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CN113564099A - Artificial pancreas and construction method thereof - Google Patents

Artificial pancreas and construction method thereof Download PDF

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Publication number
CN113564099A
CN113564099A CN202110795355.4A CN202110795355A CN113564099A CN 113564099 A CN113564099 A CN 113564099A CN 202110795355 A CN202110795355 A CN 202110795355A CN 113564099 A CN113564099 A CN 113564099A
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cells
stem cells
islet
nerve
differentiating
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Inventor
李宸
周志敏
郭传家
汤江海
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Institute of Biomedical Engineering of CAMS and PUMC
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Institute of Biomedical Engineering of CAMS and PUMC
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0697—Artificial constructs associating cells of different lineages, e.g. tissue equivalents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components
    • C12N2500/34—Sugars
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C12N2502/1352—Mesenchymal stem cells
    • C12N2502/137—Blood-borne mesenchymal stem cells, e.g. Msc from umbilical cord blood
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/22—Coculture with; Conditioned medium produced by pancreatic cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C12N2533/40—Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
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Abstract

The invention discloses an artificial pancreas and a construction method thereof, wherein the construction method comprises the following steps: putting the functional cells into a culture medium containing PLGA microspheres for culturing to obtain PLGA microspheres planted with the functional cells, wherein the functional cells are selected from at least one of vascular endothelial cells, nerve cells, lymphatic vessel cells and stem cells capable of differentiating into vascular endothelial cells, nerve cells or immune cells; placing islet cells or stem cells capable of differentiating into islet cells into a culture medium containing PLGA microspheres planted with functional cells for culturing to obtain the artificial pancreas; the method for constructing the artificial pancreas takes the porous microspheres as supports, so that cells capable of forming blood vessels/neural networks and islet cells or stem cells capable of being differentiated into the islet cells are planted and grown in the microspheres in a programmed manner, and the constructed artificial pancreas not only has a cell mass with an islet physiological structure, but also has a vascular neural network structure abundant in a natural pancreas.

