High content screening of 3D cell culture environments for biopharmaceutical discovery

Project description

3D cell cultures grow greater numbers of higher-quality cells with lower costs than the traditional liquid suspension or 2D cultures used in biopharmaceutical industries. However, biopharma’s adoption of 3D cell culture remains limited due to current dependence on high content screening (HCS) for high-throughput 2D culture optimisation or drug screening. Our collaborative team has engineered high-throughput microchip platforms where single-cells can be live-imaged to track stem cell expansion in 3D hydrogels, creating the first 3D HSC platforms. We aim to establish a robust microchip 3D culture platform and computer software for biopharmaceutical industry adoption.

Aims:
1.Design and fabricate ultra-thin, scalable microfluidic chips for imaging and automation-friendly 3D cell culture, surpassing the limitations of 2D cell culture models.
2.Construct biophysical models of the 3D culture environment to screen the effects of the hydrogel in the culture microenvironment and optimize performance.
3.Validate the new combined HCS platform by conducting rigorous tests on our microchips across cell types and environments, ensuring industry-standard compatibility and reliability for drug testing.

Methodology:
1. Microchips will be fabricated at UQ and injected with hydrogels of different consistency, with or without adherent and suspension cell lines, with or without fluorescent reporters, at different densities. We will evaluate the microchip’s ability to (1) fully incorporate the hydrogel, (2) image all cells, and (3) be amendable to automation during culture.
2.A biophysical model of cell migration and growth within varied hydrogel architectures will be developed at IIT Delhi. The model will integrate the local cell-hydrogel-soluble factor interactions and predict optimal culture designs to be validated experimentally using analysis of the imaged data.
3.Hydrogel microchips and software will be deployed for continuous imaging of varied cell culture and soluble factor (drug) screening experiments with selected end-user platforms and requirements, as compared with existing 2D cultures.

Outcomes

Here we assume a 3.5y PhD. Many of the below milestones will continue to be developed after their completion date, for instance, the proof-of-concept microchip [Year 1] may be refined from HCS outcomes [Year 2].

[Year 1] Custom microfluidic chips designed, manufactured, and validated in 3D cell culture experiments.
[Year 1] Thesis Chapter 1 – Literature Review for Confirmation Report.
[Year 1] Thesis Chapter 2 and Publication – Completion of a Proof-Of-Concept HCS Microchip.
[Year 1] UQ PhD Confirmation.
[Year 2] Preliminary Image Analysis and Biophysics Models Established and Validation Under-Way.
[Year 2] Thesis Chapter 3 and Publication – Completion of a Computational Screening Software.
[Year 2] UQ Mid-Stage Review.
[Year 3] Biophysics Model trained, and Validation Experiments Completed.
[Year 3] Thesis Chapter 4 and Publication – Platform Validation for a Variety of End-User Needs.
[Year 3] Thesis Chapter 5 and Publication – Packaged Platform and Software for End-User Implementation.
[Year 3] UQ Late-Stage Review.
[Year 3.5] Thesis Chapter 6 – Discussion and Outcomes.
[Year 3.5] Thesis Submission.

Essential capabilities

Background in engineering, mathematics, physics, or computer science, showcasing taught experience in experimental sciences and mathematics or computer programming.

Desireable capabilities

Prior experience in human cell culture and 3D biomaterial cell culture, prior experience in computational modelling and image analysis in Python or a similar language.

Expected qualifications (Course/Degrees etc.)

At least a Bachelors degree with Honors in an aligned field such as biomedical engineering, chemical engineering, mechanical engineering, electrical engineering, mathematics, physics, or computer science.