UK researchers have uncovered a cell signaling phenomenon that they admittedly don't understand, but have extrapolated that it could have implications for the use of nanomaterials as well as some of the metals currently used in artificial joints. In short, they've discovered that nanoparticles can damage the DNA of cells without crossing cellular barriers in the body.

"To our great surprise, not only could we see damage on the other side of the barrier, but we saw as much damage as if we had no barrier at all and put materials in direct contact with the cells underneath," said Patrick Case, MD, consultant senior lecturer in Orthopaedic Surgery and Pathology, Bristol Implant Research Centre, Southmead Hospital (Bristol, UK). "We don't understand it at all. Some sort of signal is going on from the top cell to middle and bottom cells. At the bottom, that cell is then responding and sending out some message and causing this DNA damage without significant cell death to the cells beneath."

Case and his colleagues set up an experiment to address the growing concerns about nanoparticles' ability to infiltrate past barriers. But they discovered that those particles don't actually have to go through a barrier to inflict damage. They used ultra-high concentrations of metals on cells grown in culture, those typically used in orthopedic implants.

But in addition to raising concerns over nanomaterials' abilities to cross barriers – or in this case affect cells without crossing – their discovery opens a Pandora's box of opportunities to deliver novel therapies across barriers without having to cross them. Medication could exert influence without having to cross something like the blood brain barrier.

"We were not trying to make a model of the human body. And we're not trying to say this is going to happen in a human body," Case said during a press conference in London on Thursday. "We've just asked a question: Is the barrier a barrier? Our basic message is that there is something strange going on. There is this signaling process that's jolly exciting across a barrier."

Case's team grew a multi-layer of human cells in the lab to mimic a specialized protective barrier which was used to study the indirect effects of cobalt-chromium nanoparticles – which are typically generated from wear and tear of bone implants – on the cells that were lying behind this barrier.

"Here, we show that cobalt-chromium nanoparticles (29.5±6.3 nm in diameter) can damage human fibroblast cells across an intact cellular barrier without having to cross the barrier," Case and team wrote in a Nature Nanotechnology article.

Another co-author of the study, Gevdeep Bhabra, MD, also of the University of Bristol, explained how the experiment worked. "We measured DNA damage after exposure to the alloy particles," Bhabra said. "We looked at levels of damage after indirect exposure and direct exposure and found the levels of damage are comparable. One of the obvious questions: Is the metal passing through the barrier? We measured levels of metal and found there was no increase. So we don't think metal was passing through the cells. We also found the barrier didn't become more leaky. We know that cells in close contact, like in the barrier, exhibit cell communication. We used a variety of compounds to block it. We found that DNA damage does occur through indirect exposure to cobalt-chromium and this is dependent on intercellular signaling rather than the passage of metal through the barrier."

To lend some perspective to the findings, Case pointed out that "we all have DNA damage, but it's not necessarily significant."

The team concluded by suggesting that, going forward, as scientists evaluate nanoparticle safety, they should not be focused entirely on whether or not nanoparticles penetrate, but rather the "genotoxic potential for both direct and indirect effects to avoid any potential risks to targets on the distal side of cellular barriers," they wrote.

To get the most comprehensive assessment of the burgeoning nanotechnology market, with focused emphasis on the most promising subsector: medical technologies, check out the Medical Device Daily Nanotechnology R&D Report 2009. For more information, call 800-688-2421 or visit ww.medicaldevicedaily.com.

Lynn Yoffee, 770-361-4789;
lynn.yoffee@ahcmedia.com