A paper authored by 15 researchers, including Dr. Joe Alexander and Dr. Tetsuhiko Teshima of the NTT Research Medical & Health Informatics Lab, unveiled a new material technology—three-dimensional “micro-rolls” composed of two-dimensional materials—used to build three-dimensional structures formed of cells mimicking the architecture and function of real organs. Published in ACS Applied Materials & Interfaces, “Self-foldable 3D biointerfaces by strain engineering of 2D layered materials on polymers,” marks an important step forward in biointerface development to support the MEI Lab’s vision for a cardiovascular bio digital twin (CV BioDT), which aims to mathematically characterize human heart and circulatory function in a manner that enables health care providers to interface patient-specific device therapies and/or customize drug regimens to advance precision care.
2DLMs and Micro-Rolls
Micro-rolls are predetermined three-dimensional microstructures constructed using two-dimensional layered materials (2DLMs) that mimic the architecture and function of real organs, enabling researchers to study organ development, model diseases and test new therapeutics in a controlled and physiologically relevant environment.
2DLMs have gained increasing attention in bioelectronic research due to their favorable electrical, optical and mechanical properties. In this research, scientists constructed 2DLM micro-rolls using three different materials: graphene, hexagonal boron nitride (hBN) and molybdenum disulfide (MoS₂).
Gaphene’s high charge carrier mobility, chemical stability and biocompatibility has made it a promising material for integration into field-effect transistors (FETs) for electrophysiology studies. hBN is an approximately 5-eV-wide bandgap insulator with a similar breakdown voltage to silicon dioxide, high thermal conductivity and chemical stability, making it ideal for use as a protective layer or dielectric substrate in electronic devices. MoS₂ is a semiconductor with a bandgap dependent on the number of layers and optoelectronic responsiveness, which makes it suitable for use in field-effect transistors and photodetectors.
All three materials exhibit a high degree of transparency, which is essential for applications that require simultaneous optical and electrical readouts. So, combining them can thus lead to flexible, ultra-thin integrated electronic components. But, it is the ability to transform these materials into complex 3D shapes, the researchers argue, that “is a key strategic step towards creating conformal biointerfaces with cells and applying them as scaffolds to simultaneously guide their growth to tissues and enable integrated bioelectronic monitoring.”
Additionally, introducing self-folding capabilities to these structures was vital to bridge the gap between advanced material properties and the intricate demands of modern biological systems. Self-folding is a convenient method to realize the broad range of curvature radii and parallelization, as self-folding structures can be transformed simultaneously into a predefined shape upon a trigger mechanism.
Process
To create these self-folding, three-dimensional structures, researchers applied strain engineering, “the process of tuning a material’s properties by altering its mechanical or structural attributes,” according to a 2018 University of Illinois and Argonne National Laboratory paper. They followed a three-step process:
Wet Transfer: First, researchers transferred the 2DLMs onto a silicon dioxide (SiO2) substrate coated with calcium (Ca)-alginate via a wet transfer process.
Lamination: Next, the substrates with the 2DLMs were wholly laminated with parylene-C—the driving force for the self-folding process—and micro-patterned via reactive ion etching (RIE) with oxygen (O2) plasma through a photoresist mask.
Dissolution: Finally, researchers used an ethylenediaminetetraacetic acid (EDTA) solution to dissolve Ca-alginate, a “sacrificial layer,” to facilitate the release of the structures. Doing so through physiological conditionals, as opposed to previous methods (such as aggressive chemicals, elevated temperatures or pH changes, made this process ideal for cell encapsulation.
Ultimately, the multiple stacked 2DLM layers, in conjunction with their diverse electrical properties, facilitate the development of more complex, self-foldable, transparent bio-sensing components, such as FETs. These sensors offer simultaneous optical, electrical and chemical monitoring of cells, significantly improving real-time, long-term tracking of engineered tissues and organoids without the drawbacks of conventional and non-transparent 2D biosensors.
Results
Ultimately, the researchers highlighted three key results: First, they demonstrated controllable self-folding of monolayer MoS2 and hBN by simply transferring a parylene-C film on top, with the lack of in-plane strain in the 2DLM layer contributing to a damage-free, stable folding of the 2DLMs.
Second, researchers showed that 2DLM micro-rolls were capable of guiding the aggregation and maintaining the physiological functions of encapsulated hiPSC-CMs, making them suitable as tissue engineering platforms. The stable adhesion between different 2DLMs and parylene-C suggests compatibility with other 2D materials, further expanding the range of functional devices that can be built using this approach.
Finally, researchers determined parylene-C-based self-folding of 2DLMs is not only limited to in vitro applications but could also be expanded for implants, such as self-folding bioelectronic devices for nerve cuff interfacing.
This research group included two members of the NTT Research MEI Lab: Lab Director Joe Alexander (M.D., Ph.D.) and Tatsuhiko Teshima (Ph.D.), who leads the MEI Lab’s Munich office. Co-authors included members of the Technical University of Munich, The University of Tokyo and Keio University.
For more information about this research, access “Self-Foldable Three-Dimensional Biointerfaces by Strain Engineering of Two-Dimensional Layered Materials on Polymers” online via ACS Publications.
