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WO2019090897A1 - Échafaudage artificiel d'ovaire biologique imprimé en 3d capable d'activer des follicules primordiales, ses ovaires artificiels et son utilisation - Google Patents

Échafaudage artificiel d'ovaire biologique imprimé en 3d capable d'activer des follicules primordiales, ses ovaires artificiels et son utilisation Download PDF

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Publication number
WO2019090897A1
WO2019090897A1 PCT/CN2017/116620 CN2017116620W WO2019090897A1 WO 2019090897 A1 WO2019090897 A1 WO 2019090897A1 CN 2017116620 W CN2017116620 W CN 2017116620W WO 2019090897 A1 WO2019090897 A1 WO 2019090897A1
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Prior art keywords
primordial
follicle
scaffold
ovary
ovarian
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Ceased
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PCT/CN2017/116620
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English (en)
Chinese (zh)
Inventor
张键
杨雅莉
赵华山
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms

Definitions

  • the present invention relates to the field of biotechnology, and in particular to the preparation of a 3D printed biological scaffold capable of activating primordial follicles in the ovarian cortex.
  • menopause With the increase of age, female ovarian function gradually declines to permanent menstruation, this physiological phenomenon is called menopause.
  • the follicles in the ovary are used up, or the remaining follicles lose their response to gonadotropins, the follicles do not develop and secrete estrogen, and do not stimulate endometrial growth, leading to menopause.
  • hormone replacement/supplementation which is supplemented with exogenous hormones when menopausal women are deficient in hormones.
  • hormone therapy is not suitable for all people, patients with breast, uterine disease and diabetes, high blood pressure and other diseases need to be used with caution; hormone therapy The amount required by each person is different, it is difficult for doctors to give the most appropriate dose, and excessive hormones in the body can cause uncontrollable side effects such as endometrial cancer, ovarian cancer or breast cancer; exogenously administered hormones are artificial Synthetic, regardless of composition or proportion, can not replace the effect of its own secretion of hormones.
  • premature ovarian failure The average natural menopausal age of women is around 50 years old. When this phenomenon occurs before the age of 40, it is called premature ovarian failure, which accounts for about 1% to 3% of women of childbearing age. Premature ovarian failure is mainly caused by premature depletion of primordial follicles in the ovary or inability of primord follicles to develop.
  • assisted reproductive technologies such as IVF technology have become the key technology for the treatment of infertility.
  • IVF technology the key to IVF technology is that mothers must be provided with a high-quality mature egg. If the mother has no eggs, it can be discharged or ovulated. Low function, such as for patients with premature ovarian failure, then this technology can not help.
  • PCOS Polycystic ovary syndrome
  • the incidence rate is 6-10% of women of childbearing age. It is mainly characterized by menstrual thinning or amenorrhea, infertility, ovarian polycystic Sexual change, obesity, hairy, hyperandrogenism, etc.
  • Treatment for patients with PCOS including surgery, medication, and assisted reproductive technology.
  • PCOS patients use assisted reproductive technology, especially for PCOS patients who have ovulation but still not pregnant after 6 months of ovulation induction therapy, or multiple drug ovulation therapy and adjuvant therapy without ovulation and urgent treatment
  • assisted reproductive technology including in vitro fertilization (IVF) and in vitro maturation (IVM).
  • Ovarian cancer is a malignant tumor with high incidence in the ovary. In addition to interfering with the normal secretion of ovarian hormones, it also destroys most ovarian tissues, causing infertility and seriously endangering women's reproductive health.
  • ovarian cancer The treatment of ovarian cancer is mainly surgery, supplemented by chemotherapy, radiation, and immunotherapy. Surgical treatment is the most effective treatment. In principle, the scope of surgery should be as far as possible to remove the primary tumor and all metastases. For those with fertility requirements, those who meet the conditions can maintain conservative fertility.
  • Ovarian cortical tissue freezing is a common fertility protection measure today, how to make it in subsequent in vitro culture. Its activation, growth and ovulation are the current research hotspots.
  • the present invention utilizes 3D printing technology to activate primordial follicle activators and promote follicles.
  • the developing hormones and growth factors are mixed into the scaffold material, printed, and then transferred into the ovarian cortical fragments containing the original follicles. After transplanting back into the body, the cortical fragments can have better scaffold protection and richer nutrient supply.
  • the bioscaffold is slow in the body. Degradation, sustained release of follicle activators, continuous activation of primordial follicles.
  • One aspect of the present invention provides a bioscaffold that mimics an artificial ovary, which is obtained by a 3D printing method, and the printing material used for 3D printing is a mixture of a biocompatible material, a primordial follicle activator, and a primordial follicle development promoter.
