Bioelectronic medicines: a research roadmap

Realizing the vision of a new class of medicines based on modulating the electrical signalling patterns of the peripheral nervous system needs a firm research foundation. Here, an interdisciplinary community puts forward a research roadmap for the next 5 years.
With the rapid rise in technology for the precision detection and modulation of electrical signalling patterns in the nervous system, a new class of treatments known as bioelectronic medicines seems within reach1. Specifically, the peripheral nervous system will be at the centre of these advances, as the functions it controls in chronic diseases are extensive and its small number of fibres per nerve renders them more tractable to targeted modulation.
The vision for bioelectronic medicines is one of miniature, implantable devices that can be attached to individual peripheral nerves anywhere in the viscera, extending beyond early clinical examples in hypertension2 and sleep apnoea3. Such devices will be able to decipher and modulate neural signalling patterns, achieving therapeutic effects that are targeted at single functions of specific organs. This precision could be further enhanced through closed-loop control: that is, devices that can record neural electrical activity and physiological parameters, analyse the data in real time and modulate neural signalling accordingly1. For this vision to be realized, a solid research foundation for bioelectronic medicines is needed. This article puts forward a roadmap for the next 5 years towards generating that base.
An emerging community of ‘bioelectricians’
This roadmap has its origins in a meeting of research leaders from academia, industry and government in December 2013, for which neurophysiologists, neural engineers, disease biologists, neurosurgeons, as well as data and material scientists came together to define the research path towards bioelectronic medicines. Three principal research areas crystallized in the meeting: the creation of a visceral nerve atlas; the advancement of neural interfacing technology; and the early establishment of therapeutic feasibility. The direction in these areas has been further synthesized and refined by the authors of this roadmap, with the intention of engaging and expanding an emerging research community interested in bioelectronic medicines. Key elements of the plans in these three areas are summarized here, with detailed points and references provided inSupplementary information S1 (box).
Creation of a visceral nerve atlas
As with the large-scale genome and brain projects (see the NIH interim report for further information), a biological map of structure and function — underpinned by data recording standards and central repositories that enable collaborative data mining — will be crucial. The roadmap focuses on the innervation of visceral organs, such as the lungs, heart, liver, pancreas, kidney, bladder, gastrointestinal tract and lymphoid and reproductive organs. Their specific innervation, including sympathetic, parasympathetic, sensory and enteric systems, needs to be mapped, with the goal of achieving resolution at the level of nerve fibres and action potentials.
Structurally, knowledge of the detailed peripheral nerve wiring will guide the selection of organ-specific points of investigation. The key research steps towards establishing such a structural map are to expand the toolkit for high-resolution tracing and fingerprinting of visceral nerve fibres, establish the intra- and interspecies variation of organ innervation, and then build detailed maps in the most appropriate animal model for each organ. Another important early priority is to advance techniques for imaging the anatomical course and targets of visceral nerves in humans, paving the way for precision implantation of bioelectronic medicines in the clinic.
Functionally, the focus should be on decoding the neural signalling patterns that control individual organs. This approach will hinge on simultaneous recordings of both neural signalling and biomarkers of organ function (for example, blood pressure and cytokine release) that should be mined for correlations, and on stimulation and blocking experiments to test causation. The research should be iterative, drilling deeper into the signals as higher-resolution interfacing technology emerges until the functional units of nerve fibres and their signalling patterns are established.
Advancement of interface technology
Neural interfacing technology provides the basis for mapping neural signals and for bioelectronic medicines. Electrode-based interfaces have long been a work horse in electrophysiology and neuromodulation, but they must be adapted and miniaturized to interrogate visceral nerves effectively: cuff and array electrodes need to be scaled to <100 μm nerve diameter, and new materials and architectures should be pursued that can best address largely unmyelinated nerve structure, irregular neuroanatomy and movement in the viscera. Beyond electrodes, biophysical techniques can both help reveal the complex details of action potential patterns in peripheral nerves and pave the way for less invasive precision neuromodulation in the longer term. Such methods include optogenetic and nanoparticle approaches for deciphering, stimulating and blocking action potentials in a large set of nerve fibres in parallel4, and ultrasonic and tomography techniques for non-invasive recording and modulation.
To capitalize on these advances, we also need to develop platform electronics that control the nerve interfaces and integrate high-bandwidth wireless data transfer, power management and signal processing5. Such platforms need to be made both smaller and more reliable to facilitate long-term recording, stimulation and blocking experiments across animal models. A particular need is to make them compatible with experiments in rodents, for which a wealth of disease models exist — something that was recognized in the innovation challenge singled out by the participants in the December 2013 meeting (see the Innovation Challenge for further information). Miniaturization will also be an important requirement to achieve the broad-reaching clinical application of bioelectronic medicines.
Early establishment of therapeutic feasibility
Therapeutic promise is the real impetus for the research described here. Therefore, a range of proof-of-principle experiments should be initiated. Where successful, these should be followed by optimization of the ‘treatment codes’ — the specific signalling patterns to be introduced in nerves to most effectively treat disease.
Proof of principle here means defining which neural circuits exert influence over disease progression in a representative animal model. By focusing on two types of experiments, rapid read-outs could be achieved across visceral organs and functions: the first is to examine the correlation of neural signals and biomarker patterns during disease progression, and the second is to investigate the effect of blocking and stimulating neural activity during established disease.
A longer experimental phase should then be pursued to determine the treatment code. This testing can be broadly split into four types of investigation. First, the best intervention point on the nerve needs to be established: near to the target organ on small nerve branches or farther from the organ on the larger, mixed preganglionic bundles of nerves. Second, the equivalent to dose–response curves should be developed in the multi-dimensional neural signal pattern space. Third, the potential added benefit of ‘closing the loop’ — self-tuning of the modulation in response to neural patterns and disease biomarkers — needs to be evaluated. Last, the long-term safety of disease-modifying neuromodulation needs to be assessed, including potential immune reactions, neural responses and physiological adaptation. Together, these investigations would lay a solid foundation upon which multiple future bioelectronic medicines could be prototyped.
The research outlined here, and detailed further in Supplementary information S1 (box), aims to serve as a guide for the growing community entering the field of bioelectronic medicines. If executed successfully, it will help bring a new class of precision medicines to patients.
Source: nature


