Untethered mobile microrobots have the potential to leverage minimally invasive theranostic functions precisely and efficiently in hard-to-reach, confined, and delicate inner body sites. However, such a complex task requires an integrated design and engineering, where powering, control, environmental sensing, medical functionality, and biodegradability need to be considered altogether. The present study reports a hydrogel-based, magnetically powered and controlled, enzymatically degradable microswimmer, which is responsive to the pathological markers in its microenvironment for theranostic cargo delivery and release tasks. We design a double-helical architecture enabling volumetric cargo loading and swimming capabilities under rotational magnetic fields and a 3D-printed optimized 3D microswimmer (length = 20 μm and diameter = 6 μm) using two-photon polymerization from a magnetic precursor suspension composed from gelatin methacryloyl and biofunctionalized superparamagnetic iron oxide nanoparticles. At normal physiological concentrations, we show that matrix metalloproteinase-2 (MMP-2) enzyme could entirely degrade the microswimmer in 118 h to solubilized nontoxic products. The microswimmer rapidly responds to the pathological concentrations of MMP-2 by swelling and thereby boosting the release of the embedded cargo molecules. In addition to delivery of the drug type of therapeutic cargo molecules completely to the given microenvironment after full degradation, microswimmers can also release other functional cargos. As an example demonstration, anti-ErbB 2 antibody-tagged magnetic nanoparticles are released from the fully degraded microswimmers for targeted labeling of SKBR3 breast cancer cells in vitro toward a potential future scenario of medical imaging of remaining cancer tissue sites after a microswimmer-based therapeutic delivery operation.

Advances in design and fabrication of functional micro/nanomaterials have sparked growing interest in creating new mobile microswimmers for various healthcare applications, including local drug and other cargo ( e. g., gene, stem cell, and imaging agent) delivery. Such microswimmer-based cargo delivery is typically passive by diffusion of the cargo material from the swimmer body; however, controlled active release of the cargo material is essential for on-demand, precise, and effective delivery. Here, we propose a magnetically powered, double-helical microswimmer of 6 μm diameter and 20 μm length that can on-demand actively release a chemotherapeutic drug, doxorubicin, using an external light stimulus. We fabricate the microswimmers by two-photon-based 3D printing of a natural polymer derivative of chitosan in the form of a magnetic polymer nanocomposite. Amino groups presented on the microswimmers are modified with doxorubicin by means of a photocleavable linker. Chitosan imparts the microswimmers with biocompatibility and biodegradability for use in a biological setting. Controlled steerability of the microswimmers is shown under a 10 mT rotating magnetic field. With light induction at 365 nm wavelength and 3.4 × 10 W/cm intensity, 60% of doxorubicin is released from the microswimmers within 5 min. Drug release is ceased by controlled patterns of light induction, so as to adjust the desired release doses in the temporal domain. Under physiologically relevant conditions, substantial degradation of the microswimmers is shown in 204 h to nontoxic degradation products. This study presents the combination of light-triggered drug delivery with magnetically powered microswimmer mobility. This approach could be extended to similar systems where multiple control schemes are needed for on-demand medical tasks with high precision and efficiency.

Recent advances in the versatility and sophistication of design, fabrication, and control methods of mobile microrobots could have a transforming impact on future healthcare technologies. Self-propelled or remotely actuated, synthetic, or biohybrid microrobots can navigate to difficult-to-reach regions in the human body to deliver therapeutics for microscopically localized medical interventions. Here, recent progress in the design of microrobotic systems concerning therapeutic delivery of drugs, cells, and genetic materials is reported. This perspective prioritizes the design aspects of microrobots for medical cargo loading, navigation in biologically relevant environments, and controlled cargo release. In the final section, future prospects and a discussion on the critical shortcomings for the benchside-to-bedside translation of medical microrobots are provided.

Small-scale soft-bodied machines that respond to externally applied magnetic field have attracted wide research interest because of their unique capabilities and promising potential in a variety of fields, especially for biomedical applications. When the size of such machines approach the sub-millimeter scale, their designs and functionalities are severely constrained by the available fabrication methods, which only work with limited materials, geometries, and magnetization profiles. To free such constraints, here, we propose a bottom-up assembly-based 3D microfabrication approach to create complex 3D miniature wireless magnetic soft machines at the milli- and sub-millimeter scale with arbitrary multimaterial compositions, arbitrary 3D geometries, and arbitrary programmable 3D magnetization profiles at high spatial resolution. This approach helps us concurrently realize diverse characteristics on the machines, including programmable shape morphing, negative Poisson’s ratio, complex stiffness distribution, directional joint bending, and remagnetization for shape reconfiguration. It enlarges the design space and enables biomedical device-related functionalities that are previously difficult to achieve, including peristaltic pumping of biological fluids and transport of solid objects, active targeted cargo transport and delivery, liquid biopsy, and reversible surface anchoring in tortuous tubular environments withstanding fluid flows, all at the sub-millimeter scale. This work improves the achievable complexity of 3D magnetic soft machines and boosts their future capabilities for applications in robotics and biomedical engineering.

