An organic brain-inspired platform with neurotransmitter closed-loop control, actuation and reinforcement learning.

Organic neuromorphic platforms have recently received growing interest for the implementation and integration of artificial and hybrid neuronal networks. Here, achieving closed-loop and learning/training processes as in the human brain is still a major challenge especially exploiting time-dependent biosignalling such as neurotransmitter release. Here, we present an integrated organic platform capable of cooperating with standard silicon technologies, to achieve brain-inspired computing via adaptive synaptic potentiation and depression, in a closed-loop fashion. The microfabricated platform could be interfaced and control a robotic hand which ultimately was able to learn the grasping of differently sized objects, autonomously.

Concealing Organic Neuromorphic Devices with Neuronal-Inspired Supported Lipid Bilayers.

Neurohybrid systems have gained large attention for their potential as in vitro and in vivo platform to interrogate and modulate the activity of cells and tissue within nervous system. In this scenario organic neuromorphic devices have been engineered as bioelectronic platforms to resemble characteristic neuronal functions. However, aiming to a functional communication with neuronal cells, material synthesis, and surface engineering can yet be exploited for optimizing bio-recognition processes at the neuromorphic-neuronal hybrid interface. In this work, artificial neuronal-inspired lipid bilayers have been assembled on an electrochemical neuromorphic organic device (ENODe) to resemble post-synaptic structural and functional features of living synapses. Here, synaptic conditioning has been achieved by introducing two neurotransmitter-mediated biochemical signals, to induce an irreversible change in the device conductance thus achieving Pavlovian associative learning. This new class of in vitro devices can be further exploited for assembling hybrid neuronal networks and potentially for in vivo integration within living neuronal tissues.

Negatively-charged supported lipid bilayers regulate neuronal adhesion and outgrowth.

One of the main challenges in neuroelectronics is the implementation of electronic platforms able to secure a tight coupling with neuronal cells and achieve an optimal signal to noise ratio during stimulation/recording of electrophysiological activity. In this context, supported lipid bilayers (SLBs), recapitulating the structure and the dynamicity of the biological plasma membrane, offer a promising biomimetic approach to trick cells to recognize a device as part of their native environment, tightening the cell-chip coupling. Among possible functionalization strategies used to improve cell adhesion on SLBs, the modification of the bilayer surface charge has been exploited to enhance the electrostatic interaction between the artificial membrane and its biological counterpart. In this work, several SLBs with different lipidic composition were synthesized and interfaced with primary neurons. Starting from a neuron-inspired biomembrane, the negative charges were increased through the addition of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) (succinyl-PE), a lipid exposing phosphate (PO4 -) groups; furthermore, the reactivity of the succinyl carboxylate group enabled the subsequent addition of negatively charged sulfonate (SO3 -) groups. The synthesized SLBs were then tested as platforms for neuronal adhesion and network formation. Despite the expected repulsive electrostatic interactions, our work suggests that negatively charged SLBs may influence neurite elongation and branching, highlighting the potential of surface charge to tune neuronal processes at the neuron-SLB interface.

Supported Lipid Bilayers Coupled to Organic Neuromorphic Devices Modulate Short-Term Plasticity in Biomimetic Synapses.

Synaptic plasticity is a fundamental process for neuronal communication and is involved in neurodegeneration. This process has been recently exploited to inspire the design of next-generation bioelectronic platforms. Neuromorphic devices have emerged as ideal candidates in mimicking brain functionalities, thanks to their ionic-to-electronic signal transduction, biocompatibility, and their ability to display short- and long-term memory as biological synapses. However, these devices still fail in bridging the gap between electronics and biological systems due to the lack of biomimetic features. Here, a biomembrane-based organic electrochemical transistor (OECT) is implemented and the supported-lipid-bilayer-mediated short-term depression of the device is investigated. After morphological and electrical characterization of the lipid bilayer, its ionic barrier behavior is exploited to enhance the neuromorphic operation of the OECT. Such biomimetic neuromorphic devices pave the way toward the implementation of synapses-resembling in vitro platforms to investigate and characterize neurodegenerative processes involving synaptic plasticity loss.

Advances in Cell-Conductive Polymer Biointerfaces and Role of the Plasma Membrane.

The plasma membrane (PM) is often described as a wall, a physical barrier separating the cell cytoplasm from the extracellular matrix (ECM). Yet, this wall is a highly dynamic structure that can stretch, bend, and bud, allowing cells to respond and adapt to their surrounding environment. Inspired by shapes and geometries found in the biological world and exploiting the intrinsic properties of conductive polymers (CPs), several biomimetic strategies based on substrate dimensionality have been tailored in order to optimize the cell-chip coupling. Furthermore, device biofunctionalization through the use of ECM proteins or lipid bilayers have proven successful approaches to further maximize interfacial interactions. As the bio-electronic field aims at narrowing the gap between the electronic and the biological world, the possibility of effectively disguising conductive materials to "trick" cells to recognize artificial devices as part of their biological environment is a promising approach on the road to the seamless platform integration with cells.

Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders.

Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

New Frontiers for Selective Biosensing with Biomembrane-Based Organic Transistors.

Biosensing plays vital roles in multiple fields, including healthcare monitoring, drug screening, disease diagnosis, and environmental pollution control. In recent years, transistor-based devices have been considered to be valid platforms for fast, low-cost sensing of diverse analytes. Without additional functionalization, however, these devices lack selectivity; several strategies have been developed for the direct immobilization of bioreceptors on the transistor surface to improve detection capabilities. In this scenario, organic transistors have gained attention for their abilities to be coupled to biological systems and to detect biomolecules. In this Perspective, we discuss recent developments in organic-transistor-based biosensors, highlighting how their coupling with artificial membranes provides a strategy to improve sensitivity and selectivity in biosensing applications. Looking at future applications, this class of biosensors represents a breakthrough starting point for implementing multimodal high-throughput screening platforms.

A biohybrid synapse with neurotransmitter-mediated plasticity.

Brain-inspired computing paradigms have led to substantial advances in the automation of visual and linguistic tasks by emulating the distributed information processing of biological systems1. The similarity between artificial neural networks (ANNs) and biological systems has inspired ANN implementation in biomedical interfaces including prosthetics2 and brain-machine interfaces3. While promising, these implementations rely on software to run ANN algorithms. Ultimately, it is desirable to build hardware ANNs4,5 that can both directly interface with living tissue and adapt based on biofeedback6,7. The first essential step towards biologically integrated neuromorphic systems is to achieve synaptic conditioning based on biochemical signalling activity. Here, we directly couple an organic neuromorphic device with dopaminergic cells to constitute a biohybrid synapse with neurotransmitter-mediated synaptic plasticity. By mimicking the dopamine recycling machinery of the synaptic cleft, we demonstrate both long-term conditioning and recovery of the synaptic weight, paving the way towards combining artificial neuromorphic systems with biological neural networks.

A nanostructure platform for live-cell manipulation of membrane curvature.

Membrane curvatures are involved in essential cellular processes, such as endocytosis and exocytosis, in which they are believed to act as microdomains for protein interactions and intracellular signaling. These membrane curvatures appear and disappear dynamically, and their locations are difficult or impossible to predict. In addition, the size of these curvatures is usually below the diffraction limit of visible light, making it impossible to resolve their values using live-cell imaging. Therefore, precise manipulation of membrane curvature is important to understanding how membrane curvature is involved in intracellular processes. Recent studies show that membrane curvatures can be induced by surface topography when cells are in direct contact with engineered substrates. Here, we present detailed procedures for using nanoscale structures to manipulate membrane curvatures and probe curvature-induced phenomena in live cells. We first describe detailed procedures for the design of nanoscale structures and their fabrication using electron-beam (E-beam) lithography. The fabrication process takes 2 d, but the resultant chips can be cleaned and reused repeatedly over the course of 2 years. Then we describe how to use these nanostructures to manipulate local membrane curvatures and probe intracellular protein responses, discussing surface coating, cell plating, and fluorescence imaging in detail. Finally, we describe a procedure to characterize the nanostructure-cell membrane interface using focused ion beam and scanning electron microscopy (FIB-SEM). Nanotopography-based methods can induce stable membrane curvatures with well-defined curvature values and locations in live cells, which enables the generation of a library of curvatures for probing curvature-related intracellular processes.

Photogenerated Electrical Fields for Biomedical Applications.

The application of electrical engineering principles to biology represents the main issue of bioelectronics, focusing on interfacing of electronics with biological systems. In particular, it includes many applications that take advantage of the peculiar optoelectronic and mechanical properties of organic or inorganic semiconductors, from sensing of biomolecules to functional substrates for cellular growth. Among these, technologies for interacting with bioelectrical signals in living systems exploiting the electrical field of biomedical devices have attracted considerable attention. In this review, we present an overview of principal applications of phototransduction for the stimulation of electrogenic and non-electrogenic cells focusing on photovoltaic-based platforms.

Cells Adhering to 3D Vertical Nanostructures: Cell Membrane Reshaping without Stable Internalization.

The dynamic interface between the cellular membrane and 3D nanostructures determines biological processes and guides the design of novel biomedical devices. Despite the fact that recent advancements in the fabrication of artificial biointerfaces have yielded an enhanced understanding of this interface, there remain open questions on how the cellular membrane reacts and behaves in the presence of sharp objects on the nanoscale. Here we provide a multifaceted characterization of the cellular membrane's mechanical stability when closely interacting with high-aspect-ratio 3D vertical nanostructures, providing strong evidence that vertical nanostructures spontaneously penetrate the cellular membrane to form a steady intracellular coupling only in rare cases and under specific conditions. The cell membrane is able to conform tightly over the majority of structures with various shapes while maintaining its integrity.