promote the formation of surrounding tissues. In addition, the addition of elastin-derived peptides to the artificial bionic annulus fibrosus 2 can simulate the mechanical properties of the natural annulus fibrosus, improve the elasticity and flexibility of the stent, and make it more adaptable to the physiological environment of the intervertebral disc. The multi-level grid structure of the microchannel unit 4 increases the inner surface area of ​​the microchannel, forms more diffusion paths, and provides more contact points for the exchange of nutrients, oxygen, and metabolic waste, which is more conducive to the uniform distribution and rapid exchange of substances inside the microchannel. The complex microchannel increases the path redundancy of material exchange. Even if part of the microchannel is blocked, nutrients and signal molecules can still be transmitted through other paths. At the same time, the possibility of microchannel blockage can be reduced under the action of the self-cleaning coating 41 in the microchannel. At the same time, the abnormal parameters related to microchannel blockage are monitored by the micro-biosensor 51, such as the oxygen concentration or nutrient concentration gradient in the shell 1, so as to respond in time when there is a possibility of blockage.

[0057] like Figure 4 As shown, the self-cleaning coating 41 comprises a biocompatible polymer having anti-fouling and lubricating properties.

[0058] Biocompatible polymers can not only prevent dirt and bacteria from adhering to the joint surface and reduce the risk of infection, but also ensure that no harm is caused to the human body during long-term contact with human tissues and body fluids.

[0059] like Figure 6 and Figure 7 As shown, the intelligent response system 5 includes:

[0060] A data receiving module 52, which is used to receive detection data from the micro biosensor 51;

[0061] A data analysis module 53, which is configured to process and analyze the data receiving module 52 to determine whether the parameter deviates from a preset normal range;

[0062] A trigger module 54, which can initiate a corresponding response action when the data analysis module 53 determines that the key parameter deviates from the normal range;

[0063] The response execution module 55 includes but is not limited to a slow-release unit 6 activation unit, which is used to trigger the slow-release unit 6 pre-embedded in the shell 1 to release the corresponding bioactive substance to improve the material exchange efficiency.

[0064] The sustained-release unit 6 includes a plurality of sustained-release modules containing different bioactive substances and distributed in different areas of the shell 1, wherein at least one sustained-release module contains an angiogenic factor, at least one sustained-release module contains a nutritional supplement, and at least one sustained-release module contains an anti-inflammatory factor.

[0065] By adopting the above technical solution, when the micro biosensor 51 detects that the pressure, pH value, oxygen concentration, cytokine concentration and other parameters in the shell 1 are abnormal, the data analysis module 53 in the intelligent response system 5 will analyze the data collected by the sensor, and compare it with the preset normal range. When it is found that some parameters deviate from the normal range and meet the characteristic mode of microchannel blockage, the system will determine that the microchannel may be blocked. At this time, the trigger module 54 will start the corresponding response action. The sustained-release unit 6 is composed of a plurality of tiny sustained-release capsules, which are evenly distributed around the intervertebral disc organoid filling cavity 31 and near the microchannel and other key areas. For example, near the wall of the intervertebral disc organoid filling cavity 31, A sustained-release capsule is arranged at a certain interval. When the trigger module 54 issues a command, certain parts of the capsule shell, such as electrical signals or chemical signals, open specific nanochannels, and moisture in the external environment enters the sustained-release capsule due to the effect of osmotic pressure. As the volume of the liquid in the sustained-release capsule increases, the internal pressure increases, thereby squeezing the bioactive substance through the semipermeable sustained-release capsule to achieve release. The released angiogenic factors, anti-inflammatory factors, and nutritional supplements can reduce the inflammatory response caused by microchannel blockage, and the intelligent response system 5 can send data to external user terminals and other receiving devices through wireless transmission technology, so that doctors or researchers can understand the changes in tissue microenvironment during the intervertebral disc repair process.

[0066] like Figure 2 As shown, the inner surface of the shell 1 is also provided with a micro-nano structure 12 capable of promoting cell adhesion and proliferation.

[0067] A degradable metal wire reinforcement skeleton 101 is provided inside the mounting block 11 to enhance the mechanical strength of the mounting block 11 . A fiber structure 13 is also provided inside the shell 1 , and the fiber structure 13 is annularly wound around the outside of the plurality of microchannel units 4 .