Description

Artificial pancreas and construction method thereof
Technical Field
The invention relates to the technical field of artificial pancreas, in particular to an artificial pancreas and a construction method thereof.
Background
Diabetes is a chronic metabolic disease, and in recent years, the incidence of diabetes in children worldwide has also increased at an average rate of 3% per year, while insulin, which is the diabetes treatment gold standard, is used as the primary treatment for the side effects and risks in a population of children patients who are high in metabolic rate, large in activity, and in growth and development. Therefore, the search for new therapeutic means for diabetes is very necessary.
Islet transplantation is currently the best option for treating severe diabetes, however donor shortages and graft inactivation and loss of function severely limit its clinical treatment. The pancreas is composed primarily of peripheral pancreatic tissue (peripheral pancreatic cells and extracellular matrix material), the islets of langerhans, and blood vessels, lymphatic vessels, and intra-pancreatic nerves, among others. Wherein the islets of Langerhans contain different types of cells, and can secrete insulin hormones such as insulin and glucagon according to peripheral glucose changes and neurotransmitter stimulation and the like. More importantly, the blood flow and the neural network of the pancreatic islets in the body are very rich, and the vascularization of the pancreatic islets cannot be completed by the conventional artificial pancreatic islet reconstruction, so that the function of the reconstructed pancreatic islets is unstable. Therefore, the problem of vascularization of the pancreatic islet/pancreatic organ is very important in pancreatic islet transplantation and artificial pancreatic islet/pancreatic gland construction, and is not only directly related to the activity and function of the transplanted organ, but also a great difficulty in artificial organ construction.
Polylactic-co-glycolic acid (PLGA) is a high molecular weight polymer approved by the Food & Drug Association (FDA) of the United states for use as a human pharmaceutical adjuvant. Researches show that PLGA has good biodegradability and biocompatibility and has wide application as a biological material in clinical application. The porous microspheres with low density are used, and are often used as inhalation type pulmonary drug delivery research (Science 1997, 276, 1868); and is concerned with injectable cell carriers by virtue of its porous structure material transport properties and cell loading function (Biomaterials 2012, 33, 4069). Meanwhile, the porous microspheres are used as components to form the composite gel, which has application prospect in the aspect of implantable insulin long-acting slow release (patent application 201610493506.X, a glucose-sensitive porous microsphere/polymer composite gel and a preparation method and application thereof). In addition, artificial islets or artificial pancreas can also be constructed by utilizing a pancreas "string bag" like structure approximated by a porous sphere, specifically loaded with islet cells (patent application 201910924259.8). However, none of the above methods solves the physicochemical problems of vascularization, neurogenesis, etc. of the constructed artificial islets.
Disclosure of Invention
The invention aims to provide an artificial pancreas and a construction method thereof, and the artificial pancreas obtained by the construction method not only has a cell mass of an islet physiological structure, but also has abundant blood vessels and neural network structures in a natural pancreas.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the invention provides a construction method of an artificial pancreas, which comprises the following steps:
(a) putting the functional cells into a culture medium containing PLGA microspheres for culturing to obtain PLGA microspheres planted with the functional cells, wherein the functional cells are selected from at least one of vascular endothelial cells, nerve cells, lymphatic vessel cells and stem cells capable of differentiating into vascular endothelial cells, nerve cells or immune cells;
(b) and placing the islet cells or stem cells capable of differentiating into the islet cells into a culture medium containing PLGA microspheres planted with functional cells for culturing to obtain the artificial pancreas.
Preferably, in the step (a), the particle size of the PLGA microspheres is 50-500 μm, and the pore diameter is 5-50 μm.
Preferably, in the step (a), the number ratio of the functional cells to the PLGA microspheres is (10)4～107)∶1。
Preferably, in step (a), the medium is CMRL, DMEM, RPMI, MEM + 10% fetal bovine serum, a custom medium or a conditioned medium; the concentration of the PLGA microspheres in the culture medium is 100-5000/mL;
