Table 1 Organ chips that mimic each organ of the female reproductive system
From: Organ-on-a-chip: future of female reproductive pathophysiological models
Model category | Cell types | Culture environment | Device characteristics | Culture characteristics | Significance | Year/Reference |
|---|---|---|---|---|---|---|
Ovary-on-a-chip | λ Early secondary preantral follicles of female deer mice | λ Medium: conditioned medium + 5 µg/ml insulin + 5 µg/ml transferrin + 5 ng/ml selenium + 100 mIU/mL FSH λ Temperature: 37 °C; CO2: 5%; Humidity: 95% | λ The first layer: 100 μm λ The additional layer: 50 μm λ The third layer: 50 μm λ Device material: PDMS λ Fabrication method: soft lithography | λ Flow rate: Core: 50 µl/h; Dispatching: 30 µl/h; Shell: 120 µl/h; Oil: 2 ml/h; Aqueous extracting fluids: 4 ml/h. λ Coating: alginate (harder) and collagen (softer) | To reveal the crucial role of mechanical heterogeneity in the mammal ovary in regulating follicle development and ovulation. | 2014/ [42] |
Ovary-on-a-chip | λ Single human pre-antral follicle | λ Medium: 50% MEM-α + 50% F-12 + 1 mg/mL FBS + 5 µg/mL insulin + 5 µg/mL transferrin human + 5 µg/mL sodium selenite + 3 mg/mL BSA + 1:100 rFSH λ Temperature: 37 °C; CO2: 5%; Humidity: 95% | λ Upper PDMS layer: 2 mm λ Middle PDMS layer: 5 mm λ Lower PDMS layer: 1 mm λ Device material: two plates of PMMA substrate + three layers of PDMS plates λ The entire device: 6 × 4 × 0.8 cm3 λ Fabrication method: soft lithography | λ Flow rate: 8.33 µL/h λ Coating: 0.5% of sodium alginate and 0.5% of sodium alginate | To culture a single human ovarian follicle and explore the hormonal changes and their interactions during folliculogenesis. | 2017/ [43] |
Ovary-on-a-chip | λ Ditto | λ Ditto | λ Ditto | λ Ditto | To explore the toxicity and possible mechanisms of doxorubicin | 2020/ [44] |
Ovary-on-a-chip in mice models | λ Cumulus-oocyte complex of CD-1 female mouse | λ Medium: MEM-α + 10% FBS + 10 ng/mL EGF + cumulus cell expansion stimulator + 25 × 10− 3 M HEPES. λ Temperature: 37 °C; O2: 95%; CO2: 5% | λ Top layer: polyester membrane: 200 μm; acrylic layer: 0.862 mm λ Bottom layer: 200 μm λ Device material: two PDMS layers λ Fabrication method: soft lithography | λ Flow rate: varies from step to step λ Coating: / | For analyzing and screening the effects of potential contraceptive agents on the maturation of the cumulus-oocyte complex. | 2019/ [45] |
Ovary-on-a-chip in large mammal models | λ Ovarian cortex and follicle of domestic cat and dog | λ Medium: Cat: MEM + 4.2 µg/ml insulin + 3.8 µg/ml transferrin + 5 ng/ml selenium + 2 mM L-glutamine + 100 µg/ml penicillin G sodium and streptomycin sulfate + 0.05 mM ascorbic acid + 0.1% w/v polyvinyl alcohol + 10 ng/ml FSH + 100 ng/ml EGF; Dog: MEM-α + 3 mg/ml BSA + 4.2 µg/ml insulin + 3.8 µg/ml transferrin + 5 ng/ml selenium + 2 mM glutamine + 10 IU/ml penicillin G + 10 µg/ml streptomycin + 10 µg/ml FSH λ Temperature: 38.5 °C; CO2: 5%; Humidity:/ | λ Top layer: 3 mm PMMA λ Channel layer: 1.5 mm PMMA λ Base layer: 2 mm Polystyrene λ Complete chip: 40 × 24 × 6.5 mm3 λ Device material: PMMA and Polystyrene λ Fabrication method: soft lithography | λ Flow rate: 2 µL/min or 10 µL/min λ Coating: 1% alginate hydrogel | To support the in vitro survival of domestic cat and dog follicles enclosed within the ovarian cortex or isolated from the ovarian cortex. | 2018/ [46] |
