Regenerative medicine technology targets cause of low back pain
Most adults have experienced low back pain, at least temporarily. But for some, the pain is constant and debilitating.
In addition to its effects on quality of life, chronic low back pain exerts a significant socioeconomic burden, primarily through lost work days and treatment costs. As many of its sufferers try to manage the pain with prescription drugs, it also has contributed to the growing opioid crisis, which is now a national research priority.
Biomedical Engineering Professors Devina Purmessur and Natalia Higuita-Castro lead an interdisciplinary team at The Ohio State University focused on an underlying cause of the pain, intervertebral disc (IVD) degeneration.
They recently earned a five-year, $2.5 million National Institutes of Health (NIH) R01 award to advance their research and development of novel minimally invasive and non-addictive therapies for low back pain.
According to Purmessur, director of the Spinal Therapeutics Lab and faculty member of the Spine Research Institute, most current surgical and non-surgical treatments focus on alleviating the pain. “The problem with focusing on just the pain, is that it doesn’t fix the disease,” she explained. “You’re just treating the symptoms.”
Therefore the optimal therapy would target both structural restoration and pain reduction. For some time, Purmessur has questioned if diseased and deteriorating IVD cells could be coaxed to revert their phenotype—the cell’s observable characteristics—back to original function and health. An opportunity to explore further came in 2018 when she learned about another Ohio State biomedical engineering team’s breakthrough—tissue nanotransfection (TNT)—that can convert skin cells into blood vessels and nerve cells.
“It started with a conversation with Natalia and Daniel (Gallego-Perez) about their work,” she said. “If they can take a cell and differentiate it into a completely different cell type, can we take a diseased cell and reverse it back to its healthy state through tissue engineering?”
Higuita-Castro believes they can. Their proposal employs a multi-disciplinary approach to determine the effects of non-viral delivery of developmental proteins – specifically transcription factors – to reprogram diseased IVD cells. It could potentially revolutionize spine surgery by providing clinicians with the ability to deliver a minimally invasive and non-addictive treatment of the underlying disease mechanisms in the operating room.
“Our delivery system is unique,” Higuita-Castro said. “We are using extracellular vesicles (EVs) we have engineered as nanocarriers to selectively deliver a cocktail of reprogramming factors to the diseased cells in the painful disc joint.” Extracellular vesicles contain various biomolecules including DNAs, RNAs, proteins, and metabolites, and play a pivotal role in cell-to-cell communication.
Their cell reprogramming concept has been proven in the lab and has led to two peer-reviewed publications, the first in the July 9, 2019 issue of the Journal of Orthopaedic Research and then in the January 2021 issue of European Cells & Materials. Biomedical engineering PhD candidates Nina (Shirley) Tang and Ana Salazar-Puerta performed the experimental work overseen by Purmessur and Higuita-Castro. The NIH-funded R01 project will build on a previous NIH R61 award and serve to further validate the technology and quantify the effects of non-viral delivery of transcription factors. The investigators have recently demonstrated the beneficial and synergistic effects of “combining” multiple transcription factors as well as decorating the vesicles with guidance cues to “home” or target the therapy to a particular cell to limit off-target effects. The team have used engineered vesicles in controlled lab experiments with human patient-derived cells, and also in rodent back pain models evaluating the animals’ spinal function and pain behavior.
Since the intervertebral disc does not have a blood supply, traditional cell-based regenerative medicine techniques such as stem cell injection have encountered roadblocks in the spine. Purmessur explained that their approach is not introducing any other cell type into the body or removing cells to treat and reintroduce later.
“Whether during a back surgery or through minimally invasive techniques, the factors can be delivered to the cells where they are, giving them a kickstart to help the cells make healthy proteins and rebuild their extracellular matrix,” she said.
According to Higuita-Castro, another major advantage over other biological delivery systems, like viruses, is that the extracellular vesicles are naturally-derived, which minimizes inflammatory immune system response.
Co-investigators on this grant include Ohio State Spine Surgeon Safdar Khan, Biomedical Engineering Assistant Professor Benjamin Walter, Neuroscience Assistant Professor Olga Kokiko-Cochran and Biostatistician Brett Klamer.