SYSTEM COMPRISING PARTICLES AND A REMOVABLE DEVICE

Abstract

The present invention relates to advantageous particles and to a system comprising such particles as well as a removable device, wherein the particles are preferably below 100 μm, are stably interacting with hair follicles, biological cells of the dermis and/or epidermis, LTMRs and/or end-organs, and are preferably activated by a signal emitted by the removable device.

Claims

1-19. (canceled)

20. A system (A) comprising particles (B) and a removable device (C), wherein the size of particles (B) is below 100 μm, particles (B) are stably interacting with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs of a subject, and particles (B) are prepared from a material selected from a conductor, a semiconductor, a semiconductor with direct bandgap, an insulator, a piezoelectric and a magnetoelectric material, and are activable by a signal emitted by the removable device (C), and the removable device (C) collects an input signal which is, optionally processed and, used to activate the particles (B), the removable device being wearable by a subject.

21. The system according to claim 20, wherein the biological cell is selected from a keratinocyte, melanocyte, Merkel cell, Langerhans cell, fibroblast, mast cell, macrophage, lymphocyte and platelet, the LTMR is selected from SAI-LTMR, SAII-LTMR, RAI-LTMR, RAII-LTMR, Aδ-LTMR and C-LTMR and/or the end-organ is selected from Ruffini corpuscle, Meissner corpuscle, Pacinian corpuscle and longitudinal lanceolate ending.

22. The system according to claim 20, wherein the removable device (C) is stably interacting with particles and, both the removable device and particles are not located at a biological area of the subject corresponding to fingertips, mouth, lips and foot soles.

23. The system according to claim 20, wherein the device (C) comprises a collector module (c1) collecting an input signal which is selected from a physical signal, a chemical signal and a biological signal, the collector module (c1) being capable of processing the signal when required, and a stimulator module (c2).

24. The system according to claim 23, wherein the collector module (c1) comprises a module (c1′) collecting an input signal and a processing module (c1″) encoding the input signal into an output signal readable by the stimulator module (c2).

25. The system according to claim 23, wherein the stimulator module (c2) comprises a source of energy which is selected from an electrical source, a light source, a magnetic source and a mechanical source, said source using the output signal to activate the particles (B).

26. The system according to claim 23, wherein the device (C) is included in jewelry, in clothing or in a medical device.

27. The system according to claim 26, wherein the device (C) is a bracelet, a ring, a necklace, an artificial skin, a patch, a bandage, a mitt or a glove.

28. The system according to claim 20, wherein particles (B) are incorporated in a composition which is a liquid, a tattoo ink, or a gel, or are part of a needle or a microneedle or are a part of a tip of a needle or microneedle.

29. The system according to claim 25, wherein: i) when the source of energy is an electrical source, the particle is prepared from a material selected from a conductor, a semi-conductor, an insulator and a piezoelectric material; ii) when the source of energy is a light source, the particle is prepared from a material selected from a semiconductor with a direct band gap material and a conductor made of carbon atoms; iii) when the source of energy is a mechanical source, the particle is prepared from a piezoelectric material; and iv) when the source of energy is a magnetic source, the particle is prepared from a magnetoelectric material.

30. A method for sensory enhancement in a healthy subject or for creating new sensory means in a healthy subject comprising providing said healthy subject with a system according to claim 20 and implanting or injecting particles (B) into a site of said subject to allow the perception of a physical signal, chemical signal and/or biological signal which are not perceived by a sense of the subject when stimulated by the removable device (C).

31. A method for providing touch sensory restoration in an amputee or in a burn victim, or for sensory substitution in a subject at least partially deprived of taste, smell, hearing, balance and/or vision comprising implanting or injecting particles into said amputee, burn victim, or subject at least partially deprived of taste, smell, hearing, balance and/or vision or a composition comprising said particles, such that said particles interact with hair follicles, biological cells of the dermis and/or epidermis, LTMRs and/or end-organs of the subject and activating said particles or said composition comprising said particles with an external source of energy, wherein the size of each particle is below 100 μm, and the particles are prepared from a material selected from a conductor, a semiconductor, a semiconductor with direct bandgap, an insulator, a piezoelectric and a magnetoelectric material.

32. The method according to claim 31, wherein the composition is a liquid, a tattoo ink, or a gel.

33. The method according to claim 31, wherein the source of energy is selected from an electrical source, a light source, a mechanical source and a magnetic source.

