CN100457900C - Metal microcapsule for transplanting cell and tissue - Google Patents
Metal microcapsule for transplanting cell and tissue Download PDFInfo
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- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000463 material Substances 0.000 claims abstract description 26
- 239000010936 titanium Substances 0.000 claims abstract description 26
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000956 alloy Substances 0.000 claims abstract description 11
- 229910001069 Ti alloy Inorganic materials 0.000 claims abstract description 10
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000010931 gold Substances 0.000 claims abstract description 6
- 229910052737 gold Inorganic materials 0.000 claims abstract description 6
- 229910052742 iron Inorganic materials 0.000 claims abstract description 6
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- 238000002054 transplantation Methods 0.000 claims description 9
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
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Abstract
Description
技术领域 technical field
本发明涉及一种细胞微囊，特别是涉及采用金属或合金材料制成对生物细胞或组织进行包埋移植的微囊。The invention relates to a cell microcapsule, in particular to a microcapsule made of metal or alloy material for embedding and transplanting biological cells or tissues.
背景技术 Background technique
大多数做完细胞或器官移植手术的患者在经历了痛苦的移植手术后，仍需花费一生的时间进行免疫抑制治疗，以对抗免疫排斥反应。目前，一个解决方案是将外源性的细胞或器官包埋在半透明性的人工膜中，进行隔离，然后再移植到体内，从而避免植入的细胞或器官与具有免疫效应的细胞和体液进行直接接触，从而起到免疫隔离的作用。该技术起源于20世纪60年代，通常采用具有凝胶态的天然高分子材料或合成高分子材料作为微包囊的材料，如藻酸盐，琼脂，壳聚糖，聚丙烯酸脂，聚乙二醇，聚丙烯腈—氯乙烯共聚物等。从材料方面考虑，高分子材料的分子质量，强度，化学组成以及包囊膜的厚度或层数等的变化会使膜的通透性发生变化，从微包囊的制备工艺考虑，制作微包囊所用高聚物溶液的浓度，凝胶化反应的时间，体系PH值以及添加剂的种类和用量等都会对膜的通透性和生物相容性产生显著影响，使细胞在包埋过程中凋亡或功能丧失。而且，这类材料的微包囊在移植过程中，发现往往存在体积过大的问题。例如以胰岛细胞移植为例，为维持人体正常的血糖水平，一般应该维持15,000～20,000islets/kg的人体重量浓度水平，当采用通常制备的直径为500μm左右的微包囊时，则为达到与一个胰岛所具有的相同数目胰岛细胞，所需的微包囊总体积约为一个标准胰岛体积的37倍。同时，在生理环境下，采用凝聚态材料制成的微包囊还会发生吸水膨胀，导致微包囊体积变大和变形，从而会影响细胞功能的正常发挥和在体内的长期稳定性。Most patients who undergo cell or organ transplants spend a lifetime on immunosuppressive therapy to fight immune rejection following the painful transplant. At present, a solution is to embed exogenous cells or organs in a translucent artificial membrane, isolate them, and then transplant them into the body, so as to avoid the implanted cells or organs from interacting with cells and body fluids with immune effects direct contact, thus playing the role of immune isolation. This technology originated in the 1960s, usually using natural polymer materials or synthetic polymer materials with a gel state as microencapsulation materials, such as alginate, agar, chitosan, polyacrylate, polyethylene glycol Alcohol, polyacrylonitrile-vinyl chloride copolymer, etc. From the perspective of materials, changes in the molecular weight, strength, chemical composition of polymer materials, and the thickness or number of layers of the encapsulation membrane will change the permeability of the membrane. The concentration of the polymer solution used in the capsule, the time of the gelation reaction, the pH value of the system, and the type and amount of additives will have a significant impact on the permeability and biocompatibility of the membrane, making the cells wither during the embedding process. death or loss of function. Moreover, during the transplantation process, the microencapsulation of such materials often has the problem of excessive volume. For example, taking pancreatic islet cell transplantation as an example, in order to maintain normal blood sugar levels in the human body, the body weight concentration level of 15,000-20,000 islets/kg should generally be maintained. With the same number of islet cells in one islet, the total volume of microencapsulation required is about 37 times the volume of a standard islet. At the same time, in a physiological environment, the microcapsules made of condensed matter materials will also absorb water and swell, resulting in the increase in volume and deformation of the microcapsules, which will affect the normal function of cells and long-term stability in the body.