Acupuncture Reduces Neuropathy Associated With Bortezomib.

Acupuncture may be able to reduce neuropathy associated with the use of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.) in multiple myeloma patients, suggest new data. The results are early, but patients treated with acupuncture appeared to experience both subjective and objective improvements in symptoms.

“Acupuncture is feasible and safe for treating multiple myeloma patients with persistent and moderate pain due to bortezomib-induced peripheral neuropathy [BIPN],” said Ting Bao, MD, an assistant professor of medicine at the University of Maryland, in Baltimore. She noted that all patients appeared to have decreased pain and improved function, as evidenced by improved scores on standardized measures.

Dr. Bao presented her results here at the 10th International Conference of the Society for Integrative Oncology (SIO).

Bortezomib is an effective treatment for multiple myeloma, but its use can cause sensory neuropathy, which can limit dose and duration of treatment, she explained. “Peripheral neuropathy is one of the most common and severe toxicities, and treatment is limited to symptom management.”

Symptoms are often difficult to manage, and available treatment options frequently do not provide total relief and can cause adverse effects. Conversely, Dr. Bao pointed out, acupuncture has no side effects, and several studies have demonstrated the efficacy of acupuncture in treating peripheral neuropathy.

“As such, we hypothesized that acupuncture was a safe, feasible, and effective approach to treating BIPN, and that it works through modulating serum cytokines,” Dr. Bao said. “So as a first step in testing this hypothesis, we designed a single-arm, single-institution study.”

Safe and Feasible

For their pilot study, Dr. Bao and colleagues enrolled 27 patients with multiple myeloma who were experiencing persistent bortezomib-induced peripheral neuropathy of grade 2 or greater, despite receiving adequate medical intervention, and who were no longer using the agent.

All patients in the cohort received 10 acupuncture treatments for 10 weeks (2x/week for 2 weeks, 1x/week for 4 weeks, and then biweekly for 4 weeks), and their responses to treatment were evaluated with the Clinical Total Neuropathy Score (TNSc), the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) questionnaire, and the Neuropathy Pain Scale (NPS).

The TNSc was evaluated by a trained research nurse using both subjective and objective measurements. The researchers also obtained serial serum levels of proinflammatory and neurotrophic cytokines at baseline and at weeks 1, 2, 4, 8, and 14.

Dr. Bao explained that all of the patients had grade 3 to 4 neuropathy, and the median time after discontinuing bortezomib was 19 months, making spontaneous recovery not very feasible. “Neuropathy was already affecting their daily activity,” she said.

