Heart organ chip and preparation method

Abstract

The present invention discloses a heart organ chip and a preparation method. The heart organ chip includes a swing arm, a detection platform, a flexible hinge, a first myocardial microtissue and a measurement module. The two ends of the swing arm form a fixed end and a movable end respectively. The detection platform includes a first fixed part and a second fixed part. The two ends of the flexible hinge are respectively connected to the first fixed part and the fixed end. The two ends of the first myocardial microtissue are respectively connected to the second fixed part and the first connecting part. The measurement module is used to obtain the contraction force of the first myocardial microtissue according to the swing information of the swing arm. The preparation method is used to prepare a heart organ chip. The swing arm can swing relative to the first fixed part following the contraction and relaxation of the first myocardial microtissue. The flexible hinge is flexible and can be deformed during the swinging process of the swing arm. When the swing arm swings based on the first fixed part, the movable end has a large range of motion. The swing arm can respond quickly, thereby improving the sensitivity and stability of myocardial tissue detection.

Description

Technical Field

[0001] The present invention relates to the field of biomedical testing technology, and in particular to a heart organ chip and a preparation method thereof. Background Art

[0002] Heart-on-a-chip is an in vitro microphysiological system composed of myocardial microtissues, flexible structures, and measurement modules. This technology can provide a technical platform that can supplement or replace animal drug testing for the cardiac toxicity testing of new drugs, and provide new ideas for the study of cardiac physiology and pathology in precision medicine. The working principle of heart-on-a-chip is generally to integrate myocardial microtissues and micro-flexible structures into one. The contraction of the myocardium drives the deformation of the flexible structure, and then the contraction force of the myocardial tissue is inferred by measuring the deformation of the flexible structure.

[0003] There are two types of measurement methods in related technologies. One is to monitor the displacement of the structure through microscope imaging and image processing. During imaging, the cells need to be removed from the incubator, causing myocardial damage and shortening the survival time of the cells. Based on the above reasons, the other type of measurement method uses strain gauges based on electrical principles to monitor strain and avoid microscope illumination. However, strain sensors have problems such as large discreteness, aging, and the need for insulation packaging. In addition, the strain is small, resulting in low sensitivity and stability of the chip. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a heart organ chip that can improve the sensitivity and stability of myocardial tissue detection.

[0005] The present invention also provides a method for preparing the above-mentioned heart organ chip.

[0006] A heart organ chip according to a first aspect of the present invention comprises:

[0007] A swing arm, with two ends forming a fixed end and a movable end respectively, a first connecting portion being provided on a side of the swing arm, and the first connecting portion being located between the center of the swing arm and the fixed end;

[0008] The detection platform comprises a first fixing portion and a second fixing portion, wherein the second fixing portion is located on a side of the swing arm;

[0009] A flexible hinge having flexibility, wherein two ends of the flexible hinge are respectively connected to the first fixing portion and the fixing end;

[0010] A first myocardial microtissue, two ends of which are respectively connected to the second fixing portion and the first connecting portion;

[0011] A measuring module, used for acquiring the contractile force of the first myocardial microtissue according to the swing information of the swing arm;

[0012] The swing arm can swing relative to the first fixing part following the contraction and relaxation of the first myocardial microtissue, and drive the flexible hinge to deform.

[0013] The heart organ chip according to the embodiment of the present invention has at least the following beneficial effects:

[0014] The fixed end of the swing arm is fixed to the first fixed part, and the movable end of the swing arm can move freely. The swing arm swings relative to the first fixed part following the contraction and relaxation of the first myocardial microtissue. The flexible hinge is flexible and can be deformed during the swing of the swing arm. The present invention constructs a mechanical system that drives the swing arm to swing through the contraction and relaxation of the myocardial microtissue, forming a micro-heart organ chip with a large swing characteristic. When the swing arm swings based on the first fixed part, the movable end has a large movable amplitude, and the displacement of the movable end is amplified. When the first myocardial microtissue contracts and relaxes, the swing arm can respond quickly, and the chip has high sensitivity, thereby improving the sensitivity and stability of myocardial tissue detection.

[0015] According to some embodiments of the present invention, the heart organ chip also includes a flexible elastomer, the swing arm also includes a second connecting portion, the first connecting portion and the second connecting portion are respectively located on two opposite sides of the swing arm, the detection platform also includes a third fixing portion, the third fixing portion and the second fixing portion are respectively located on two opposite sides of the swing arm, and two ends of the elastomer are respectively connected to the second connecting portion and the third fixing portion; the elastomer is used to provide a force that drives the swing arm to swing away from the first myocardial microtissue.

