University of Connecticut bioengineers have used piezoelectric biodegradable nanofiber tissue scaffold technology to successfully regrow cartilage directly in a rabbit’s knee, an achievement that could represent a promising hop toward healing joints and treating disorders such as osteoarthritis, in humans.

The team, headed by UConn bioengineer Thanh Nguyen, PhD, implanted a biodegradable piezoelectric poly(L-lactic acid) (PLLA) nanofiber tissue scaffold into the knee of rabbits with major cartilage defects. The polymer effectively acts as a battery-less electrical stimulator, which generates a tiny burst of electric current when subjected to force—for example, when the rabbit walked or hopped. This charge promoted cell colonization and growth into the cartilage of the test animals. Encouragingly, rabbits treated using the piezoelectric scaffold implant in combination with 1–2 months of treadmill exercise demonstrated completely healed cartilage.

A rabbit hops along a treadmill, stimulating a piezoelectric charge in its bioengineered knee. The charge encourages the regrowth of fresh, mechanically robust cartilage, making the knee as strong and functional as it was before it was injured. [Thanh Nguyen/University of Connecticut and UConn Health]

The results are exciting, although the researchers are cautious. “This is a fascinating result, but we need to test this in a larger animal,” one with a size and weight closer to a human, Nguyen said. The UConn team reported on its studies in Science Translational Medicine, in a paper titled “Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits,” in which they concluded: “The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.”

Arthritis is a common, painful disease caused by damage to the joints. Normally pads of cartilage cushion those spots, but injury or age can wear it away. As cartilage deteriorates, bone begins to hit bone, and everyday activities like walking become painful. Osteoarthritis (OA) is among the leading causes of pain and disability in the United States, affecting more than 32.5 million individuals, the authors noted.

The best treatments available try to replace the damaged cartilage with a healthy piece taken from elsewhere in the body or a donor. But healthy cartilage is in limited supply. If it’s the patient’s own, transplanting it could injure the place it was taken from; if it’s from someone else, the recipient’s immune system is likely to reject it. “Despite many advantages, replacement autografts and allografts have some disadvantages, including donor site morbidity (such as pain and scarring), infection, immune reactions (such as allograft response), and limited supplies of graft tissue,” the investigators commented.

The best possible treatment would be to regrow healthy cartilage in the damaged joint itself. Some researchers have tried amplifying chemical growth factors to induce the body to grow cartilage on its own; other attempts rely on a bioengineered scaffold to give the body a template for the fresh tissue. But neither of these approaches works, even in combination. The widespread use of synthetic scaffolds is limited, the investigators noted, due to the inefficiency of generating hyaline cartilage after implantation. Such grafts often fail to become load bearing in normal cartilage tissues. “The regrown cartilage doesn’t behave like native cartilage. It breaks, under the normal stresses of the joint”, said Nguyen. “It is therefore necessary to seek a different approach that can effectively stimulate and accelerate cartilage growth,” the authors added.

Nguyen’s lab has also been working on cartilage regeneration, and they’ve discovered that electrical signals are key to normal growth. Cartilage is sensitive to electrical stimulation (ES), the team pointed out, but current devices used for ES have limitations. For their reported study, the scientists designed a tissue scaffold made out of nanofibers of PLLA, a biodegradable polymer often used to stitch up surgical wounds. The nanomaterial demonstrates piezoelectricity, which means that when it is squeezed, it produces a small burst of electrical current. The regular movement of a joint, such as a person walking, can cause the PLLA scaffold to generate a weak but steady electrical field that encourages cells to colonize it and grow into cartilage. No outside growth factors or stem cells (which are potentially toxic or risk undesired adverse events) are necessary, and crucially, the cartilage that grows is mechanically robust.

Nguyen’s team wanted to see whether this property of PLLA could be applied directly to help repair damaged joints. “We hypothesized that a piezoelectric scaffold under applied force (from the exercise-induced joint motion) could produce surface charge that may be beneficial to the chondrogenesis of stem cells and to cartilage regeneration,” they wrote.

To test their hypothesis they implanted a PLLA tissue scaffold in the knee of injured rabbits with osteochondral (OC) defects. The rabbits had been trained to use a treadmill before their scaffold implant surgery. After implantation surgery the animals were given a month’s rest, and then started on a regular exercise regimen on the treadmill. Regenerative outcomes were evaluated after one and two months of exercise, so two and three months after implantation surgery, taking into account the month’s rest. Encouragingly, and just as predicted, the results confirmed that the cartilage grew back normally in those animals receiving the implants and undertaking the exercise regimen. “Compared to the sham and control groups, the piezo scaffold and exercise group with one month of exercise showed the most regeneration, with an entire OC defect filled with neocartilage tissues and a healthy hyaline cartilage structure similar to surrounding native cartilage,” the team wrote. “Similar results were found in the piezoelectric scaffold and exercise group with two-month exercise.”

Acknowledging limitations of their study, the authors concluded, “The current work provides proof of concept that a biodegradable piezoelectric PLLA scaffold, in association with physical exercise, can be used to treat OC defects … With controlled mechanical stimulation, the piezoelectric scaffold presented here could generate beneficial surface charge for cartilage growth and thus serve as a battery-free biodegradable stimulator. The results highlight the potential benefits of a biodegradable piezoelectric scaffold to regenerate cartilage tissues and treat OA.”

“Piezoelectricity is a phenomenon that also exists in the human body,’ said Yang Liu, PhD a postdoctoral fellow in Nguyen’s group and the lead author of the published work. “Bone, cartilage, collagen, DNA, and various proteins have a piezoelectric response … Our approach to healing cartilage is highly clinically translational, and we will look into the related healing mechanism.”

Although the reported results are encouraging, Nguyen’s lab does want to observe the animals treated for at least a year, probably two, to make sure the cartilage is durable. And it would be ideal to test the PLLA scaffolds in older animals, too. Arthritis is normally a disease of old age in humans. Young animals heal more easily than old—if the piezoelectric scaffolding helps older animals heal as well, it truly could be a bioengineering breakthrough.