the culture temperature is 0 ℃ or 37 ℃, and the culture time is 2-30 days.
Preferably, in the step (a), the stem cells that can differentiate into vascular endothelial cells are human umbilical cord blood stem cells, endothelial progenitor cells, hematopoietic stem cells, bone marrow stem cells, mesenchymal stem cells, pluripotent stem cells or embryonic stem cells; the vascular endothelial cells are primary vascular endothelial cells or express one or more vascular endothelial cells containing CD31, CD34, vWH, alpha-SMA, lectin, isolectin and VEGF vascular markers;
the stem cells capable of differentiating into nerve cells are bone marrow stem cells, endothelial progenitor cells, mesenchymal stem cells, pluripotent stem cells, embryonic stem cells or nerve stem cells in various tissues; the nerve cells are primary nerve cells or express one or more nerve cells containing nestin, SOX2, neural marker class III beta-tubulin (TUJ1), GFAP, NF200, Phox2b, ACh, PGP9.5 and Tyrosin Hydroxyylase (TH) nerve cell markers;
the stem cells capable of differentiating into immune cells are hematopoietic stem cells or bone marrow stem cells; the immune cells are primary lymphatic vessel cells or lymphatic vessel cells expressing LYVE-1 lymphatic vessel markers.
Preferably, the number ratio of the islet cells or stem cells capable of differentiating into islet cells to the functional cells in the step (b) is (1-5000): 1.
Preferably, in step (b), the islet cells are primary islet cells, MIN6, beta-TC-6, INS-1, NIT-1, insulin-secreting cells, glucagon-secreting cells, somatostatin secreting cells, islet hormone or polypeptide secreting cells, pancreatic progenitor cells, alpha-TC cells; the stem cells capable of differentiating into islet cells are mesenchymal stem cells, pluripotent stem cells, embryonic stem cells or bone marrow stem cells.
Preferably, in step (b), the culture temperature is 0 ℃ or 37 ℃; the culture time is 2-30 days.
The invention provides an artificial pancreas constructed by the construction method.
Compared with the prior art, the invention has the beneficial effects that at least:
the method for constructing the artificial pancreas takes the porous microspheres as supports, so that cells capable of forming blood vessels/neural networks and islet cells or stem cells capable of being differentiated into the islet cells are planted and grown in the microspheres in a programmed manner, and the constructed artificial pancreas not only has a cell mass with an islet physiological structure, but also has a vascular neural network structure abundant in a natural pancreas.
The artificial pancreas constructed by the invention is stable, has high cell survival rate and intact shape, and can release insulin under the stimulation of high sugar and form a vascular network; in addition, the construction method of the invention can be used for perfusion of various cells in a programmed way so as to meet the physiological requirements of vascularization, nervonisation and the like of the constructed artificial pancreas.
Drawings
In order to more clearly illustrate the detailed description of the invention or the technical solutions in the prior art, the drawings that are needed in the detailed description of the invention or the prior art will be briefly described below. Throughout the drawings, like elements or portions are generally identified by like reference numerals. In the drawings, elements or portions are not necessarily drawn to scale.
FIG. 1 is a microscopic observation of an artificial pancreas prepared in example 1 of the present invention;
FIG. 2 is a bright field microscope observation of the artificial pancreas prepared in example 1 of the present invention;
FIG. 3 is a microscopic observation of an artificial pancreas prepared in comparative example 1 of the present invention;
FIG. 4 is a microscopic observation of an artificial pancreas prepared in comparative example 2 of the present invention;
FIG. 5 shows the secretion of insulin under sugar stimulation of the artificial pancreas prepared in example 1 of the present invention.
Detailed Description
The following describes embodiments of the present invention in detail with reference to the following embodiments. The following examples are only for illustrating the technical solutions of the present invention more clearly, and therefore are only examples, and the protection scope of the present invention is not limited thereby.
It is to be noted that, unless otherwise specified, technical or scientific terms used herein shall have the ordinary meaning as understood by those skilled in the art to which the invention pertains.
The following examples used the following starting materials:
PLGA microspheres: the preparation method is carried out according to the preparation method in the patent application number 201910924259.8, and the preparation method comprises the following steps:
200 mg of PLGA (molecule)10000-100000) are fully dissolved in 8 ml of dichloromethane to prepare an oil phase, and 1 percent of NH is dripped under the stirring condition4HCO3The solution (porogen) forms colostrum;
transferring the primary emulsion to a 0.1% PVA aqueous solution to form a multiple emulsion, and stirring for 3 hours; collecting the PLGA porous microspheres.
Washing with deionized water for 3 times, washing with 0.1M NaOH solution for 20 min, washing with deionized water for 3 times, and packaging.
And freeze-drying to obtain PLGA porous microsphere solid powder.
The average grain diameter of the PLGA porous microspheres is 50-500 μm, and the diameter of the holes in the porous microsphere structure is 5-50 μm.
Example 1
The embodiment of the invention provides a construction method of an artificial pancreas, which comprises the following steps:
(a) resuspending PLGA porous microspheres, and removing the suspension for later use; digesting human umbilical cord blood stem cells by pancreatin, counting, and taking 4 × 107Placing the human umbilical cord blood stem cells into a 20ml syringe, fixing the volume to 4ml, performing negative pressure pumping for 50 times, then placing the human umbilical cord blood stem cells into a culture medium added with PLGA microspheres, and culturing for 10 days at 37 ℃ to obtain PLGA microspheres planted with the human umbilical cord blood stem cells, wherein the culture medium is RPMI; the concentration of PLGA microspheres in the culture medium is 800/mL; the number ratio of the human umbilical cord blood stem cells to the PLGA microspheres is 1x106:1；
(b) Will be 1 × 109And (3) putting MIN6 cells into a 20ml syringe, fixing the volume to 4ml, performing suction beating for 50 times under negative pressure, and then putting the MIN6 cells into a culture medium containing PLGA microspheres planted with human umbilical cord blood stem cells to culture for 8 days at 37 ℃ to obtain the artificial pancreas.
The artificial pancreas obtained in the above example was observed under an optical microscope, and the observation results are shown in fig. 1 and 2;
as can be seen from fig. 1 and 2:
observing under a mirror, forming a cell secretion matrix on the surface of the porous microspheres after the human umbilical cord blood stem cells (vascular endothelial cells) and the islet cells are planted and cultured in a programmed manner, and connecting the adjacent porous microspheres, wherein each microsphere is internally provided with insulin secreting cells and has a good cell shape; the overall appearance and the size are similar to those of normal mouse islets; after further culture, the human umbilical cord blood stem cells (vascular endothelial cells) and islet cells are planted and cultured in a programmed manner, and then a structure similar to a vascular network can be formed, so that the artificial pancreas with physiological integrity (vascularization) is constructed.
Comparative example 1
This comparative example is a method of constructing an artificial pancreas, which is substantially the same as the method of example 1 except that the number ratio of islet cells to PLGA microspheres in step (a) is 1X103:1。
The artificial pancreas obtained by the above preparation was observed under an optical microscope, and the observation results are shown in fig. 3;
as can be seen from fig. 3:
the above artificial pancreas can visualize sporadic cells near the cell-loaded porous sphere and cannot form any "whole" tissue structure.
Comparative example 2
This comparative example is a method of constructing an artificial pancreas, which is substantially the same as that of example 1 except that the number ratio of human umbilical cord blood stem cells to PLGA microspheres in step (a) is 1X1031, the number ratio of the human cord blood stem cells to the islet cells is 1:105。
The artificial pancreas obtained by the above preparation was observed under an optical microscope, and the observation results are shown in fig. 4;
as can be seen from fig. 4:
no formed vascular network was observed around the porous spheres loaded with functional cells and islet cells.
Example 2
The artificial pancreas obtained in example 1 was subjected to an insulin release test: respectively adding 20mmol/L high-concentration glucose solution and 2mmol/L low-concentration glucose solution into the artificial pancreas, and detecting the insulin content in the system; the detection results are shown in FIG. 5;
as can be seen from fig. 5:
the artificial pancreas prepared by the invention can release insulin under the stimulation of 20mmol/L high-concentration glucose solution, and forms a structure with a vascular network, and the structure can be used for constructing a vascularized artificial pancreas on the surface.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the present invention, and they should be construed as being included in the following claims and description.