[0016] According to some embodiments of the present invention, the heart organ chip further includes a second myocardial microtissue, the swing arm further includes a second connecting portion, the first connecting portion and the second connecting portion are respectively located on two opposite sides of the swing arm, the detection platform further includes a third fixing portion, the third fixing portion and the second fixing portion are respectively located on two sides of the swing arm, and two ends of the second myocardial microtissue are respectively connected to the second connecting portion and the third fixing portion;

[0017] Wherein, one of the first myocardial microtissue and the second myocardial microtissue is configured as atrial muscle tissue, and the other is configured as ventricular muscle tissue.

[0018] According to some embodiments of the present invention, the first direction is the direction of the movable end toward the fixed end, and the second direction is the arrangement direction of the swing arm and the first fixed portion;

[0019] Wherein, the swing arm comprises a transition portion, the length of the transition portion along the second direction gradually decreases in the first direction, and the fixed end is arranged at an end of the transition portion facing away from the movable end;

[0020] And / or, the flexible hinge includes a connected swinging part and a deforming part, the swinging part is connected to the fixed end, the length of the deforming part along the second direction is smaller than the length of the swinging part along the second direction, and the deforming part can deform following the swing of the swing arm.

[0021] According to some embodiments of the present invention, the measuring module includes an observation unit, and the observation unit is used to obtain the displacement of the movable end by observing the swing image of the swing arm;

[0022] Alternatively, the swing arm is magnetic, and the measuring module comprises a magnetic sensor, and the magnetic sensor is used to detect the swing angle of the swing arm according to the change of the magnetic field of the swing arm.

[0023] According to some embodiments of the present invention, the heart organ chip also includes a supporting portion, which is flexible, and whose two ends are respectively connected to the first connecting portion and the second fixing portion, and the supporting portion has a growth space for accommodating the first myocardial microtissue, and the supporting portion is used to guide the myocardial cells to grow along the extension direction of the supporting portion to form the first myocardial microtissue.

[0024] According to some embodiments of the present invention, the detection platform further includes a base, the first fixing portion and the second fixing portion are both fixed to a supporting surface of the base, and a lubricating medium is provided between a surface of the swing arm facing the base and the supporting surface.

[0025] A method for preparing a cardiac organ chip according to a second aspect of the present invention is used to prepare the cardiac organ chip according to the first aspect of the present invention, comprising:

[0026] Forming the swing arm, the detection platform, and the flexible hinge by 3D printing, and connecting the flexible hinge to the swing arm and the first fixing portion;

[0027] The first myocardial microtissue cells are cultured between the second fixing part and the first connecting part, so that the first myocardial microtissue cells are connected to the first connecting part and the second fixing part through growth, and form the first myocardial microtissue.

[0028] According to some embodiments of the present invention, a flexible supporting portion is formed between the second fixing portion and the swing arm by 3D printing, and first myocardial microtissue cells are cultured in the supporting portion;

[0029] When culturing the first myocardial microtissue cells, the supporting portion is stretched along the extension direction of the supporting portion so that the first myocardial microtissue cells generate pre-strain parallel to the extension direction of the supporting portion, thereby inducing the first myocardial microtissue cells to grow and arrange along the extension direction of the supporting portion and form the first myocardial microtissue.

[0030] According to some embodiments of the present invention, the swing arm is formed by 3D printing using a polymer containing magnetic powder, and when culturing the first myocardial microtissue cells, a magnetic field is applied to the swing arm to drive the swing arm to swing and stretch the supporting portion.

[0031] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0033] Figure 1 A schematic diagram of an embodiment of a heart organ chip of the present invention;

[0034] Figure 2 is a schematic diagram of another embodiment of a heart organ chip of the present invention;

[0035] Figure 3 FIG. 4 is a schematic diagram of another embodiment of the heart organ chip of the present invention.

[0036] Reference numerals:

[0037] Swing arm 100, fixed end 110, movable end 120, first connecting part 130, second connecting part 140, transition part 150; detection platform 200, first fixed part 210, second fixed part 220, third fixed part 230; flexible hinge 300, swing part 310, deformation part 320; first myocardial microtissue 400; measurement module 500, magnetic sensor 510; elastomer 600; second myocardial microtissue 700; supporting part 800. DETAILED DESCRIPTION

[0038] Embodiments of the present invention are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and cannot be understood as limiting the present invention.

[0039] In the description of the present invention, it should be understood that descriptions involving orientations, such as up, down, front, back, left, right, etc., and orientations or positional relationships indicated are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0040] In the description of the present invention, "several" means more than one, "many" means more than two, "greater than", "less than", "exceed", etc. are understood to exclude the number itself, and "above", "below", "within", etc. are understood to include the number itself. If there is a description of "first" or "second", it is only used for the purpose of distinguishing the technical features, and cannot be understood as indicating or implying the relative importance or implicitly indicating the number of the indicated technical features or implicitly indicating the order of the indicated technical features.

