WO2022200297A1 - Particles as neural interfaces - Google Patents

Particles as neural interfaces Download PDF

Info

Publication number
WO2022200297A1
WO2022200297A1 PCT/EP2022/057395 EP2022057395W WO2022200297A1 WO 2022200297 A1 WO2022200297 A1 WO 2022200297A1 EP 2022057395 W EP2022057395 W EP 2022057395W WO 2022200297 A1 WO2022200297 A1 WO 2022200297A1
Authority
WO
WIPO (PCT)
Prior art keywords
particle
nano
subject
particles
objects
Prior art date
Application number
PCT/EP2022/057395
Other languages
French (fr)
Inventor
Agnès Pottier
Original Assignee
Xphelyum
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xphelyum filed Critical Xphelyum
Publication of WO2022200297A1 publication Critical patent/WO2022200297A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/0404Electrodes for external use
    • A61N1/0408Use-related aspects
    • A61N1/0456Specially adapted for transcutaneous electrical nerve stimulation [TENS]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B19/00Selenium; Tellurium; Compounds thereof
    • C01B19/007Tellurides or selenides of metals

Definitions

  • the present invention relates to the field of human machine interface(s). Inventors more particularly describe advantageous particle(s) which may be used as neural interface(s), and composition(s) comprising such particles.
  • the longest dimension of a typical particle as herein described is of at least 1 ⁇ m and below 100 ⁇ m.
  • the particle typically comprises conductor nano-objects or (both) conductor and semiconductor nano-objects, the conductor, and semiconductor (if present), nano-objects being at least partially embedded in an insulating biocompatible matrix.
  • the present description further relates to a system comprising such particles and a removable device wearable by a subject.
  • the particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of the subject.
  • the particles may also be non-invasively administered to the subject (i.e., administered at the dermis level of the subject, like a tattoo).
  • the removable device collects an input signal which is, optionally processed and, used to activate the particles.
  • the design of a neural interface is crucial.
  • the efficiency for coding and/or decoding information in the brain of a subject which includes in particular the ability for the interface(s) to achieve high spatial and temporal resolutions to efficiently stimulate/modulate and/or detect neural signals, remains to be improved;
  • the robustness/reliability of the neural interface which depends in particular of the permanency and biocompatibility (i.e., safety) of the interface(s) at the most relevant location/site/position in a subject, remains to be improved.
  • the longest dimension of the particle is of at least 1 ⁇ m and below 100 ⁇ m
  • the particle comprises:
  • a volume fraction of at least about 0.005% of conductor nano-objects and a volume fraction of at least about 0.1 % of semiconductor nano-objects, based on the total volume of the particle, and iii) the conductor nano-objects, and optionally the semiconductor nano-objects if present in the particle, are at least partially embedded in an insulating biocompatible matrix.
  • the particle of the invention is the simplest object usable to date as an efficient neural interface. Among other qualities it is small, i.e., not bulky, and it can be used non-invasively and efficiently in any mammal, in particular in a human being.
  • Magnetic nanoparticles embedded in polymer microparticles describes hybrid magnetic materials comprising typically nanoparticles (in particular iron oxide (FesCU) nanoparticles) embedded in non-magnetic microparticles (in particular polymer microparticles). These materials can be used to directionally orient and impart an ordered structure to a variety of materials in the context of user-friendly methods to manufacture filled plastic parts and composites via, for example, compression molding.
  • the resulting microparticles are magnetic microparticles, i.e., they respond to/can be stimulated by a magnetic signal and thus, can be oriented in a magnetic field to construct structures that have tailored mechanical and physical properties as a result of the magnetically controlled orientation and morphology of its building blocks.
  • WO2019/204468 does not relate to human machine interface and does not describe particles capable of generating on demand both efficient and robust/reliable neural signals.
  • a particular particle comprises several nano-objects, the nano-objects being:
  • each nanoplate having one dimension between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, - nanofiber(s), each nanofiber having two dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, and/or
  • each nanoparticle having three dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm.
  • the particle is for use for treating a subject via an acupuncture effect when the particle is administered to the subject at an acupoint, and then activated by:
  • the particle is for use for sensory restoration in a subject when the particle is administered in the dermis and/or hypodermis of the subject, and then activated by:
  • the particle is for use for sensory substitution in a subject when the nanoparticle is administered in the dermis and/or hypodermis of the subject, and then activated by:
  • a preferred particle comprises semiconductor nano-objects made with a direct bandgap material (such particles are emitting light).
  • the particle is non-invasively administered to the subject.
  • composition comprising particles as herein described and a pharmaceutically acceptable carrier.
  • Inventor also herein describe a system comprising particles as herein described and a removable device, wherein the particles are located at an acupoint of a subject, in the dermis and/or hypodermis of a subject, or are non-invasively administered to a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to activate the particles by external signal(s), the removable device being wearable by a subject.
  • dimension (also identified in the art as the “external dimension”) is used in its usual sense and designates in particular the length, width, height or thickness of an object.
  • a dimension typically follows an “axis” x, y or z in a volume.
  • the term “nano-object” designates any object having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm.
  • ID one dimension
  • 2D two dimensions
  • 3D three dimensions
  • a nano-object also herein designates an aggregate of nano-objects, said aggregate having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm.
  • ID one dimension
  • 2D two dimensions
  • 3D three dimensions
  • nanoparticle designates any object having three dimensions (along the perpendicular x, y and z axes) above about 0.3 nm, or preferably above about 0.5 nm or about 1 nm, and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, and where the lengths of the longest and the shortest axes of the nano-object do not differ by more than three.