34. The method according to claim 33, wherein: i) when the source of energy is an electrical source, the particle is prepared from a material selected from a conductor, a semi-conductor, an insulator and a piezoelectric material; ii) when the source of energy is a light source, the particle is prepared from a material selected from a semiconductor with a direct band gap material and a conductor made of carbon atoms; iii) when the source of energy is a mechanical source, the particle is prepared from a piezoelectric material; and iv) when the source of energy is a magnetic source, the particle is prepared from a magnetoelectric material.

35. A kit comprising at least two distinct populations of particles, optionally together with a tool designed to deposit and/or position particles at the adequate site of the subject's body for them to stably interact with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs of a subject, wherein the size of particles is below 100 μm, and particles are prepared from a material selected from a conductor, a semiconductor, a semiconductor with direct bandgap, an insulator, a piezoelectric and a magnetoelectric material, and are activable.

36. The kit according to claim 35, wherein the tool is one or more needles, one or more microneedles, a patch or an injector.

37. A kit comprising particles (B), a removable device (C), and one or several tools selected from a sensor, an electrode, a memory and a processor, wherein the removable device (C) is wearable by a subject, the size of particles (B) is below 100 μm, and particles (B) are i) prepared from a material selected from a conductor, a semiconductor, a semiconductor with direct bandgap, an insulator, a piezoelectric and a magnetoelectric material, and ii) activable by a signal emitted by the removable device (C).

Description

LEGENDS TO THE FIGURES

[0205] FIG. 1: Biological components of dermis and epidermis.

[0206] Epidermis (zone I). The epidermis comprises the stratum corneum (nonviable epidermis) layer, the stratum lucidum (viable epidermis) layer, the stratum granulosum (viable epidermis) layer, the stratum spinosum (viable epidermis) layer, and the stratum basal (viable epidermis) layer. The epidermis comprises the following biological cells: the keratinocytes which represent 95% of cells and are present in each layer, and the melanocytes, the Merkel cells, and the Langerhans cells which represent 5% of the remaining cells and are present in viable epidermis. The epidermis also comprises the following appendages: hairs (hairy skin), sweat glands, sebaceous glands and lipids.

[0207] Dermis (zone II). The dermis comprises the following biological cells: fibroblasts, mast cells, macrophages, lymphocytes and platelets. The dermis also comprises the following appendages: collagen fibrils, elastic connective tissue, mucopolysaccharides, highly vascularized network, lymph vessels, sensory nerves/nerve fibers, free nerve endings, end-organs such as Pacinian corpuscles, Meissner corpuscles, Ruffini corpuscles and/or longitudinal lanceolate endings, hair follicles, sebaceous gland and sweat glands.

[0208] FIG. 2: Electromagnetic signals from the electromagnetic spectrum showing the range of wavelengths and frequencies spanned by electromagnetic radiations.

[0209] FIG. 3: System (A) comprising particles (B) and a removable device (C).

[0210] The particles (B) are below 100 μm, are stably interacting with hairs, hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs, preferably with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs, and are activated by a signal emitted by the removable device (C). The removable device (C) collects an input signal which is, optionally processed and, used to activate the particles (B), the removable device being wearable by a subject.

[0211] The device (C) typically comprises: [0212] a collector module (c1) collecting an input signal which is selected from a physical signal, a chemical signal and/or a biological signal. The input signal may typically be a physical signal, a chemical signal and/or a biological signal perceived by our natural senses, or be a physical, chemical and/or biological signal which cannot be perceived by one of the five natural senses (such as an infrared signal, an ultrasound signal, etc.). The collector module may comprise a collector module (c1′) collecting an input signal and a processing module (c1″) encoding the input signal into an output signal readable by the stimulator module (c2); [0213] a stimulator module (c2) comprising a source of energy which is selected from an electrical source, a light source, a magnetic source and a mechanical source, said source using the output signal to activate the particles (B).

[0214] The spikes, generated in response to input signal(s) from the collector module, confirm the successful reading of the output signal by the stimulator module present in the system (A) as well as the successful stimulation of the particles by the source of energy used to stimulate the peripheral nerves which will then convey/transmit a signal to the central nervous system which it can interpret.

[0215] FIG. 4: Schematic representation of a stimulus (current)/amplitude response curve.

[0216] Schematic representation of a theoretical stimulus (current)/amplitude response curve recorded in a Sensory Nerve Conduction (SNC) experiment. The amplitude response is given in % and normalized to the size of amplitude obtained at the plateau (i.e., the maximal amplitude response).