[0041] In the description of the present invention, unless otherwise clearly defined, terms such as setting, installing, connecting, etc. should be understood in a broad sense, and technicians in the relevant technical field can reasonably determine the specific meanings of the above terms in the present invention based on the specific content of the technical solution.

[0042] In the description of the present invention, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0043] Traditional heart organ chips are generally divided into two categories: one is a "displacement type" chip that directly measures the displacement of the flexible structure, and the other is a "strain type" chip that directly measures the strain of the flexible structure. In the "displacement type" chip, microscopic imaging and image processing are used to monitor the displacement. When the cells are microscopically imaged, the cells need to be taken out of the incubator. The cells are subject to temperature changes, CO2 concentration changes, and light, which will cause certain damage to the myocardial tissue and shorten the survival time of the cells. For this reason, the "strain type" chip based on electrical principles is used to monitor the strain. The advantage of this solution is that it can avoid the light of the microscope, but the electrical strain sensor made of polymer in the liquid has large discreteness, aging, and the need for insulation packaging. In addition, the strain of this type of flexible structure is small when it is deformed, which cannot meet the requirements of high sensitivity and high stability of the heart organ chip.

[0044] Based on the above, the present invention provides a heart organ chip (hereinafter referred to as chip), referring to Figure 1 The heart organ chip includes a swing arm 100, a detection platform 200, a flexible hinge 300, a first myocardial microtissue 400 and a measurement module 500. The swing arm 100 includes a fixed end 110 and a movable end 120 respectively located at both ends thereof, and a first connecting portion 130 located at the side of the swing arm 100. In the length direction of the swing arm 100, the first connecting portion 130 is located between the center of the swing arm 100 and the fixed end 110; the detection platform 200 includes a first fixing portion 210 and a second fixing portion 220, and the second fixing portion 220 is located at the swing arm 100. The first fixing part 210 is located at the end of the swing arm 100; the flexible hinge 300 is flexible and can be driven to deform and automatically recover after the external force is removed, and the two ends of the flexible hinge 300 are respectively connected to the first fixing part 210 and the fixed end 110; the first myocardial microtissue 400 is located at the side of the swing arm 100, and the two ends of the first myocardial microtissue 400 are respectively connected to the second fixing part 220 and the first connecting part 130; the measuring module 500 is used to obtain the contraction force of the first myocardial microtissue 400 according to the swing information of the swing arm 100.

[0045] The first myocardial microtissue 400 has the characteristics of contraction and relaxation. The fixed end 110 of the swing arm 100 is fixed to the first fixed part 210, and the movable end 120 of the swing arm 100 can move freely. The swing arm 100 follows the contraction and relaxation of the first myocardial microtissue 400 and swings relative to the first fixed part 210. The flexible hinge 300 is flexible and can be deformed during the swinging process of the swing arm 100, so that the swing arm 100 can swing freely; that is, when the first myocardial microtissue 400 contracts, the swing arm 100 moves toward the first myocardial microtissue 400. Swinging. When the first myocardial microtissue 400 relaxes, the swing arm 100 swings away from the first myocardial microtissue 400. Since the first connecting portion 130 is located between the center of the swing arm 100 and the fixed end 110, when the swing arm 100 swings based on the first fixed portion 210, the movable end 120 has a larger movable amplitude, and the displacement of the movable end 120 is amplified. When the first myocardial microtissue 400 contracts and relaxes, the swing arm 100 can respond quickly, and the chip has a high sensitivity, which improves the sensitivity and stability of myocardial tissue detection.

[0046] The present invention constructs a mechanical system that drives the swing arm 100 to swing through the contraction and relaxation of myocardial microtissues, forming a micro-heart organ chip with a large swing characteristic, and realizing long-term real-time measurement of myocardial contractility of the chip without the influence of light. The mechanical system converts the contraction and relaxation of myocardial microtissues into the swing of the swing arm 100, and the displacement of the active end 120 of the swing arm 100 can amplify the contraction and relaxation of the myocardial microtissues. The measurement module 500 obtains the contraction force of the first myocardial microtissue 400 based on the swing information of the swing arm 100, and the detection accuracy is high.

[0047] It is understandable that the ends and the sides of the swing arm 100 are respectively located at the edges in different directions of the swing arm 100. Exemplarily, the fixed end 110 and the movable end 120 are respectively located at the two ends of the swing arm 100 in the first direction, and the first connecting portion 130 is located on one side of the swing arm 100 in the second direction, and the first direction intersects with the second direction; in some specific embodiments, the first direction is set to be perpendicular to the second direction to simplify the mechanical model of the chip and improve the convenience of detecting the contractility of myocardial tissue.