  • nanofiber designates any object having two dimensions above about 0.3 nm, for example above about 0.5 nm or about 1 nm, and below about 100 nm or about 50 nm, and the third dimension being larger, for example having a third dimension at least three times larger than the other two, and not necessarily below 100 nm.
  • nanoplate designates any object having one dimension (its thickness) above about 0.3 nm, for example above about 0.5 nm or about 1 nm, and below about 100 nm or about 50 nm, and the two other dimensions being larger, for example having the two other dimensions at least three times larger than the other one, and not necessarily below 100 nm.
  • nanolayer or “nanosheet” is typically used when the object is made of a monolayer of material;
  • nanosheet is typically used when the object is made of more than one layer and up to ten (10) layers of material(s);
  • nanoplatelet is typically used when the object is made of more than ten (10) layers of material(s).
  • Carbon-based nano-objects are typically carbon nanotubes (single-wall or multi-walls nanotubes), carbon ball, carbon black, graphite, or graphene-related nano-objects which differ by their structures (e.g., graphene-related nanosheets, graphene -related nanoflakes, graphene-related nanoplates) or by their compositions (e.g., pristine graphene, graphene oxide, reduced graphene oxide).
  • Electrical percolation in the particle of the invention refers to the electrical conductivity (also herein identified as “conductivity”) allowed by the presence of conductor nano-objects at least partially embedded in an insulating biocompatible matrix.
  • the presence of conductor nano-objects at least partially embedded in the insulating biocompatible matrix creates an increase of the electrical conductivity of the particle, typically by several orders of magnitude (when compared to the same particle which would have been made with the insulating biocompatible matrix only, i.e., without any conductor nano-objects).
  • a conducting network occurs at a specific conductor nano-objects loading (i.e., at a specific volume fraction of conductor nano-objects within the particle), which corresponds to the percolation threshold.
  • a conductive particle, in particular a conductive particle of the invention can be obtained by adding conductor nano-objects to an insulating biocompatible matrix.
  • the conductivity of the particle rises suddenly.
  • the conductivity of the particle evolves from insulating to percolating and conducting when the volume fraction of conductor nano-objects within the particle reaches and increases above the percolation threshold.
  • An intermediary conductivity typically exists thanks to the tunneling effect when conductor nano-objects (at least partially embedded in an insulating biocompatible matrix) are closed to each other but not in direct contact.
  • the material the particles are made of is not magnetic (i.e., the orientation or motion of particles of the invention is not influenced by exposition to a magnetic field, contrary to what is observed for example with ferrimagnetic particles). Indeed, and without wishing to be bound by any particular theory, it is inventor’s belief that magnetism may be detrimental to the efficient technical effect allowed by the invention (i.e., the coding effect). Thus, in a preferred embodiment, the particles are neither ferrimagnetic nor ferromagnetic particles.
  • the “aspect ratio” of a nano-object corresponds to the ratio of the longest dimension over the shortest dimension of the nano-object.
  • a nanosphere is a nanoparticle having typically an aspect ratio of about 1.
  • a nanoparticle with a spheroid shape or an ellipsoid shape has typically an aspect ratio of about 2 or less than about 3.
  • a nanorod, a nanotube, a nanofiber, a nanoplate, a nanosheet or a nanoflake has typically an aspect ratio above about 3, preferably above about 5, even more preferably above about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, up to for example 1 000, 10000 or 100000.
  • a conductor nano-object with a large aspect ratio is preferred when the nano-object is at least partially embedded in the insulating biocompatible matrix in order to reach the percolation threshold at a low volume fraction (of nano-objects).
  • s so(f - fo)' (only when f > fe), wherein s and so are respectively the conductivities of the particle and of the insulating biocompatible matrix; f is the volume fraction of conductor nano-objects and fe is the volume fraction of conductor nano-objects at the percolation threshold.
  • the exponential factor “t” (which corresponds to the critical power law exponent and depends on the dimensionality of the network) is generally set about 2.
  • the conductive behavior in the insulating, percolating and conductive regimes can be identified from the microstructure of the particle: if there is no electric conductive path through the conductor nanoobjects which are at least partially embedded in an insulating biocompatible matrix, no charge can flow, and the particle remains insulating. On the other hand, if the conductor nano-objects form a directly connected network within the insulating biocompatible matrix, electrons can move through this network, and the particle is conductive. Between these two extremes, conduction takes place when the conductor nano-objects are not in contact but are connected via electrons tunneling through an interface formed between the nano-objects and the matrix; in this case, the conductivity is lower than that observed where a direct network has been formed.
  • This tunneling conduction/effect is a quantum phenomenon.
  • action potential “action potential”, “evoked potential” or “evoked action potential”, refer to the electrical response from a tissue to stimulation.
  • stimulation comes typically from (artificial) external electric signals and/or from artificial external light signals.
  • External electric or artificial external light signals are signals which are not natural (i.e., which are different from signals coming from the nature), but on the contrary are generated by external manmade device(s), typically removable/wearable device(s) which are in contact with (typically touch) the surface of the skin of a subject.
  • external manmade device(s) typically removable/wearable device(s) which are in contact with (typically touch) the surface of the skin of a subject.
  • artificial means that the light signals used to stimulate the tissue (typically a tissue comprising the herein described particles) is not generated by natural light (i.e., light coming from or generated by the sun).
  • the subject in the context of the invention is typically a mammal subject, preferably a human being.
  • the particle or the composition comprising the particles is “non-invasively administered” to a subject
  • the particle or the composition comprising the particles is typically administered in the skin at a depth corresponding to that of a tattoo procedure (typically at the dermis level of the subject, in particular not deeper in the skin such as at the hypodermis level), i.e., the administration is non-invasive and is not to be considered as a physical intervention on the human or animal body.
