(Top left) A photo of an alginate capsule loaded with iron oxide nanoparticles. (Top right) Inset shows a schematic of the capsule interior containing nanoparticles and the calcium cross-linked alginate capsule wall. (Bottom) A sequence of photos showing capsules before and after ultrasonic rupture demonstrating the rapid release of the payload. (Courtesy of Stephen Kennedy.)Delivering drugs at specific times or sequences of different agents could offer a powerful new approach to medical treatments from tissue engineering to cancer. Polymeric capsules that can be triggered to release a drug cargo by an ultrasonic signal could be the answer, according to researchers.
The team, from Harvard University, University of Rhode Island, Brown University, and the Royal College of Surgeons in Ireland, has designed capsules made from a cross-linked alginate hydrogel that burst in response to an ultrasonic signal [Kennedy et al., Biomaterials 75 (2015) 91].
The capsules are simple to make: a solution containing calcium (or similar) ions, sucrose, and the cargo (gold or iron oxide nanoparticles) is added drop by drop into alginate (Fig. 1). The cations create a cross-linked alginate network that forms the capsule walls.
Cleverly, the amount or type of cross-linker can be varied to engineer ‘stronger’ or ‘weaker’ alginate capsules that respond to different ultrasonic signals. The weaker and stronger capsules can also be engineered to contain different payloads, so a system containing a mixture of the two could be triggered to release a sequence of active agents on demand.
“This is a critical capability in regenerative processes, which are inherently characterized by a highly choreographed sequence of growth factor signaling deliveries,” explains first author of the study, Stephen Kennedy. “Our system will allow us to investigate how the timing and sequence of different growth factor signals can impact regenerative outcomes,” he adds.
As proof-of-principle, the researchers loaded capsules with 25 nm-diameter gold nanoparticles decorated with bone morphogenetic protein-2, which stimulates the development of bone. Because the nanoparticles are too large to diffuse through the capsule walls, they are retained for up to week with little leakage. But when exposed to a 10-100 second ultrasonic pulse, the capsules burst to release the entire cargo immediately.
But more than just the timing and sequence of drug delivery could be controlled in this way. The researchers demonstrate that if the amplitude of the ultrasonic signal is reduced, a longer duration pulse is required to release the entire payload and vice versa. Varying the ultrasonic amplitude and duration, therefore, could be used to control how much of the capsule’s cargo is released.
The capsules can also be readily incorporated into hydrogel scaffolds, which can be implanted into the body. Ultrasonic signals can still rupture the capsules, but do so without adversely affecting the surrounding hydrogel scaffold.
“We believe that these capsules could be integrated into implantable scaffolds,” says Kennedy, “enabling the development of enhanced treatment strategies in a wide range of areas from pain management, to immunotherapy, diabetes, and cancer.”