Next generation microfluidic organ on chip models for pancreatic cancer
Lead Research Organisation:
University of Leeds
Department Name: Physics and Astronomy
Abstract
This project will involve the design, fabrication and development of 'pancreas on chip' models for assessing therapeutics for pancreatic cancer. The models will take the form of cell culture, spheroids and multi-cellular tissues inside microfluidic devices. Microfluidic devices will be optimised to provide the most suitable physical microenvironment for the tissues in terms of fluid flow and pressures. In addition, the use of fresh ex-vivo tissue from patients for rapid and multi-drug screening could also be investigated.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509681/1 | 01/10/2016 | 30/09/2021 | |||
| 2090560 | Studentship | EP/N509681/1 | 01/10/2017 | 31/12/2021 | Delanyo Kpeglo |
| Description | This work aims to develop a humane in vitro culture model of pancreatic ductal adenocarcinoma (PDAC) with microfluidics for the therapeutic assessment of cultures with microbubbles. Key to the ineffective treatment of PDAC, is the pervasive growth of scar-like tissue or dense fibrotic tissue which constitutes to about 90% of the tumour volume, stiffens the tumour microenvironment and shields the cancer cells from therapeutics. The fibrotic tissue is from the production and accumulation of matrix proteins and cells i.e. collagen and hyaluronan, and fibroblast cells (culprits for the production of collagen and hyaluronan), and it induces growth-induced solid stress as the cancer cells proliferate. These together distorts and collapses blood vessels (given that the pancreas is a highly perfused organ) which are needed for the delivery of therapeutics to the cancer cells. Microfluidics, the control of fluids on a micron-scale, provides a versatile way of modelling and studying cells and tissues as observed in vivo, humanely in 3D. It enables the development of intricate microchannels that recapitulate the physical environment of cells and tissues. Using microfluidics, we aim to mimic the stress observed in vivo with the culture of the pancreatic cancer cells, Panc-1, and the main fibroblastic cells of the pancreas, pancreatic stellate cells (PSCs). We have fabricated a microfluidic device which confines the culture, and reflecting on the stress observed in vivo, we are looking at the flow velocity of medium with cell culture in the devices. Preliminary assessment with just the matrix gel, basement membrane gel extract, shows that flow velocity may be within what is reported in literature. Additionally, in mimicking the stiffness of the tumour microenvironment of PDAC (and as this characteristic is key to the malignancy of the disease), the Elastic Young's modulus of the microfluidic culture of Panc-1: PSCs will be measured. Preliminary assessment with the shear modulus assessment of the cultures, using rheology, shows that PSCs (as fibroblasts) are essential for the stiffness of the tumour microenvironment of PDAC. Moreover, culture stiffness is observed to further increase with TGF- ß1 supplement in the medium; TGF- ß1 has been reported to enhance the matrix production within the tumour microenvironment of cancers. Towards, therapeutic assessment of our microfluidic cultures, we aim to additionally assess the effects of anti-fibrotic drugs which have been reported to act via the TGF-ß1 signalling pathway. By knowing that the stiff tumour microenvironment is key to the effective delivery of therapeutics, with our microfluidic culture we aim to assess 1) the effect of anti-fibrotic drugs (to reduce the matrix and therefore culture stiffness); 2) the effects of the clinically used drug, Gemcitabine, and 3) microbubbles which will sensitise the cells to the effects of Gemcitabine after the matrix environment has been depleted. Microbubbles are gas filled spheres (1 - 8 µm) with specific acoustic properties shown to increase cell membrane permeability and enhance drug uptake, and this is trivial for the need of effective therapeutics for PDAC. |
| Exploitation Route | Mechanomedicine, which is the study of tissue mechanics and how the stiffness of tissues can be therapeutically targeted, is and emerging field, and therefore this study may provide the impetus for further studies into how the biomechanics of cancer tissues (particularly for PDAC) influences therapeutics to patients. It will help, clinically, in determining an approach as to how best to treat patients with PDAC. As with a stiff tissue, there is the accumulation of solid stress, low perfusion and elevated interstitial fluid pressure which will affect the perfusion of drugs to the cancer cells. |
| Sectors | Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Outreach talks to high school students on the use of microbubbles as therapeutic agents |