  • Acupuncture points are located on the surface of a human body and are quantified as 361 classical acupoints by the World Health Organization (WHO) [WHO Standard Acupuncture Point Locations in the western pacific region, World Health Organization, 2008; A proposed standard international acupuncture nomenclature, Report of a WHO scientific Group, World Health Organization 1991].
  • WHO World Health Organization
  • the particle or the composition comprising the particles When the particle, or the composition comprising the particles, is administered at an acupoint of a subject, the particle or the composition comprising the particles is typically administered in the skin at a depth corresponding to that of the dermis and/or hypodermis of the subject, and may even been administered deeper, typically at a depth corresponding to the muscle located below the skin of the subject.
  • acupuncture effect is typically generated when acupoints are stimulated: neuroactive components at acupoints are non-neuronal tissues and biological cells as well as the various mediators capable of modulating afferent signals via local biochemical reactions which are released by these tissues and cells upon activation. In addition, biophysical reactions at acupoints are triggered by the activation of mechanoreceptors. Multiple central neural pathways convey afferent impulses from stimulated acupoints. A distributed network of widespread brain regions that respond to acupuncture provides the neural substrate for broad therapeutic effects of acupuncture. Clinical studies have revealed that acupuncture treatment was capable of normalizing abnormal neuroimaging activity in patients with Alzheimer’s disease, major depressive disorder, etc.
  • fMRI functional magnetic resonance imaging
  • PET positron emission topography
  • the skin comprises the epidermis, the dermis and the hypodermis.
  • 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, 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.
  • 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.
  • the hypodermis comprises lipocytes. It also comprises the following appendages: loose connective tissue (lipocytes, collagen, elastin fibers), blood vessels, nerves and muscle spindles.
  • LTMRs Low Threshold Mechanoreceptors
  • cutaneous sensory neurons may be classified as either Ab, Ad or C based on their cell body sizes, axon diameter, degree of myelination and axonal conduction velocities.
  • their firing pattern to sustain mechanical stimuli is variable, ranging from slow (SA) to intermediate (IA) and to rapidly adapting (RA).
  • SA slow
  • IA intermediate
  • RA rapidly adapting
  • LTMRs associated cutaneous end-organs encode touch stimuli and this encoding is then integrated and processed within the central nervous system.
  • Both hairy and hairless (also named non-hairy or glabrous) skin areas contain discrete sets of LTMRs and associated end-organs (also named endings), and these different sets of LTMRs detect specific tactile modalities.
  • Ab LTMRs also herein identified as SAI-LTMRs
  • Ab SA2-LTMRs also herein identified as SAII-LTMRs
  • RVAI-LTMRs Ab RAl-LTMRs
  • Meissner innervate Meissner’s corpuscles in dermal papillae
  • Ab RA2- LTMRs also herein identified as RAI-LTMRs
  • hair follicles are for example innervated by LTMR termination collars located just below the level of sebaceous gland.
  • LTMR termination collars located just below the level of sebaceous gland.
  • the 3 types of lanceolate-ending LTMRs have identical terminal structures [A. Zimmerman et al. The gentle touch receptors of mammalian skin. Science, 2014; 346(6212), 940-954; A. Handler et al. The mechanosensory neurons of touch and their mechanisms of activation. Nature Review Neuroscience, 2021; 22, 521-537].
  • bonds when the conductor and semiconductor nano-objects are connected, it means that bonds exist between the conductor and semiconductor nano-objects (cf. Figure 2). Bonds are typically direct (i.e., the particles are in contact) or indirect (i.e., the particles are in contact via a linker) covalent bonds, direct or indirect complexing bonds, or direct or indirect ionic bonds, which hold the nano-objects together within the particle. Linkers are typically used when indirect bonds connect the nano-objects together. Linkers from the groups of organosilanes, organothiols, organophosphates and/or cyclic or linear oligomers or polymers of phosphates are preferably used to connect the nano-objects.
  • an ‘insulating biocompatible matrix or material’ is a matrix or a material which does not conduct (or conduct very poorly) electricity and is compatible with living tissues or a living system in that it is not toxic, injurious, or physiologically reactive and does not cause immunological rejection.
  • “stimulating” or “activating” the particle by an (artificial) external source of energy also means “exposing” the particle to an external source of energy, the exposition being typically through the subject’s skin where the particle is located.
  • Particle comprising conductor nano-objects or (both) conductor and semiconductor nano-objects, said nano-objects being at least partially embedded in an insulating biocompatible matrix.
  • the particle comprises conductor nano-objects with an electrical bulk conductivity s of at least lxlO 4 S/m at 20°C, preferably of at least lxlO 5 S/m at 20°C, typically of at least lxlO 6 S/m at 20°C, or lxlO 7 S/m at 20°C, the electrical bulk conductivity corresponding to the electrical conductivity of the bulk material.
  • a preferred conductor nano-object can be selected from a metal nano-object, a crystallized metal oxide nano-object, an amorphous oxide nano-object, a transition metal dichalcogenide nano-object, a carbon- based nano-object, an organic nano-object, and any mixture thereof.
  • the conductor nano-object is made of material(s) selected from the group consisting of metal, crystallized metal oxide, amorphous oxide, transition metal dichalcogenide, carbon- based, and any mixture thereof.
  • the nano-object When the nano-object is a metal, it is typically made of gold (Au) element (“gold nano-object”), Copper (Cu) element (“copper nano-object”), Silver (Ag) element (“silver nano-object”), Molybdenum (Mo) element (“molybdenum nano-object”), Aluminum (AI) element (“aluminum nano-object”), Palladium (Pd) element (“palladium nano-object”), platinum (Pt) element (“platinum nano-object”), or any mixture thereof.
