Search

Micro-and nanorobots have the potential to perform non-invasive drug delivery, sensing, and surgery in living organisms, with the aid of diverse medical imaging techniques. To perform such actions, microrobots require high spatiotemporal resolution tracking with real-time closed-loop feedback. To that end, photoacoustic imaging has appeared as a promising technique for imaging microrobots in deep tissue with higher molecular specificity and contrast. Here, we present different strategies to track magnetically-driven micromotors with improved contrast and specificity using dedicated contrast agents (Au nanorods and nanostars). Furthermore, we discuss the possibility of improving the light absorption properties of the employed nanomaterials considering possible light scattering and coupling to the underlying metal-oxide layers on the micromotor’s surface. For that, 2D COMSOL simulation and experimental results were correlated, confirming that an increased spacing between the Au-nanostructures and the increase of thickness of the underlying oxide layer lead to enhanced light absorption and preservation of the characteristic absorption peak. These characteristics are important when visualizing the micromotors in a complex in vivo environment, to distinguish them from the light absorption properties of the surrounding natural chromophores.

The advancement of micro and nanotechnology has led to the manufacturing of miniaturized sensors with improved functionalities for highly sensitive point of care devices. This work is particularly focused on analysing cancer cells and the effect of a model drug on their survival rate. To that end, we developed a highly sensitive rolled-up micro-electrochemical impedance spectroscopy sensor, encapsulated into a microfluidic channel. The sensor was built by strain engineering of shapeable materials and with diameters close to the cell size to improve their sensitivity. To demonstrate the platform performance, we first carried out measurements with different electrode geometries using cell medium at different concentrations. We also performed measurements using cancer cell suspensions, obtaining distinct signals from single cells, cell clusters and cellular debris. Finally, cancer cells were treated with an anticancer drug (Camptothecin), at different concentrations, over the same period, and further analysed using the developed platform.

We develop biohybrid magnetic microrobots by electrostatic self-assembly of nonmotile sperm cells and magnetic nanoparticles. Incorporating a biological entity into microrobots entails many functional advantages beyond shape templating, such as the facile uptake of chemotherapeutic agents to achieve targeted drug delivery. We present a single-step electrostatic self-assembly technique to fabricate IRONSperms, soft magnetic microswimmers that emulate the motion of motile sperm cells. Our experiments and theoretical predictions show that the swimming speed of IRONSperms exceeds 0.2 body length/s (6.8 ± 4.1 µm/s) at an actuation frequency of 8 Hz and precision angle of 45°. We demonstrate that the nanoparticle coating increases the acoustic impedance of the sperm cells and enables localization of clusters of IRONSperm using ultrasound feedback. We also confirm the biocompatibility and drug loading ability of these microrobots, and their promise as biocompatible, controllable, and detectable biohybrid tools for in vivo targeted therapy.

The fast evolution of medical micro- and nanorobots in the endeavor to perform non-invasive medical operations in living organisms has boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic imaging (PAI), considered a functional technique, has shown to be promising for the visualization of micromotors in deep tissue with high spatiotemporal resolution as it possesses the molecular specificity of optical methods and the penetration depth of ultrasound. However, the precise maneuvering and function's control of medical micromotors, in particular in living organisms, require both anatomical and functional imaging feedback. Therefore, herein, the use of high-frequency ultrasound and PAI is reported to obtain anatomical and molecular information, respectively, of magnetically-driven micromotors in vitro and under ex vivo tissues. Furthermore, the steerability of the micromotors is demonstrated by the action of an external magnetic field into the uterus and bladder of living mice in real-time, being able to discriminate the micromotors’ signal from one of the endogenous chromophores by multispectral analysis. Finally, the successful loading and release of a model cargo by the micromotors toward non-invasive in vivo medical interventions is demonstrated.

The next generation of biomedical tools requires reshapeable electronics to closely interface with biological tissues. This will offer unique mechanical properties and the ability to conform to irregular geometries while being robust and lightweight. Such devices can be achieved with soft materials and thin-film structures that are able to reshape on demand. However, reshaping at the submillimeter scale remains a challenging task. Herein, shape-controlled microscale devices are demonstrated that integrate electronic sensors and electroactive polymer actuators. The fast and biocompatible actuators are capable of actively reshaping the device into flat or curved geometries. The curvature and position of the devices are monitored with strain or magnetic sensors. The sensor signals are used in a closed feedback loop to control the actuators. The devices are wafer-scale microfabricated resulting in multiple functional units capable of grasping, holding, and releasing biological tissues, as demonstrated with a neuronal bundle.

Cellular micromotors are attractive for locally delivering high concentrations of drug, and targeting hard-to-reach disease sites such as cervical cancer and early ovarian cancer lesions by non-invasive means. Spermatozoa are highly efficient micromotors perfectly adapted to traveling up the female reproductive system. Indeed, bovine sperm-based micromotors have shown potential to carry drugs toward gynecological cancers. However, due to major differences in the molecular make-up of bovine and human sperm, a key translational bottleneck for bringing this technology closer to the clinic is to transfer this concept to human material. Here, we successfully load human sperm with Doxorubicin (DOX) and perform treatment of 3D cervical cancer and patient-representative ovarian cancer cell cultures, resulting in strong anticancer cell effects. Additionally, we define the subcellular localization of the chemotherapeutic drug within human sperm, using high-resolution optical microscopy. We also assess drug effects on sperm motility and viability over time, employing sperm samples from healthy donors as well as assisted reproduction patients. Finally, we demonstrate guidance and release of human drug-loaded sperm onto cancer tissues using magnetic microcaps, and show the sperm microcap loaded with a second anticancer drug, camptothecin (CPT), which unlike DOX is not suitable for directly loading into sperm due to its hydrophobic nature. This co-drug delivery approach opens up novel targeted combinatorial drug therapies for future applications.

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.