A novel method for finding and delivering healing drugs to newly formed microcracks in bones has been invented by a team of chemists and bioengineers at Penn State and Boston University. The method involves the targeted delivery of the drugs, directly to the cracks, on the backs of tiny self-powered nanoparticles.
The energy that revs the motors of the nanoparticles and sends them rushing toward the crack comes from a surprising source -- the crack itself.
This research-microscope image shows the increasing density at the bone-crack site during a 40-minute test of particles carrying the bone-healing medication. The particles were treated with a red-glowing fluorescent dye. Image: Sen laboratory, Penn State University
"When a crack occurs in a bone, it disrupts the minerals in the bone, which leach out as charged particles -- as ions -- that create an electric field, which pulls the negatively charged nanoparticles toward the crack," said Penn State professor of chemistry Ayusman Sen, a co-leader of the research team. "Our experiments have shown that a biocompatible particle can quickly and naturally deliver an osteoporosis drug directly to a newly cracked bone."
Sen said that the formation of this kind of an electric field is a well-known phenomenon, but other scientists previously had not used it as both a power source and a homing beacon to actively deliver bone-healing medications to the sites most at risk for fracture or active deterioration. "It is a novel way to detect cracks and deliver medicines to them," said team co-leader and Boston University professor Mark Grinstaff.
The method is more-energetic and more-targeted than current methods, in which medications ride passively on the circulating bloodstream, where they may or may not arrive at microcracks in a high-enough dosage to initiate healing. The new method holds the promise of treating -- as soon as they form -- the microcracks that lead to broken bones in patients with osteoporosis and other medical conditions.
To find a way to heal microcracks before they grow into breaks, Sen and his graduate student Vinita Yadav teamed their chemistry lab up with Grinstaff's chemistry/biomedical-engineering lab. The scientists then did a series of experiments in each of their labs. A scientific paper that describes these experiments is published this month in the international chemistry journal Angewandte Chemie.
Sen and Yadav's first series of experiments tested their novel way to deliver medicines in a model system using bone from a human tibia and femur, and very small fluorescent particles called quantum dots made from a synthetic material. Sen said, "We added fluorescence to these particles because fluorescence makes them so easy to see under a microscope." This first series of tests showed that negatively charged quantum dots did, indeed, move toward and pile up on a newly formed crack.
The scientists next tested their system using a natural biological material -- a protein molecule -- to see if it would perform on human bone as well as the synthetic quantum dots behaved. The results of these tests were encouraging. So the team led by Sen and Grinstaff set the bar even higher, doing their next set of experiments with nanomotors made from both a biological material and a synthetic material. They wanted to see if they could attach the biological material -- a drug used to treat osteoporosis -- onto a synthetic material that could carry it, like a nanotruck, to a crack in a human bone. The synthetic material the scientists selected to carry the osteoporosis drug (polylactic-co-glycolic acid) has been approved by the Federal Drug Administration and is in wide use in medical devices. The goal of this set of experiments was to make a self-powered nanotruck that could carry the osteoporosis drug (sodium alendronate) and would have a good chance of being safe for use inside the human body.
Like the nanoparticles in the previous tests, the FDA-approved nanotruck material had a little fluorescent molecule attached to it so its movements could be seen under a microscope. "Our experiments show that this bio-safe nanomotor can, in fact, successfully carry the osteoporosis drug to a fresh crack in a human bone," Sen said. He explained that, even when these nanomotors were loaded with millions of molecules of their bone-healing cargo, each one still was 30 to 40 times smaller than a red blood cell.
In a final set of experiments, done in the Grinstaff lab at Boston University, graduate student Jonathan Freedman tested the same osteoporosis drug on live human bone cells. "The treated bone cells increased in number as compared with those that were not treated with the osteoporosis drug, which confirms other studies that have shown that this drug is effective in repairing human bones," Grinstaff said.
"What makes our nanomotors different is that they can actively and naturally deliver medications to a targeted area," Sen said. "Current methods, in contrast, involve taking a drug and hoping that enough of it gets to where it is needed for healing." Now that this nanomotor-powered medication-delivery system has gotten a start, it will need many more tests and much further development before it may be proven safe and effective for preventing broken bones in patients with conditions like osteoporosis.
The research was supported by the Penn State Center for Nanoscale Science with funding from the National Science Foundation, the Penn State Materials Research Institute Nanofabrication Laboratory, the National Science Foundation, Boston University and a T32 Pharmacology Training grant.