CN117530814A - Skeletal organoid construction system and use method thereof - Google Patents
Skeletal organoid construction system and use method thereof Download PDFInfo
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- CN117530814A CN117530814A CN202311219797.XA CN202311219797A CN117530814A CN 117530814 A CN117530814 A CN 117530814A CN 202311219797 A CN202311219797 A CN 202311219797A CN 117530814 A CN117530814 A CN 117530814A
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Abstract
The invention discloses a construction system of a bone organoid and a use method thereof, wherein the construction system comprises the following modules: the bone defect data module is used for acquiring volume inspection data of a bone defect area acquired by a patient through a medical radiography technology and acquiring medical image data of the bone defect area of the patient; the three-dimensional simulation module is used for converting the acquired medical image data into a three-dimensional image and carrying out three-dimensional simulation on a bone defect area of a patient; generating a three-dimensional data model of the bone organoid to be constructed according to the three-dimensional image of the bone defect area; and the three-dimensional construction module is used for selecting a proper biocompatible bracket according to a three-dimensional data model of the bone organoid to be constructed, and planting the cultured osteoblast layer on the biocompatible bracket so as to enable the osteoblast layer to grow in a bone microenvironment and form the bone organoid. The invention can construct and form the bone organoid matched with the shape and structure of the bone defect area, thereby better completing clinical treatment.
Description
Technical Field
The invention relates to the technical field of bone organoids, in particular to a construction system of a bone organoid and a use method thereof.
Background
Organoids are small cellular structures that mimic the anatomy and function of human organs, and this model of organs cultured in the laboratory plays an increasingly important role in modern medical research. Organoid technology can utilize the characteristics of mammalian pluripotent stem cells or adult tissue-derived stem cell self-tissues to construct in vitro 3D microenvironments similar to those in vivo, and construct organoids with multicellular types, which are already highly similar to corresponding in vivo tissue organs in complexity, thus providing an ideal platform for studying development, regeneration and pathology of tissue organs.
In orthopaedics, bone defects occur in a large number of people each year due to wounds, inflammations, tumor excision and the like, but a large section of critical bone defects cannot be regenerated and repaired by a human body, and external surgical intervention is needed to restore the normal state in most cases. The bone graft materials commonly used in clinic at present are as follows: autologous bone, namely the material is taken from the body of a patient, is an ideal repair, but has the problems of secondary injury, complications of multiple operation areas and supply areas, insufficient sources and the like; allogeneic bone is mostly donated from cadavers or animals, and has the problems of immune response, potential infection risk, medical ethics and the like; bone filling prostheses have problems of rejection, poor bone ingrowth success, need to be repaired after a long time, and the like. Thus, the clinical treatment can be better completed by adopting the organoid technology to construct organoids which are highly similar to the bone organs in the body.
However, organoids that mimic brain, lung and other organs have been known for a long time in organoid technology, but it is very difficult to build organoid models for skeletal tissue. For example, chinese patent application publication No. CN115154674a discloses a 3D bioprinting bone-like tissue engineering scaffold based on bone-like organ, which directly encapsulates cells in the scaffold during printing process, can be manufactured with high throughput and precisely controls the cells, but the application easily generates differentiation damage to cells during 3D printing process, resulting in distortion of the constructed bone-like organ, and difficulty in constructing the required bone-like organ because different types of bone cells exist in a special extracellular matrix (ECM), and the extracellular matrix is a set of network composed of collagen and minerals, which are constantly in a changing state, so that it is difficult to construct the bone-like organ adapted to the bone defect area.
Disclosure of Invention
The invention provides the following technical scheme for solving the technical problem that the construction of the bone organoids which are suitable for the bone defect areas is difficult in the prior art.
The invention relates to a construction system of a bone organoid, which comprises the following modules:
the bone defect data module is used for acquiring volume inspection data of a bone defect area acquired by a patient through a medical radiography technology and acquiring medical image data of the bone defect area of the patient;
the three-dimensional simulation module is used for converting the acquired medical image data into a three-dimensional image and carrying out three-dimensional simulation on a bone defect area of a patient; generating a three-dimensional data model of the bone organoid to be constructed according to the three-dimensional image of the bone defect area;
the three-dimensional construction module selects a proper biocompatible bracket according to a three-dimensional data model of the bone organoid to be constructed, and the cultured osteoblast layer is planted on the biocompatible bracket to enable the osteoblast layer to grow in a bone microenvironment, and the osteoblast layer grows and forms the bone organoid along with the growth of time.
