A 3D Bioprinter Specifically Designed for the High-Throughput Production of Matrix-Embedded Multicellular Spheroids

2020 ◽  
Author(s):  
Robert H. Utama ◽  
Lakmali Atapattu ◽  
Aidan P. O'Mahony ◽  
Christopher M. Fife ◽  
Jongho Baek ◽  
...  
Keyword(s):  
High Throughput ◽  
Multicellular Spheroids

scholarly journals Rapid formation of size-controllable multicellular spheroids via 3D acoustic tweezers

Lab on a Chip ◽  
2016 ◽  
Vol 16 (14) ◽  
pp. 2636-2643 ◽  
Author(s):  
Kejie Chen ◽  
Mengxi Wu ◽  
Feng Guo ◽  
Peng Li ◽  
Chung Yu Chan ◽  
...  
Keyword(s):  
High Throughput ◽  
Potential Field ◽  
Multicellular Spheroids ◽  
Rapid Formation ◽  
Acoustic Tweezers ◽  
High Throughput Manner

A 3D acoustic tweezers platform is developed to fabricate size-controllable multicellular spheroids in a rapid and high-throughput manner, utilizing the acoustic Gor'kov potential field and microstreaming.

scholarly journals Computational Modelling and Big Data Analysis of Flow and Drug Transport in Microfluidic Systems: A Spheroid-on-a-Chip Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Sina Kheiri ◽  
Eugenia Kumacheva ◽  
Edmond W.K. Young
Keyword(s):  
Parameter Space ◽  
Microfluidic Device ◽  
High Throughput ◽  
In Silico ◽  
Design Parameter ◽  
Drug Transport ◽  
Computational Modelling ◽  
Operating Conditions ◽  
Computational Time ◽  
Multicellular Spheroids

Microfluidic tumour spheroid-on-a-chip platforms enable control of spheroid size and their microenvironment and offer the capability of high-throughput drug screening, but drug supply to spheroids is a complex process that depends on a combination of mechanical, biochemical, and biophysical factors. To account for these coupled effects, many microfluidic device designs and operating conditions must be considered and optimized in a time- and labour-intensive trial-and-error process. Computational modelling facilitates a systematic exploration of a large design parameter space via in silico simulations, but the majority of in silico models apply only a small set of conditions or parametric levels. Novel approaches to computational modelling are needed to explore large parameter spaces and accelerate the optimization of spheroid-on-a-chip and other organ-on-a-chip designs. Here, we report an efficient computational approach for simulating fluid flow and transport of drugs in a high-throughput arrayed cancer spheroid-on-a-chip platform. Our strategy combines four key factors: i) governing physical equations; ii) parametric sweeping; iii) parallel computing; and iv) extensive dataset analysis, thereby enabling a complete “full-factorial” exploration of the design parameter space in combinatorial fashion. The simulations were conducted in a time-efficient manner without requiring massive computational time. As a case study, we simulated >15,000 microfluidic device designs and flow conditions for a representative multicellular spheroids-on-a-chip arrayed device, thus acquiring a single dataset consisting of ∼10 billion datapoints in ∼95 GBs. To validate our computational model, we performed physical experiments in a representative spheroid-on-a-chip device that showed excellent agreement between experimental and simulated data. This study offers a computational strategy to accelerate the optimization of microfluidic device designs and provide insight on the flow and drug transport in spheroid-on-a-chip and other biomicrofluidic platforms.

scholarly journals Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter

2020 ◽  
Author(s):  
Robert H. Utama ◽  
Lakmali Atapattu ◽  
Aidan P. O’Mahony ◽  
Christopher M. Fife ◽  
Jongho Baek ◽  
...  
Keyword(s):  
Cell Cultures ◽  
High Throughput ◽  
Cell Number ◽  
Drug Dose ◽  
3D Bioprinting ◽  
Multicellular Spheroids ◽  
Drop On Demand ◽  
3D Cell Cultures ◽  
The Impact

Abstract3D in vitro cancer models are important therapeutic and biological discovery tools, yet formation of multicellular spheroids in a throughput and highly controlled manner to achieve robust and statistically relevant data, remains challenging. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of high-throughput printing of 96-well plates of spheroids. 3D-multicellular spheroids are embedded inside a tissue-like matrix with precise control over size and cell number. Application of 3D bioprinting for high-throughput drug screening was demonstrated with doxorubicin. Measurements showed that IC50 values were sensitive to spheroid size, embedding and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust high-throughput platform to screen biological and therapeutic parameters.Significance StatementIn vitro 3D cell cultures serve as more realistic models, compared to 2D cell culture, for understanding diverse biology and for drug discovery. Preparing 3D cell cultures with defined parameters is challenging, with significant failure rates when embedding 3D multicellular spheroids into extracellular mimics. Here, we report a new 3D bioprinter we developed in conjunction with bioinks to allow 3D-multicellular spheroids to be produced in a high-throughput manner. High-throughput production of embedded multicellular spheroids allowed entire drug-dose responses to be performed in 96-well plate format with statistically relevant numbers of data points. We have deconvoluted important parameters in drug responses including the impact of spheroid size and embedding in an extracellular matrix mimic on IC50 values.

scholarly journals Actinomycin D downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma

2020 ◽  
Vol 22 (9) ◽  
pp. 1289-1301 ◽  
Author(s):  
Jessica T Taylor ◽  
Stuart Ellison ◽  
Alina Pandele ◽  
Shaun Wood ◽  
Erica Nathan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Population ◽  
High Throughput ◽  
Actinomycin D ◽  
Recurrent Glioblastoma ◽  
Stem Cell Population ◽  
Preclinical Models ◽  
Multicellular Spheroids

Abstract Background Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.

scholarly journals High-throughput acoustofluidic fabrication of tumor spheroids

Lab on a Chip ◽  
2019 ◽  
Vol 19 (10) ◽  
pp. 1755-1763 ◽  
Author(s):  
Bin Chen ◽  
Yue Wu ◽  
Zheng Ao ◽  
Hongwei Cai ◽  
Asael Nunez ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Response ◽  
Three Dimensional ◽  
3D Culture ◽  
Multicellular Spheroids ◽  
Tumor Spheroids

Three-dimensional (3D) culture of multicellular spheroids, offering a desirable biomimetic microenvironment, is appropriate for recapitulating tissue cellular adhesive complexity and revealing a more realistic drug response.

Hydrogel Thin Film with Swelling-Induced Wrinkling Patterns for High-Throughput Generation of Multicellular Spheroids

2014 ◽  
Vol 15 (9) ◽  
pp. 3306-3312 ◽  
Author(s):  
Ziqi Zhao ◽  
Jianjun Gu ◽  
Yening Zhao ◽  
Ying Guan ◽  
X. X. Zhu ◽  
...  
Keyword(s):  
Thin Film ◽  
High Throughput ◽  
Multicellular Spheroids

scholarly journals A 3D Bioprinter Specifically Designed for the High-Throughput Production of Matrix-Embedded Multicellular Spheroids

iScience ◽  
2020 ◽  
Vol 23 (10) ◽  
pp. 101621
Author(s):  
Robert H. Utama ◽  
Lakmali Atapattu ◽  
Aidan P. O'Mahony ◽  
Christopher M. Fife ◽  
Jongho Baek ◽  
...  
Keyword(s):  
High Throughput ◽  
Multicellular Spheroids
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