Menstrual cycle-on-a- chip/Ovary-on-a-chip/ Multi organ chip | λ Primary/early secondary follicles of female CD-1 mice; Quintet-MFP: murine ovary, human fallopian tube, endometrium, ectocervix, liver tissues | λ Medium: Follicular phase: growth medium (50% MEM-α + 50% F-12 + 3 mg/mL BSA + 0.5 mg/mL bovine fetuin + 5 µg/mL insulin + 5 µg/mL transferrin + 5 µg/mL selenium) + 10 mIU/ml recombinant FSH; Luteal phase: growth media without FSH λ Temperature: 37 °C; CO2: 5% | λ Solo-MFP: a coupled donor/acceptor module and a module for tissues λ Duet-MFP: a donor module, two modules for tissues, and a separate acceptor module λ Quintet-MFP: a donor module, five modules for tissues, and a separate acceptor module λ Device material:/ λ Fabrication method: Solo-MFP and Duet-MFP: pneumatic actuation technology; Quintet-MFP: embedded electromagnetic actuation technology | λ Flow rate: Solo-MFP: 40 µL/h; Duet-MFP: 0 µL/h; Quintet-MFP: 100 µL/h λ Coating: 0.5% alginate drop or 1% alginate hydrogels | To develop platforms that could sustain tissue-level function for the length of the human menstrual cycle (that is, 28 days). | 2017/ [17] |
Oviduct-on-a-chip | λ Bovine oviduct epithelial cells | λ Medium: DMEM/Ham’s F-12 + 5 µg/mL insulin + 5 µg/mL transferrin + 10 mM glutathione + 100 µg/mL gentamycin + 10 ng/mL EGF + 50 nM trans-retinoic acid + 5% FCS + 2.5 mg/mL amphotericin B λ Temperature: 38.5 °C; O2: 7%; CO2: 5% | λ Two independent compartments: 3 × 2.8 × 0.37mm3 λ Device material: PDMS λ Fabrication method: / | λ Flow rate: 5 µL/h λ Coating: / | To investigate the mechanisms related to genetic reprogramming and the degree to which they differ between in vitro and in vivo embryos. | 2018/ [18] |
Oviduct-on-a-chip | λ Human fallopian tube epithelium | λ Medium: normal: low testosterone concentration of 0.8 nM; PCOS-like: high testosterone concentration of 2 nM; MEM + 0.3% BSA + 0.5 mg/ml fetuin + 1% penicillin/streptomycin + 1% ITS λ Temperature: 37 °C; CO2: 5% | λ Solo-MFP: a coupled donor/acceptor module and a module for tissues λ Device material: / λ Fabrication method: Solo-MFP: pneumatic actuation technology | λ Flow rate: 35 ~ 50 µL/h; λ Coating: 0.5% alginate drop or 1% alginate hydrogels | To investigate how exposure to testosterone-rich environments affects the function and gene expression of the human fallopian tube epithelium. | 2020/ [54] |
Oviduct-on-a-chip | λ Mouse primary oviduct epithelial cells λ Embryos of CD-1 mice | λ Medium: DMEM/F-12 containing 20% FBS λ Temperature: 37 °C; CO2: 5% CO2 of mouse oviduct secretory epithelial cells while 6% CO2 of embryos | λ The circular hole on both ends of the channels: 3 mm λ The chamber: 5 mm λ The whole channels: 20 × 1 × 10mm3 λ Device material: PDMS λ Fabrication method: Multilayer soft lithography technology | λ Flow rate: 1.0 µL/h λ Coating: / | Reduce intracellular ROS levels to optimize embryo culture conditions. | 2022/ [53] |
Uterus-on-a-chip | λ Mouse oocytes λ Mouse endometrial cells | λ Medium: Endometrial cells: M16 medium; Oocytes: M6 medium λ Temperature: 37 °C; CO2: 5% | λ Top layer: contained a zigzag shaped channel (500 μm in width and 110 μm in height) λ Porous membrane: pore size of 8 μm λ Bottom layer: contained 4 parallel rectangular channels (6 × 3 × 0.11mm3) λ Device material: Top layer and bottom layer: PDMS; Porous membrane: polycarbonate λ Fabrication method: soft lithography technology | λ Flow rate: 10 µL/h λ Coating: 0.5% gelatin solution | To achieve higher morula rates and blastocyte rates. | 2013/ [15] |