As a further technical scheme, the medical contrast data comprises one or more of data such as X-ray imaging, ultrasonic imaging, electronic Computed Tomography (CT), magnetic Resonance Imaging (MRI), positron emission tomography (PET-CT) and the like.
As a further technical scheme, in the process of converting the acquired medical image data into the three-dimensional image, the original three-dimensional image of the bone defect area is restored and compared with the three-dimensional image of the defect part corresponding to the defect area.
As a further technical scheme, the three-dimensional construction module further comprises a microenvironment unit for providing a growth environment for the osteoblast layer, a planting unit for planting the osteoblast layer on the biocompatible scaffold, and a construction unit for continuously constructing a bone organoid matched with the bone defect area.
As a further technical solution, the microenvironment unit is used for creating a microenvironment for osteoblast growth, including providing cells related to bone tissue formation and an environment required for growth of a skeletal organoid to be constructed, and simultaneously culturing an osteoblast layer and three-dimensional bone tissue.
As a further embodiment, the cells associated with bone tissue formation include at least one cell or a combination of cells such as bone marrow stromal cells, bone progenitor cells, pre-osteoblasts, bone lining cells, bone cells or osteoclasts.
As a further technical scheme, the structure of the biocompatible scaffold is determined according to the actually detected bone defect area in the planting unit, the cultured osteoblast layer is planted on the biocompatible scaffold, and the growing osteoblast layer is promoted to be aligned or stretched in a specific direction, so that the osteoblast layer grows in an osteogenic microenvironment.
As a further technical scheme, the construction unit is used for continuously constructing a bone organoid matched with a bone defect area, and simulating the pressure required by human bone formation by using mechanical force according to different bone organoids and different microenvironments, so that bone marrow stem cells are converted into various osteoblasts such as osteoblasts and growth regulating bone cells required by the growth of the bone organoid to be constructed, and the bone organoid matched with the shape and structure of the bone defect area is further formed.
The invention also comprises a method for using the construction system of the bone organoids, which comprises the following steps:
s1: detecting a bone defect area of a patient, and acquiring volume inspection data of the bone defect area, which is acquired by the patient through a medical radiography technology;
s2: converting the acquired medical image data into a three-dimensional image by using computer three-dimensional auxiliary software, and performing three-dimensional simulation on a bone defect area of a patient to generate a three-dimensional data model of a bone organoid to be constructed;
s3: according to the three-dimensional data model of the bone organoid to be constructed, a proper biocompatible scaffold is selected, and a cultured osteoblast layer is planted on the biocompatible scaffold, so that the osteoblast layer grows in a bone microenvironment, and grows and forms the bone organoid along with the time.
As a further technical scheme, the step S3 further includes a step S301 of creating a microenvironment for osteoblast growth by using the stem cells of human origin, that is, creating cells related to bone tissue formation, and simultaneously culturing an osteoblast layer and three-dimensional bone tissue;
further comprising step S302, planting the cultured osteoblast layer on a biocompatible scaffold adapted to the bone defect area to form a construct;
and step S303, continuously constructing a bone organoid matched with the bone defect area, and simulating the pressure required by human bone formation by using mechanical force according to different structures and microenvironments of different bone organoids so as to convert bone marrow stem cells into various osteoblasts such as osteoblasts, growth regulating bone cells and the like required by the growth of the bone organoid to be constructed.