[0217] FIG. 5. Schematic representation of a stimulus (current)/amplitude response curve when conductor, semiconductor or insulator particles of the invention are present.

[0218] (A) Schematic representation of a theoretical stimulus/response curve when semiconductor or conductor particles (B) are stably interacting with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs, and are activated by the signal emitted by the removable device (C) (herein typically an electrical signal generated by a stimulating electrode). In dotted black line, the amplitude response curve in presence of conductor or semiconductor particles is shifted to the left when compared to the amplitude response curve in the absence of any particles (in full black line).

[0219] (B) Schematic representation of a theoretical stimulus/response curve when insulator particles (B) are stably interacting with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs, and are activated by the signal emitted by the removable device (C) (herein typically an electrical signal generated by a stimulating electrode). In dotted black line, the amplitude response curve in presence of insulator particles is shifted to the right when compared to the amplitude response curve in the absence of any particles (in full black line).

[0220] FIG. 6. Experimental procedure.

[0221] (A) Naïve animals; (B) Animals receiving one injection of “control solution” or “particles' suspensions” (X1) at day 0 (D0); (C) Animals receiving two injections of “control solution” or “particles' suspensions” (X2, X3) at day 0 (D0) and day 3 (D3).

[0222] FIG. 7. stimulus (current)/response curve of animal subcutaneously injected with “control solution”.

[0223] Current threshold (0.3 mA) and stimulus response curve observed in one animal subcutaneously injected with “control solution” at day 0 (D0) and day 3 (D3). Baseline recording (at D0) is represented in dotted black line, recording at day 1 (D1) is represented in full black line and recording at day 4 (D4) is represented in large dotted black line. The stimulus response curve is normalized to the size obtained at the plateau (which corresponds to a current intensity of 5 mA).

[0224] FIG. 8. Current threshold of animals subcutaneously injected with “particles' suspension” X2.

[0225] Current threshold observed at baseline (day 0, D0) and at day 4 (D4) for naïve animals (2 animals) and “particles' suspension” X2 (3 animals). At baseline (D0), 100% of animals in all groups presented a current threshold at 0.3 mA. At D4, 100% of animals from “naïve animal” group presented a current threshold at 0.3 mA whereas only 33% of animals from “particles' suspension X2” group presented a current threshold at 0.3 mA. Instead, at D4, 67% of animals from “particles' suspension X2” group presented a current threshold at 0.5 mA.

[0226] FIG. 9. Stimulus (current)/response curve of animals subcutaneously injected with “particles' suspension” X1.

[0227] (A) Amplitude response (at day 1, D1) observed in one rat subcutaneously injected with “particles' suspension” X1 (doted black line) when compared to baseline (day 0, D0) (full black line). A left shift of the curve due to an increase of amplitude response at low current intensity is observed in the rat with particles X1 when compared to baseline (no particles). (B) The percentage (%) of amplitude response at current intensity between 0.5 mA and 1 mA for rats (2 animals) with particles X1 (D1, dotted black line) is increased by more than 1.5 when compared to the % of amplitude response at baseline (D0, full black line).

[0228] FIG. 10. Stimulus (current)/response curve of animal subcutaneously injected with “particles' suspension” X3.

[0229] The percentage (%) of amplitude response (at day 4, D4) at current intensity 0.5 mA and 0.7 mA for one rat subcutaneously injected with particles X3 (full black line) at day 0 (D0) and day 3 (D3) is increased by more than 3 when compared to the % of amplitude response at baseline (D0), dotted black line).

EXPERIMENTAL PART

Particles of the Invention

[0230] Particles can be manufactured/synthesized according to synthesis methods described in the literature. Characterization of these “as synthesized particles” typically includes the analysis of particles size, composition and structure, the analysis of the composition and surface charge of the particles' surface, as well as the analysis of the hydrophilic or hydrophobic behavior of the particles.

[0231] Typical particles syntheses are described for example in the following publications: [0232] Semiconductor particles of FeSe [J. Kwon et al. FeSe quantum dots for in vivo multiphoton biomedical imaging. Science Advances 2019; 5: eaay0044]; [0233] Conductor particles made of gold [G. Frens. Controlled Nucleation for the Regulation of the Particle Size in Monodisperse Gold Suspensions. Nature Physical Science volume 241, pages 20-22(1973)]; [0234] Conductor particles made of ReO.sub.2 [A. L. Ivanovskii et al. Structure and electronic properties of new rutile-like rhenium (IV) dioxide ReO.sub.2. Physics Letters A 348 (2005) 66-70]; [0235] Conductor particles made of Poly(3,4-ethylenedioxythiophene) [E. Cloutet et al. Synthesis of PEDOT latexes by dispersion polymerization in aqueous media. Materials Science and Engineering: C Volume 29, Issue 2, 1 Mar. 2009, Pages 377-382]; [0236] Insulator (piezoelectric or not piezoelectric) particles made of BN [A. Merlo et al. Boron nitride nanomaterials: biocompatibility and bio-applications. Biomater. Sci., 2018, 6, 2298].