  • One aspect of the present invention provides an artificial ovary comprising a biological scaffold and a tissue fragment containing the primordial follicle embedded in the biological scaffold, wherein the bio scaffold is obtained by 3D printing, and the printed material is a biocompatible material, a primordial follicle A mixture of activators, follicle developmental enhancers.
  • the biocompatible material simulates a component contained in ovarian tissue selected from the group consisting of collagen I, sodium alginate, gelatin, agarose, Matrigel, hyaluronic acid, chitosan.
  • a component contained in ovarian tissue selected from the group consisting of collagen I, sodium alginate, gelatin, agarose, Matrigel, hyaluronic acid, chitosan.
  • One or a combination of any of several kinds of dextran Preferred is a mixture of sodium alginate and gelatin, a mixture of sodium alginate and matrigel, a mixture of gelatin and matrigel, a mixture of collagen I and sodium alginate and gelatin, collagen I and a mixture of gelatin and matrigel.
  • the prepared biological scaffold is first UV-crosslinked and then cross-linked with CaCl 2 .
  • CaCl 2 can be soaked in CaCl 2 for -20 ° C for short-term storage, or -80 ° C refrigerator for long-term storage, soaked in PBS or saline before use.
  • the hormone or growth factor for promoting follicular development is selected from the group consisting of follicle stimulating hormone (FSH), luteinizing hormone (LH), epidermal growth factor (EGF), and insulin-transferrin-selenium (ITS).
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • EGF epidermal growth factor
  • ITS insulin-transferrin-selenium
  • follicle stimulating hormone a combination of follicle stimulating hormone and luteinizing hormone
  • a combination of follicle stimulating hormone and luteinizing hormone and epidermal growth factor follicle stimulating hormone and luteinizing hormone and epidermal growth factor and insulin-transferrin- A combination of selenium.
  • the amount of follicle stimulating hormone (FSH) is 10-1000 mIU/ml, luteinizing hormone (LH) 1-100 mIU/ml, epidermal growth factor (EGF) 0.1-100 ng/ml, insulin-transferrin-selenium (ITS).
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • EGF epidermal growth factor
  • ITS insulin-transferrin-selenium
  • Insulin-transferrin-selenium contains 1-100 ug/ml recombinant human insulin, 1-100 ug/ml human transferrin (essentially iron-free) and 0.1-100 ng/ml sodium selenite.
  • the primordial follicle activator comprises a signaling pathway agonist or inhibitor associated with primordial follicle activation, and a basal culture fluid.
  • the relevant signaling pathway agonist or inhibitor is selected from the group consisting of a PTEN inhibitor, a PI3K signaling pathway activator, an AKT signaling pathway activator, a mTOR signaling pathway activator, or a combination of several.
  • the PTEN inhibitor is selected from the group consisting of SF1670 (0.5-100 uM), VO-Ohpic trihydrate (0.1-100 nM), pic bpv (0.1-100 nM), and phen type bpv (0.1-100 nM). Combination of species or multiples;
  • the PI3K signaling pathway agonist is selected from the group consisting of 1,3-diacyl quinic acid (0.1-100 uM), 740Y-P (PDGFR 740Y-P) (0.1-300 ug/ml) or A variety of combinations.
  • the AKT signaling pathway agonist is selected from the group consisting of 1,3-diacyl quinic acid (0.1-100 uM), deoxyandrographolide (0.1-100 mM), and SC79 (0.1-10 ug/ml). A combination of one or more.
  • the mTOR signaling pathway agonist is selected from the group consisting of MHY1485 (0.1-10 uM), PA (0.1-200 uM), PRO (0.1-100 uM), or a combination thereof.
  • the basal culture solution comprises a culture solution for culturing the primordial follicle, preferably comprising a medium, an antibiotic, a carbon source, a protease inhibitor, preferably comprising ⁇ MEM, FBS/BSA, sodium pyruvate, penicillin. Streptomycin. More preferably, ⁇ MEM is used as a mother liquor containing 10% FBS, 5.5 mg/ml sodium pyruvate, 100 IU/ml penicillin, and 100 ug/ml streptomycin.
  • the biocompatible stent has a void, and the diameter of the void is 1.5 to 3 times, preferably 2-2.5 times, the size of the ovarian cortex.
  • the 3D printing size of the biocompatible stent is: pore size (R): 100 ⁇ m-800 ⁇ m, preferably 150 ⁇ m, 200 ⁇ m, 250 ⁇ m, 300 ⁇ m, 350 ⁇ m, 400 ⁇ m, 450 ⁇ m, 500 ⁇ m, 550 ⁇ m. , 600 ⁇ m, 650 ⁇ m, 700 ⁇ m, 750 ⁇ m; line stacking angle: 0°-180°, preferably 5°, 10°, 15°, 20°, 30°, 40°, 50°, 60°, 70°, 80 °, 90°, 100°, 110°, 120°, 130°, 140°, 150°, 160°, 170°, 175°.
  • R pore size
  • the shape of the biological scaffold may be various shapes such as a circle, an ellipse, a rectangle, a square, an irregular shape, and the like.
  • the tissue fragments comprising the primordial follicles are activated for soaking for 0.1-24 hours, preferably 0.5-6 hours, prior to implantation into the bioscaffold using the primordial follicle activator.
  • the tissue fragments comprising the primordial follicle are selected from ovarian tissue fragments comprising primordial follicles, more preferably ovarian cortical fragments comprising primordial follicles.
  • Another aspect of the invention provides a method of preparing an artificial ovary comprising the steps of:
  • the biocompatible scaffold is printed by 3D printing, and the biocompatible scaffold is printed with a biocompatible material and a mixture of primordial follicle activator and primordial follicle development promoter.
  • Another aspect of the invention provides a method of preparing an artificial ovary comprising the steps of:
  • step 3 Inject the activated ovarian cortical fragments onto the 3D printed biocompatible scaffold obtained in step 1) to obtain an artificial ovary.