The method has the beneficial effects that the three-dimensional data of the bone defect area of the patient is obtained through the medical influence technology, the obtained medical image data is converted into the three-dimensional image, the three-dimensional simulation is carried out on the bone defect area of the patient, and the three-dimensional data model of the bone organoid to be constructed is generated according to the three-dimensional image of the bone defect area; then according to the three-dimensional data model of the bone organoid to be constructed, a proper biocompatible bracket is selected, a cultured osteoblast layer is planted on the biocompatible bracket, and according to different structures and microenvironments of different bone organoids, the pressure required by human bone formation is simulated by using mechanical force, so that bone marrow stem cells are converted into various osteoblasts such as osteoblasts and growth regulating bone cells required by the bone organoid growth to be constructed, the growth of extracellular matrix (ECM) is stimulated, the process is very similar to the growth of human bone tissue, and all proteins required by the subsequent functions are secreted by the cells, so that the bone organoid matched with the shape and structure of a bone defect area is finally formed.
Drawings
FIG. 1 is a schematic block diagram of a system for constructing a skeletal organoid of the present invention;
FIG. 2 is an EM diagram of an osteoblast layer of the bone organoid construct system of the present invention;
FIG. 3 is a schematic representation of bone tissue grafting in one embodiment of a bone organoid construction system of the present invention;
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
The flow diagrams in the figures are merely exemplary flow illustrations and do not represent that all of the elements, operations, and steps in the flow diagrams must be included in the aspects of the present invention, nor that the steps must be performed in the order shown in the figures. For example, some operations/steps in the flowcharts may be decomposed, some operations/steps may be combined or partially combined, etc., and the order of execution shown in the flowcharts may be changed according to actual situations without departing from the gist of the present invention.
The block diagrams in the figures generally represent functional entities and do not necessarily correspond to physically separate entities. That is, the functional entities may be implemented in software or hardware, or one or more operational steps or methods may be presented, or may be implemented in a different processing unit, operational method or experimental step.
The invention relates to a construction system of a bone organoid, which comprises the following modules:
a bone defect data module 1, configured to acquire volumetric inspection data of a bone defect area acquired by a patient through a medical imaging technique, that is, acquire medical image data of the bone defect area of the patient; the medical contrast data comprises one or more of X-ray imaging, ultrasonic imaging, electronic Computed Tomography (CT), magnetic Resonance Imaging (MRI), positron emission tomography (PET-CT) and other data;
the three-dimensional simulation module 2 is used for converting the acquired medical image data into a three-dimensional image and carrying out three-dimensional simulation on a bone defect area of a patient; namely, collecting image data of a bone defect area of a patient, comparing an original three-dimensional image of a reduced bone defect area with a three-dimensional image of a defect part corresponding to the defect area, and generating a three-dimensional data model of a bone organoid to be constructed according to the three-dimensional image of the bone defect area;
the three-dimensional construction module 3 selects a proper biocompatible scaffold according to a three-dimensional data model of the bone organoid to be constructed, and plants the cultured osteoblast layer on the biocompatible scaffold to enable the osteoblast layer to grow in a bone microenvironment, and the osteoblast layer grows and forms the bone organoid along with the growth of time.
The three-dimensional construction module 3 further comprises a microenvironment unit 301, a planting unit 302 and a construction unit 303, wherein the microenvironment unit 301 is used for creating a microenvironment for osteoblast growth, and cells in the microenvironment unit 301 for creating an osteoblast microenvironment comprise cells related to bone tissue formation, that is, at least one cell or a combination of cells including bone marrow stromal cells, osteoprogenitor cells, preosteoblasts, osteoblasts, bone lining cells, bone cells or osteoclasts.
In the unit, an osteoblast layer and a three-dimensional bone tissue can be simultaneously cultured, wherein the osteoblast layer is formed by carrying out two-dimensional plane culture on mesenchymal stem cells and differentiating the mesenchymal stem cells into the osteoblast layer; culturing the three-dimensional bone tissue refers to three-dimensional culturing and differentiating the mesenchymal stem cells into three-dimensional spherical bone tissue.
It should be understood that the osteoblast layer refers to various osteoblasts obtained by differentiation of stem cells including human, and further includes osteoblasts cultured from bone tissue, which mainly refer to cells having multi-directional differentiation and renewal such as mesenchymal stem cells, embryonic stem cells, pluripotent stem cells, and undifferentiated progenitor cells, among which mesenchymal stem cells are preferably used.