Uterus-on-a-chip | λ Human endometrial stromal cell λ Mouse embryos | λ Medium: Human endometrial stromal cell:75% DMEM and 25% MCDB 105 medium + 100U/ml penicillin + 100U/ml streptomycin + 5 µg/mL insulin + 10% charcoal-stripped FBS + 10% FBS + antibody; Mouse embryos: HTF medium λ Temperature: 37 °C; O2: 95%; CO2: 5% | λ Concentration gradient generator: width: 250 μm, height: 230 μm λ Diamond-shaped passive micro-mixer: width: 200 μm, height: 230 μm λ Culture chamber: radius: 3 mm, height: 230 μm λ Perfusion channel: width: 250 μm, height: 230 μm λ Device material: PDMS λ Fabrication method: soft lithography technologyλ | λ Flow rate: 1 µL/min λ Coating: / | Successfully demonstrated its ability to support embryonic development from the 8-cell stage to the hatching stage in 48 h. | 2016/ [61] |
Endometrial perivascular stroma-on-a-chip | λ Human endometrial stromal cells λ HUVECs | λ Medium: HUVECs: EBM-2 medium + EGM™-2 Single Quot growth factors; Human endometrial stromal cells: phenol red-free DMEM/F-12 + 10% charcoal-stripped calf serum + 1nM 17-β estradiol + 1× antibiotic-antimycotic solution (stromal complete growth medium) λ Temperature: 37 °C; O2: 95%; CO2: 5%; Humidity: saturated humidity | λ Two microfluidic chambers: 4.75 × 6.2mm2 λ Porous membrane: pore size of 2 μm λ Device material: PDMS λ Fabrication method: soft lithography technology | λ Flow rate: 2.5µL/min λ Coating: / | The endometrial perivascular stroma model was sustainable for up to 4 weeks. | 2017/ [63] |
Endometrial perivascular stroma-on-a-chip | λ Human endometrial stromal cells λ HUVECs | λ Medium: HUVECs: EGM™-2MV BulletKit™; Human endometrial stromal cells: phenol red-free DMEM/F-12 + 5% charcoal-stripped calf serum + 1nM 17-β estradiol + 1× antibiotic-antimycotic solution (stromal complete growth medium) λ Temperature: 37 °C; O2: 95%; CO2: 5%; Humidity: saturated humidity | λ Ditto | λ Flow rate: 1µL/min λ Coating: collagen type IV (10 µg/cm2) | Revealed that the perfused-vascular endothelium enhancing the decidualization response. | 2019/ [64] |
Endometrium-on-a-chip | λ HUVECs λ Human endometrial epithelial cells λ Human endometrial stromal fibroblasts | λ Medium: HUVECs: EGM-2 medium; Endometrial epithelial cells and endometrial stromal fibroblasts: DMEM/F12 + 10% FBS + 1% penicillin–streptomycin λ Temperature: 37 °C; CO2: 5% | λ Five microchannels: two central channels (channel SC and channel VC) + fibroblast channel + media channels 1 + media channels 2 λ Device material: PDMS λ Fabrication method: soft lithography and replica molding | λ Flow rate: / λ Coating: fibrin gel solution (2.5 mg/ml fibrinogen with 0.15 U/ml aprotinin) | Recapitulates in vivo endometrial vasculo-angiogenesis and hormonal responses displaying key features of the proliferative and secretory phases of the menstrual cycle. | 2021/ [65] |
Endometrium-on-a-chip | λ Human endometrial cellular components λ Human ovarian follicular cells λ HUVEC λ Primary human stromal cells | λ Medium: Human endometrial cellular components: StemPro MSC SFM CTS™; HUVEC: EBM-2 medium; Primary human stromal cells: DMEM medium + 10%FBS; Human ovarian follicular cells: M-199/MCDB-105(1:1 mixture) + 10%FBS λ Temperature: 37 °C; O2: 95%; CO2: 5% | λ Dual chamber chip platform: 34 × 34 × 5mm3 λ Triangular uterine endometrial chamber: 20 × 16 × 3mm3 λ Dual circular ovarian chambers: 7 × 7 × 3mm3 λ Media channel: 2 × 3 × 3mm3 λ Device material: PDMS λ Fabrication method: 3D printing | λ Flow rate: / λ Coating: / | Developed a ‘dual reproductive organ-on-a-chip’ that was used to predict the reproductive toxicity of various hazardous materials. | 2020/ [68] |