[0048] The length of the swing arm 100 in the first direction is greater than the length of the swing arm 100 in the second direction, so that the swing arm 100 is in a long strip shape as a whole. On the one hand, the distance between the fixed end 110 and the movable end 120, as well as the swing force arm of the swing arm 100 are increased, thereby amplifying the movement displacement of the movable end 120; on the other hand, the weight of the swing arm 100 is reduced, the swing resistance of the swing arm 100 is reduced, and the swing sensitivity of the swing arm 100 is further improved.

[0049] Define that the distance between the fixed end 110 and the first connecting part 130 in the first direction is L1, and the distance between the movable end 120 and the first connecting part 130 in the first direction is L2. L1 / L2 is set to 1 / 4-2 / 3, such as 1 / 4, 1 / 3, 1 / 2, etc., so that the contraction and relaxation of the myocardial microtissue can effectively drive the swing arm 100 to swing, and amplify the displacement of the movable end 120, thereby ensuring the high sensitivity and high stability of the chip's detection effect.

[0050] The swing information of the swing arm 100 is not limited to the swing angle of the swing arm 100, the displacement of the active end 120, the swing speed of the swing arm 100, the swing force arm length of the swing arm 100, etc. In one embodiment, the measuring module 500 includes an observation unit, which is used to obtain the displacement of the active end 120 by observing the swing image of the swing arm 100. Exemplarily, the observation unit is set as an optical microscope, which can clearly display the subtle swinging form of the swing arm 100 during the swinging process, so as to facilitate the observation of the swing image of the swing arm 100, and the swing image is not limited to the instantaneous image of the swing arm 100 and the image of the swing arm 100 within a preset time; the displacement of the active end 120 can be obtained according to the swing image of the swing arm 100 displayed by the optical microscope, and then the contraction force of the myocardial microtissue can be obtained according to the displacement of the active end 120. Alternatively, in other embodiments, the observation unit is set as a camera, which is used to shoot the swing image of the swing arm 100, and the displacement of the active end 120 can be further obtained according to the swing image of the swing arm 100 shot by the camera, and the contraction force of the myocardial microtissue can be obtained.

[0051] Alternatively, in another embodiment, the measuring module 500 includes a magnetic sensor 510, the swing arm 100 has magnetism, and the magnetic sensor 510 is used to detect the swing angle of the swing arm 100 according to the change of the magnetic field of the swing arm 100. Specifically, when the swing arm 100 swings following the contraction and relaxation of the myocardial microtissue, the magnetic induction intensity sensed by the magnetic sensor 510 changes, and then the swing angle of the swing arm 100 is obtained according to the relationship between the magnetic induction intensity and the rotation angle of the swing arm 100, and then the contraction force of the myocardial microtissue is further obtained according to the swing angle of the swing arm 100.

[0052] Furthermore, the measuring module 500 may also include an analysis unit, which can receive the swing information of the swing arm 100 detected by the observation unit or the magnetic sensor 510, obtain the contraction force of the myocardial microtissue by analysis and calculation, and further output the detection result. The analysis unit is not limited to a storage medium, a mobile terminal, etc. that integrates information collection and calculation functions.

[0053] In the present invention, the chip further includes a flexible elastic body 600, the swing arm 100 further includes a second connecting portion 140, the first connecting portion 130 and the second connecting portion 140 are respectively located on opposite sides of the swing arm 100, the detection platform 200 further includes a third fixing portion 230, the third fixing portion 230 and the second fixing portion 220 are respectively located on opposite sides of the swing arm 100, the two ends of the elastic body 600 are respectively connected to the second connecting portion 140 and the third fixing portion 230, the elastic body 600 deforms following the swing of the swing arm 100, and can provide a force to drive the swing arm 100 to swing back to the first myocardial microtissue 400, so as to simulate the recovery function of the heart. It can be understood that since the first myocardial microtissue 400 and the elastic body 600 are respectively located on opposite sides of the swing arm 100, when the first myocardial microtissue 400 contracts, the elastic body 600 stretches, and when the first myocardial microtissue 400 relaxes, the elastic body 600 compresses.

[0054] When the chip is in different test environments, the first myocardial microtissue 400 is subjected to different degrees of external stimulation. When the external stimulation is more intense, the first myocardial microtissue 400 is easily damaged. The first myocardial microtissue 400 itself has insufficient contraction and relaxation capabilities. Based on this, an elastomer 600 is provided in the present invention. The elastomer 600 is used to apply a force to the swing arm 100 toward the first myocardial microtissue 400 when the first myocardial microtissue 400 is relaxed, so as to assist the swing arm 100 in returning to its original position, so as to make the first myocardial microtissue 400 start to contract when the swing arm 100 is in the initial state, thereby driving the swing arm 100 to swing, thereby avoiding errors in the swing information of the swing arm 100 due to the swing arm 100 not returning to its original position, thereby affecting the contraction force detection accuracy of the first myocardial microtissue 400.