Untethered mobile microrobots have the potential to transform medicine radically. Their small size and wireless mobility can enable access to and navigation in confined, small, hard-to-reach, and sensitive inner body sites, where they can provide new ways of minimally invasive interventions and targeted diagnosis and therapy down to the cellular length scales with high precision and repeatability. The exponential recent progress of the field at the preclinical level raises anticipations for their near-future clinical prospects. To pave the way for this transformation to happen, however, the formerly proposed microrobotic system designs need a comprehensive review by including essential aspects that a microrobot needs to function properly and safely in given in vivo conditions of a targeted medical problem. The present review provides a translational perspective on medical microrobotics research with an application-oriented, integrative design approach. The blueprint of a medical microrobot needs to take account of microrobot shape, material composition, manufacturing technique, permeation of biological barriers, deployment strategy, actuation and control methods, medical imaging modality, and the execution of the prescribed medical tasks altogether at the same time. The incorporation of functional information pertaining each such element to the physical design of the microrobot is highly dependent on the specific clinical application scenario. We discuss the complexity of the challenges ahead and the potential directions to overcome them. We also throw light on the potential regulatory aspects of medical microrobots toward their bench-to-bedside translation. Such a multifaceted undertaking entails multidisciplinary involvement of engineers, materials scientists, biologists and medical doctors, and bringing their focus on specific medical problems where microrobots could make a disruptive or radical impact.

Biohybrid microrobots, composed of a living organism integrated with an artificial carrier, offer great advantages for the miniaturization of devices with onboard actuation, sensing, and control functionalities and can perform multiple tasks, including manipulation, cargo delivery, and targeting, at nano- and microscales. Over the past decade, various microorganisms and artificial carriers have been integrated to develop unique biohybrid microrobots that can swim or crawl inside the body, in order to overcome the challenges encountered by the current cargo delivery systems. Here, we first focus on the locomotion mechanisms of microorganisms at the microscale, crucial criteria for the selection of biohybrid microrobot components, and the integration of the selected artificial and biological components using various physical and chemical techniques. We then critically review biohybrid microrobots that have been designed and used to perform specific tasks in vivo. Finally, we discuss key challenges, including fabrication efficiency, swarm manipulation, in vivo imaging, and immunogenicity, that should be overcome before biohybrid microrobots transition to clinical use.

The structural design parameters of a medical microrobot, such as the morphology and surface chemistry, should aim to minimize any physical interactions with the cells of the immune system. However, the same surface-borne design parameters are also critical for the locomotion performance of the microrobots. Understanding the interplay of such parameters targeting high locomotion performance and low immunogenicity at the same time is of paramount importance yet has so far been overlooked. Here, we investigated the interactions of magnetically steerable double-helical microswimmers with mouse macrophage cell lines and splenocytes, freshly harvested from mouse spleens, by systematically changing their helical morphology. We found that the macrophages and splenocytes can recognize and differentially elicit an immune response to helix turn numbers of the microswimmers that otherwise have the same size, bulk physical properties, and surface chemistries. Our findings suggest that the structural optimization of medical microrobots for the locomotion performance and interactions with the immune cells should be considered simultaneously because they are highly entangled and can demand a substantial design compromise from one another. Furthermore, we show that morphology-dependent interactions between macrophages and microswimmers can further present engineering opportunities for biohybrid microrobot designs. We demonstrate immunobots that can combine the steerable mobility of synthetic microswimmers and the immunoregulatory capability of macrophages for potential targeted immunotherapeutic applications.

Poor retention rate, low targeting accuracy, and spontaneous transformation of stem cells present major clinical barriers to the success of therapies based on stem cell transplantation. To improve the clinical outcome, efforts should focus on the active delivery of stem cells to the target tissue site within a controlled environment, increasing survival, and fate for effective tissue regeneration. Here, a remotely steerable microrobotic cell transporter is presented with a biophysically and biochemically recapitulated stem cell niche for directing stem cells towards a pre-destined cell lineage. The magnetically actuated double-helical cell microtransporters of 76 µm length and 20 µm inner cavity diameter are 3D printed where biological and mechanical information regarding the stem cell niche are encoded at the single-cell level. Cell-loaded microtransporters are mobilized inside confined microchannels along computer-controlled trajectories under rotating magnetic fields. The mesenchymal stem cells are shown retaining their differentiation capacities to commit to the osteogenic lineage when stimulated inside the microswimmers in vitro. Such a microrobotic approach has the potential to enable the development of active microcarriers with embedded functionalities for controlled and precisely localized therapeutic cell delivery.