Cervical epithelial layer-on-a-chip | λ Immortalized ectocervical cells λ Immortalized endocervical epithelial cells | λ Medium: Immortalized ectocervical and endocervical epithelial cells: KSFM medium + 30 µg/mL bovine pituitary extract + 0.1 ng/mL EGF + 0.4 mM CaCl2 + 0.5 mg/mL primocin λ Temperature: 37 °C; CO2: 5% | λ The first microchannel layer: 5 μm deep λ The second cell culture chamber layer: 500 μm deep λ Device material: PDMS λ Fabrication method: soft lithography technology | λ Flow rate: / λ Coating: IV collagen | To simulate the effects of cell death, migration, EMT, and inflammatory cytokine secretion in bacterial infection and inflammatory states. | 2021/ [73] |
Vagina-cervix-decidua-organ-on-a-chip | λ Immortalized ectocervical cells λ Immortalized endocervical epithelial cells λ Cervical stromal cells λ Vaginal epithelial cell λ Human decidua cells λ Transformation zone | λ Medium: Vaginal epithelial cells: KSFM medium + 30 µg/mL bovine pituitary extract + 0.1 ng/mL EGF + 0.4 mM CaCl2 + 0.5 mg/mL primocin + KGM™-2 Keratinocyte Growth Medium Bulletkit™; Ectocervical epithelial and endocervical epithelial cells: complete KSFM medium; Cervical stromal cells: DMEM/F-12 + 10% FBS + 50 IU/ml penicillin/50 µg/ml streptomycin + 2.5 µg/ml amphotericin B; Human decidual cells: DMEM/F-12 + 10% FBS + 50 IU/ml penicillin/50 µg/ml streptomycin + 2.5 µg/ml amphotericin B λ Temperature: 37 °C; CO2: 5% | λ The vagina, ectocervical, transformation zone, cervical stroma, and decidua layers: interconnected by an array of 24 microchannels (300 × 30 × 5µm3) λ Endocervical epithelia layer: interconnected by an array of 72 microchannels (600 × 30 × 5µm3) λ Device material: PDMS λ Fabrication method: soft lithography technology | λ Flow rate: / λ Coating: IV collagen | Ureaplasma parvum infection was found not to promote a large-scale inflammatory response. | 2022/ [74] |
Vagina-cervix-decidua-organ-on-a-chip | λ Ditto | λ Ditto λ THP-1 monocytes: RPMI 1640 medium + 0.05 mM 2-mercaptoethanol + 10% FBS λ Temperature: 37 °C; CO2: 5% | λ Ditto | λ Ditto | Revealed that exosomes from Ureaplasma parvum-infected ectocervical epithelial cells promote feto-maternal interface inflammation but are insufficient to cause preterm delivery. | 2022/ [75] |
Vagina-on-a-chip | λ Human vaginal epithelium cells λ Human vaginal stromal fibroblasts | λ Medium: vaginal epithelium cells: vaginal epithelium growth medium; human uterine fibroblasts cells: fibroblast growth medium (Uterine fibroblasts were used to replace primary human vaginal fibroblasts) λ Temperature: 37 °C; CO2: 5% | λ The apical channel: 16.7 × 1 × 1mm3 λ The basal channel: 16.7 × 1 × 0.2mm3 λ The porous membrane: pore size of 7 μm λ Device material: PDMS λ Fabrication method: / | λ Flow rate: 40µL/h λ Coating: the apical channel: collagen IV (30 µg/mL) and collagen I (200 µg/mL); the basal channel: collagen I (200 µg/mL) | Demonstrates the vagina-on-a-chip can be used to better understand interactions between the vaginal microbiome and host tissues. | 2022/ [77] |