Protocol

[0237] In a typical experiment, the selected particles of the invention are administered on one, several or each of the following sites: hairs, hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and end-organs, preferably hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and end-organs. Particles are subsequently activated by an appropriate external source of energy.

[0238] The recording of a signal at the peripheral nervous system level or at the central nervous system level, confirms the activation of the particles and their action on the nervous system. Concretely, an output signal read by the stimulator module (c2) comprising the appropriate source of energy is converted into a signal that stimulates the peripheral nerves. Then, the peripheral nerves convey the information to the brain for neural coding and touch sensory restoration, sensory substitution, sensory enhancement or new sensory perception.

Evaluation of the Effect of Particles of the Invention on Sensory Nerve Conduction (SNC) in the Caudal Nerves of Rats.

Preamble

[0239] In the present experiment, the impact of subcutaneous administration of particles of the invention on the orthodromic sensory nerve conduction (SNC) was studied in the caudal nerve of rats. The investigation was conducted after 1 injection (on day 0, D0) or after 2 injections (on DO and day 3, D3) of the particles of the invention.

[0240] Sensory nerve action potential (SNAP) was obtained by stimulating sensory fibers and recording the nerve action potential (AP) at a point further along that nerve. The SNAP is a sum of APs of all stimulated nerve fibers in the tested nerve (in the present example, the caudal nerve of the rat). The SNAP onset indicates the AP arrival at the recording site (i.e., the recording electrode). The onset latency is also the time of the AP propagation between the stimulating and recording sites (i.e., the time to complete the distance between the stimulating and the recording electrodes), and can be used to compute the conduction velocity. In SNAP measurement, the onset latency depends on the fastest conducting nerve fibers and the conduction velocity reflects conduction in the fastest axons, while peak latency is an expression of the mean conduction velocity value among all nerve fibers participating in the SNAP. Recording the SNAP orthodromically refers to distal nerve stimulation and AP recording more proximally (the direction in which physiological sensory conduction occurs in the living subject).

[0241] The SNAP amplitude (typically expressed in μV) represents the number of sensory nerve fibers activated when exposed to a given current intensity (typically expressed in mA). When increasing the current intensity, a threshold current is first observed which corresponds to the minimal current intensity that produces detectable action potential responses. As the current intensity further increases, more sensory nerve fibers become activated and the SNAP amplitude increases. This will continue until all nerve fibers supplying the tested nerve are stimulated. The amplitude response therefore reaches a maximum value beyond which further increase of current intensity does not trigger further increase of activated sensory nerve fibers. Such intensity is called “maximal” (see a typical theoretical stimulus (current)/response curve on FIG. 4).

[0242] In the context of the present example, the particles of the invention (particles (B)) are intended to work through an “on”/“off” mode of action, meaning that when stably interacting with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs, and activated by an external source of energy, they act as transducers and convert the incoming signal into an output signal of different nature, or modulate/relay locally the incoming signal, thereby acting on peripheral nerves to convey an information to the brain for neural coding (i.e., processing of information).

[0243] In this context, FIG. 5A presents the theoretical stimulus (current)/response curve when semiconductor or conductor particles are used, and FIG. 5B presents the theoretical stimulus (current)/response curve when insulator particles are used, i.e., when they are inserted into the skin and are then activated by an external electrical source of energy (in the present example, by a stimulating electrode).

[0244] The semiconductor or conductor particles of the invention will typically create, where they are located/administered/injected, a “high conducting medium/spot”. Therefore, under a given current intensity stimulus, they will modulate/enhance locally the number of activated nerve fibers (i.e., increase the amplitude of the response and/or decrease the current threshold), when compared to the number of nerve fibers activated in the absence of any semiconductor or conductor particles (i.e., resulting in a left shift of the stimulus/response curve).

