Hypoxia-on-chip : from technological developments to biological applications
Bibliographic record
Abstract
In vivo tumor cells experience low oxygen levels (15mmHg ( for lung cancer), called“hypoxia”, as compared to “physioxia” seen in healthy tissue (40mmHg ( for lung). Thishypoxic environment is mainly due to the fast proliferation rate of tumor cells along with the creation of abnormal vasculature. Hypoxia promotes malignant progression and reduces drug efficiency. Tumor on chip are promising models to reca pitulate in vitro the 3D architecture and the physiology of human solid tumor, such as cell cell and cell matrix interactions as well as biochemical gradients of drugs and nutrients. It is not yet possible to experimentally reproduce in vitro physio pathological hypoxia because the most adopted technology hypoxic incubator come with two major drawbacks: the lack of measurement of the oxygen level in the medium and the long equilibratio n time . At the beginning of my thesis , there we re no commercial systems capable to reproduce gradients of oxygen and pH inside microfluidic systems, mimicking not only global hypoxia, but also the fluctuations of local oxygen concentration due to angiogene sis and vessel leakages. I developed OXALIS (Oxygen ALImentation System), a new system to control the dissolved oxygen level in cell culture medium while perfusing a microfluidic chip withunprecedented performance in terms of response time (200sec), accur acy (2mmHg) and liquid flow control accuracy (0.1µL/min) min).To ensure proper oxygen control, microfluidic chips must be made of materials with lowoxygen permeability. Thermoplastics like cyclic olefin copolymer possess permeabilityapproximately 1,000 tim es lower than polydimethylsiloxane but retain oxygen due to their high oxygen solubility. Therefore, glass is the best material for hermetic chips, but its production necessitates clean rooms and specialized equipment. I worked on a cost effective chip fabrication procedure that eliminates the need for clean rooms, involving the assembly of glass slides using an adhesive layer. A comparative analysis of different adhesives was conducted to determine the adhesive with optimal properties for oxygen control, m inimizing the response time required to reach the desired oxygen levels and ensuring long term maintenance of the target oxygen concentrations. These findings demonstrate the feasibility of constructing a microfluidic chip that achieves optimal oxygen cont rol performance similar to that of glass .I then applied these technological developments to the biological question of hypoxiainduced drug resistance. I first demonstrated the capacity of OXALIS to recapitulate on chip the oxygen dependent transcriptomic modulations : the expression of the CA9 gene, a well established hypoxia inducible factors (HIF) target robustly increased after 1h of perfusion with OXALIS at 15mmHg (2 % O 2 )). Hypoxia can lead to various alterations in cell b ehaviour, including abnormal fusion of mitochondria, which may contribute to drug resistance. Despite the significance of these mitochondrial changes, comprehensive studies on real time mitochondrial phenotypes, particularly at the cellular population leve l, are lacking. This limitation is primarily due to the technical difficulties in combining live imaging and oxygen control in cell culture. Using two populations of A549 lung cancer cells, one resistant and one sensitive to paclitaxel, we performed continuous monitoring of mitochondrial shape under tightly controlled hypoxic conditions.By developing an innovative oxygen controller for tumoron chip models, I have successfully overcome technological barriers related to precision and response time. I exp lored novel biological inquiries, such as the evolution of mitochondrial morphology over time in response to varying oxygen concentrations and its correlation with resistance to anti cancer treatments.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".