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Magnetically Bioprinted Human Myometrial 3D Cell Rings as A Model for Uterine Contractility.

ABSTRACT: Deregulation in uterine contractility can cause common pathological disorders of the female reproductive system, including preterm labor, infertility, inappropriate implantation, and irregular menstrual cycle. A better understanding of human myometrium contractility is essential to designing and testing interventions for these important clinical problems. Robust studies on the physiology of human uterine contractions require in vitro models, utilizing a human source. Importantly, uterine contractility is a three-dimensionally (3D)-coordinated phenomenon and should be studied in a 3D environment. Here, we propose and assess for the first time a 3D in vitro model for the evaluation of human uterine contractility. Magnetic 3D bioprinting is applied to pattern human myometrium cells into rings, which are then monitored for contractility over time and as a function of various clinically relevant agents. Commercially available and patient-derived myometrium cells were magnetically bioprinted into rings in 384-well formats for throughput uterine contractility analysis. The bioprinted uterine rings from various cell origins and patients show different patterns of contractility and respond differently to clinically relevant uterine contractility inhibitors, indomethacin and nifedipine. We believe that the novel system will serve as a useful tool to evaluate the physiology of human parturition while enabling high-throughput testing of multiple agents and conditions.

SUBMITTER: Souza GR

PROVIDER: S-EPMC5412269 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Magnetically Bioprinted Human Myometrial 3D Cell Rings as A Model for Uterine Contractility.

Souza Glauco R GR Tseng Hubert H Gage Jacob A JA Mani Arunmani A Desai Pujan P Leonard Fransisca F Liao Angela A Longo Monica M Refuerzo Jerrie S JS Godin Biana B

International journal of molecular sciences 20170323 4

Deregulation in uterine contractility can cause common pathological disorders of the female reproductive system, including preterm labor, infertility, inappropriate implantation, and irregular menstrual cycle. A better understanding of human myometrium contractility is essential to designing and testing interventions for these important clinical problems. Robust studies on the physiology of human uterine contractions require in vitro models, utilizing a human source. Importantly, uterine contrac ...[more]

PMID: 28333087

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Project description:BACKGROUND:In a previous study we found a significant correlation between dystocia and hyponatraemia that developed during labour. The present study examined a possible causal relationship. In vitro studies often use area under the curve (AUC) determined by frequency and force of contractions as a measure of myometrial contractility. However, a phase portrait plot of isometric contraction, obtained by plotting the first derivate of contraction against force of contraction, could indicate that bi-or multiphasic contractions might be less effective compared to the smooth contractions. MATERIAL AND METHODS:Myometrial biopsies were obtained from 17 women undergoing elective caesarean section at term. Each biopsy was divided into 8 strips and mounted isometrically in a force transducer. Seven biopsies were used in the first part of the study when half of the strips were immersed in the hyponatraemic study solution S containing Na+ 120 mmol/L and observed for 1 hour, followed by 1 hour in normonatraemic control solution C containing Na+ 136 mmol/L, then again in S for 1 hour, and finally 1 hour in C. The other half of the strips were studied in reverse order, C-S-C-S. The remaining ten biopsies were included in the second part of the study. Response to increasing doses of oxytocin (OT) in solutions S and C was studied. In the first part of the study we calculated AUC, and created phase portrait plots of two different contractions from the same strip, one smooth and one biphasic. In both parts of the study we registered frequency and force of contractions, and described appearance of the contractions. RESULTS:First part of the study: Mean (median) contractions per hour in C: 8.7 (7.6), in S 14,3 (13). Mean (SD) difference between groups 5.6 (4.2), p = 0.018. Force of contractions in C: 11.8 (10.2) mN, in S: 10.8 (9.2) mN, p = 0.09, AUC increased in S; p = 0.018. Bi-/multiphasic contractions increased from 8% in C to 18% in S, p = 0.001. All changes were reversible in C. Second part of the study: Frequency after OT 1.65 x 10-9 M in C:3.4 (2.9), in S: 3.8 (3.2), difference between groups: p = 0.48. After OT 1.65 x 10-7 M in C: 7.8 (8.9), increase from previous OT administration: p = 0.09, in S: 8.7 (9.0), p = 0.04, difference between groups, p = 0.32. Only at the highest dose of OT dose was there an increase in force of contraction in S, p = 0.05, difference between groups, p = 0.33. Initial response to OT was more frequently bi/multiphasic in S, reaching significance at the highest dose of OT(1.65 x 10-7 M), p = 0.015. when almost all contractions were bi/multiphasic. CONCLUSION:Hyponatraemia reversibly increased frequency of contractions and appearance of bi-or multiphasic contractions, that could reduce myometrial contractility. This could explain the correlation of hyponatraemia and instrumental delivery previously observed. Contractions in the hyponatraemic solution more frequently showed initial multiphasic contractions when OT was added in increasing doses. Longer lasting labours carry the risk both of hyponatraemia and OT administration, and their negative interaction could be significant. Further studies should address this possibility.

Project description:Background3D bioprinting cardiac patches for epicardial transplantation are a promising approach for myocardial regeneration. Challenges remain such as quantifying printability, determining the ideal moment to transplant, and promoting vascularisation within bioprinted patches. We aimed to evaluate 3D bioprinted cardiac patches for printability, durability in culture, cell viability, and endothelial cell structural self-organisation into networks.MethodsWe evaluated 3D-bioprinted double-layer patches using alginate/gelatine (AlgGel) hydrogels and three extrusion bioprinters (REGEMAT3D, INVIVO, BIO X). Bioink contained either neonatal mouse cardiac cell spheroids or free (not-in-spheroid) human coronary artery endothelial cells with fibroblasts, mixed with AlgGel. To test the effects on durability, some patches were bioprinted as a single layer only, cultured under minimal movement conditions or had added fibroblast-derived extracellular matrix hydrogel (AlloECM). Controls included acellular AlgGel and gelatin methacryloyl (GELMA) patches.ResultsPrintability was similar across bioprinters. For AlgGel compared to GELMA: resolutions were similar (200-700 μm line diameters), printing accuracy was 45 and 25%, respectively (AlgGel was 1.7x more accurate; p < 0.05), and shape fidelity was 92% (AlgGel) and 96% (GELMA); p = 0.36. For durability, AlgGel patch median survival in culture was 14 days (IQR:10-27) overall which was not significantly affected by bioprinting system or cellular content in patches. We identified three factors which reduced durability in culture: (1) bioprinting one layer depth patches (instead of two layers); (2) movement disturbance to patches in media; and (3) the addition of AlloECM to AlgGel. Cells were viable after bioprinting followed by 28 days in culture, and all BIO X-bioprinted mouse cardiac cell spheroid patches presented contractile activity starting between day 7 and 13 after bioprinting. At day 28, endothelial cells in hydrogel displayed organisation into endothelial network-like structures.ConclusionAlgGel-based 3D bioprinted heart patches permit cardiomyocyte contractility and endothelial cell structural self-organisation. After bioprinting, a period of 2 weeks maturation in culture prior to transplantation may be optimal, allowing for a degree of tissue maturation but before many patches start to lose integrity. We quantify AlgGel printability and present novel factors which reduce AlgGel patch durability (layer number, movement, and the addition of AlloECM) and factors which had minimal effect on durability (bioprinting system and cellular patch content).

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Magnetically Bioprinted Human Myometrial 3D Cell Rings as A Model for Uterine Contractility.

Publications

Magnetically Bioprinted Human Myometrial 3D Cell Rings as A Model for Uterine Contractility.

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