3D Printed Microtransporters: Compound Micromachines for Spatiotemporally Controlled Delivery of Therapeutic Agents

Abstract

Functional compound micromachines are fabricated by a design methodology using 3D direct laser writing and selective physical vapor deposition of magnetic materials. Microtransporters with a wirelessly controlled Archimedes screw pumping mechanism are engineered. Spatiotemporally controlled collection, transport, and delivery of micro particles, as well as magnetic nanohelices inside microfluidic channels are demonstrated. Biological systems are exquisitely sensitive to the location, dose, and timing of physiologic cues and pharmaceuticals. This spatiotemporal sensitivity indicates that diagnostic and therapeutic approaches with minimal off-target effects can be particularly efficacious. Targeted delivery of drugs, genetic material, and cells increases the effectiveness of therapies while minimizing side effects.1 Several micro- and nanoparticles have been developed to safely carry these therapeutic payloads.2, 3 Systemic injection of these particles results in their dilution and only a small fraction of the particles reaches the treatment region. Magnetically active particles can be guided directly to the treatment region, which decreases the delivery of their payload to other undesirable locations.4 They can be magnetically agitated to promote mixing after delivery, which increases mass transport into the target tissues compared to passive diffusion.5, 6 Unfortunately, controlled navigation of individual nanoagents to target sites within a complex biological system is challenging due to the agent's small size and weak magnetization. Furthermore, the immune system, hostile environmental conditions, and physical barriers can neutralize them. Thus, a targeted delivery method is required that can not only release its contents at the target site in a dose-dependent manner, but also contain and protect the payload during transport. Untethered, miniaturized robotic devices can enable us to perform minimally invasive operations in 3D, complex microenvironments.7, 8 These remotely actuated operations can perturb or investigate biological systems in a flexible and on-demand manner. A variety of simple micromachines have recently been developed including microstructures controlled by oscillating magnetic fields,9-11 helical swimmers demonstrating corkscrew motion,12 thermally or magnetically actuated microgrippers,13-16 self-propelled micromotors,17 electrostatic18 and impact-driven microactuators.19 These machines can interact with objects both through physical contact and fluid flow generated around their body.20-25 The diagnostic and therapeutic potential of robotics in these microbiological contexts can be greatly enhanced with the development of compound micromachines that have multiple mechanisms working together to perform complicated tasks, such as the transport and release of therapeutic agents. We call these devices microtransporters, and they have uses beyond targeted delivery. For example, they can noninvasively collect biological samples from remote pathological sites for diagnostic purposes. Stimuli responsive mobile microcapsules have been introduced to achieve similar goals,15, 26 but their payload is released en masse and they have neither an active loading nor mixing mechanism. Here, we report a microtransporter that can actively collect, encapsulate, transport, and controllably release micro- and nanoagents. The fabrication method is based on 3D direct laser writing and selective physical vapor deposition of magnetic materials (Figure 1a). The two-photon induced photopolymerization process enables the manufacturing of custom shaped microparts,27-34 which we use to create a compound micromachine without requiring further assembly.35-37 As the integrated mechanical system contains parts that must move relative to each other, it is important to generate magnetic actuation only at specific locations. This is achieved through selective coating of magnetic materials. After printing the main assembly, a 3D sacrificial struc