发明内容 Contents of the invention
本发明所要解决的技术问题是克服上述现有技术中的不足，提供采用金属或合金材料制成的对生物细胞或组织进行包埋移植的微囊，利用该金属微囊对生物细胞进行细胞包埋，能够减小移植的微包囊体积，使微包囊移植入人体后，不会在生理环境下发生吸水膨胀现象，使植入的细胞能正常发挥其功能和在体内的长期稳定性。The technical problem to be solved by the present invention is to overcome the deficiencies in the above-mentioned prior art, to provide microcapsules made of metal or alloy materials for embedding and transplanting biological cells or tissues, and to use the metal microcapsules to encapsulate biological cells. Embedding can reduce the volume of the transplanted microcapsules, so that after the microcapsules are transplanted into the human body, they will not swell when they absorb water under the physiological environment, so that the implanted cells can normally perform their functions and maintain long-term stability in the body.
为解决上述技术问题，本发明的细胞和组织移植用金属微囊由具有良好生物兼容性的金属或合金材料制成，金属微囊基本呈空心球状，其内空腔用于放置经分离、处理后的若干细胞或生物组织；所述金属微囊的外半径在0.05～5mm之间，金属微囊的囊壁厚在0.001～0.5mm之间，金属微囊的囊壁上设置有若干基本呈圆形的通孔，通孔的直径在0.00005～0.01mm之间。In order to solve the above technical problems, the metal microcapsule for cell and tissue transplantation of the present invention is made of a metal or alloy material with good biocompatibility, the metal microcapsule is basically hollow spherical, and its inner cavity is used to place After several cells or biological tissues; the outer radius of the metal microcapsule is between 0.05 and 5 mm, the wall thickness of the metal microcapsule is between 0.001 and 0.5 mm, and the metal microcapsule wall is provided with several basically shaped A circular through hole, the diameter of the through hole is between 0.00005 and 0.01 mm.
所述金属微囊可以由钛制成。所述金属微囊也可以由钛合金制成。The metal microcapsules can be made of titanium. The metal microcapsules can also be made of titanium alloy.
所述金属微囊可以是由金作为基底材料制成，该基底材料的表面设置有钛镀层；所述金属微囊可以是由金作为基底材料制成，该基底材料的表面设置有钛合金镀层。The metal microcapsule can be made of gold as the base material, and the surface of the base material is provided with a titanium coating; the metal microcapsule can be made of gold as the base material, and the surface of the base material is provided with a titanium alloy coating .
所述金属微囊也可以是由铁作为基底材料制成，该基底材料的表面设置有钛镀层；所述金属微囊由铁作为基底材料制成，该基底材料的表面设置有钛合金镀层。The metal microcapsule can also be made of iron as the base material, and the surface of the base material is provided with a titanium coating; the metal microcapsule is made of iron as the base material, and the surface of the base material is provided with a titanium alloy coating.
所述的微囊由两个碗状半球组成，两个碗状半球之间通过紧配合、压接、粘接或激光焊接方式连接为一个整体。The microcapsule is composed of two bowl-shaped hemispheres, and the two bowl-shaped hemispheres are connected as a whole through tight fitting, crimping, bonding or laser welding.