[0055] The first connection portion 130 and the second connection portion 140 are arranged symmetrically with respect to the swing arm 100 . The swing arm 100 is subjected to the opposite forces from the first myocardial microtissue 400 and the elastic body 600 , so that the swing of the swing arm 100 is more stable.

[0056] In another embodiment, referring to Figure 2 The chip also includes a second myocardial microtissue 700, two ends of which are respectively connected to the second connecting portion 140 and the third fixing portion 230. One of the first myocardial microtissue 400 and the second myocardial microtissue 700 is set as atrial muscle tissue, and the other is set as ventricular muscle tissue. The first myocardial microtissue 400 and the second myocardial microtissue 700 are respectively located on opposite sides of the swing arm 100. When the first myocardial microtissue 400 contracts, the second myocardial microtissue 700 relaxes. Similarly, when the first myocardial microtissue 400 relaxes, the second myocardial microtissue 700 contracts. In this way, the first myocardial microtissue 400 and the second myocardial microtissue 700 contract and relax alternately, which can simulate the atrium and ventricle structure of the heart, better fit the actual state of the heart organ, and can simultaneously detect the contractility of the atrial microtissue and the ventricular microtissue.

[0057] The first fixing portion 210, the second fixing portion 220 and the third fixing portion 230 may be independent or separate from each other, or Figure 3 As shown, a first fixing portion 210, a second fixing portion 220 and a third fixing portion 230 are connected to form an integral structure.

[0058] Reference Figure 1 and Figure 2 The swing arm 100 also includes a transition portion 150, and the length of the transition portion 150 along the second direction gradually decreases in the first direction. The fixed end 110 is arranged at the end of the transition portion 150 that is away from the movable end 120. The first direction is the direction of the movable end 120 toward the fixed end 110, and the second direction is the arrangement direction of the swing arm 100 and the first fixed portion 210; the transition portion 150 is in a gradually shrinking state in the direction toward the first fixed portion 210, and the cross-sectional area and the length of the transition portion 150 along the second direction are both reduced, which can reduce the weight of the swing arm 100 and the swing resistance of the swing arm 100, and maximize the reduction of the area of ​​the fixed end 110, avoid interference between the swing arm 100 and the first fixed portion 210 when the swing arm 100 swings, and reduce the length of the flexible hinge 300 in the second direction, so as to facilitate the deformation of the flexible hinge 300.

[0059] In addition, if Figure 2As shown, the flexible hinge 300 includes a swinging portion 310 and a deforming portion 320 connected to each other, the swinging portion 310 is connected to the fixed end 110, the length of the deforming portion 320 along the second direction is less than the length of the variable portion along the second direction, and the deforming portion 320 can deform following the swing of the swing arm 100. The deformation portion 320 with a smaller length is provided in the flexible hinge 300, so that the bending stiffness of the flexible hinge 300 can be reduced, so that the flexible hinge 300 is more easily deformed, the swing resistance of the swing arm 100 is reduced, and the swinging portion 310 and the fixed end 110 have a sufficient connection area, so that the flexible hinge 300 and the swing arm 100 are firmly connected. It can be understood that the bending stiffness of the flexible hinge 300 can also be adjusted by changing the modulus; for example, the modulus of the flexible hinge 300 can be reduced, the flexibility of the flexible hinge 300 can be increased, and the bending stiffness can be reduced, so that the flexible hinge 300 is more easily deformed, and will not be permanently deformed or broken due to excessive bending.

[0060] like Figure 1 and Figure 2 The chip further includes a supporting portion 800, the two ends of which are connected to the first connecting portion 130 and the second fixing portion 220 respectively. The supporting portion 800 has a growth space for accommodating the first myocardial microtissue 400. The first myocardial microtissue 400 is formed by culturing myocardial cells in the growth space. The supporting portion 800 is used to guide the myocardial cells to grow along the extension direction of the supporting portion 800, so that one end of the grown first myocardial microtissue 400 is connected to the first connecting portion 130, and the other end is connected to the second fixing portion 220. The supporting portion 800 provides space for the cultivation and growth of myocardial cells, guides the growth direction of myocardial cells, and improves the biocompatibility of the first myocardial microtissue 400 with the swing arm 100 and the first myocardial microtissue 400 with the first fixing portion 210.