The planting unit 302 may plant the cultured osteoblast layer on a biocompatible scaffold, specifically, in order to make the cultured osteoblast and bone tissue form a three-dimensional form more similar to that of a human body, a biocompatible scaffold made of biocompatible polymer is used, and the scaffold is generally provided with a groove or mesh structure, on which the osteoblast layer can be planted, and the basic shape or pattern of the biocompatible scaffold causes the growing osteoblast to be aligned or stretched in a specific direction so as to grow in an osteogenic microenvironment. This is because the biocompatible scaffold is biodegradable and biocompatible, it is compatible with biological systems and degrades naturally within the system without any toxic effects.
It should be appreciated that there are two different structures of normal bone tissue in the human body: cancellous bone and cortical bone, the cancellous bone is a porous structure, and has a porosity of 45% -90%; the cortical bone is more compact and distributed on the diaphysis and the bone tissue surface, and the porosity is 5% -20%. However, whether cancellous or cortical bone, the interconnected pore structure is important in order to promote continuous ingrowth of bone tissue. This is because the interconnected pores allow nutrient and oxygen transport into the interior of the biocompatible scaffold, promote the growth of cells and bone tissue into the internal structure of the scaffold, promote the formation of vascularization of the scaffold and the removal of metabolites. The structure of the biocompatible scaffold can be adjusted according to the actually detected bone defect area so as to facilitate incubation of three-dimensional bone tissue on the osteoblast layer and induce self-assembly.
The construction unit 303 is configured to continuously construct a bone organoid adapted to a bone defect area, simulate the pressure required for human bone formation by using mechanical force according to different structures and microenvironments of the bone organoid, transform bone marrow stem cells into osteoblasts such as osteoblasts and growth regulating bone cells required for growth of the bone organoid to be constructed, stimulate growth of extracellular matrix (ECM), and make the cell secrete all proteins required for subsequent functions. This is because the bone must be subjected to some mechanical stress during growth to achieve its normal shape, and each movement, weight and muscles exert pressure on the bone, which results in minimal deformation. These deformations are necessary for bone development to the proper size, shape and strength. Over time, osteoblasts grow together to form bone tissue and further form a skeletal organoid that matches the shape and structure of the bone defect area.
The skeleton organoid construction of the invention is suitable for various skeletons such as femur, tibia, humerus, ulna, radius, meniscus, parietal bone and the like, and can customize corresponding skeleton organoids individually according to the requirements of actual bone defect areas.
The invention also relates to a method for using the construction system of the bone organoids, which comprises the following steps of;
s1: detecting a bone defect area of a patient, and acquiring volume inspection data of the bone defect area, which is acquired by a medical radiography technology, of the patient, wherein the volume inspection data comprises a plurality of data such as X-ray imaging, ultrasonic imaging, electronic Computed Tomography (CT), magnetic Resonance Imaging (MRI), positron emission tomography (PET-CT) and the like;
s2: converting the acquired medical image data into a three-dimensional image by using computer three-dimensional auxiliary software, and performing three-dimensional simulation on a bone defect area of a patient to generate a three-dimensional data model of a bone organoid to be constructed;
s3: according to the three-dimensional data model of the bone organoid to be constructed, a proper biocompatible scaffold is selected, and a cultured osteoblast layer is planted on the biocompatible scaffold, so that the osteoblast layer grows in a bone microenvironment, and grows and forms the bone organoid along with the time.
In the step S3, a step S301 is further included of creating a microenvironment for the growth of osteoblasts, that is, creating cells related to bone tissue formation, that is, at least one cell or a combination of cells including bone marrow stromal cells, osteoprogenitor cells, preosteoblasts, osteoblasts, bone lining cells, bone cells, or osteoclasts, by using human stem cells. The method can also be used for simultaneously culturing an osteoblast layer and a three-dimensional bone tissue, wherein the osteoblast layer is formed by culturing mesenchymal stem cells in a two-dimensional plane and differentiating the mesenchymal stem cells into the osteoblast layer; culturing the three-dimensional bone tissue refers to three-dimensional culturing and differentiating the mesenchymal stem cells into three-dimensional spherical bone tissue.