  • Au gold
  • Au gold nano-object
  • Copper (Cu) element Copper nano-object”
  • Silver (Ag) element silver nano-object”
  • Molybdenum (Mo) element Molybdenum (Mo) element
  • Aluminum (AI) element (“aluminum nano-object”)
  • Palladium (Pd) element palladium nano-object”
  • platinum (Pt) element platinum nano-object”
  • platinum nano-object platinum nano-object
  • the nano-object When the nano-object is a crystallized metal oxide particle, it typically comprises rhenium element.
  • the nano-object can typically be a rhenium (VI) trioxide (RcOd nano-object or a rhenium (IV) dioxide nanoobject (ReCh, also named rhenium oxide nano-object).
  • the nano-object When the nano-object is an amorphous oxide, it typically consists of a mixture of at least two metal elements, typically indium and tin to form the indium-tin oxide (ITO) nano-object, indium and zinc to form the indium-zinc oxide (IZO) nano-object, or aluminum and zinc to form the aluminum-zinc oxide (AZO) nano-object.
  • ITO indium-tin oxide
  • IZO indium-zinc oxide
  • AZO aluminum-zinc oxide
  • the nano-object is a transition metal dichalcogenide
  • it is typically a FeS nano-object, a FeSe nano-object, a FeTe nano-object, a TaS nano-object, a TaSe nano-object, a TaTe nano-object or a NbSe nano-object.
  • the nano-object When the nano-object is made of carbon-based material, it has typically a graphene structure, a singlewall carbon nanotube structure, a multi-wall carbon nanotube structure, a reduced graphene oxide structure, a graphite structure or a carbon black structure.
  • the nano-object is made of an organic material
  • it is typically made of polypyrrole, polyaniline, polythiophene or a derivative thereof such as Poly(3,4-ethylenedioxythiophene) or Poly(3,4- ethylenedioxythiophene)-poly(styrenesulfonate).
  • nano-objects comprising a mixture of any one of the herein above described conductor materials as well as nano-objects having a core-shell structure, the core and the shell being prepared from distinct conductor materials, each material being selected from any one of the herein above described conductor materials, and their uses in the context of the present invention, for example in a method as herein taught.
  • the particle of the invention comprises conductor nano-objects, wherein the conductor nano-object is made of material(s) selected from the group consisting of gold, silver, platinum, Poly(3,4-ethylenedioxythiophene), transition metal dichalcogenide, carbon-based material and any mixture thereof.
  • the conductor nano-object is made of material(s) selected from the group consisting of gold, silver, platinum, Poly(3,4-ethylenedioxythiophene), transition metal dichalcogenide, carbon-based material and any mixture thereof.
  • Such a particle has an electrical conductivity of at least 10 4 S/m.
  • the particle of the invention can, in addition to the conductor nano-objects, comprises semiconductor nano-objects having an electrical bulk conductivity s of at least 1x10 3 S/m at 20°C, preferably between lxlO 3 S/m and lxlO 2 S/m at 20°C, even more preferably below lxlO 2 S/m at 20°C, even more preferably of at least 1x10 2 S/m at 20°C, between 1x10 2 S/m and lxlO 2 S/m at 20°C, or below lxlO 2 S/m at 20°C, the electrical bulk conductivity corresponding to the electrical conductivity of the bulk material.
  • a preferred semiconductor nano-object can be selected from a metal oxide nano-object, an organic nanoobject, a silicon or a germanium nano-object, a transition metal dichalcogenide nano-object, a quantum dot, a perovskite nano-object, and any mixture thereof.
  • the semiconductor nano-object is made of material(s) selected from the group consisting of metal oxide, silicon, germanium, transition metal dichalcogenide, perovskite, a ternary I-III-VI2 nanocrystal wherein I is selected from Cu + and Ag + ; III is selected from Al 3+ , Ga 3+ , and In 3+ ; and VI is selected from S 2_ , Se 2_ , and Te 2_ , and any mixture thereof.
  • the mixture is in the form of a quantum dot, in particular in the form of a carbon- based quantum dot such as graphene quantum dot.
  • the nano-object When the nano-object is a metal oxide, it typically consists of a mixture of at least two metal elements, typically of three metal elements such as indium, gallium and zinc to form an indium-gallium-zinc oxide (a-IGZO) nano-object.
  • the metal oxide may also be prepared with a single metal element, typically the zinc element to form a zinc oxide (ZnO) nano-object, the titanium element to form a titanium dioxide (also named titanium oxide) (T1O2) nano-object, the tin element to form a tin oxide (SnO) nano-object.
  • the nano-object When the nano-object is made from an organic material, it typically consists in, or comprises, small molecules or polymers, for example pentacene, poly(3-hexylthiophene) (P3HT), poly(diketopyrrolopyrrole-terthiophene) (PDPP3T), 5, 50-bis-(7-dodecyl-9H-fluoren-2-yl)-2, 20- bithiophene (DDFTTF) and/or polyisoindigobithiophene-siloxane (PiI2T-Si).
  • P3HT poly(3-hexylthiophene)
  • PDPP3T poly(diketopyrrolopyrrole-terthiophene)
  • DDFTTF poly(diketopyrrolopyrrole-terthiophene)
  • PiI2T-Si polyisoindigobithiophene-siloxane
  • the nano-object When the nano-object is made of silicon, it typically has an amorphous (a-Si) structure, a polycrystalline structure or a crystalline structure.
  • the nano-object When the nano-object is made of germanium, it typically has an amorphous structure or a crystalline structure.
