Configuration and protocol of the microcarrier-microbioreactor. Credit: Journal of Translational Medicine (2024). DOI: 10.1186/s12967-024-05373-7
A new approach to making cells that secrete and deliver therapies to specific parts of the body has taken a big step toward repairing joints and damage after heart attacks, combating transplant rejection and curing currently incurable lung diseases.
The cells, called mesenchymal stromal cells, can differentiate, like stem cells, into connective tissue cells in cartilage, bone, fat, and many organs. They can also be induced to secrete mRNA drugs naturally produced by the cells to induce repair, and then deliver that payload to needed areas using a sharpening mechanism similar to that of immune cells.
While these cell therapies promise to revolutionize the treatment of many diseases, research faces technological hurdles. Scientists do not yet fully understand the cellular properties needed to safely and effectively treat a disease, and it is difficult to develop a method to reliably increase the number of cells during manufacturing.
However, a study published in the Journal of Translational Medicine describes a system designed and tested at Cornell and the Massachusetts Institute of Technology that addresses these challenges.
“We don’t know how to increase the number of cells without unintentionally changing the attributes of the cells, so we need to understand what those attributes are supposed to be in the first place,” said Krystyn Van Vliet, vice president for research and innovation and professor of materials science in Cornell Engineering’s Meinig School of Biomedical Engineering and senior author of the paper.
“These two problems are linked; you have to measure what’s important, and then you have to maintain that measurement while you try to increase the cells to a good dosage,” she said.
The researchers, including first author Brandon Krupczak, a PhD student in Van Vliet’s lab, designed a “microcarrier-microbioreactor” platform that allowed them to control many variables (cell signaling characteristics, pH, temperature, gases) and create a high-quality environment for the cells. Early results suggest that this approach could prime these cells to produce more therapeutic proteins to treat diseases.
“We believe this microcarrier-microbioreactor approach does a much better job than the conventional gold standard, maintaining very tight control and regulatory conditions during the manufacturing process,” Krupczak said.
For the study, the researchers developed a microcarrier, a support structure made from a soluble gelatin that allows mesenchymal stromal cells to anchor and grow. These cells were placed in a microbioreactor made by the company that contains milliliter-sized culture vessels that the researchers had to modify for their purposes. The entire cell culture apparatus is about the size of a smartphone.
The study itself represents proof of principle for creating mesenchymal stromal cells that could potentially treat acute respiratory distress syndrome, a disorder that causes uncontrollable inflammation in the lungs and is the leading cause of death from COVID.
Using the microcarrier-microbioreactor platform, the team cultured stromal cells from three different donors, then repeated the experiment three times for cells from the same donor. They took several steps to ensure that their data were legitimate and reproducible across donors and within a single donor. They compared their results to the currently used flask technique, using polystyrene tissue culture flasks with culture medium to grow cells, which served as an experimental control.
To put things in context, Kupczak said, when the gene expression of cells under experimental conditions is three to five times higher than in the control, the results are generally considered a success.
“In some cases for this study, we had results up to 400 times higher in our experimental conditions compared to the vial control, which would indicate that there are 400 times more of our therapeutic particles floating around in our experimental conditions than in the vial control,” he said.
By making the environment more consistent through the microcarrier-microbioreactor process and measuring these variables, they found that the method provided high-quality control and primed the cells to start producing more proteins that are correlated with treating acute respiratory distress syndrome, although they did not test their effects in a mouse or human.
The study paves the way for using the new manufacturing process and quality controls to advance cell therapy production toward clinical application, the authors said.
Camille Farruggio, a materials scientist at MIT, is a co-author.
More information:
Brandon Krupczak et al., Fabrication of mesenchymal stromal cells in a microcarrier-microbioreactor platform can improve cell yield and quality attributes: A case study in acute respiratory distress syndrome, Journal of Translational Medicine (2024). DOI: 10.1186/s12967-024-05373-7
Provided by Cornell University
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