  • Another aspect of the invention provides the use of the artificial ovary of the invention as a drug screening, follicular research model.
  • Another aspect of the invention provides the use of the artificial ovary of the invention for treating follicular dysplasia diseases.
  • the follicular development disorder disease is selected from the group consisting of ovarian failure, premature ovarian failure, polycystic ovary syndrome, ovarian cancer, and ovarian injury caused by trauma.
  • Another aspect of the invention provides a method of treating a follicular developmental disorder comprising the step of transplanting an artificial ovary of the invention into a subject.
  • Another aspect of the invention provides the use of the artificial ovary-like bioscaffold of the invention for the preparation of an artificial ovary.
  • Another aspect of the present invention provides the use of the artificial ovary-like biological scaffold of the present invention for preparing a medical device simulating an artificial ovary.
  • a biocompatible scaffold containing a primordial follicle activator and a hormone or growth factor for promoting follicular development is produced by 3D printing, and the frozen fresh ovarian cortical fragments containing primordial follicles are different in different concentrations. After incubation for 0.5 to 6 hours in the basal medium of the combined primordial follicle activator, it is transferred into the interior of the biocompatible scaffold and then transplanted back into the body.
  • the egg cell, the follicle, the primordial follicle, the tissue containing the primordial follicle, for example, the ovarian cortex including the follicle, and the like are non-human cells, or the egg cells, follicles, and primordial follicles used in the present invention.
  • Tissues containing primordial follicles are commercially available.
  • the invention adopts an active substance mixed with hormones, growth factors and the like in the stent, which can be slowly released. After the cortical fragments are injected into the 3D printing stent and transplanted back into the body, the cortical fragments can have better stent protection and richer. Nutritional supply. The bioscaffold slowly degrades in the body, releasing the follicle activator and continuously activating the primordial follicle.
  • the follicle activates and secretes a large amount of hormone regulating body secretion, and provides a new research direction for improving the menopausal syndrome and delaying aging.
  • the ITS commercial product used in the present invention contains 1.0 mg/ml recombinant human insulin, 0.55 mg/ml human transferrin (substantially iron-free) and 0.5 ⁇ g/ml sodium selenite.
  • CAD computer aided design
  • the shape of the 3D bio scaffold is selected as a circle, a rectangle, a square, an ellipse or an irregular shape, and the internal structure is connected, Pore; pore size (R): 400 ⁇ m; line stacking angle: 30-120 degrees;
  • a 3D printed biological scaffold printing material comprising a mixture of a biocompatible material, a primordial follicle activator, and a primordial follicle development promoter; the biocompatible material is 3%-5% sodium alginate and 8%- The mass ratio of 10% gelatin, sodium alginate and gelatin is 1:1, and it gels at room temperature after mixing. 740Y-P 10ug/ml, PA 8uM, PRO 2uM, FSH 100mIU, LH 10mIU, EGF 5ng/ml, ITS (used after 100-fold dilution) were added to the biocompatible material.
  • the prepared scaffold is first UV-crosslinked for 10 minutes, then cross-linked with CaCl 2 , soaked in CaCl 2 for -20 ° C for short-term storage, or -80 ° C for long-term storage in the refrigerator, soaked in PBS or saline before use. .
  • the stent prepared in Example 2 was the same as the method of Example 1, except that the formulation of the printing material in the step (2) was carried out, and the formulation of the printing material was carried out in the proportions listed in the following table.
  • mice of 3 days old were sacrificed by cervical dislocation. After disinfecting the skin, the ovaries were aseptically removed from the back and placed in the separation medium (L-15+10% FBS+100 IU/ml penicillin+100 ug/ml chain). Mycin). The attached tissue around the ovary was removed under a stereoscopic microscope and washed 3 times in the separation solution. The ovary is then dosed with insulin under the microscope, and the mouse ovary is divided into tissue fragments containing primordial follicles.
  • the separation medium L-15+10% FBS+100 IU/ml penicillin+100 ug/ml chain
  • Activators are agonists or inhibitors of the signaling pathways associated with primordial follicle activation and are of the prior art and are commercially available.
  • the basic broth formulation of the follicle activator is:
  • the female rats were sacrificed on the 5th, 10th, and 15th day after the transplantation, and the stents were removed. Paraffin-embedded and 5um tissue sections were taken: H&E staining to observe the follicular developmental morphology; immunohistochemical staining of PCNA to detect cell proliferation; TUNNEL Apoptosis was detected.
  • the results of the 12 groups of experiments showed the state of primordial follicle activation and development. It can be seen from the photos that some of the primordial follicles successfully activated and developed into the preantral follicle stage, and the developing follicular granulosa cells proliferated. . It is indicated that the scaffold and artificial ovary of the present invention successfully activates the primordial follicle of the mouse in vivo and promotes its development, and can provide an alternative for ovarian disease caused by loss or damage.

