Highly Integrated Nanoscale Robots for Targeted Delivery to the Central Nervous System

Project Information

HINBOTS

Grant agreement ID: 771565

DOI

10.3030/771565

Project closed

EC signature date 31 January 2018

Start date 1 September 2018

End date 31 August 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 998 720,00

EU contribution

€ 1 998 720,00

Coordinated by

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Switzerland

Periodic Reporting for period 4 - HINBOTS (Highly Integrated Nanoscale Robots for Targeted Delivery to the Central Nervous System)

Reporting period: 2023-03-01 to 2023-08-31

Summary of the context and overall objectives of the project

HINBOTS has pioneered advanced micro- and nanoscale robots for tissue electrostimulation, with a primary focus on addressing central nervous system (CNS) diseases, particularly spinal cord injury (SCI). Our main challenge involves achieving precise and targeted delivery of therapeutic agents to specific CNS sites, presenting a breakthrough for effective, localized, and minimally invasive treatments.

To meet this challenge, we've developed highly integrated magnetoelectric micro- and nanorobots featuring magnetoelectric micro- and nanostructures, incorporating magnetostrictive cores and piezoelectric shells. Upon magnetic stimulation, these structures become electrically polarized, enabling the wireless delivery of electric fields to cells and tissues. A noteworthy achievement includes the successful development and optimization of multiple magnetoelectric microrobots capable of differentiating pre-neuronal and primary neuronal cells. Our diverse portfolio of micro-/nanorobot designs encompasses self-rolled and spherical microdevices, helical structures, and cell-based spheroids.

Biocompatibility and biodegradability have been key aspects in our project, with micro-/nanorobots fabricated from various hydrogels, polymers, sucrose, and innovative biotemplating methods used to incorporate piezoelectric and other functional nanomaterials within micro- and nanorobotic platforms.

In conjunction with these advancements, we've designed magnetic catheters for precise deployment of microrobots within the cerebrospinal fluid. The efficacy of this method has been tested in 3D-printed spinal cord phantoms, demonstrating successful deployment of magnetic nanoparticle swarms with the catheter and their manipulation in an environment mimicking cerebrospinal fluid dynamics, pivotal for translating magnetoelectric small-scale robots into medical procedures. We have also developed a table-top electromagnetic navigation system (eMNS) for future in vivo studies with small animals.

Finally, in vivo studies using an SCI model were conducted to validate the effectiveness of magnetoelectric nanoparticles-based robots for SCI treatment. Notably, we've successfully demonstrated the reconnection of the SCI in the model, marking a significant stride towards realizing the therapeutic potential of magnetoelectric small-scale robots.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

From the beginning until the end of the project, we have made key developments in the fabrication of magnetoelectric (ME) and piezoelectric (PE) materials for several micro and nanorobotic designs. (Adv. Funct. Mater. 2020, 30 (17), 1910323). Key innovations involve the tuning of the crystalline orientation of PE nanoparticles (NPs) for enhanced performance (Adv. Funct. Mater. 2022, 32 (35), 2202180), and the use of multiferroic core-shell NPs to trigger the hydrogen evolution reaction (Adv. Mater. 2022, 34 (19), 2110612) for future hydrogen therapies. We have also developed ME bilayers with enhanced magnetoelectric (ME) coupling. Within this particular research we have also discovered the occurence of the shape-memory effect in ME bilayers at nanoscale for the first time (Nat. Commun. 2023, 14 (1), 750). Finally, we have also discovered a novel way to generate ME: magnetopyroelectricity, which exploits magnetothermal efects to generate electrical fields (Mater. Horiz. 2023, 10 (7), 2627–2637). We have also developed porous materials (MOFs) coupled with piezoelectric shells. Various manipulation strategies and the fabrication of diverse micro-/nanorobots were explored, such as self-rolled designs, spherical, and helical devices.

We have also developed several magnetic catheter designs. In this last period, a microcatheter featuring a reservoir for nanorobot storage and deployment has been succesfully realized. Successful demonstrations included NP deployment and swarm locomotion in a phantom of the spinal cord recreating the cerebrospinal fluid dynamics.

Additionally, we've developed a table-top electromagnetic navigation system intended for future in vivo studies with small animals (rodents, rabbits). The successful magnetic navigation of micro- and nanorobots using this system has been validated, bridging the gap between laboratory innovation and preclinical utility.

Paying attention to biocompatibility, we created micro-/nanorobots from polymeric materials, e.g. biodegradable hydrogels (e.g. Adv. Funct. Mater. 2020, 30 (17), 1910323); polymers with tuneable stability (Adv. Funct. Mater. 2023, 2212952); and sucrose (Adv. Mater. 2020, 32 (52), 2005652.). We successfully developed (bio)templating methods for incorporating functional materials onto the templates, for example, for piezoelectric detoxification of protein aggregates (Nanoscale 2023, 15 (36), 14800–14808), and neuronal electrostimulation (Mater. Horiz. 2022, 9 (12), 3031–3038). We have also evaluated the biodegradation of ME nanomaterials and micro-/nanoswimmers to predict their lifespan in biological environments.

During the last period of the project, we conducted an in vivo demonstration of spinal cord injury (SCI) treatment,using an in vivo SCI model. We successfully verified the efficiency of our ME nanoparticles-based robots for SCI treatment by performing whole-mount immunohistochemistry of the SCI model. Moreover, successful in vivo magnetic navigation of dye labelled ME robots were demonstrated by effectively guiding them to the SCI site using developed table-top eMNS.

Our results have been disseminated in several international conferences (e.g. MRS, MARSS, Actuators) and we are now considering the possibility to create an startup for the exploitation of ME materials.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

- We developed a novel method (magnetopyroelectricity) for transforming magnetic fields into electrical signals
- We demonstrated the enhanced magnetoelectric (ME) coupling between micropatterned multiferroic layers and shape memory effects on these flexible thin film structures
- We demonstrated to trigger the hydrogen evolution reaction (HER) using multiferroic core-shell NPs,
- We built a portable setup for the manipulation of magnetic microrobots.
- We developed several kinds of microcatheter for small-scale robots injection.
- We demonstrated the catheter-aided NP deployment and swarm locomotion in the developed phantom of the spinal cord
- We realized a biodegradable magnetoelectric robot capable of transporting neuron-like cells, and promote their differentiation under magnetic field application.
- We developed other alternative biodegradable systems such as the sucrose-based microrobots.
- We created micro-/nanorobots from soft matters, e.g. biodegradable hydrogels; polymers with tuneable stability; multiferroic composites; and porous materials such as MOFs.
- We developed biotemplating methods for incorporating these functional materials onto the biological templates (Spirulina platensis or cells) to perform targeted drug delivery, cancer cell killing, detoxification of protein aggregates, and selective cell stimulation.
- We integrated magnetoelectric core-shell NPs with cells to generate cell-templated robots for in-situ selective cell stimulation and differentiation at central nervous system (CNS).
- We demonstrated in vivo performance of multiferroic nanoparticles-based robots for spinal cord injury (SCI) treatment employing a model organism.
- We demonstrated in-vivo magnetic navigation of dye labelled robots by effectively guiding them to the SCI site of the model.

Biodegradable magnetoelectric microrobots for cell transportation & magnetoelectric differentiation