  • the nano-object is a transition metal dichalcogenide
  • it is typically a M0S 2 nano-object, a MoSe 2 nano-object, a MoTe 2 nano-object, a WS 2 nano-object, a WSe 2 nano-object, a ReS 2 nano-object, a ReSe 2 nano-object, a FeSe nano-object or a FlfS 2 nano-object.
  • the nano-object is a quantum dot (also named a semiconductor nanocrystal), it is typically a carbon-based quantum dot, a GaN quantum dot, a InN quantum dot, a SnO quantum dot, a ZnO quantum dot, a ZnS quantum dot, a SnS quantum dot, a SnSe quantum dot, a FeSe quantum dot, a CdS quantum dot, a CdSe quantum dot, a ZnSe quantum dot, a CdTe quantum dot, a ZnTe quantum dot, a InSb quantum dot, a GeSe quantum dot, a InAs quantum dot, a GaAs quantum dot, a InP quantum dot, a GeTe quantum dot, a GaSb quantum dot, a Germanium quantum dot, a Silicon quantum dot, a SnTe quantum dot, a ternary I-III-VI2 quantum dot
  • Ternary quantum dots are typically CuInSe2, AgBiTe2 or AgBiSe2.
  • the nano-object When the nano-object is a perovskite, it has typically the following structures ABX3, ABCX3, or ABCDX 6 (corresponding to a double perovskite structure), where A is an organic or an inorganic element, B, C and D are inorganic elements, and X is an halide ion or oxygen.
  • the nano-object is KBaTeBiOi, or Ba ⁇ AglO f ,.
  • nano-objects comprising a mixture of any one of the herein above described semiconductor materials as well as nano-objects having a core-shell structure, the core and the shell being prepared from distinct semiconductor materials, each material being selected from any one of the herein above described semiconductor materials, preferably each material being selected from any one of the herein above described quantum dots, and their uses in the context of the present invention, for example in a method as herein taught.
  • the particle comprises semiconductor nano-objects, wherein the semiconductor nano-object is made of material(s) selected from the group consisting of a ternary I-III-VI2 nanocrystal wherein I is selected from Cu + and Ag + ; III is selected from Al 3+ , Ga 3+ , and In 3+ ; and VI is selected from S 2_ , Se 2_ , and Te 2_ , a transition metal dichalcogenide, and any mixture thereof.
  • the mixture is in the form of a quantum dot, in particular of a core-shell quantum dot.
  • the particle comprises semiconductor nano-objects, wherein the semiconductor nano-object is made of carbon-based quantum dot.
  • the semiconductor nano-object is made of semiconductor material(s) with direct bandgap.
  • the conductor and semiconductor nano-objects are connected directly or indirectly and are at least partially embedded within an insulating biocompatible matrix (cf. Figure 2).
  • the nano-objects are objects having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below aboutlOOO nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm.
  • ID one dimension
  • 2D two dimensions
  • 3D three dimensions
  • the size and the aspect ratio of the conductor and semiconductor nano-objects are typically measured using electron microscopy (EM) such as transmission electron microscopy (TEM) or Cryo-TEM, and/or Atomic Force Microscopy (AFM).
  • EM electron microscopy
  • TEM transmission electron microscopy
  • AFM Atomic Force Microscopy
  • At least 100 nano-objects of a population are measured in both their longest dimensions and their shortest dimensions.
  • the aspect ratio of the nano-objects of the population comprising at least 100 nano-objects is obtained by calculating the ratio of the longest dimension over the shortest dimension for each nano-object of the population.
  • Nano-objects having an aspect ratio typically between about 1 and less than about 3, and having 3 dimensions above about 0.3 nm and below about 1000 nm, about 500 nm, about 100 nm, are typically defined as ‘nanoparticles’ (i.e., they belong to the nanoparticle category of nano-objects (cf. Figure 3.A)).
  • Nano-objects having an aspect ratio of more than about 3, preferably of more than about 5, or of more than about 10, and having two dimensions above about 0.3 nm and below about 100 nm are typically defined as ‘nanofibers’ (i.e., they belong to the nanofiber category of nano-objects (cf. Figure 3.B)).
  • nanofibers i.e., they belong to the nanofiber category of nano-objects (cf. Figure 3.B)).
  • the third dimension of objects that fall in the nanofiber category is typically larger, typically more than three times, larger than the two other dimensions.
  • Nano-objects having an aspect ratio of more than about 3, preferably of more than about 5 or of more than about 10, and having one dimension above about 0.3 nm and below about 100 nm (i.e., corresponding to its thickness) are defined as ‘nanoplates’ (i.e., they belong to the nanoplate category of nano-objects (cf. Figure 3C)).
  • nanoplates i.e., they belong to the nanoplate category of nano-objects (cf. Figure 3C)).
  • objects that fall in the nanoplate category have two dimensions larger, typically more than three times, larger than the third dimension, i.e., than the thickness of the nano-object.
  • the nano-objects are nanoparticles
  • said nano-objects have three dimensions (along the perpendicular x, y and z axes). Each dimension is typically above about 0.3 nm, in particular above about 1 nm, and below about 1000 nm, about 500 nm, about 100 nm, preferably above about 1 nm, and below about 100 nm.
  • nano-objects are nanofibers
  • said nano-objects have two dimensions (along the perpendicular x and y, x and z, or y and z axes) over three which are typically above about 0.3 nm, preferably above about 1 nm, and below about 100 nm.
  • said nano-objects have one dimension (along the x, y or z axis) over two which is typically above about 0.3 nm, preferably above about 1 nm, and below about 100 nm.
  • the particle of the invention comprises several nano-objects.