At weeks 10 and 14, TNSc, FACT/GOG-Ntx, and NPS all showed significant reduction, suggesting decreased pain, improved function, and improved objective neuropathy measurement (P-values were 0.02 and 0.03 for TNSc at weeks 10 and 14, respectively, and <.0001 for both FACT/GOG-Ntx and NPS at weeks 10 and 14).

Mechanism Unclear

However, results of nerve conduction studies did not significantly change between baseline assessment and end of study. “Fifteen patients had nerve conduction studies before and after acupuncture,” said Dr. Bao. “The majority did not show change.”

“Disappointingly, there was no correlation between symptom reduction and nerve conduction studies,” she continued. “And more disappointingly, 12 serum biomarkers did not show any significant change over time. So the mechanism remains unclear.”

Dr. Bao concluded that even though the mechanism of action still remains unclear, acupuncture is safe, feasible, and may be able to reduce pain and improve function, and that they are planning a follow-up randomized trial.

“These results were very promising, and the next step will be to look at a randomized controlled trial, and that will ultimately be the next step to see if acupuncture is effective in treating bortezomib-induced neuropathy,” said Richard Lee, MD, assistant professor of general oncology at the University of Texas MD Anderson Cancer Center in Houston.

Acupuncture may also be useful in treating other types of neuropathy, said Dr. Lee, who was approached byMedscape Medical News for an independent comment. “This is a very active area of investigation. Our group at MD Anderson, Dr. Bao’s group, and others are looking at peripheral neuropathy.”

“There are many different types of chemotherapy that can cause neuropathy, such as platinum-based agents and taxanes,” he continued. “Whether or not this type of treatment is universal for all types of chemotherapy, we don’t know. We really need further studies to investigate its use with other agents.


Fluoroquinolone Labels Updated to Reflect Heightened Risk for Peripheral Neuropathy.

The FDA is requiring that the labels of fluoroquinolone antibiotics warn of the drugs’ increased risk for peripheral neuropathy.

The risk has been observed with oral and injectable fluoroquinolones, but not topical agents. Patients could experience peripheral neuropathy any time during their treatment, and it could persist for months or years or be permanent.

Patients should contact their healthcare providers if they develop symptoms consistent with peripheral neuropathy in the arms and legs, including pain, burning, numbness, or weakness; change in sensation to touch, pain, or temperature; or change in the sense of body position.

Patients who develop these symptoms should stop taking the antibiotic and receive alternative therapies unless the benefit of the fluoroquinolone outweighs the risk.

Source: FDA MedWatch safety alert

The therapeutic potential of ex vivo expanded CD133+ cells derived from human peripheral blood for peripheral nerve injuries.

CD133+ cells have the potential to enhance histological and functional recovery from peripheral nerve injury. However, the number of CD133+ cells safely obtained from human peripheral blood is extremely limited. To address this issue, the authors expanded CD133+ cells derived from human peripheral blood using the serum-free expansion culture method and transplanted these ex vivo expanded cells into a model of sciatic nerve defect in rats. The purpose of this study was to determine the potential of ex vivo expanded CD133+ cells to induce or enhance the repair of injured peripheral nerves.


Phosphate-buffered saline (PBS group [Group 1]), 105 fresh CD133+ cells (fresh group [Group 2]), 105 ex vivo expanded CD133+ cells (expansion group [Group 3]), or 104 fresh CD133+ cells (low-dose group [Group 4]) embedded in atelocollagen gel were transplanted into a silicone tube that was then used to bridge a 15-mm defect in the sciatic nerve of athymic rats (10 animals per group). At 8 weeks postsurgery, histological and functional evaluations of the regenerated tissues were performed.


After 1 week of expansion culture, the number of cells increased 9.6 ± 3.3–fold. Based on the fluorescence-activated cell sorting analysis, it was demonstrated that the initial freshly isolated CD133+ cell population contained 93.22% ± 0.30% CD133+ cells and further confirmed that the expanded cells had a purity of 59.02% ± 1.58% CD133+ cells. However, the histologically and functionally regenerated nerves bridging the defects were recognized in all rats in Groups 2 and 3 and in 6 of 10 rats in Group 4. The nerves did not regenerate to bridge the defect in any of the rats in Group 1.


The authors’ results show that ex vivo expanded CD133+ cells derived from human peripheral blood have a therapeutic potential similar to fresh CD133+ cells for peripheral nerve injuries. The ex vivo procedure that can be used to expand CD133+ cells without reducing their function represents a novel method for developing cell therapy for nerve defects in a clinical setting.

Source: Journal of Neurosurgery.