[0245] On the contrary, the insulator particles of the invention will typically create, where they are located/administered/injected, an “insulating medium/spot”. Therefore, under a given current intensity stimulus, they will modulate/decrease locally the number of activated nerve fibers (i.e., increase the current threshold and/or decrease the amplitude of the response), when compared to the number of nerve fibers activated in the absence of any insulator particles (i.e., resulting in a right shift of the stimulus/response curve).

[0246] However, for insulator, semiconductor and conductor particles, the maximum amplitude response value is not expected to be modified as the total volume/number of nerve fibers that can be activated when increasing the current intensity remains constant (corresponding to the total number of nerves fibers of the tested nerve).

Materials and Methods

Test Animals

[0247] Adult female Sprague-Dawley rats of about 6 and 12 weeks of age were used.

Particles of the Invention

[0248] Particles X1, X2, X3 were supplied as suspension (“particles' suspensions”) in sterile tubes.

[0249] X1 corresponds to particles made of gold.

[0250] X2 corresponds to particles made of boron nitride.

[0251] X3 corresponds to particles made of graphene (i.e., particles made of carbon atoms).

[0252] All “particles' suspensions” for injection were prepared at room temperature within typically 4 hours prior subcutaneous injection as follows:

[0253] a) each tube containing the particles suspension was prepared by adding a sterile solution of glucose in order to have a suspension ready for injection (i.e., with the appropriate osmolarity for animal subcutaneous injection). A “control solution” was prepared by diluting sterile solution of glucose in water for injection to a final concentration in glucose equal to 5%; and

[0254] b) the as prepared “particles' suspensions” and “control solution” were vortexed for 5 minutes, and

[0255] c) the “particles' suspension” and “control solution” were used within 4 hours.

Experimental Procedure

[0256] Rats were randomly distributed in experimental groups with 3 or 4 rats per group. Two (2) naïve rats served as control without any injection (See FIG. 6 for the schematic representation of the experimental procedure).

Step 1: Baseline Recording

[0257] At day 0 (D0), all rats were anaesthetized using isoflurane-oxygen using a nose cone. The orthodromic SNAP recording was performed with an electromyograph. Subcutaneous monopolar needle electrodes were used for both stimulation and recording at the animal's tail. However, for the experiments, the stimulating electrodes were not implanted in the animals' tails but remained in contact with the surface of the animals' tails (i.e., they were used as “transcutaneous” electrodes, meaning that only the current penetrates the skin). The stimulating and recording electrode anodes were separated by a fixed standard distance (50 mm) with the recording electrode close to the tail base. A minimum distance between the recording electrode and the stimulating electrode located above the biological area where the particles are located is required (preferably at least 2 cm, for example 5 cm as in the present experiment). A ground was placed between the stimulating and recording electrodes.

[0258] SNAP recording was performed at incremented stimulus intensity (typically from 0.1 mA to 10 mA, such as: 0.1 mA-0.3 mA-0.5 mA-0.7 mA-1 mA-2 mA-5 mA-10 mA). Each stimulation pulse was a monophasic square wave current of 200 μs duration. The caudal nerve was stimulated with 20 series of pulses at a frequency of 1 Hz and the arithmetic average of the SNAP signal was recorded.

[0259] Typical SNAP parameters analyzed were: [0260] the minimal current intensity corresponding to the threshold that produces detectable (evoked) action potential responses (current threshold); [0261] the amplitudes of SNAP and the smallest currents that result in a maximal amplitude response (stimulus (current)/response curve); [0262] the “onset latency”, “peak latency” and sensory nerve conduction velocity.

Step 2: Impact of Particles of the Invention on Snap

[0263] Under animal anesthesia, “control solution” or “particles' suspensions” (X1, X2, X3) were subcutaneously administered to the animal (day 0, D0) at a volume of 50 μL. The site of injection was located just under the stimulating electrode.

[0264] Twenty-four (24) hours following “control solution” or “particles' suspensions” administration (Day 1, D1), SNAP recording as described in STEP 1 was repeated.

[0265] Specifically, for “particles' suspensions” X2 and X3, and “control solution”, 72 hours after the first injection (i.e., at day 3, D3) a second subcutaneous administration was performed at the same site of injection. The site of injection was located just under the stimulating electrode. Twenty-four (24) hours following the second administration (days 4, D4), SNAP recording as described in STEP 1 was repeated.

Results

Clinical Sign and Body Weight

[0266] There was no macroscopically visible change in the behavior of rats after the injection of the “particles' suspensions” or of the “control solution”. There was no sign of body weight loss during the study.

SNAP Measures.

