Tiny device could help improve safety, effectiveness of cell therapy for spinal cord injury patients

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A small device developed by scientists at MIT and the Singapore-MIT Alliance for Research and Technology could be used to improve the safety and efficacy of cell therapy treatments for patients with spinal cord injuries.

In cell therapy, doctors reprogram certain skin or blood cells taken from a patient known as induced pluripotent stem cells. To treat spinal cord injury, they will turn these pluripotent stem cells into progenitor cells, which are destined to differentiate into spinal cord cells. These progenitors are then transplanted back into the patient.

These new cells can regenerate the injured spinal cord. However, pluripotent stem cells that do not fully transform into progenitors can form tumors.

This research team developed a microfluidic cell sorter that can remove about half of the individual cells -; Those who may be a potential tumor -; in a batch, without damaging the fully formed progenitor cells.

The high-throughput device, which requires no special chemicals, can sort more than 3 million cells per minute. In addition, researchers have shown that multiple devices chained together can sort more than 500 million cells per minute, making it a more effective method to someday improve the safety of cell therapy treatments.

Also, the plastic chip that houses the microfluidic cell sorter can be mass-produced in a factory at very low cost, so the device will be easy to implement at scale.

“Even if you have a life-saving cell therapy that works wonders for patients, if you can’t make it cost-effectively, reliably and safely, its impact may be limited. Our team is passionate about that problem -; we want these therapies to make it more reliable and easily accessible,” said Jonghyun Han, MIT professor of electrical engineering and computer science and biological engineering, member of the Research Laboratory of Electronics (RLE) and co-principal investigator of CAMP. Singapore-MIT Alliance for Research and Technology (SMART) Research Group (Critical Analysis for Developing Personalized Medicine).

Co-senior author Sing Yan Chiu, a professor of chemistry, chemical engineering and biotechnology at the Lee Kong Chian School of Medicine and Materials Science and Engineering at Nanyang Technological University in Singapore and a CAMP principal investigator; Co-lead author Tan Dai Nguyen, a CAMP researcher; Wai Hon Chui, a Senior Research Fellow at the Singapore Agency for Science, Technology and Research (A*STAR); and Hyungkook Jeon, an MIT postdoc; as well as others at NTU and A*STAR. The research appears today Stem Cell Translational Medicine.

risk reduction

One of the most important challenges in this type of cell therapy is the risk of cancer caused by unintended induced pluripotent stem cells.

Even if you have a very small population of cells that are not fully differentiated, they can still turn into cancer-like cells.”


Jonghyun Han, MIT professor of electrical engineering and computer science and biological engineering

Doctors and researchers often try to identify and remove these cells by looking for specific markers on their surface, but until now researchers have not found a marker specific to these inviolable cells. Other methods use chemicals to selectively destroy these cells, yet chemical treatment techniques can be harmful to individual cells.

The high-throughput microfluidic sorter, which can sort cells based on size, was developed by the CAMP team after more than a decade of previous work. It has previously been used to select immune cells and mesenchymal stromal cells (another type of stem cell), and now the team is expanding its use to other stem cell types such as induced pluripotent stem cells, Hahn said.

“We are interested in regenerative strategies to enhance tissue repair after spinal cord injury, as these conditions lead to devastating functional impairment. Unfortunately, there are currently no effective regenerative treatments for spinal cord injury,” said Chew. “Spinal cord progenitor cells derived from pluripotent stem cells hold great promise, as they can generate all types of cells found in the spinal cord to restore tissue structure and function. To be able to use these cells effectively, the first step will be to ensure their safety, which we The goal of work.”

The team discovered that pluripotent stem cells tend to grow larger than the progenitors they are derived from. It is hypothesized that before a pluripotent stem cell differentiates, its nucleus contains a large number of genes that are not turned off or repressed. As it differentiates for a specific function, the cell suppresses many genes that are no longer needed, significantly shrinking the nucleus.

The microfluidic device uses this size difference to sort the cells.

Spiral Sort

The microfluidic channels on the quarter-sized plastic chip form an inlet, a spiral, and four outlets that output cells of different sizes. As the cells are forced through the spiral at very high speeds, various forces, including centrifugal forces, act on the cells. These forces prevent cells from focusing at a particular point in the fluid flow. This focusing point will depend on the size of the cell, effectively sorting through different outlets.

The researchers found that they could improve the Sorter’s activity by running it twice, first at a lower speed so that larger cells stick to the wall and sort the smaller cells, then at a higher speed to sort the larger cells.

In a sense, the device works like a centrifuge, but the microfluidic sorter doesn’t require human intervention to sort the selected cells, Hahn added.

The researchers showed that their device could remove about 50 percent of large cells with one pass. They tested and confirmed that the larger cells they removed were indeed associated with higher tumor risk.

“Even though we can’t remove 100 percent of these cells, we still believe it’s going to significantly reduce the risk. Hopefully, the original cell type is good enough that we don’t have too many different cells. Then this process can make these cells safer. ,” he said.

Importantly, the low-cost microfluidic sorter, which can be produced at scale with standard manufacturing techniques, does not use any form of filtration. Filters can become clogged or broken, so a filter-free device can be used for much longer.

Now that they’ve shown success on a small scale, researchers are starting larger studies and animal models to see if purified cells work better in vivo.

Undifferentiated cells can turn into tumors, but they can have other random effects on the body, so removing more of these cells can increase the effectiveness of cell therapy, as well as improve safety.

“If we can demonstrate these benefits convincingly in vivo, there may be more exciting applications for this technology in the future,” Hahn said.

This research was partially supported by the National Research Foundation of Singapore and the Singapore-MIT Alliance for Research and Technology.

Source:

Journal Reference:

Nguyen, TD, etc (2024) Label-free and high-throughput removal of residual undifferentiated cells from iPSC-derived spinal cord progenitor cells.. Stem Cell Translational Medicine. doi.org/10.1093/stcltm/szae002.



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