  • these nano-objects are: nanoplates, each nanoplate having one dimension between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, nanofibers, each nanofiber having two dimensions, each dimension being between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, and/or nanoparticles, each nanoparticle having three dimensions, each dimension being between about 0.3 nm and about 1000 nm, about 500 nm, about 100 nm, even more preferably between about 0.5 nm and about 50 nm.
  • the surface of the conductor and semiconductor nano-object is functionalized using a surface coating agent.
  • the surface coating agent is preferably selected based on its ability to establish strong bonds/links with the surface of the nano-object, typically on its ability to establish complexing or covalent bonds. Typical covalent bonds are found between silane-based compounds (i.e., the coating agents) and the surface of the oxide material.
  • bonds considered as exhibiting a strength intermediate between the strength exhibited by covalent bonds and that exhibited by complexing bonds are found between phosphate-based or phosphonate-based compounds (i.e., the coating agents) and the surface of the oxide material, or between thiol-based compounds (i.e., the coating agents) and the surface of the metal (metallic material).
  • the insulating biocompatible matrix is typically made of a biodegradable or non-biodegradable insulating inorganic material, a biodegradable or non-biodegradable insulating organic material, or a mixture thereof.
  • an insulating biocompatible inorganic material is typically an insulating biocompatible polymer such as polydimethylsiloxane (PDMS) or an insulating biocompatible oxide such as zirconium oxide (ZrCP).
  • PDMS polydimethylsiloxane
  • ZrCP zirconium oxide
  • an insulating biocompatible organic material is typically an insulating biocompatible polymer, such as an acrylate polymer or co-polymer, a polyurethane, a polycarbonate or a polytetrafluoroethylene.
  • the insulating biocompatible organic material is an acrylate polymer or co-polymer, it is typically prepared from acrylate monomers such as ethyl acrylate monomers, ethylene- methyl acrylate monomers, methyl methacrylate monomers, 2-chloroethyl vinyl ether monomers, 2- hydroxyethyl acrylate monomers, hydroxyethyl methacrylate monomers, etc.
  • a typical insulating biocompatible acrylate polymer usable in the context of the present invention is the polymethylmethacrylate (PMMA) or the poly(2 -hydroxy ethyl methacrylate).
  • the particle comprises an insulating biocompatible matrix made of a material selected from the group consisting of polymethylmethacrylate, polycarbonate, non-biodegradable polyurethane and any mixture thereof. Conductor and semiconductor nano-objects partially embedded in an insulating biocompatible matrix.
  • the conductor nano-objects, or the conductor and semiconductor nano-objects are at least partially embedded in an insulating biocompatible matrix as herein described (cf. Figure 1A).
  • ‘partially embedded’ means that at least 20%, 30% or 40%, preferably at least 50%, of the surface of the particle is covered with the insulating biocompatible material.
  • the surface of the particle is analyzed using for example Atomic Force Microscopy (AFM): about 5 particles are typically observed, and a map of their surface’s electric property is established.
  • AFM Atomic Force Microscopy
  • the relative ratio (in %) of insulating biocompatible material present at the surface of the particle can be established easily with such a method.
  • the conductor nano-objects, or the conductor and semiconductor nano-objects are fully/ completely embedded in an insulating biocompatible matrix as herein described (i.e., about 100% of the particle’s surface is constituted of the insulating biocompatible material (as shown for example on Figure IB).
  • a two-step process is typically performed.
  • the particle is typically submitted to a thermogravimetric analysis (TGA) under a nitrogen atmosphere, with a heating rate typically between 2°C/min and 10°C/min to determine the weight fraction (wt.%) of conductor and semiconductor nano-objects, based on the total weight of the particle.
  • TGA thermogravimetric analysis
  • the quantitative analysis of the ratio (in weight) of semiconductor and conductor nano-objects (r semiconductor/conductor ) is calculated in the particle using typically the inductively coupled plasma mass spectrometry (ICP-MS) or the inductively coupled plasma optical emission spectroscopy (ICP-OES).
  • the weight fractions of the conductor (wt.% CO nductor) and semiconductor (wt.% semiconductor ) nano-objects within the particle is deduced from the following equations:
  • r semiconductor/conductor correspond to the weight ratio of semiconductor over conductor material.
  • p C onductor, Psemiconductor, and Pmatrix are the (theoretical) bulk density of the conductor, the semiconductor, and the insulating biocompatible matrix, respectively.
  • the volume fraction of the conductor nano-objects in the particle is typically of at least about 0.005%, at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.25%, at least about 0.5% and typically below 100%, for example below about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, preferably below about 35%, based on the total volume of the particle.
  • the volume fraction of the conductor nano-objects in the particle is typically of at least about 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%.
  • the volume fraction of the conductor nano-objects in the particle is for example of at least about 40, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • the volume fraction of the semiconductor nano-objects in the particle is typically of at least about 0.005%, at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.25%, at least about 0.5% and typically below about 40%, preferably below about 35%, based on the total volume of the particle.
  • the volume fraction of the semiconductor nano-objects in the particle is typically of at least about 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%.
  • Mixture of particles can be used wherein the volume fraction of the conductor nano-objects in each particle constituting the mixture is typically of at least 0.005% and typically below 100%.
  • the particle comprises:
  • a particular and preferred object is a particle, wherein i) the longest dimension of the particle is of at least 1 ⁇ m and below 100 ⁇ m, ii) the particle comprises:
  • the size of the particle is typically measured using electron microscopy (EM), such as the scanning electron microscopy (SEM), and/or Atomic Force Microscopy (AFM).