[0267] Animals Subcutaneously Injected with “Control Solution”

[0268] FIG. 7 represents a typical stimulus response curve obtained for animals subcutaneously injected with the “control solution”. The current threshold is 0.3 mA and the minimum current intensity that results in a maximal amplitude response is observed at 5 mA. A repeatable stimulus response curve is observed at 3 different time points, i.e., DO (baseline recording), D1 and D4.

[0269] “Control solution” and naïve animals showed similar results (data not shown), highlighting the absence of impact of vehicle (sterile glucose 5%) injection on SNAP measures.

[0270] For all “particles' suspensions” the maximal amplitude response fell between the maximal amplitude response found in both naïve animals and animal injected with the “control solution”. The minimum current intensity that produced the maximum response was about 5 mA. Therefore, normalization of the amplitude response to the size obtained at 5 mA was used to interpret the stimulus/response curves of “particles' suspensions” groups.

“Particles Suspensions” Groups

“Particles' Suspension” X2

[0271] At D0, D1 and D4, a current threshold of about 0.3 mA was observed for naïve rats and “control solution”. However, an increase in the threshold intensity (from 0.3 mA to 0.5 mA) was observed in 1 out of 3 rats at D1 and in 2 out of 3 rats at D4 for “particles' suspension” X2, indicating a right shift of the stimulus response curve. The increased number of rats presenting a threshold intensity at 0.5 mA was correlated with the increased number of particles X2 subcutaneously injected (FIG. 8).

“Particles' Suspension” X1

[0272] Rats with subcutaneous injection at DO of “particles' suspension” X1 beneath the stimulating electrode showed at D1 a left shift of the stimulus/response curves with typically a more than 1.5-fold increase of the percentage of amplitude response observed at current intensity between 0.5 mA and 1 mA when compared to baseline (no particles) (FIG. 9).

“Particles' Suspension” X3

[0273] Rats with subcutaneous injection at DO and D3 of “particles' suspension” X3 showed at D4 a more than 3-fold increase of the percentage of amplitude response observed at current intensity 0.5 mA and 0.7 mA when compared to baseline (no particles), corresponding to a left shift of the stimulus/response curves when compared to baseline (no particles) (FIG. 10).

Onset Latency, Peak Latency and Conduction Velocity (Data not Shown)

[0274] The onset response latency reflects the action potential propagation time for the largest, fastest sensory axons and was used to calculate the sensory nerve conduction velocity (SNCV). SNCV was already found maximal at the current stimulus threshold. There was no major difference in terms of onset latency and SNCV among all groups.

[0275] The peak latency reflects the latency (conduction velocity) along the majority of axons and is measured at the peak of the action potential. There was no major difference in the peak latency among all groups.

CONCLUSION

[0276] The obtained results indicate that: [0277] the treatment with “control solution” did not modify the SNAP response as measured in the caudal nerves of rats when compared to naïve animals. [0278] X2 particles of the invention shifted the stimulus/response curves (amplitude) to the right, which showed a reduced number of fibers that responded to the given intensity (below 5 mA) when compared to animals without particles. [0279] X1 and X3 particles of the invention did not interfere with the SNAP and shifted the stimulus/response curves (amplitude) to the left, which showed an increased number of fibers that responded to the given intensity (below 5 mA) when compared to animals without particles. [0280] None of the tested particles affected the maximal stimulation (current) intensity, showing a lack of interference with the excitability of the majority of excitable fibers at high stimulation intensity.

[0281] The results showed the efficiency of the herein described particles of the invention to modulate incoming external signal(s), thanks to the stable interaction of the particles with hair follicles, biological cells of the dermis and/or epidermis, Low Threshold Mechanoreceptors (LTMRs) and/or end-organs (stability being directly correlated to the design of the particles), and their activation by the signal emitted by the removable device (C) (herein the electrical signal generated by the stimulating electrode), thereby acting on peripheral nerves to convey an information to the brain for neural coding.

[0282] Interestingly, multiple injections with conductor, semiconductor and/or insulator “particles suspensions” can be performed thereby offering the possibility of creating multiple levels of electrical modulation of the nerve fibers for coding.

[0283] Alternatively, other external source of energy can be used. Typically, for particles made of semiconductors with direct band gap material or for particles made of conductors prepared with carbon atoms, such as graphene, a light source can be used to activate the particles which will thus be capable of acting on peripheral nerves to convey an information to the brain for neural coding.

[0284] A similar system can be used also to restore or enhance the functioning of organ(s) or tissue(s) by allowing the stimulation of motor nerve(s).