Untethered miniature robots for minimally invasive thrombus treatment: From bench to clinical trials

Abstract

Untethered miniature robots (MRs) offer a minimally invasive way to address adverse vascular blockages, such as cerebrovascular thromboembolism, myocardial infarction, and pulmonary embolism. This review explores three key questions: what are the design principles of MRs from both engineering and clinical perspectives? How can visible intervention of MRs in three-dimensional (3D) branched vessels be achieved? What is the clinical procedure for treating thrombus using designed MRs? Recent progress in MRs for thrombus removal is summarized, and, more importantly, the pros and cons of MRs are discussed. We also evaluate the challenges that may hinder their clinical deployment and propose future research directions, bridging the gap between the bench and the bedside.

Keywords: clinical trial; miniature robots; minimally invasive intervention; thrombus treatment.

Graphical abstract

Figure 1

Properties of the cerebral vascular environment (A) Schematic of cerebral blood vessels. (B) Real CT imaging of human cerebral blood vessels. Copyright 2014, The Authors.

Figure 2

Comparison between direct i.v. injection and catheterization for long-distance delivery of MRs

Figure 3

Actuation mechanism of various MRs, including light-driven, magnetic-driven, acoustic-driven, chemical-driven, and biohybrid-driven MRs ∇p refers to the pressure gradient; ∇T refers to the temperature gradient; λ refers to the wavelength of acoustic waves; d refers to the dimension of the MRs; F_drive refers to the driving force; F_drag refers to the viscous drag force; V_bubble refers to the bubble’s velocity; V₀ is the velocity of the initial horizontal component of the detached bubble; F_N refers to the normal drag force perpendicular to the tail surface; F_T refers to the tangential drag force parallel to the tail surface; v, M, B, τ, and F denote the volume and magnetization of the MR, magnetic flux of the external magnetic field, magnetic torque, and magnetic gradient force, respectively. Part of the schematic was created using BioRender.com.

Figure 4

Examples of common imaging modalities used for imaging and localization of MRs (A–F) Various imaging tools used for MRs, including (A) fluorescence imaging (FI), Copyright 2021, The Authors; (B) photoacoustic computed tomography (PACT) imaging, Copyright 2022, The Authors; (C) laser speckle contrast imaging (LSCI), Copyright 2024, The Authors; (D) ultrasound (US) imaging, Copyright 2021, The Authors; (E) magnetic resonance imaging (MRI), Copyright 2022, The Authors; and (F) X-ray fluoroscopy imaging. Copyright 2024, The Authors. (G) Comparison of imaging modalities in terms of spatial resolution, temporal resolution, and penetration depth.

Figure 5

Thrombus removal using millimeter-scale robots Two typical examples of millimeter-scale robots for thrombus removal by mechanical disruption (A) (Copyright 2020, IEEE) and a combination of mechanical disruption and chemical degradation (B). Copyright 2015, AIP.

Figure 6

Mechanisms of thrombus removal using micro/nanometer-scale robots Various thrombus removal mechanisms, including (A) hydrodynamic convection, Copyright 2014, American Chemical Society; (B) photothermal ablation, Copyright 2018, American Chemical Society; (C) sonodynamic therapy, Copyright 2021, American Chemical Society; (D) mechanical interaction, Copyright 2017, WILEY-VCH; (E) chemical lysis, Copyright 2020, The Authors; and (F) mechanical interaction with chemical lysis and hydrodynamic convection. Copyright 2024, The Authors.

Figure 7

Drug-delivery modes and blood-clot removal mechanisms (A) The scheme of thrombus removal using MRs with three drug-delivery modes. (B) Scheme of primary thrombus removal mechanisms, including enzyme catalysis, mechanical rubbing, and hydrodynamic convection.

Figure 8

Schematic of detailed intervention procedures using MRs for ischemic stroke treatment Part of the schematic was created using BioRender.com.

Figure 9

A proposed pathway toward clinical translation of MRs designed for endovascular recanalization Part of the schematic was created using BioRender.com.