In the step S3, a step S302 is further included, in which a cultured osteoblast layer is planted on a biocompatible scaffold to form a construct, and the biocompatible scaffold made of a biocompatible polymer is used, and it should be noted that the biocompatible scaffold has the same or similar structure as that of the bone defect region, and an osteoblast layer may be planted thereon, and the basic shape or pattern of the biocompatible scaffold promotes alignment or expansion of the growing osteoblast in a specific direction.
In the step S3, a step S303 is further included, in which a bone organoid adapted to the bone defect area is continuously constructed, and according to the different structures and microenvironments of the bone organoids, the mechanical force is used to simulate the pressure required for forming human bones, so that bone marrow stem cells are converted into osteoblasts and various osteoblasts such as bone cells required for growth of the bone organoids to be constructed, growth of extracellular matrix (ECM) is stimulated, and all proteins required for performing subsequent functions are secreted by the cells. Over time, osteoblasts grow together to form bone tissue and further form a skeletal organoid that matches the shape and structure of the bone defect area.
In one embodiment, a three-dimensional data model of a bone organoid to be constructed and a biocompatible scaffold are firstly generated according to three-dimensional data of a bone defect area of a patient, mesenchymal stem cells are extracted and cultured and proliferated by adopting the prior art, then the obtained mesenchymal stem cells are inoculated on a plane and cultured in a CO2 incubator of 5% -7% at 36-37.5 ℃, the cells are treated with an osteogenic differentiation medium every 2-4 days, and then the cells are treated again by replacing a new medium, and the mesenchymal stem cells are differentiated into an osteoblast layer, so that microenvironment required for bone tissue growth is simultaneously cultured under the same conditions. The osteogenic differentiation medium comprises 30 μg/ml to 40 μg/ml ascorbic acid 2-phosphate, 80nM to 120nM dexamethasone, 10ng/ml TGF- β1. The TFG-beta 1 transforming growth factor is used for stimulating mesenchymal stem cells and promoting the osteogenic differentiation of the mesenchymal stem cells. GAG matrix formation levels were then fixed by treating cells in the osteoblast layer with 10% formaldehyde for 30 minutes.
In the cultivation of three-dimensional bone tissue cells, 3×10 mesenchymal stem cells were placed in 25ml polypropylene tube and centrifuged for 10 minutes, and then the mesenchymal stem cells were cultured in a 5% -7& co2 incubator with osteogenic differentiation medium at 36. Incubation is carried out at 5-37℃for 24-48 hours to produce three-dimensional spherical bone tissue.
The obtained three-dimensional spherical bone tissue is loaded on an osteoblast layer with differentiated cells and then is attached to a biocompatible scaffold matched with a bone defect area, and mechanical force is applied to the biocompatible scaffold, the bone tissue and the osteoblast layer, wherein the mechanical force is between 0.8MPa and 20MPa according to different bone defect positions. The application of mechanical force may grow bone tissue into skeletal organoids in an incubator, but it is also possible to naturally grow and self-assemble biocompatible scaffolds and bone tissue and osteoblast layers directly in the bone defect region, as shown in fig. 3. This is because the bone must be subjected to some mechanical stress during growth to achieve its normal shape, and each movement, weight and muscles exert pressure on the bone, which results in minimal deformation. These deformations are necessary for bone development to the proper size, shape and strength. The three-dimensional spherical bone tissue can grow and self-assemble on the biocompatible scaffold, and the grown osteoblasts and bone tissue align or stretch in a specific direction of the scaffold, and further form a skeletal organoid matching the shape and structure of the bone defect area.
While the preferred embodiments and examples of the present invention have been described in detail with reference to the drawings, the present invention is not limited to the above embodiments and examples, and various changes and equivalent substitutions can be made therein without departing from the spirit of the present invention within the knowledge of those skilled in the art, and therefore, the present invention is not limited to the embodiments disclosed herein, and all embodiments falling within the scope of the claims of the present application are intended to be included in the scope of the present invention.