  • EM electron microscopy
  • SEM scanning electron microscopy
  • AFM Atomic Force Microscopy
  • the size of the particle is measured as follows: using the electron microscopy images, the longest dimension of the particle is measured and reported. At least 100 particles of a population are taken, and the measurement of their longest dimension is reported. The median size (which corresponds to the median longest dimension) of the particles of the population is calculated. The “size” (also corresponding to the “longest dimension”) of the particles designates the median size (i.e., the median longest dimension) of the particles of a population comprising at least 100 particles.
  • the longest dimension of the particle is preferably of at least 1 ⁇ m, or of at least 5 ⁇ m, and below 100 ⁇ m.
  • the longest dimension of the particle is for example of at least 1 ⁇ m, 2 ⁇ m, 3 ⁇ m, 4 ⁇ m, 5 ⁇ m, 10 ⁇ m, 15 ⁇ m, 20 ⁇ m, 25 ⁇ m, 30 ⁇ m, 31 ⁇ m, 32 ⁇ m, 33 ⁇ m, 34 ⁇ m, 35 ⁇ m, 36 ⁇ m, 37 ⁇ m, 38 ⁇ m, 39 pm or 40 pm, and below 100 pm.
  • the longest dimension of the particle is of at least 20 pm, preferably of at least 40 pm, and below 100 pm.
  • the shape of the particle is not critical for the invention. However, a particle with a homogeneous shape is preferred.
  • the expression “homogeneous shape” designates particle the sizes of which have been measured in the 3 dimension (x, y, z) and presenting a ratio which does not exceed a factor 3 between each dimension (i.e., x/y ⁇ 3, y/z ⁇ 3 and z/x ⁇ 3).
  • the electrical conductivity of the particle is typically measured on a specimen of millimeter-size range.
  • the specimen of millimeter-size range is prepared from pressed pellet of pure powder of particles.
  • a four-probe station and a source meter in Direct Current (DC) regime is typically chosen for conductivity measurement and silver paste electrodes are typically deposited on the specimen to eliminate the contact resistance between the probe and the specimen.
  • DC Direct Current
  • the material used to press the particles is used as electrode and the electrical conductivity of the specimen is measured using a LCR meter (i.e., an equipment which measures the inductance (L), the capacitance (C), and the resistance (R) of the specimen).
  • LCR meter i.e., an equipment which measures the inductance (L), the capacitance (C), and the resistance (R) of the specimen.
  • the (electrical) conductivity of the specimen results from the combination of the respective conductivity of the particles themselves and of the boundaries between the particles. Said conductivity of the specimen is assimilated to the electrical conductivity of the particle.
  • the electrical conductivity of the particle is typically of at least 10 4 S/m (Siemens per meter), and for example of at least 10 4 S/m and below 10 s S/m, preferably of at least 10 3 S/m and below 10 7 S/m, or of at least 10 2 S/m and below 10 6 S/m, even more preferably of at least 10° S/m and below 10 7 S/m.
  • the electrical conductivity of the particles can be measured in suspension (see for instance Robert Gloukhovski et al. Measurements of the Electric Conductivity of MWCNT Suspension Electrodes with Varying Potassium Bromide Electrolyte Ionic Strength. Journal of The Electrochemical Society, 2020 167020528).
  • the particle of the invention has an electrical conductivity of at least 10 4 S/m.
  • the particle has an electrical conductivity of at least 10 4 S/m and the conductor nano-object is made of material(s) selected from the group consisting of metal, crystallized metal oxide, amorphous oxide, transition metal dichalcogenide, carbon elements, and any mixture thereof.
  • the following particle characterization methods can be performed in the context of the present invention with for example the following purposes: (1) the Fourier-transform infrared (FTIR) spectroscopy or Raman spectroscopy to study the interactions between the nano-objects and the insulating biocompatible matrix; (2) the electron microscopy (EM), such as scanning EM (SEM) or transmission EM (TEM) to study the dispersion and the percentage (%) of the nano-objects embedded in an insulating biocompatible matrix; (3) the energy-dispersive X-ray spectroscopy (EDX) to identify (i.e. to learn on the chemical composition of) the nano-objects within an insulating biocompatible matrix.
  • FTIR Fourier-transform infrared
  • EM electron microscopy
  • SEM scanning EM
  • TEM transmission EM
  • EDX energy-dispersive X-ray spectroscopy
  • the preparation of the particle typically relies on physical dispersion of the nano-objects within an insulating biocompatible matrix.
  • Physical dispersion typically uses ultrasonic agitation (such as the ultrasonic bath or the ultrasonic probe), or shear mixing (such as the use of an Ultra-Turrax®) [cf. Nanoparticle-doped electrically-conducting polymers for flexible nano-microsystems. A. Khosla. The Electrochemical Society Interface. Fall-Winter 2012, pp 67-70; Electrical percolation in graphene- polymer Composites A J Marsden et al 2018 2D Mater. 5 032003].
  • the particle is prepared by ‘melt compounding’: the nano-objects are added to an insulating biocompatible matrix, typically made of an organic material (i.e., such as an organic polymer), and the resulting compound is compounded typically at temperature above the insulating biocompatible matrix’s Tg (Glass Transition Temperature), extruded, molded and subsequently annealed at a temperature sufficiently above the insulating biocompatible matrix’s Tg for enough time.
  • Tg Glass Transition Temperature
  • the particle is prepared by the ‘solvent casting method’: an insulating biocompatible matrix, typically made of an organic material (i.e., such as an organic polymer), is dissolved in an appropriate solvent. A dispersion of nano-objects using a solvent compatible with the insulating biocompatible matrix solution is then added to the insulating biocompatible matrix solution under vigorous stirring. The resulting compound is poured into a mold and the solvent is evaporated.