[0068] like Figure 6 and Figure 7As shown, the micro-nano structure 12 can be nanofibers, nanopores or micro-concave-convex structures to improve the integration ability of the stent with the host tissue, promote the adhesion and proliferation of cells on the surface of the stent, and thus accelerate the regeneration and repair of the tissue. In the initial stage after the shell 1 is implanted in the human body, the mounting block 11 needs to withstand various mechanical loads from spinal activities, such as pressure, shear force, etc. The degradable metal wire reinforced skeleton 101 can significantly enhance the mechanical strength of the mounting block 11, making it stronger. With the passage of time and the progress of the intervertebral disc repair process, the requirements for the mechanical properties of the mounting block 11 will change, and the degradable metal wire will gradually degrade, so that the mechanical properties of the mounting block 11 can dynamically match the repair process. In the process of gradual regeneration of the intervertebral disc tissue and gradual stabilization of the stent's own structure, the mechanical strength of the mounting block 11 is appropriately reduced to avoid the mounting block 11 being too strong and causing damage to the intervertebral disc. The surrounding new tissue produces an adverse stress shielding effect, which is beneficial for the new tissue to better adapt to the physiological mechanical environment and promote the natural repair of the intervertebral disc. When 3D bioprinting the mounting block 11, the degradable metal wire can be pre-placed in the path of the printing nozzle so that it can be wrapped inside the mounting block 11 material during the printing process to form an integral structure. This can ensure that its position in the mounting block 11 is accurate and evenly distributed, and it has good bonding force with the mounting block 11 material, thereby effectively playing its role in enhancing mechanical properties. The fiber structure 13 can be made of collagen fibers, nanofibers, etc., which can enhance the strength of the scaffold and provide more sites for cell attachment. These fibers can be arranged in a ring shape, which helps to better withstand torsional and tensile stresses, just like in the annulus fibrosus of a natural intervertebral disc, the collagen fibers are arranged in an orderly manner to maintain its mechanical stability.

[0069] The intervertebral disc organoid microspheres are pre-treated before filling to improve their survival rate, proliferation ability and differentiation potential.

[0070] The shell 1 is integrally printed by a multi-nozzle bioprinter, and the gradient distribution of different materials in space is precisely controlled during the printing process.

[0071] The manufacturing process of the shell 1 also includes post-processing the printed shell 1, such as heat treatment, chemical treatment or bioactivation treatment, to further improve its biocompatibility and mechanical properties.

[0072] By adopting the above technical scheme, in the pretreatment of the intervertebral disc organoid microspheres and the post-treatment of the shell 1, the unreacted chemicals or impurities that may remain on the surface of the stent can be removed, which helps to reduce the immune response or rejection reaction that may be caused after the microspheres are implanted, improve the success rate of the operation and the comfort of the patient, and by precisely controlling the spatial gradient distribution of different materials, such as gradually increasing the proportion of materials with higher bioactive components in the area close to the intervertebral disc organoid filling cavity 31, it is possible to provide a more favorable local microenvironment for the microspheres, and appropriately increase the proportion of materials with higher mechanical strength in the artificial bionic fiber ring 2 that bears a larger mechanical load, so that it can better bear the mechanical effects of pressure, tension, shear force, etc. during the movement of the spine, thereby achieving precise adaptation of materials in different functional areas of the shell 1, so that the entire shell 1 can not only meet the biological needs of the growth of intervertebral disc organoid microspheres, but also adapt to the requirements of the mechanical environment of the spine.

[0073] The workflow of the technical solution of the present invention is as follows:

[0074] First, collect patient data, prepare various biological materials for printing the shell 1 according to the formula, and formulate biological ink with suitable rheological properties to ensure that it can pass through the print nozzle smoothly. After the tissue scaffold is printed, it is treated by heat treatment, chemical treatment or biological activation treatment.

[0075] Then, according to the degenerative position of the patient's intervertebral disc, the bioprinted intervertebral disc tissue engineering scaffold is carefully placed in the cleaned intervertebral space, ensuring that the mounting blocks 11 at both ends of the scaffold are in close contact with the adjacent vertebral bones.

