09 Feb 2021   |   Network Updates   |   Update from Politecnico di Milano
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Politecnico di Milano: ERC-funded project to develop bioreactor which could reduce failures rates of drug testing


New drugs typically cost from EUR 1 billion for chemical drugs, up to several billion for biodrugs. The response to the covid-19 pandemic has produced authorizations in a few months for the marketing of new vaccines in a state of emergency, but usually the process can take 10 years for traditional drugs, and up to 20 years for biodrugs. In fact, regulatory approval must be sought following trials first in cell cultures, then on animals and finally on humans.

It is a complex and expensive process, as Prof. Mauela Raimondi of the Department of Chemicals, Materials and Chemical Engineering "Giulio Natta" of the Politecnico di Milano explains:

"The failure rate of pre-clinical stages can reach 96 %, as testing drugs in cell monolayers provides indications of their effectiveness that are almost never confirmed in animals"

Thus, the idea of the project: to develop a bioreactor, a cell culture device called MOAB, combined with novel scaffolds (nichoids), to perform drug tests on mini tissues in vitro, more realistic than cell monolayers. Both inventions have been patented for international use.

These mini-models of living tissue reproduced a cell response to drugs, such as chemotherapy agents and gene-modified stem cells, similar to animal models. Our design demonstrates the suitability of these models as a pre-screening to reduce, refine and partly replace animal models, adds Raimondi.

The European Research Council's support enabled the team to engage a business developer, and after attracting an investor, MOAB srl was established to commercialise the MOAB-nichoid device. Over ten customers have been identified in Europe and the United States.

HOW MOAB AND NICHOID WORK TOGETHER

In many diseases such as cancer, in vivo responses to drugs are the result of dynamic and complex interactions amongst three-dimensional configurations of several cell populations. Monolayer cell cultures conventionally used for in vitro drug testing cannot replicate those complex interactions.

The MOAB bioreactor consists of three miniature culture chambers. Each can host 3D organoids, which are tissue models made up of living cells, a few millimetres in size and perfused with a nourishing culture medium. The team integrated a 3D nano-patterned microscopic grid for stem cell culture, called the "nichoid", into the MOAB.

The nichoid was fabricated in collaboration with the colleagues of Politecnico's Department of Physics and CNR, using two-photon laser polymerisation: a pulsed laser is focused on a nanometre-sized spot of liquid polymer to induce polymerisation. The beam is then manipulated to form the geometry of the microgrid on top of a glass coverslip.

The nichoid increases the adhesion and expression of stemness of stem cells in a way reminiscent of their natural physiological environment.

The nichoid-patterned coverslip is then glued to the body of the MOAB bioreactor to create the "MOAB-nichoid" cell culture device. The device, which can host several million cells, is inspectable to fluorescence microscopy for real-time study of cultured mini tissues.

With the culture medium in direct contact with living cells, its flow had to be precisely calibrated to avoid cell damage.

THE FUTURE OF DRUG TESTING

MOAB srl is now creating a cell model to test the potential tumorigenicity of a new therapy of gene-edited haematopoietic stem cells, to cure blood-related monogenic diseases such as sickle cell anaemia and haemophilia.

In the therapy, haematopoietic stem cells are collected from patients, then edited to correct mutation, before being reinfused back into the patients.

"The MOAB-nichoid will provide an innovative in vitro testing platform, able to verify the safety of gene-edited haematopoietic stem cells. The method could also partially replace animal testing.", explains Prof. Raimondi.

Inputs from regulatory bodies such as the European Medicines Agency will now help standardise the MOAB-nichoid for new in vitro drug testing.

This article was first published on 5 February by Politecnico di Milano.

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