与现有技术相比，本发明具有以下技术效果：(一)利用该金属微囊对生物细胞进行细胞包埋，能够减小移植的微包囊体积，使微包囊移植入人体后，不会在生理环境下发生吸水膨胀现象，使植入的细胞能正常发挥其功能和在体内的长期稳定性；(二)金属微囊采用对人体无害且具有较好的生物相容性的金属或合金材料制成，如钛金属，由于重量轻、生物相容性好、无毒性、耐腐蚀性好、体内安定性良好、热膨胀系数小、熔点高等优点，从而可避免了采用高分子材料所具有的弊端：机械强度低、降解去向不明、使用寿命短、使异种细胞暴露在人体内可能导致不明病毒进入人体和基因转移等问题。Compared with the prior art, the present invention has the following technical effects: (1) Utilizing the metal microcapsules for cell embedding of biological cells can reduce the volume of transplanted microcapsules, so that after the microcapsules are transplanted into the human body, no Water absorption and swelling will occur in physiological environment, so that the implanted cells can normally perform their functions and have long-term stability in the body; (2) the metal microcapsules are made of metals that are harmless to the human body and have good biocompatibility Or alloy materials, such as titanium, due to the advantages of light weight, good biocompatibility, non-toxicity, good corrosion resistance, good stability in the body, small thermal expansion coefficient, high melting point, etc., thus avoiding the use of polymer materials. Disadvantages: low mechanical strength, unknown degradation destination, short service life, exposing heterogeneous cells to the human body may lead to problems such as unknown viruses entering the human body and gene transfer.
具体实施方式 Detailed ways
许多金属和合金由于对人体无害，较好的生物相容性等优点而被广泛应用于临床治疗中，例如钛金属由于重量轻、生物相容性好、无毒性、耐腐蚀性好、体内安定性良好、热膨胀系数小、熔点高等优点而得到广泛的应用，尤其在口腔医学中的牙体种植中。通过精密铸造将钛金属制成半球或半胶囊状的薄壳，然后通过镀膜工艺，在金属表面镀上一层防止氧化反应的薄膜。采用激光打孔技术在镀膜后的薄壳上打上一排排小进制通孔，这些小通孔允许维持细胞存活的营养物质和氧的供给以及细胞代谢产生的废物排除，同时保证细胞分泌产生的特定因子可以通过扩散作用进入全身的细胞外间隙，并且具有免疫效应的细胞不能通过小通孔与移植细胞进行直接接触，从而起到免疫隔离作用。将需移植的细胞放入薄壳中，将两个半球或半胶囊状的薄壳通过点焊的方式在接缝处进行焊接。最后将焊接好的微胶囊通过微创手术植入人体内。Many metals and alloys are widely used in clinical treatment due to their harmlessness to the human body and good biocompatibility. Good stability, small coefficient of thermal expansion, high melting point and other advantages have been widely used, especially in dental implants in stomatology. The titanium metal is made into a hemispherical or semi-capsule-shaped thin shell through precision casting, and then a layer of film to prevent oxidation reaction is coated on the metal surface through the coating process. Laser drilling technology is used to punch rows of small through-holes on the coated thin shell. These small through-holes allow the supply of nutrients and oxygen to maintain cell survival and the removal of waste generated by cell metabolism, while ensuring the secretion of cells. Specific factors can enter the extracellular space of the whole body through diffusion, and cells with immune effects cannot directly contact transplanted cells through small through holes, thus playing an immune isolation role. The cells to be transplanted are put into the thin shell, and the two hemispherical or semi-capsular thin shells are welded at the seams by spot welding. Finally, the welded microcapsules are implanted into the human body through minimally invasive surgery.
