Source: Newcastle University
Source: Newcastle University

Researchers at Newcastle University report a significant advance in the continuous production and collection of cells. The process removes the limit on the number of cells that can be grown in a culture dish, which previously was determined by its surface area, according to the scientists.

The study (“Developing a Continuous Bioprocessing Approach to Stromal Cell Manufacture”), published in ACS Applied Materials & Interfaces, describes how the team developed a coating that allows individual stromal cells to “peel away” from the surface on which they are grown. This results in more space so that additional cells can continuously grow in their place. The process works across a range of stromal cells, including mesenchymal stem cells (MSCs).

“To this day, the concept of continuous bioprocessing has been applied mostly to the manufacture of molecular biologics such as proteins, growth factors, and secondary metabolites with biopharmaceutical uses. The present work now sets to explore the potential application of continuous bioprocess methods to source large numbers of human adherent cells with potential therapeutic value,” write the investigators. 

“To this purpose, we developed a smart multifunctional surface coating capable of controlling the attachment, proliferation, and subsequent self-detachment of human corneal stromal cells. This system allowed the maintenance of cell cultures under steady-state growth conditions, where self-detaching cells were continuously replenished by the proliferation of those remaining attached. This facilitated a closed, continuous bioprocessing platform with recovery of approximately 1% of the total adherent cells per hour, a yield rate that was maintained for 1 month. Moreover, both attached and self-detached cells were shown to retain their original phenotype. Together, these results represent the proof-of-concept for a new high-throughput, high-standard, and low-cost biomanufacturing strategy with multiple potentials and important downstream applications.”

“This allows us to move away from the batch production of cells to an unremitting process. Remarkably, with this continuous production technique even a culture surface the size of a penny can, over a period of time, generate the same number of cells as a much larger-sized flask,” says Che Connon, Ph.D., professor of tissue engineering. “This concept also represents an important innovation for cell-based therapies, where treatments can require up to a billion cells per patient. With our new technology, one square meter would produce enough cells to treat 4000 patients, while traditional methods would require an area equivalent to a football pitch.”

The technique also offers complete control over the rate of cell production, so it could be scaled up using existing stacked culture flasks to produce one billion cells per week, or scaled down so as to fit a bioreactor “on the head of a pin,” he adds.

Cells are usually grown in the lab over the surface area of a flask and then detached chemically or enzymatically for use. The cells are created in batches, with batch size limited to the area upon which the cells are grown. This limitation is a well-recognized bottleneck in therapeutic cell manufacture. 

The team’s study addresses this challenge, describing a special “peptide amphiphile” coating that allows adherent cells to reach a steady balance between growth and detachment. The self-detaching cells are then produced in a continuous bioprocess and available for use in a variety of downstream applications without losing their original characteristics. The potential reduced size of a continuous cell bioprocess has obvious advantages in terms of lower production costs and increased coverage and application. 

There are a number of cell-based therapies in later-stage development, and it is estimated that 10 million patients could potentially benefit from cardiac cell therapy each year. However, the traditional approach would require an area equivalent to that of Central London and Midtown Manhattan running simultaneously to produce enough, says Dr. Connon.

According to Martina Miotto, a Ph.D. student from the Institute of Genetic Medicine, “The concept of a continuous bioprocess is currently used to produce biopharmaceuticals such as vaccines and anticancer antibodies, but never before for cells. There is a fantastically high number of patients in need of cell therapy, such as those suffering from heart-, cartilage-, skin-, and cancer-related diseases. Our new technology provides a much-needed solution while saving costs, reducing materials, and improving the quality and the standardization of the final product.”