Claims (10)
1. A system for constructing a skeletal organoid, comprising the following modules:
the bone defect data module (1) is used for acquiring volume inspection data of a bone defect area acquired by a patient through a medical radiography technology and acquiring medical image data of the bone defect area of the patient;
the three-dimensional simulation module (2) is used for converting the acquired medical image data into a three-dimensional image and carrying out three-dimensional simulation on a bone defect area of a patient; generating a three-dimensional data model of the bone organoid to be constructed according to the three-dimensional image of the bone defect area;
and the three-dimensional construction module (3) selects a proper biocompatible bracket according to a three-dimensional data model of the bone organoid to be constructed, and the cultured osteoblast layer is planted on the biocompatible bracket so as to grow in a bone microenvironment, and the osteoblast layer grows and forms the bone organoid along with the growth of time.
2. A bone organoid building system according to claim 1, wherein: the medical contrast data comprises one or more of X-ray imaging, ultrasonic imaging, electronic Computed Tomography (CT), magnetic Resonance Imaging (MRI), positron emission tomography (PET-CT) and the like.
3. A bone organoid building system according to claim 1, wherein: in the process of converting the acquired medical image data into the three-dimensional image, the original three-dimensional image of the bone defect area is reduced and compared with the three-dimensional image of the defect part corresponding to the defect area.
4. A bone organoid building system according to claim 1, wherein: the three-dimensional construction module (3) further comprises a microenvironment unit (301) for providing a growth environment for the osteoblast layer, a planting unit (302) for planting the osteoblast layer on the biocompatible scaffold, and a construction unit (303) for continuously constructing a bone organoid adapted to the bone defect area.
5. The bone organoid building system according to claim 4, wherein: the microenvironment unit (301) is used for creating a microenvironment for osteoblast growth, comprising providing cells involved in bone tissue formation and an environment required for growth of a skeletal organoid to be constructed, while simultaneously culturing osteoblast layers and three-dimensional bone tissue.
6. The bone organoid building system according to claim 5, wherein: the cells related to bone tissue formation comprise at least one cell or a combination of cells such as bone marrow stromal cells, bone progenitor cells, preosteoblasts, osteoblasts, bone lining cells, bone cells or osteoclasts.
7. The bone organoid building system according to claim 4, wherein: the structure of the biocompatible scaffold is determined according to the actually detected bone defect area in the planting unit (302), and the cultured osteoblast layer is planted on the biocompatible scaffold, so that the growing osteoblast is aligned or stretched in a specific direction, and the osteoblast is grown in an osteogenic microenvironment.
8. The bone organoid building system according to claim 4, wherein: the construction unit (303) is used for continuously constructing a bone organoid matched with a bone defect area, simulating the pressure required by human bone formation by using mechanical force according to different bone organoids and different microenvironments, converting bone marrow stem cells into various osteoblasts such as osteoblasts and growth regulating bone cells required by the growth of the bone organoid to be constructed, and further forming the bone organoid matched with the shape and structure of the bone defect area.
9. A method of using a system for constructing a skeletal organoid, comprising the steps of:
s1: detecting a bone defect area of a patient, and acquiring volume inspection data of the bone defect area, which is acquired by the patient through a medical radiography technology;
s2: converting the acquired medical image data into a three-dimensional image by using computer three-dimensional auxiliary software, and performing three-dimensional simulation on a bone defect area of a patient to generate a three-dimensional data model of a bone organoid to be constructed;
s3: according to the three-dimensional data model of the bone organoid to be constructed, a proper biocompatible scaffold is selected, and a cultured osteoblast layer is planted on the biocompatible scaffold, so that the osteoblast layer grows in a bone microenvironment, and grows and forms the bone organoid along with the time.
10. The method of using a bone organoid building system according to claim 9, wherein; in the step S3, the method further includes a step S301 of creating a microenvironment for osteoblast growth, that is, creating cells related to bone tissue formation, by using the human stem cells, and simultaneously culturing osteoblast layers and three-dimensional bone tissue;
further comprising step S302, planting the cultured osteoblast layer on a biocompatible scaffold adapted to the bone defect area to form a construct;
and step S303, continuously constructing a bone organoid matched with the bone defect area, and simulating the pressure required by human bone formation by using mechanical force according to different structures and microenvironments of different bone organoids so as to convert bone marrow stem cells into various osteoblasts such as osteoblasts, growth regulating bone cells and the like required by the growth of the bone organoid to be constructed.
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