A microrobotic system guided by photoacoustic computed tomography for targeted navigation in intestines in vivo

Abstract

Recently, tremendous progress in synthetic micro/nanomotors in diverse environment has been made for potential biomedical applications. However, existing micro/nanomotor platforms are inefficient for deep tissue imaging and motion control in vivo. Here, we present a photoacoustic computed tomography (PACT) guided investigation of micromotors in intestines in vivo. The micromotors enveloped in microcapsules are stable in the stomach and exhibit efficient propulsion in various biofluids once released. The migration of micromotor capsules toward the targeted regions in intestines has been visualized by PACT in real time in vivo. Near-infrared light irradiation induces disintegration of the capsules to release the cargo-loaded micromotors. The intensive propulsion of the micromotors effectively prolongs the retention in intestines. The integration of the newly developed microrobotic system and PACT enables deep imaging and precise control of the micromotors in vivo and promises practical biomedical applications, such as drug delivery.

Fig. 1.. Schematic of PAMR in vivo.

(A) Schematic of the PAMR in the GI tract. The MCs are administered into the mouse. NIR illumination facilitates the real-time photoacoustic imaging of the MCs, and subsequently triggers the propulsion of the micromotors in targeted areas of the GI tract. (B) Schematic of PACT of the MCs in the GI tract in vivo. The mouse was kept in the water tank surrounded by an elevationally focused ultrasound transducer array. NIR side-illumination onto the mouse generates PA signals, which are subsequently received by the transducer array. Inset figure: Enlarged view of the cyan dashed box region, illustrating the confocal design of light delivery and PA detection. MC, micromotor capsule; US, ultrasound; CL, conical lens; DAQ, data acquisition system; NIR, near infrared. (C) Enteric coating prevents the decomposition of MCs in the stomach. (D) External continuous-wave (CW) NIR irradiation induces the phase transition and subsequent collapse of the MCs on demand in the targeted areas and activates the movement of the micromotors upon unwrapping from the capsule. (E) Active propulsion of the micromotors promotes the retention and cargo delivery efficiency in intestines.

Fig. 2.. Characterization of the MCs.

(A) Scanning electron microscopy (SEM) image of an ingestible micromotor. Scale bar, 10 μm. (B) Microscopic images of the MCs with different sizes. Scale bars, 50 μm. (C) PACT images of Mg particles, blood, and MCs in silicone rubber tubes with laser wavelengths at 720, 750, and 870 nm, respectively. Scale bar, 500 μm. (D) PACT spectra of MCs (red line), blood (blue line), and Mg particles (black line), respectively. (E and F) PACT images (E) and the corresponding PA amplitude (F) of the MCs with different micromotor loading amounts, and the dependence of the PA amplitude on the fluence of NIR light illumination (inset in F). Scale bar in E, 500 μm. (G) Dependence of PA amplitude of the MCs (red line) and blood (black line) on the depth of tissue, and the normalized PA amplitude and fluorescence intensity of the MCs under tissues (inset). Norm., normalized; amp., amplitude; Fl., fluorescence; int., intensity. Error bars represent the standard deviations from 5 independent measurements.

Fig. 3.. Characterization of the dynamics of the PAMR.

(A and B) Schematic (A) and time-lapse PACT images in deep tissues (B) illustrating the migration of an MC in the model intestine. Scale bar, 500 μm. The thickness of the tissue above the MC is 10 mm. (C–E) Schematic (C) and time-lapse microscopic images (D and E) showing the stability of the MCs in gastric acid and intestinal fluid (D) without CW NIR irradiation, and the use of CW NIR irradiation to trigger the collapse of an MC and the activation of the micromotors (E). Scale bars in D and E, 50 μm.

Fig. 4.. PACT evaluation of the PAMR dynamics in vivo.

(A) The time-lapse PACT images of the MCs in intestines for 7.5 hours. The MCs migrating in the intestine are shown in color, the mouse tissues are shown in gray. Scale bar, 2 mm. (B and C) The movement displacement caused by the migration of the MCs in the intestine (B) and by the respiration motion of the mouse (C). (D) Comparison of the speeds of the MC migration and the respiration-induced movement.

Fig. 5.. Evaluation of the PAMR for targeted retention and delivery.

(A) Schematic of the use of the PAMR for targeted delivery in intestines. (B) The time-lapse PACT images of the migration of an MC toward a model colon tumor. Scale bar, 500 μm. (C and D) PACT images (C) and overlaid time-lapse bright field and fluorescence microscopic images (D) showing the retention of the micromotors in intestines via the NIR-activated propulsion of the micromotors. Scale bars in C and D are 200 μm and 20 μm, respectively. (E) Microscopic images showing the in vivo retention of the control microparticles and the micromotors in intestines (left) and the quantitative analysis of the particle retention in intestines (right). Control 1 and Control 2 represent passive Mg and Au-Mg microparticles, respectively. Scale bar, 100 μm. Error bars represent the standard deviations from 5 independent measurements. (F) Microscopic image displaying the change of pH of the surrounding environment upon the micromotors in PBS. (G) The schematic (left) and the experimental (right) diffusion profiles of the control silica particles and the ingestible micromotors in mucus after 1 hour. Error bars represent the standard deviations from 5 independent measurements. (H) Histology analysis for the duodenum, jejunum, and distal colon of the mice treated with the MCs or DI water as the control for 12 hours. Scale bar, 100 μm.