Stanford pediatric surgeon James Dunn specialises in helping children with short gut syndrome – a congenital disease in which children are born with short intestinal tracts.

“I’ve been working to grow new intestinal tissue by applying a mechanical force to the intestine – stretching it – but I didn’t have a way to demonstrate that this new tissue is functioning exactly like normal intestine,” he explains.

In seeking a solution, he reached out to Zhenan Bao, director of the Stanford Wearable Electronics Initiative (eWEAR), who has become well known for developing skinlike electrical circuits such as her electronic skin that can sense the weight of a butterfly and the heat of a flame. The result of their collaboration is NeuroString, a multichannel, soft, thread-like implantable biosensor/stimulator.

NeuroString is just a quarter of a millimetre in diameter – about the width of a human hair – and can host hundreds to thousands of independent electronic ‘channels’, each of which can sense neurochemicals, stimulate muscle or nerve, sense gut movement patterns or monitor the activity of a single neuron, among many other promising possibilities. The team details its NeuroString work in the latest issue of the journal Nature.

Unmet needs

“There is great need, in both research and clinical settings, for these minimally invasive sensing and stimulation bioelectronics because currently, clinical tools boil down to rigid and bulky needlelike probes or stiff wires with limited functionality,” explains Xiang Qian, co-director of Stanford’s eWear Initiative and a medical doctor who specialises in neuromodulation to treat severe pain. “It is a high-density electronic fibre that’s also exceptionally biocompatible due to its softness. It can stay inside the body for months at a time or longer and it’s so soft and small that it can be implanted without discomfort or harm to the patient.”

Beyond the thin and soft circuitry, Bao’s team has also developed a clever roll-up fabrication technique. They have prepared a video of the method that shows a prototype with 20 electronic channels laid out on a thin, transparent skin-like material. The film is then rolled tightly into a spindle so thin it is described as one-dimensional. All 20 electrical connecting wires in the example are spiralled inside the string, while the 20 sensors are exposed on the surface. Each independent sensor/stimulator is connected by a discrete wire running the length of the NeuroString to deliver valuable data.

Bao says the approach allows precise control of the positioning and distribution of the active components, and her team has demonstrated a fibre with a remarkable 1,280 individual channels, and many more channels can be added in longer fibres.

New frontiers

On a practical front, the team used the implanted NeuroString to monitor the intestines of a pig and to observe individual neurons in the brain of a mouse over four months.

Dunn explains that, in his field, measuring basic things like how the intestine contracts without interrupting normal activities may sound easy, but it has so far been out of reach, not to mention that the intestine also does a lot of things like absorbing nutrients and secreting biochemicals like serotonin that he might want to track.

“To be able to stimulate the muscle and measure all these other things in a specific region will be transformative for my research and, potentially, my medical practice – NeuroString is a platform for us to understand how the intestine works,” he says.

The research team anticipates that such devices could have far-reaching impacts in fields ranging from neuroscience to gastroenterology. It could, for example, yield robotic pills that can be swallowed to diagnose medical conditions throughout the gastrointestinal tract or be wrapped around an optical fibre to create an ultra-thin endoscope.

Qian thinks NeuroString could introduce an era of minimally invasive, closed-loop neural stimulation techniques – devices that can both sense nerve dysfunction and instantly intervene.

“You only need to stimulate when you detect this abnormal electric signal to shut it down,” he explains. “It will be ten times smaller than conventional alternatives and much safer, with fewer complications.”

In a tubelike form the NeuroString could deliver drugs to precise locations inside the body such as a new form of implantable insulin pump that both senses blood sugar and delivers the life-sustaining hormone on demand, much like the pancreas.

Synthetic organs

One area of research that Bao finds particularly intriguing is organoids – lab-grown tissues that function like real tissue for use in research. Her team, together with Xiaoke Chen, associate professor of biology in the School of Humanities and Sciences, initially developed a NeuroString with only one neurochemical sensor seeded by Bio-X seed funding. The team’s initial development of this advanced NeuroString came under the aegis of the Brain Organogenesis Big Ideas in Neuroscience programme at the Wu Tsai Neurosciences Institute.

The Brain Organogenesis programme is pursuing new models of human brain circuits to understand how the brain develops and what is happening when things go wrong, as in numerous neurological and psychiatric diseases from depression to Parkinson’s disease.

The NeuroString technology was inspired by the need for soft sensors that can be embedded inside the growing organoids that will allow researchers deeper insights into the function and biochemistry of these lab-grown mini-organlike structures to mimic human tissues.

“We hope to thread these thin electronics inside and throughout organoids, to promote and monitor their growth,” Bao says. “That’s our vision.”

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