本发明的对生物细胞或组织进行包埋移植的金属微囊基本呈空心球状，由两个碗状半球组成。采用具有良好生物兼容性的金属或合金材料制成。将该金属或合金制成壁厚0.001～0.5mm，半径在0.05～5mm的碗状半球，视应用场合的不同在半球的球壁上打0.00005～0.01mm的小通孔，将分离、处理后的若干细胞或生物组织放入半球中，然后通过紧配合、压接、粘接或激光焊接等方式将两个半球合为一个整体，成为金属或合金材料制成微囊，然后移植到人或生物体内。用于疾病的治疗或替代某种器官的功能。The metal microcapsule for embedding and transplanting biological cells or tissues of the present invention is basically hollow spherical and consists of two bowl-shaped hemispheres. Made of metal or alloy materials with good biocompatibility. The metal or alloy is made into a bowl-shaped hemisphere with a wall thickness of 0.001-0.5mm and a radius of 0.05-5mm. Depending on the application, a small through-hole of 0.00005-0.01mm is drilled on the wall of the hemisphere. A number of cells or biological tissues in the hemisphere are put into the hemisphere, and then the two hemispheres are integrated into a whole by means of tight fit, crimping, bonding or laser welding, etc., and become a microcapsule made of metal or alloy material, and then transplanted into human or human body. living organisms. It is used for the treatment of diseases or to replace the function of certain organs.
实施例之一：One of embodiment:
在石蜡或塑料上加工出半径为0.05mm的凹面，然后采用电镀(电铸)的方法将纯钛镀在石蜡或塑料模具上，壁厚为0.001mm，经过加热脱模、用激光打直径为0.00005mm的通孔，而后切割得到碗状的钛半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。Process a concave surface with a radius of 0.05mm on paraffin or plastic, and then use electroplating (electroforming) to plate pure titanium on the paraffin or plastic mold with a wall thickness of 0.001mm. A through hole of 0.00005mm is cut to obtain a bowl-shaped titanium hemisphere. On the hemisphere, after cleaning and surface treatment, living cells are put into the titanium hemisphere and assembled into microcapsules. The two hemispheres are welded at the seam by spot welding for welding.
实施例之二：The second embodiment:
在半径为1.2mm凹面规律排列的金箔上，通过电镀或离子喷镀的方式在金箔表面镀上一层钛金属，壁厚为0.11mm，再用激光打直径为0.0002mm的通孔、而后切割得到碗状的钛半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。On the regularly arranged gold foil with a radius of 1.2mm, a layer of titanium metal is plated on the surface of the gold foil by electroplating or ion spraying, with a wall thickness of 0.11mm, and then a through hole with a diameter of 0.0002mm is drilled with a laser, and then cut A bowl-shaped titanium hemisphere is obtained. On the hemisphere, after cleaning and surface treatment, living cells are put into the titanium hemisphere and assembled into microcapsules, and the two hemispheres are welded at the seam by spot welding.
实施例之三：The third embodiment:
用模具将钛合金成型为半径为2.4mm凹面的规律排列钛箔，壁厚为0.22mm，再用激光打直径为0.003mm的通孔，而后切割得到碗状的钛半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。The titanium alloy is molded into a regular arrangement of titanium foils with a radius of 2.4mm and a concave surface of 0.22mm, and then a through hole with a diameter of 0.003mm is drilled with a laser, and then a bowl-shaped titanium hemisphere is obtained by cutting. On the hemisphere, after After cleaning and surface treatment, living cells are put into titanium hemispheres and assembled into microcapsules, and the two hemispheres are welded at the seams by spot welding.
实施例之四：The fourth embodiment:
在模具上将金成型为半径为2.6mm凹面并规律排列的金箔，壁厚为0.29mm，用激光打直径为0.005mm的通孔，以此作为基底材料；在该基底材料的表面电镀上钛镀层，而后切割得到碗状的半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。On the mold, the gold is formed into a concave surface with a radius of 2.6mm and regularly arranged gold foil, the wall thickness is 0.29mm, and a through hole with a diameter of 0.005mm is drilled with a laser, which is used as the base material; titanium is electroplated on the surface of the base material Plating, and then cut to get a bowl-shaped hemisphere, on the hemisphere, after cleaning and surface treatment, live cells are put into the titanium hemisphere and assembled into microcapsules, and the two hemispheres are welded at the seam by spot welding.
