W.Y. Tong, Tommy Tong, Donna Menzies, Nico Voelcker*

 

381 Royal Parade, Monash Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, Victoria 3052, Australia

 

Introduction: 2,000 new brain cancers are diagnosed each year [1]. Glioblastoma Multiforme (GBM) is the deadliest form of cancer, with only a 5% survival rate after 5 years of initial diagnosis [2]. The mortality rate remains the same for the past few decades [1, 3], highlighting the lack of breakthroughs. Indeed, treatment development for brain disorders has been stagnant owing to the lack of knowledge in disease mechanisms, biomarkers, and importantly, the absence of predictive models that faithfully represents the pathological characteristics of the disease in the brain [3, 4]. Current In vitro and In vivo models have proven to inadequately represent the disease which depends on the molecular interplays between the tumour, brain and the blood–brain barrier (BBB).

Aim: We aim to develop a brain organoid on-a-chip for to generate a highly predictive and robust drug and treatment strategy discovery platform, composed of a microfluidic system incorporating a BBB, and the organoid, cultured from human brain cells and tumour cells.

Method: The microfluidic chip is fabricated via photolithography. Microfluidic channels was patterned as shown in Fig 1A. Polydimethysiloxane microchannels was bonded to coverslip to enable live-cell imaging. Cerebral endothelial cells (hCMEC/D3) were injected into channel 2. Constant flow was initiated over hCMEC/D3, and TEER was measured. U87 GBM cells were mixed with human astrocytes 1:1 in matrigel (Fig 1D), and was injected into channel 1. Doxorubicin was used as the model drug and infused via channel 2. The microfluidic chips were imaged under multiphoton confocal microscopy for migration study, and under IVIS for viability study. Results: We observed that GBM cultured in an organoid that resembles the native microenvironment in vivo, displayed the expected signatures such as elevated chemoresistance (Fig 2A, B), necrotic core, and diffuse infiltration (Fig2C). Permeability of the BBB in the chip that co-cultured with brain cells was also observed to be higher than those in monoculture (Fig 2D). Discussion: Brain organoid composed of a co-cultured “brain tumour” connected to a “BBB” within a microfluidic chip was developed.  The tumour displayed pathologically relevant signatures of brain parenchyma. We envisage that this model will aid drug delivery design, strategy and prognosis for brain cancer. While this research focuses on brain cancer, the predictive model developed here will benefit the treatment discovery of all brain disorders which affects 4% of total population.

[1] Australian Cancer Incidence and Mortality (ACIM) Books, Brain cancer for Australia (ICD10 C71).

[2] M.M. Mrugala, Discov Med 15(83) (2013) 221-30.

[3] D.E. Pankevich, S.E. Hyman, et al. Neuron 84(3) (2014) 546-53.

[4] P.C. Huszthy, R. Bjerkvig, et al. Neuro Oncol 14(8) (2012) 979-93.

 

Biographic Details

Name: Wing Yin Tong           

Title: Dr

Affiliation: Monash Institute of Pharmaceutical Sciences (MIPS), Monash University

Country: Australia

Phone: 0420822106; E-mail: wingyin.tong@monash.edu

Research interests: Organoid, Nanoparticles, Drug delivery, Stem cell, Microfluidics

Venue

Room: 
Hawken N202