BY CARMEN BARTIC, KOEN DE KEERSMAECKER AND ELS PARTON
To bridge the gap between biology and electronics in neurons on chip, IMEC, the University Hospital of Leuven (Leuven, Belgium) and Hebrew University (Jerusalem, Israel) researchers are exploring new transducer concepts, surface chemistry solutions and packaging techniques. We believe that the key to efficient and reliable ionoelectronic devices is surface chemistry.
Bionics: Two-way Communication Between Biology and Electronics
Direct coupling of neurons and chips is no longer science fiction. Ionoelectric devices are on the market, and the research community believes strongly in the potential of this hybrid technology. The medical world, in particular, may benefit from this development. In the short term, in-vitro applications are envisioned that enable monitoring of neuron activity — eventually becoming an indispensable tool in neuro-physiological and neurological research into important areas such as Alzheimer's disease, for example. Another important application is the use of neurons in sensors to monitor their response to neurological drugs, thus enabling fast drug screening. More visionary (in-vivo) applications include brain-controlled prostheses and implants to restore neurological or sensory functions after injury or disease.
There are roadblocks to overcome before such applications can be used in research and medicine. Multidisciplinary research teams face problems such as misalignment of neurons with respect to transducers, along with high noise levels, a low degree of reproducibility of the signals, as well as the packaging of a wet material (neurons) with electronics.
Self-assembling Monolayers and Modified FETs
Our research team is currently developing a generic technology to enable two-way communication in neuron-electronic hybrids. Electrical and chemical transducers were developed to cover the entire range of neuron activity. For the electrical transducer, a stimulated neuron shows its increased voltage across its cell membrane, called its "action potential," in respect to its resting state. For the chemical transducer, the end terminal of the axon of a communicating neuron releases chemical substances (neurotransmitters) in the synaptic cleft toward the adjacent neuron.
An electrical bi-directional transducer capacitively coupled with a neuron was developed. The CMOS-compatible transducer is a silicon depletion-type p-MOSFET with a floating gate as the sensing/stimulation area to capture and trigger action potentials. A depletion-type neuron transducer, in contrast to the more common enhancement-type neuron transducers, does not require a DC bias. This is advantageous, since the DC bias can result in serious degradation to both the silicon chip and the neuron. Use of an extended floating gate results in an increased tolerance for neuron placement and helps optimize the neuron coupling area.
Electrical and chemical neuron transducers cover the range of neuron activity. Both the action potential and release of neurotransmitters can be monitored.
We are also developing a chemical neuron transducer able to sense the presence of neurotransmitters. This transducer consists of a dual-gated, thin gallium-arsenide MESFET with a biasing gate on one side and a sensing, organic gate on the backside. The biasing gate allows regulation of the position of the conductive channel between the two gates in such a way that current can flow close to the surface of the sensing gate — making this dual-gated transducer extremely sensitive. From a packaging point of view, this configuration is promising because it completely separates the neuron interaction site (organic gate) and the electrical parts (biasing gate and current carrying source and drain contacts) at a transducer level.
Our research team is convinced that the use of surface chemistry on the chip is as important as the electronic structures in realizing efficient neuron chips. They use organic biomolecules to ensure neuronal viability; guide neuronal growth onto the active areas of the chip; intensify the neuron-electronic junction by anchoring the neuronal membrane; induce formation of pre-synaptic terminals directly on top of the sensing gate of the chemical neuron transducer; and trigger a signal in the chemical neuron transducer by a receptor binding or enzymatic action.
Packaging Challenge: Shielding the Electronics
Packaging neuron-transistor chips is a tricky business. It involves housing neurons in an aqueous solution, efficiently interfacing only the active gate area and benign materials, while at the same time keeping the electronics substrate and bonding wires dry. IMEC has developed a flip chip assembly method adapted for the particularities of the neuron chip. This kind of assembly offers the advantage that the active area of the device and the electrical connections are situated on opposite sides of the carrier, preventing wetting of electrical leads. Moreover, flip chip results in high-speed electrical performance, which may prove invaluable when interfacing a myriad of neurons with a vast array of transducers.
The transducers are flip chip bonded on a ceramic carrier, which is preferred because of performance and ease of assembly. An open window of 3 ¥ 3 mm is provided in the carrier to allow access to the active area of the chip. An open glass container with neuron culture can be glued on top of this carrier opening.
This process flow consists of eight steps:
1) A Ta2O5 layer is sputtered onto the entire wafer, except the bond pad area. This material offers good passivation and coupling oxide for the surface chemistry necessary for neuron attachment.
2) A thin Cu layer is used as a seed layer for subsequent electro-deposition of solder bumps.
3) A thick resist mold is applied to define the shape of the metal solder bumps.
4) The solder is electroplated on the bond pads.
5) Resist and seed layer are stripped.
6) A SU-8 ring is patterned, defining the neuron-transistor's active area. All of these steps are performed at wafer level.
7) The wafer is diced and the separated chips are flip chip bonded by thermo-compression onto the ceramic carriers.
8) The space under the chip is filled with a nonconductive underfill epoxy adhesive. Once the assembly has been completed, the same epoxy is used as a glob-top material to protect the backside of the chip and the electrical connections.
The potential benefits from the combination of electronics and biological technologies will take many formats in the future. Neurons-on-chip is a basic step in this advancement.
CARMEN BARTIC, R&D scientist; KOEN DE KEERSMAECKER, Ph.D candidate; and ELS PARTON, scientific editor, may be contacted at IMEC, Kapeldreef 75, B-3001, Leuven, Belgium; +32 16 281 880; email@example.com.