实施例之五：The fifth embodiment:
在模具上将金成型为半径为3.8mm凹面并规律排列的金箔，壁厚为0.41mm，用激光打直径为0.007mm的通孔，以此作为基底材料；在该基底材料的表面电镀上钛合金镀层，而后切割得到碗状的半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。On the mold, the gold is shaped into a concave surface with a radius of 3.8mm and regularly arranged gold foil, the wall thickness is 0.41mm, and a through hole with a diameter of 0.007mm is drilled with a laser, which is used as the base material; titanium is electroplated on the surface of the base material Alloy coating, and then cut to get a bowl-shaped hemisphere. On the hemisphere, after cleaning and surface treatment, living cells are put into the titanium hemisphere and assembled into microcapsules. The two hemispheres are welded at the seam by spot welding.
实施例之六：Sixth embodiment:
在模具上将铁成型为半径为4.6mm凹面并规律排列的铁箔，壁厚为0.45mm，用激光打直径为0.008mm的通孔，以此作为基底材料；在该基底材料的表面电镀上钛镀层，而后切割得到碗状的半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。On the mold, the iron is formed into a concave surface with a radius of 4.6mm and regularly arranged iron foil, the wall thickness is 0.45mm, and a through hole with a diameter of 0.008mm is drilled with a laser, which is used as the base material; the surface of the base material is electroplated Titanium coating, and then cut to get a bowl-shaped hemisphere, on the hemisphere, after cleaning and surface treatment, living cells are put into the titanium hemisphere and assembled into microcapsules, and the two hemispheres are welded at the seam by spot welding.
实施例之七：Embodiment seven:
在模具上将铁成型为半径为4.9mm凹面并规律排列的铁箔，壁厚为0.48mm，用激光打直径为0.009mm的通孔，以此作为基底材料；在该基底材料的表面电镀上钛合金镀层，而后切割得到碗状的半球，在半球上，经过清洗、表面处理，将活细胞放入钛半球后组装成微囊，将两个半球通过点焊的方式在接缝处进行焊接。On the mold, the iron is formed into a concave surface with a radius of 4.9mm and regularly arranged iron foil, the wall thickness is 0.48mm, and a through hole with a diameter of 0.009mm is drilled with a laser, which is used as the base material; the surface of the base material is electroplated Titanium alloy coating, and then cut to get a bowl-shaped hemisphere, on the hemisphere, after cleaning and surface treatment, live cells are put into the titanium hemisphere and assembled into microcapsules, and the two hemispheres are welded at the seam by spot welding .
Claims (6)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100198199A CN100457900C (en) | 2004-06-29 | 2004-06-29 | Metal microcapsule for transplanting cell and tissue |
| PCT/CN2005/000804 WO2006000143A1 (en) | 2004-06-29 | 2005-06-08 | Metal microcapsule for transplanting cell and tissue |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100198199A CN100457900C (en) | 2004-06-29 | 2004-06-29 | Metal microcapsule for transplanting cell and tissue |
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| WO2010057039A2 (en) * | 2008-11-14 | 2010-05-20 | Cythera, Inc. | Encapsulation of pancreatic cells derived from human pluripotent stem cells |
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| RU2200205C2 (en) * | 2001-03-05 | 2003-03-10 | Гюнтер Виктор Эдуардович | Porous permeable alloy on base of titanium nickelide |
| GB0119652D0 (en) * | 2001-08-11 | 2001-10-03 | Stanmore Implants Worldwide | Surgical implant |
| US20040167632A1 (en) * | 2003-02-24 | 2004-08-26 | Depuy Products, Inc. | Metallic implants having roughened surfaces and methods for producing the same |
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Non-Patent Citations (4)
| Title |
|---|
| 微囊化组织细胞移植的研究进展. 解剖科学进展，第9卷第4期. 2003 |
| 微囊化组织细胞移植的研究进展. 解剖科学进展，第9卷第4期. 2003 * |
| 微囊化胰岛研究进展. 军事医学科学院院刊，第28卷第2期. 2004 |
| 微囊化胰岛研究进展. 军事医学科学院院刊，第28卷第2期. 2004 * |
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| WO2006000143A1 (en) | 2006-01-05 |
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