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Abstract

L'invention concerne un échafaudage biologique imprimé en 3D capable d'activer des follicules primordiales dans le cortex ovarien. Au moyen d'une technologie d'impression 3D, un activateur de follicule primordiale et une hormone et un facteur de croissance qui sont capables de favoriser le développement folliculaire sont mélangés avec un matériau d'échafaudage pour la mise en forme par impression ; puis des fragments corticaux ovariens contenant des follicules primordiales sont implantés dans l'échafaudage imprimé. Après avoir été implanté dans un corps, les fragments corticaux peuvent obtenir une meilleure protection à base d'échafaudage et une alimentation en nutrition plus riche, et l'échafaudage biologique se dégrade lentement dans le corps pour libérer lentement l'activateur de follicules, activant ainsi en continu les follicules primordiales.
PCT/CN2017/116620 2017-11-07 2017-12-15 Échafaudage artificiel d'ovaire biologique imprimé en 3d capable d'activer des follicules primordiales, ses ovaires artificiels et son utilisation Ceased WO2019090897A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711085422.3A CN109749980B (zh) 2017-11-07 2017-11-07 一种能够激活原始卵泡的3d打印人造卵巢生物支架及其人造卵巢和用途
CN201711085422.3 2017-11-07

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CN114703121A (zh) * 2022-03-29 2022-07-05 广西大学 一种水牛卵巢皮质体外培养用激活培养基及体外培养方法

Citations (5)

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CN1962858A (zh) * 2001-11-16 2007-05-16 儿童医疗中心有限公司 组织改造雌性生殖器官的建造
CN104769101A (zh) * 2012-09-04 2015-07-08 人类起源公司 组织产生方法
CN105039245A (zh) * 2015-07-01 2015-11-11 浙江大学 一种利用3d打印技术促进人未成熟卵母细胞体外成熟的方法
WO2016123362A1 (fr) * 2015-01-30 2016-08-04 Northwestern University Ovaire artificiel
CN105916977A (zh) * 2013-10-07 2016-08-31 东北大学 用于使用自体细胞系统从生殖系细胞离体产生有发育能力的卵的方法和组合物

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Publication number Priority date Publication date Assignee Title
CN104130972B (zh) * 2014-07-09 2017-03-22 南京医科大学 原始卵泡激活剂及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1962858A (zh) * 2001-11-16 2007-05-16 儿童医疗中心有限公司 组织改造雌性生殖器官的建造
CN104769101A (zh) * 2012-09-04 2015-07-08 人类起源公司 组织产生方法
CN105916977A (zh) * 2013-10-07 2016-08-31 东北大学 用于使用自体细胞系统从生殖系细胞离体产生有发育能力的卵的方法和组合物
WO2016123362A1 (fr) * 2015-01-30 2016-08-04 Northwestern University Ovaire artificiel
CN105039245A (zh) * 2015-07-01 2015-11-11 浙江大学 一种利用3d打印技术促进人未成熟卵母细胞体外成熟的方法

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