[0061] It can be understood that when the first myocardial microtissue 400 and the second myocardial microtissue 700 are provided in the chip at the same time, a supporting part 800 can be respectively set between the first connecting part 130 and the second fixing part 220 and between the second connecting part 140 and the third fixing part 230, wherein ventricular cells are cultured in one supporting part 800 and atrial cells are cultured in the other supporting part 800, and eventually the first myocardial microtissue 400 and the second myocardial microtissue 700 are grown to form.

[0062] In addition, the supporting portion 800 is flexible and can deform following the contraction and relaxation of the first myocardial microtissue 400 or the second myocardial microtissue 700, so as to reduce the contraction and relaxation resistance of the first myocardial microtissue 400 or the second myocardial microtissue 700 and improve the detection accuracy of the chip. For example, the supporting portion 800 is configured as a membrane structure to enhance the flexibility of the supporting portion 800; or, the supporting portion 800 is configured to include two mutually spaced limiting edges, and a growth space is defined between the two limiting edges to reduce the cross-sectional area of ​​the supporting portion 800 and enhance the flexibility of the supporting portion 800. In addition, the supporting portion 800 can also be configured as other shapes, such as, the supporting portion 800 is configured as a tubular structure, and the hollow pipe inside the tubular structure forms a growth space; or, the supporting portion 800 is configured as a groove structure with an open top, and the internal groove body forms a growth space.

[0063] The detection platform 200 also includes a base 240, and the first fixing part 210, the second fixing part 220 and the third fixing part 230 are all fixed to the supporting surface of the base 240. The way in which the first fixing part 210, the second fixing part 220 and the third fixing part 230 are fixed to the base 240 is not limited to integral connection, bonding, etc. Exemplarily, the detection platform 200 is formed by 3D printing, and the first fixing part 210, the second fixing part 220 and the third fixing part 230 are all integrally connected to the support surface of the base 240; or, the first fixing part 210, the second fixing part 220, and the third fixing part 230 are fixed to the support surface of the base 240 by bonding, and the bonding of the first fixing part 210, the second fixing part 220 and the third fixing part 230 to the base 240 is not limited to: the first fixing part 210, the second fixing part 220 and the third fixing part 230 themselves are provided with bonding properties and are directly bonded to the base 240, or an adhesive is provided between the first fixing part 210 and the base 240, between the second fixing part 220 and the base 240, and between the third fixing part 230 and the base 240 for bonding.

[0064] A lubricating medium is provided between the surface of the swing arm 100 facing the base 240 and the supporting surface of the base 240 to reduce the resistance formed by the friction between the swing arm 100 and the surface of the base 240 when the swing arm 100 swings, thereby improving the detection accuracy of the chip. The lubricating medium is not limited to being set to water, solution, oil, etc. It should be noted that the swing arm 100 is made of a hard resin material, so that the swing arm 100 has a certain hardness and a high bending stiffness, and will not deform during the swinging process, thereby eliminating the detection accuracy of the contraction force of the myocardial tissue due to the deformation of the swing arm 100; in addition, the swing arm 100 is set in a thin sheet shape to make the swing arm 100 thinner, reduce the weight of the swing arm 100 and the resistance to the contraction and relaxation of the myocardial tissue; or, the swing arm 100 is set in a cylindrical shape to reduce the contact area between the swing arm 100 and the supporting surface, thereby reducing the swing resistance of the swing arm 100; or, the surface of the swing arm 100 facing the base 240 is set in a concave-convex shape, thereby reducing the contact area between the swing arm 100 and the supporting surface, thereby reducing the swing resistance of the swing arm 100.

[0065] The present invention also provides a method for preparing a heart organ chip, which is used to prepare the above-mentioned heart organ chip, comprising the following steps:

[0066] First, a swing arm 100, a detection platform 200, and a flexible hinge 300 are formed by 3D printing, and the flexible hinge 300 is connected to the swing arm 100 and the first fixed part 210; then, first myocardial microtissue cells are cultured between the second fixed part 220 and the first connecting part 130, so that the first myocardial microtissue cells are connected to the first connecting part 130 and the second fixed part 220 through growth, and a first myocardial microtissue 400 is formed.

[0067] By using 3D printing, structures with corresponding shapes can be formed according to the preset shapes of the detection platform 200, the flexible hinge 300 and the swing arm 100, and each structure has high molding precision and is easy to process. Different structures in the chip are formed by printing with polymers of different hardness, such as the flexible hinge 300, the elastic body 600, and the supporting part 800 are formed by printing with relatively soft polymers, so that the flexible hinge 300 and the supporting part 800 can be deformed during the swinging process of the swing arm 100, and the elastic body 600 assists the myocardial microtissue to relax and return the swing arm 100; the swing arm 100 is printed and formed by a polymer with a certain hardness to avoid deformation of the swing arm 100 during the swinging process and absorb the contraction force of the myocardial microtissue; further, in the case of using the magnetic sensor 510 to sense the swing angle of the swing arm 100 or using the magnetic field to drive the swinging and stretching supporting part 800, the swing arm 100 can be formed by printing with a polymer containing magnetic powder, so that the swing arm 100 has magnetism.

