Biomedical microrobots could revolutionize future cancer treatments, reliably delivering targeted doses of toxic cancer-fighting drugs to destroy malignant tumours while sparing healthy bodily tissues. Development of such drug-delivering microrobots is at the forefront of biomedical engineering research. However, there are many challenges to overcome before this minimally invasive technology moves from research lab to clinical use.
Microrobots must be capable of rapid, steady and reliable propulsion through various biological materials, while generating enhanced image contrast to enable visualization through thick body tissue. They require an accurate guidance system to precisely target diseased tissue. They also need to support sizable payloads of drugs, maintain their structure long enough to release this cargo, and then efficiently biodegrade – all without causing any harm to the body.
Aiming to meet this tall order, researchers at the California Institute of Technology (Caltech) and the University of Southern California have designed a hydrogel-based, image-guided, bioresorbable acoustic microrobot (BAM) with these characteristics and capabilities. Reporting their findings in Science Robotics, they demonstrated that the BAMs could successfully deliver drugs that decreased the size of bladder tumours in mice.
Microrobot design
The team, led by Caltech’s Wei Gao, fabricated the hydrogel-based BAMs using high-resolution two-photon polymerization. The microrobots are hollow spheres with an outer diameter of 30 µm and an 18 µm-diameter internal cavity to trap a tiny air bubble inside.
The BAMs have a hydrophobic inner surface to prolong microbubble retention within biofluids and a hydrophilic outer layer that prevents microrobot clustering and promotes degradation. Magnetic nanoparticles and therapeutic agents integrated into the hydrogel matrix enable wireless magnetic steering and drug delivery, respectively.
The entrapped microbubbles are key as they provide propulsion for the BAMs. When stimulated by focused ultrasound (FUS), the bubbles oscillate at their resonant frequencies. This vibration creates microstreaming vortices around the BAM, generating a propulsive force in the opposite direction of the flow. The microbubbles inside the BAMs also act as ultrasound contrast agents, enabling real-time, deep-tissue visualization.
The researchers designed the microrobots with two cylinder-like openings, which they found achieves faster propulsion speeds than single- or triple-opening spheres. They attribute this to propulsive forces that run parallel to the sphere’s boundary improving both speed and stability of movement when activated by FUS.
They also discovered that asymmetric placement of the microbubble centre from the centre of the sphere generated propulsion speeds more than twice that achieved by BAMS with a symmetric design.
To perform simultaneous imaging of BAM location and acoustic propulsion within soft tissue, the team employed a dual-probe design. An ultrasound imaging probe enabled real-time imaging of the bubbles, while the acoustic field generated by a FUS probe (at an excitation frequency of 480 kHz and an applied acoustic pressure of 626 kPa peak-to-peak) provided effective propulsion.
In vitro and in vivo testing
The team performed real-time imaging of the propulsion of BAMs in vitro, using an agarose chamber to simulate an artificial bladder. When exposed to an ultrasound field generated by the FUS probe, the BAMs demonstrated highly efficient motion, as observed in the ultrasound imaging scans. The propulsion direction of BAMs could be precisely controlled by an external magnetic field.
The researchers also conducted in vivo testing, using laboratory mice with bladder cancer and the anti-cancer drug 5-fluorouracil (5-FU). They treated groups of mice with either phosphate buffered saline, free drug, passive BAMs or active (acoustically actuated and magnetically guided) BAMs, at three day intervals over four sessions. They then monitored the tumour progression for 21 days, using bioluminescence signals emitted by cancer cells.
The active BAM group exhibited a 93% decrease in bioluminescence by the 14th day, indicating large tumour shrinkage. Histological examination of excised bladders revealed that mice receiving this treatment had considerably reduced tumour sizes compared with the other groups.
“Embedding the anticancer drug 5-FU into the hydrogel matrix of BAMs substantially improved the therapeutic efficiency compared with 5-FU alone,” the authors write. “These BAMs used a controlled-release mechanism that prolonged the bioavailability of the loaded drug, leading to sustained therapeutic activity and better outcomes.”
Self-propelling nanobots shrink bladder tumours in mice by 90%
Mice treated with active BAMS experienced no weight changes, and no adverse effects to the heart, liver, spleen, lung or kidney compared with the control group. The researchers also evaluated in vivo degradability by measuring BAM bioreabsorption rates following subcutaneous implantation into both flanks of a mouse. Within six weeks, they observed complete breakdown of the microrobots.
Gao tells Physics World that the team has subsequently expanded the scope of its work to optimize the design and performance of the microbubble robots for broader biomedical applications.
“We are also investigating the use of advanced surface engineering techniques to further enhance targeting efficiency and drug loading capacity,” he says. “Planned follow-up studies include preclinical trials to evaluate the therapeutic potential of these robots in other tumour models, as well as exploring their application in non-cancerous diseases requiring precise drug delivery and tissue penetration.”
