Ferroelectret

[Frederic Laureano]

A ferroelectret, also known as a piezoelectret, is a thin film of polymer foams, exhibiting piezoelectric and pyroelectric properties after electric charging. Ferroelectret foams usually consist of a cellular polymer structure filled with air. Polymer-air composites are elastically soft due to their high air content as well as due to the size and shape of the polymer walls. Their elastically soft composite structure is one essential key for the working principle of ferroelectrets, besides the permanent trapping of electric charges inside the polymer voids. The elastic properties allow large deformations of the electrically charged voids. However, the composite structure can also possibly limit the stability and consequently the range of applications.[1]

The most common effect related to ferroelectrets is the direct and inverse piezoelectricity, but in these materials, the effect occurs in a way different from the respective effect in ferroelectric polymers. In ferroelectric polymers, a stress in the 3-direction mainly decreases the distance between the molecular chains, due to the relatively weak van der Waals and electrostatic interactions between chains in comparison to the strong covalent bonds within the chain. The thickness decrease thus results in an increase of the dipole density and thus in an increase of the charges on the electrodes, yielding a negative d33 coefficient from dipole-density (or secondary) piezoelectricity. In cellular polymers (ferroelectrets), stress in the 3-direction also decreases the thickness of the sample. The thickness decrease occurs dominantly across the voids, the macroscopic dipole moments decrease, and so do the electrode charges, yielding a positive d33 (intrinsic or direct (quasi-)piezoelectricity).[2][3]

In recent years, alternatives to the cellular-foam ferroelectrets were developed. In the new polymer systems, the required cavities are formed by means of e.g. stamps, templates, laser cutting, etc. Thermo-forming of layer systems from electret films led to thermally more stable ferroelectrets.[4][5][6]

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Bioelectronic medicine is a rapidly growing field where targeted electrical signals can act as an adjunct or alternative to drugs to treat neurological disorders and diseases via stimulating the peripheral nervous system on demand. However, current existing strategies are limited by external battery requirements, and the injury and inflammation caused by the mechanical mismatch between rigid electrodes and soft nerves. Here we report a wireless, leadless, and battery-free ferroelectret implant, termed NeuroRing, that wraps around the target peripheral nerve and demonstrates high mechanical conformability to dynamic motion nerve tissue. As-fabricated NeuroRing can act as an ultrasound receiver that converts ultrasound vibrations into electrostimulation pulses, thus stimulating the targeted peripheral nerve on demand. This capability is demonstrated by the precise modulation of the sacral splanchnic nerve to treat colitis, providing a framework for future bioelectronic medicines that offer an alternative to non-specific pharmacological approaches.

To verify this, we further applied US to SH-SY5Y-derived neuron-like cells cultured on fibrous ferroelectret non-woven fabric for non-invasive and non-contact stimulation. It is well known that electrostimulation is able to locally change the membrane potential and trigger the opening of voltage-gated calcium channels, allowing an influx of extracellular Ca2+ that activates calmodulin kinases (Fig. 2h)3,38. Therefore, we further applied US to SH-SY5Y-derived neuron-like cells cultured on non-woven fabric for non-invasive and non-contact stimulation. We observed that the non-woven fabric was in close contact with the cell, which in this case meant that the released charges can be immediately conducted to cell membranes (Fig. 2i). The Ca2+-dependent dye Fluo-4 AM was used to fluorescently stain the cells, in which the fluorescence intensity reflects the intracellular Ca2+ concentration to a certain extent (Fig. 2j). Clearly, cells on fibrous ferroelectret non-woven fabric showed significantly enhanced Ca2+ expression (Fig. 2k, Supplementary Fig. 16). Together, US-driven electric output from the ferroelectret fibers could facilitate neural stimulation by opening voltage-gated Ca2+ channels.

Pathological tests were also conducted on vital organs, including heart, liver, spleen, lung, kidney, and brain. H&E staining was collected from these organs at different time points (days 1 and 42) after implantation. All the organs showed no deformation or abnormal lymphatic cell invasion (Supplementary Fig. 21), which further confirmed that all rats were in good health condition, and that the NeuroRing had no systemic side effects.

