Abstract
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.
Highlights
An ideal material solution should convey the idea of short-term inertness in the body, whereas a microrobot should be degradable with the lowest possible waste profile in the long term
We designed, explored, and characterized in vitro a hydrogel-based biodegradable helical microswimmer remotely controlled by rotating magnetic fields
Owing to their emergent physical properties and capability to protect labile drugs from degradation, hydrogels could be programmed for various physiochemical interactions with the encapsulated drugs to control drug release
Summary
A dvancements in interventional technologies have enabled minimally invasive strategies, such as endoscopy or robot-assisted surgery, which have markedly reduced centimeter/decimeter-size incisions of many open surgeries to millimeter-size holes, lowered postoperative patient morbidity, and shortened recovery times.[1,2] The advances and evolution of untethered mobile robots, whose size go down to the level of a single cell, can further leverage minimally invasive medicine by providing a direct access and precise control in deep and delicate body sites, such as the central nervous system, the circulatory system, the fetus, and the eye.[3−8] Recent progress along this line has already resulted in a number of synthetic and biohybrid microrobotic designs with intriguing functionalities toward their use in various pathophysiological environments.[9−14]. We report an integrated strategy for the design and fabrication of a hydrogel-based, biodegradable microrobotic swimmer, which accomplishes its tasks of therapeutic and diagnostic release in vitro based on the environmental sensing of matrix metalloproteinase 2 (MMP2) enzyme. The precursor comprises iron oxide nanoparticles dispersed in gelatin methacryloyl, a photo-cross-linkable semisynthetic polymer derived from collagen.[26] Gelatin contains target cleavage sites for MMP-2, thereby appealing as a biodegradable structural material for microrobots.[27] We show that upon the enzymatic breakdown of the microswimmer network, anti-ErbB 2 antibody-tagged magnetic contrast agents are released into the local environment for targeted cell labeling of ErbB 2 overexpressing SKBR3 cancer cells, thereby promising follow-up evaluation strategy of the preceding therapeutic intervention. The findings of the present work represent a leap toward in vivo mobile microrobots that are capable of sensing, responding to the local microenvironment, and performing specific diagnostic or therapeutic tasks using their smart composite material architectures in physiologically complex environments
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