[0076] After the placement is completed, the micro biosensor 51 embedded in the housing 1 starts to work and monitors the parameters in the housing 1 in real time.

[0077] The present invention covers any substitution, modification, equivalent method and scheme made on the essence and scope of the present invention. In order to make the public have a thorough understanding of the present invention, specific details are described in detail in the following preferred embodiments of the present invention, but those skilled in the art can fully understand the present invention without the description of these details. In addition, in order to avoid unnecessary confusion about the essence of the present invention, well-known methods, processes, procedures, components and circuits are not described in detail.

[0078] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A bioprinted intervertebral disc tissue engineering scaffold based on organoids, characterized in that: include; A shell, wherein the shell is filled with intervertebral disc organoid microspheres, and the upper end of the shell is connected to a mounting block; An artificial bionic fiber ring, which is arranged on the outside of the shell, and comprises poly(L-lactic acid), hyaluronic acid (HA), vascular endothelial growth factor, type I collagen, poly(caprolactone) PCL, collagen and nano-hydroxyapatite, wherein the vascular endothelial growth factor is encapsulated in biodegradable nanoparticles and uniformly dispersed in the fiber ring material, and the artificial bionic fiber ring also comprises elastin-derived peptides to give it better elasticity and flexibility; Ends, the ends are located at two ends of the shell, and the two ends opposite to each other are connected to an intervertebral disc organoid filling cavity, the intervertebral disc organoid filling cavity is filled with intervertebral organoid microspheres cultured in vitro, and the inner wall of the intervertebral disc organoid filling cavity is coated with a cell adhesion peptide or a specific growth factor fixing layer; A microchannel unit, wherein the microchannel unit is connected between two intervertebral disc organoid filling cavities, and the microchannel unit is composed of a plurality of microchannels forming a multi-level grid structure, and the inner wall of the microchannel unit has a self-cleaning coating to prevent the microchannel from being blocked; It also includes an intelligent response system based on sensor feedback data, wherein the sensor is a micro biosensor installed inside the shell, and the micro biosensor is used to detect physical and chemical parameter data inside the shell.

2. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The microchannels of the multi-level grid structure have different diameters and directions. The design of the microchannels includes but is not limited to spiral, grid or radial shapes to promote the uniform distribution and interaction of the intervertebral disc organ-like microspheres in the entire shell.

3. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The self-cleaning coating comprises a biocompatible polymer having anti-fouling and lubricating properties.

4. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The intelligent response system comprises: A data receiving module, which is used to receive detection data of the micro-biosensor; A data analysis module, which is configured to process and analyze the data receiving module to determine whether the parameter deviates from a preset normal range; A trigger module, which can initiate a corresponding response action when the data analysis module determines that the key parameters deviate from the normal range; The response execution module includes but is not limited to a sustained-release unit activation unit, which is used to trigger the sustained-release unit pre-embedded in the shell to release the corresponding bioactive substance to improve the material exchange efficiency.

5. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 4, characterized in that: The sustained-release unit comprises a plurality of sustained-release modules containing different bioactive substances and distributed in different areas of the shell, wherein at least one sustained-release module contains an angiogenesis-promoting factor, at least one sustained-release module contains a nutritional supplement, and at least one sustained-release module contains an anti-inflammatory factor.

6. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The inner surface of the shell is also provided with a micro-nano structure capable of promoting cell adhesion and proliferation.

7. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The intervertebral disc organoid microspheres are pre-treated before filling to improve their survival rate, proliferation ability and differentiation potential.

8. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: A degradable metal wire reinforcement skeleton is arranged inside the installation block, which is used to enhance the mechanical strength of the installation block. A fiber structure is also arranged inside the shell, and the fiber structure is arranged in a ring around the outside of a plurality of microchannel units.

9. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to claim 1, characterized in that: The shell is integrally printed by a multi-nozzle bioprinter, and the gradient distribution of different materials in space is precisely controlled during the printing process.

10. The organoid-based bioprinted intervertebral disc tissue engineering scaffold according to any one of claims 1 to 9, characterized in that: The manufacturing process of the shell also includes post-processing the printed shell, such as heat treatment, chemical treatment or bioactivation treatment, to further improve its biocompatibility and mechanical properties.

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