[0068] Further, in one embodiment, after the detection platform 200, the flexible hinge 300, the elastic body 600 and the swing arm 100 are formed respectively by 3D printing, the flexible hinge 300 is connected to the fixed end 110 and the first fixed part 210, the supporting part 800 is connected to the first connecting part 130 and the second fixed part 220, and the elastic body 600 is connected to the second connecting part 140 and the third fixed part 230; then, myocardial cells are cultured in the supporting part 800, so that the myocardial cells grow to form the first myocardial microtissue 400. Alternatively, in another embodiment, printing materials with different hardness and softness are preset in the 3D printing device, and the detection platform 200, the flexible hinge 300, the elastic body 600, the supporting part 800 and the swing arm 100 are integrally formed through a single printing, and then myocardial cells are cultured in the supporting part 800, so that the myocardial cells grow to form the first myocardial microtissue 400, so as to simplify the preparation process of the heart organ chip.

[0069] It is understandable that the printing materials of the detection platform 200, the flexible hinge 300, the elastomer 600 and the swing arm 100 have different elasticity, viscoelasticity, adhesion, breaking strength, fatigue threshold, etc., so as to change the characteristics of different components in the chip; for example, by adjusting the polymer type, concentration, printing parameters (speed, inkjet volume, etc.), etc., the stability, bending stiffness, connection performance, etc. of the component itself are changed. Exemplarily, the swing arm 100 is formed by printing a polymer whose main material is resin, so that the swing arm 100 has a certain hardness and bending stiffness; the supporting part 800 is formed by printing with hydrogel, so that the supporting part 800 has good flexibility.

[0070] When the first myocardial microtissue cells are cultured through the supporting portion 800, the supporting portion 800 is stretched along the extension direction of the supporting portion 800, so that the first myocardial microtissue cells generate pre-strain parallel to the extension direction of the supporting portion 800, so as to induce the first myocardial microtissue cells to grow and arrange along the extension direction of the supporting portion 800, and form the first myocardial microtissue 400. The growth direction of the first myocardial microtissue cells is induced by pre-strain, so that the muscle fibers of the generated first myocardial microtissue 400 have a preset orientation, the compatibility of the myocardial microtissue with the relevant components in the chip is improved, and the contraction and relaxation directions of the myocardial microtissue are matched with the swing direction of the swing arm 100, so as to prepare a heart organ chip with high sensitivity, high stability and biocompatibility. It is understandable that the second myocardial microtissue 700 can also be formed by the above-mentioned method of culturing myocardial cell growth.

[0071] In one embodiment, the swing arm 100 is pulled so that the swing arm 100 has a tendency to swing toward the third fixing portion 230. At this time, the supporting portion 800 is stretched, and the myocardial cells in the supporting portion 800 generate pre-strain along the extension direction of the supporting portion 800, so that the myocardial cells grow and arrange along the direction of the pre-strain elongation, and form the first myocardial micro-tissue 400 or the second myocardial micro-tissue 700. In another embodiment, the swing arm 100 is formed by 3D printing using a polymer containing magnetic powder. When culturing myocardial cells, a magnetic field is applied to the swing arm 100 to drive the swing arm 100 to swing, so that the swing stretches the supporting portion 800, and then the myocardial cells generate pre-strain to induce the growth and arrangement direction of the myocardial cells; by providing a magnetic swing arm 100, on the one hand, the magnetic field can be used to apply a swinging force to the swing arm 100 to achieve non-contact driving, and on the other hand, the magnetic sensor 510 is used to sense the swing angle of the swing arm 100, and then the contraction force of the myocardial micro-tissue is obtained according to the swing angle of the swing arm 100.

[0072] It should be noted that the part of the myocardial cells that contacts the support part 800 forms an extracellular matrix during the cell growth process, so that the myocardial tissue and the support part 800 can contract and relax together. Natural myocardial tissue itself has anisotropy. In the present invention, by culturing myocardial cells and inducing the growth and arrangement direction of myocardial cells during the growth of myocardial cells, anisotropic three-dimensional myocardial microtissues are obtained, so that the myocardial microtissues have different arrangement directions in various directions in space, so that the myocardial microtissues have good biocompatibility with various components in the chip, and can better simulate the structure and function of natural new myocardium, thereby studying the physiological or pathological processes of the heart.