Claims (9)

1. A method for constructing an artificial pancreas is characterized by comprising the following steps:
(a) putting the functional cells into a culture medium containing PLGA microspheres for culturing to obtain PLGA microspheres planted with the functional cells, wherein the functional cells are selected from at least one of vascular endothelial cells, nerve cells, lymphatic vessel cells and stem cells capable of differentiating into vascular endothelial cells, nerve cells or immune cells;
(b) and placing the islet cells or stem cells capable of differentiating into the islet cells into a culture medium containing PLGA microspheres planted with functional cells for culturing to obtain the artificial pancreas.
2. The method according to claim 1, wherein in step (a), the PLGA microspheres have a particle size of 50-500 μm and a pore size of 5-50 μm.
3. The method according to claim 1, wherein the ratio of the number of the functional cells to the number of the PLGA microspheres in step (a) is (10)4～107)∶1。
4. The method according to claim 1, wherein in the step (a), the medium is CMRL, DMEM, RPMI, MEM + 10% fetal bovine serum, a custom medium or a conditioned medium; the concentration of the PLGA microspheres in the culture medium is 100-5000/mL;
the culture temperature is 0 ℃ or 37 ℃, and the culture time is 2-30 days.
5. The method according to claim 1, wherein in the step (a), the stem cells capable of differentiating into vascular endothelial cells are human umbilical cord blood stem cells, endothelial progenitor cells, hematopoietic stem cells, bone marrow stem cells, mesenchymal stem cells, pluripotent stem cells or embryonic stem cells; the vascular endothelial cells are primary vascular endothelial cells or express one or more vascular endothelial cells containing CD31, CD34, vWF, alpha-SMA, lectin, isonectin and VEGF vascular markers;
the stem cells capable of differentiating into nerve cells are bone marrow stem cells, endothelial progenitor cells, mesenchymal stem cells, pluripotent stem cells, embryonic stem cells or nerve stem cells in various tissues; the nerve cells are primary nerve cells or express one or more nerve cells containing nestin, SOX2, neural marker class III beta-tubulin (TUJ1), GFAP, NF200, Phox2b, ACh, PGP9.5 and tyrosin hydroxylase nerve cell markers;
the stem cells capable of differentiating into immune cells are hematopoietic stem cells or bone marrow stem cells; the immune cells are primary lymphatic vessel cells or lymphatic vessel cells expressing LYVE-1 lymphatic vessel markers.
6. The method according to claim 1, wherein the number ratio of the islet cells or stem cells capable of differentiating into islet cells to the functional cells in step (b) is (1-5000) to 1.
7. The method according to claim 1, wherein in step (b), the islet cells are primary islet cells, MIN6, beta-TC-6, INS-1, NIT-1, insulin-secreting cells, glucagon-secreting cells, somatostatin-secreting cells, islet hormone or polypeptide-secreting cells, pancreatic progenitor cells, alpha-TC cells; the stem cells capable of differentiating into islet cells are mesenchymal stem cells, pluripotent stem cells, embryonic stem cells or bone marrow stem cells.
8. The method for constructing according to claim 1, wherein in the step (b), the culture temperature is 0 ℃ or 37 ℃; the culture time is 2-30 days.
9. An artificial pancreas constructed by the method of any one of claims 1 to 8.
CN202110795355.4A 2021-07-14 2021-07-14 Artificial pancreas and construction method thereof Pending CN113564099A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516681A (en) * 1986-04-18 1996-05-14 Advanced Tissue Sciences, Inc. Three-dimensional pancreatic cell and tissue culture system
US20170333598A1 (en) * 2014-12-08 2017-11-23 Osaka University Artificial tissue and method for producing same
CN109847102A (en) * 2019-02-28 2019-06-07 山西宾大干细胞生物科技有限公司 A kind of preparation method of mescenchymal stem cell artificial langerhans ' islet
CN110464880A (en) * 2019-09-27 2019-11-19 中国医学科学院生物医学工程研究所 A kind of artificial langerhans ' islet or artificial pancreas and preparation method thereof
CN111187749A (en) * 2018-11-14 2020-05-22 清华大学 Artificial structure for rapid regeneration of vascularized tissue and construction method and application
CN111197024A (en) * 2018-11-16 2020-05-26 杭州捷诺飞生物科技股份有限公司 Pancreas-like structure and its construction method and application
WO2021062286A1 (en) * 2019-09-27 2021-04-01 Prellis Biologics, Inc. Three-dimensional printed organs, devices, and matrices

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516681A (en) * 1986-04-18 1996-05-14 Advanced Tissue Sciences, Inc. Three-dimensional pancreatic cell and tissue culture system
US20170333598A1 (en) * 2014-12-08 2017-11-23 Osaka University Artificial tissue and method for producing same
CN111187749A (en) * 2018-11-14 2020-05-22 清华大学 Artificial structure for rapid regeneration of vascularized tissue and construction method and application
CN111197024A (en) * 2018-11-16 2020-05-26 杭州捷诺飞生物科技股份有限公司 Pancreas-like structure and its construction method and application
CN109847102A (en) * 2019-02-28 2019-06-07 山西宾大干细胞生物科技有限公司 A kind of preparation method of mescenchymal stem cell artificial langerhans ' islet
CN110464880A (en) * 2019-09-27 2019-11-19 中国医学科学院生物医学工程研究所 A kind of artificial langerhans ' islet or artificial pancreas and preparation method thereof
WO2021062286A1 (en) * 2019-09-27 2021-04-01 Prellis Biologics, Inc. Three-dimensional printed organs, devices, and matrices

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