Armed with this evidence of peripheral neuromodulation, we went on to explore the efficacy of the NeuroRing in disease treatment. We proposed sacral nerve stimulation to treat acute colitis (top, Fig. 4a). Electrostimulation of sacral nerves is expected to reduce inflammation and pain in colitis due to its direct innervation to the distal colon and rectum (Supplementary Fig. 24a)41. This can avoid potential side effects on the cardiovascular system and other internal organs that often occurred with cranial nerves and central nervous system stimulation. Besides, the inhibitory effect of sacral nerve stimulation on colonic inflammation is mediated via the spinal afferent and vagal efferent pathway in addition to the pelvic splanchnic nerve42,43. 10 days before induction of colitis, rats underwent NeuroRing implantation that tightly wrapped the splanchnic nerve extending from the S3 sacral nerve (bottom two images in Fig. 4a, Supplementary Fig. 24b). Subsequently, acute colitis was induced by feeding rats with dextran sulfate sodium (DSS) in their drinking water for 7 days. The occurrence of acute colitis can be observed directly from H&E staining (Supplementary Fig. 24c). In this process, we simultaneously performed intervention therapy triggered by US pulses.

To show the involvement of the central nervous system in both spinal afferent and vagal efferent pathways, we measured electroencephalogram (EEG) in the nucleus tractus solitarius (NTS) of the brainstem (Fig. 4b, Supplementary Fig. 25). NTS, a large and complex structure, is the principal site of termination of visceral afferent fibers in the brain. Once ultrasound activates the NeuroRing at the sacral nerve, the EEG signals change and intensify (Fig. 4b, Supplementary Movie 3). To fully evaluate the effect of US-induced electric stimulation, we used normal EEG (rats not receiving such stimulation) and US alone-induced EEG (rats not implanted with NeuroRing) as control groups. Among them, normal EEG as a basic control group was used to observe the influence of US-induced electrical stimulation on brain activity. US alone group was used to evaluate and differentiate the effects of ultrasonic waves and electrical stimulation on brain activity. NeuroRing treatment induced greater activation of neurons in the NTS, compared with US treatment alone (lower curve, Fig. 4b, Supplementary Fig. 26). Besides, thanks to the ring-shaped design, our NeuroRing was not affected by rotational misalignment. Despite some deflection of the ultrasonic transmitter, the nerves can still be effectively regulated, which is further reflected in the EEG signals (Supplementary Fig. 27).

In summary, the wireless, leadless, and battery-free NeuroRing is an innovation in biotechnology that has the potential to allow precise modulation of organ function by stimulation of peripheral nerves via ultrasonic pulse triggering. The NeuroRing exhibits high mechanical conformability with nerve tissue without affecting normal development and movement. Our results illustrate that the NeuroRing can precisely modulate the sacral splanchnic nerve to alleviate DSS-induced colitis. This study is a practical demonstration of this electrostimulator. We believe that it has promising clinical potential for targeted peripheral neuromodulation, thereby facilitating precise disease treatment.

This precision technology relies on the visceral nerve atlas that focuses on the innervation of visceral organs2,7,45, such as the lung, heart, liver, pancreas, kidney, bladder, gastrointestinal tract, and lymphoid and reproductive organs. Their specific innervation, including sympathetic, parasympathetic, sensory, and enteric systems, are still being mapped with the goal of achieving high resolution at the level of nerve fibers and electric impulses. As this visceral neural atlas is gradually refined, it creates exciting potential for precise implantation of the NeuroRing in the clinic. We envision using this atlas as a reference to implant the NeuroRing anywhere in the body for therapeutic effects. The parameters of neurostimulation can be tuned by adjusting US parameters such as frequency and intensity, to meet the multidimensional requirements for different processes evoked via neurological disorders and diseases. Our study of sacral nerve stimulation for colitis is an example of this potential and the solid foundation for electromodulation of peripheral nerves to treat disease, offering a potential alternative to non-specific pharmacological approaches and their attendant side effects46. Although our current research is to treat diseases by modulating nerve bundles through fibrous ferroelectric non-woven fabric, the core ideas and supporting technology platforms can be transferred and adapted to disease-specific neurons. For example, the non-woven fabric can be replaced by gel-state nanoparticles that are able to be injected into targeted neural tissue or even where individual neurons are located. This seductive vision is challenging but, conceptually, the neuromodulation protocols introduced here can help bring a new class of precision medicine to patients and serve as a framework for the growing field of bioelectronic medicines.

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