[0073] The embodiments of the present invention are described in detail above in conjunction with the accompanying drawings, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. Heart Organ Chip, It is characterized in that include: A swing arm, with two ends forming a fixed end and a movable end respectively, a first connecting portion being provided on a side of the swing arm, and the first connecting portion being located between the center of the swing arm and the fixed end; The detection platform comprises a first fixing portion and a second fixing portion, wherein the second fixing portion is located on a side of the swing arm; A flexible hinge having flexibility, wherein two ends of the flexible hinge are respectively connected to the first fixing portion and the fixing end; A first myocardial microtissue, two ends of which are respectively connected to the second fixing portion and the first connecting portion; A measuring module, used for acquiring the contractile force of the first myocardial microtissue according to the displacement of the active end; Wherein, the swing arm can swing relative to the first fixing part following the contraction and relaxation of the first myocardial microtissue, and drive the flexible hinge to deform; The heart organ chip also includes a flexible elastic body, the swing arm also includes a second connecting portion, the first connecting portion and the second connecting portion are respectively located on two opposite sides of the swing arm, the detection platform also includes a third fixing portion, the third fixing portion and the second fixing portion are respectively located on two opposite sides of the swing arm, and two ends of the elastic body are respectively connected to the second connecting portion and the third fixing portion; the elastic body is used to provide a force driving the swing arm to swing away from the first myocardial microtissue; Alternatively, the heart organ chip also includes a second myocardial microtissue, the swing arm also includes a second connecting portion, the first connecting portion and the second connecting portion are respectively located on two opposite sides of the swing arm, the detection platform also includes a third fixing portion, the third fixing portion and the second fixing portion are respectively located on two opposite sides of the swing arm, and two ends of the second myocardial microtissue are respectively connected to the second connecting portion and the third fixing portion; wherein, one of the first myocardial microtissue and the second myocardial microtissue is set as atrial muscle tissue, and the other is set as ventricular muscle tissue.

2. The heart organ chip according to claim 1, It is characterized in that The first direction is the direction from the movable end to the fixed end, and the second direction is the arrangement direction of the swing arm and the first fixed part; Wherein, the swing arm comprises a transition portion, the length of the transition portion along the second direction gradually decreases in the first direction, and the fixed end is arranged at an end of the transition portion facing away from the movable end; And / or, the flexible hinge includes a connected swinging part and a deforming part, the swinging part is connected to the fixed end, the length of the deforming part along the second direction is smaller than the length of the swinging part along the second direction, and the deforming part can deform following the swing of the swing arm.

3. The heart organ chip according to claim 1, It is characterized in that The measuring module includes an observation unit, which is used to obtain the displacement of the movable end by observing the swing image of the swing arm; Alternatively, the swing arm is magnetic, and the measuring module comprises a magnetic sensor, and the magnetic sensor is used to detect the swing angle of the swing arm according to the change of the magnetic field of the swing arm.

4. The heart organ chip according to claim 1, It is characterized in that The heart organ chip also includes a supporting portion, which is flexible. The two ends of the supporting portion are respectively connected to the first connecting portion and the second fixing portion. The supporting portion has a growth space for accommodating the first myocardial microtissue, and the supporting portion is used to guide myocardial cells to grow along the extension direction of the supporting portion to form the first myocardial microtissue.

5. The heart organ chip according to claim 1, It is characterized in that The detection platform further includes a base, the first fixing portion and the second fixing portion are both fixed to a supporting surface of the base, and a lubricating medium is provided between a surface of the swing arm facing the base and the supporting surface.

6. Methods for preparing heart organ chips, It is characterized in that A method for preparing a cardiac organ chip according to any one of claims 1 to 5, comprising: Forming the swing arm, the detection platform, and the flexible hinge by 3D printing, and connecting the flexible hinge to the swing arm and the first fixing portion; The first myocardial microtissue cells are cultured between the second fixing part and the first connecting part, so that the first myocardial microtissue cells are connected to the first connecting part and the second fixing part through growth, and form the first myocardial microtissue.

7. The method for preparing a heart organ chip according to claim 6, It is characterized in that forming a flexible supporting portion between the second fixing portion and the swing arm by 3D printing, and culturing first myocardial microtissue cells in the supporting portion; When culturing the first myocardial microtissue cells, the supporting portion is stretched along the extension direction of the supporting portion so that the first myocardial microtissue cells generate pre-strain parallel to the extension direction of the supporting portion, thereby inducing the first myocardial microtissue cells to grow and arrange along the extension direction of the supporting portion and form the first myocardial microtissue.

8. The method for preparing a heart organ chip according to claim 7, It is characterized in that The swing arm is formed by 3D printing using a polymer containing magnetic powder, and when culturing the first myocardial microtissue cells, a magnetic field is applied to the swing arm to drive the swing arm to swing and stretch the supporting part.

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