  • an insulating biocompatible matrix typically made of an organic material (i.e., such as an organic polymer)
  • the particle is prepared by ‘oil-in-water emulsion followed by solvent evaporation’ : an insulating biocompatible matrix, typically made of organic material, and the nano-objects are dissolved/dispersed in an appropriate solvent, typically an organic solvent (non-miscible with aqueous solution).
  • an appropriate solvent typically an organic solvent (non-miscible with aqueous solution).
  • the resulting organic suspension is then added to an aqueous solution and an emulsion is formed by vigorous mixing.
  • the solvent is evaporated typically by further stirring.
  • the resulting suspension is centrifugated and the particles are recovered.
  • the particle is prepared by ‘in situ polymerization’ of an insulating biocompatible matrix, typically made of an organic polymer: a vigorous mixing of nano-objects with organic monomers is performed and followed by polymerization of the monomers using typically a bulk polymerization method with a free radical initiator.
  • the particle is prepared by ‘in situ precipitation’ of the nano-objects in an insulating biocompatible matrix: a vigorous mixing of the precursors of the nano-objects and the insulating biocompatible matrix is performed and followed by precipitation of the precursors and formation in situ of the nano-objects, using typically heat to triggers the formation of the nano-objects.
  • conductor and semiconductor nano-objects are connected directly (i.e., are in contact) or indirectly (i.e., via a linker) prior mixing with an insulating biocompatible matrix.
  • the conductor and semiconductor nano-objects remain connected when at least partially embedded in the insulating biocompatible matrix. The connection may typically be observed using electron microscopy.
  • the particles are typically formulated in a liquid or in a gel.
  • the particles are formulated in a liquid that turns into a gel when administered to a subject.
  • the liquid-to-gel transition typically occurs between 30°C and 40°C.
  • Poly(D,L-lactic acid-co-glycolic acid)-/?- poly(ethylene glycol)-Z?-poly(D,L-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers typically are materials which exhibit a sol-gel transition upon heating.
  • the liquid-to-gel transition temperature is typically affected by the following parameters: the concentration of copolymer, the chain length of PEG, the chain length of PLGA, the molar ratio between PEG and PLGA, or the lactic acid/glycolic acid (LA:GA) ratio within the PLGA. All these parameters can be easily adjusted by the skilled person to trigger a liquid-to-gel transition at a temperature typically comprised between 30°C and 40°C, for example at the human body temperature.
  • the herein defined particles are typically part of a composition which is a liquid or a gel, in particular a liquid having a liquid-to-gel transition temperature between 30°C and 40°C.
  • a controlled release of the particles at the site of administration can be obtained by an adaptation of the gel according to methods well-known by the skilled person in the art.
  • a controlled release of the particles typically between few seconds (for example at least 2 seconds) and 1 week, can be obtained.
  • a controlled release of the particles typically between 1 hour and 1 week, can be obtained.
  • the affinity between the particles and the gel is typically characterized by the type of bonding existing between the particles and the material constituting the gel.
  • the bonding can typically be a hydrogen bonding, a bonding resulting from electrostatic interactions, a complexing bonding or a chemically cleavable covalent bonding.
  • the degradation of the gel typically consists in the swelling (i.e., expansion) of the gel or the breaking of bonds in the material(s) constituting the gel.
  • the gel is ideally biodegradable.
  • a biodegradable gel can typically comprises hydrolytic degradable polyesters blocks, such as poly(e-caprolactone) (PCL) blocks and poly(D,L-lactide- co -glycolide) (PLGA), blocks.
  • the biodegradable gel can comprise polymer blocks with enzymatically degradable peptides, such as poly(L-alanine) (PA) blocks and chitosan blocks.
  • PA poly(L-alanine)
  • the particles or composition comprising such particles herein described can be directly administered to the subject at an acupoint, in the dermis or both in the dermis and in the hypodermis, or non-invasively (i.e., in the dermis), using typically syringe(s) and needle(s) when particles are in suspension (i.e., when they are formulated as a liquid, for example as a liquid that turns into a gel when administered in a subject).
  • the particles can be directly stuck to the surface of a needle (or microneedle), the particles being released in the biological medium typically between few seconds (for example at least 2 seconds) and 10 minutes following needle insertion into the skin typically at an acupoint, in the der is or both in the der is and hypodermis, or non-invasively in a subject.
  • the particles can be formulated as a gel which stuck to the surface of a needle, the gel being released in the biological medium typically between few seconds and 10 minutes upon needle(s) insertion in vivo.
  • a linker agent containing a chemical cleavable bond, or a UV cleavable bond can typically be used.
  • This linker agent binds the particle or the gel containing the particles to the surface of the needle.
  • the linker agent is typically a linker agent containing a chemical cleavable bond such as a cleavable disulphide bond, a cleavable ester bond, or a cleavable hydrazone bond.
  • the particles can become the principal component of the needle(s), microneedle(s), or of the tip(s) of the needle(s) or microneedle(s).
  • the needle(s), microneedle(s), or the tip(s) of the needle(s) or microneedle(s) is(are) inserted in vivo and remain(s) there.
  • the erosion (such as degradation or dissolution) of the needle(s) or microneedle(s), or of the tip(s) of the needle(s) or microneedle(s) triggers the release of the particles, typically within seconds (for example about 2 seconds), hours or days following needle(s) or microneedle(s) insertion/implantation.
  • the needle(s) or microneedle(s) are left in the skin for a pre-determined period and can be removed at any time typically by extracting the part(s) of the needle(s) or microneedle(s) that has/have not been dissolved.
  • Dissolvable needle(s) or microneedle(s) or dissolvable tip(s) of the needle(s) or microneedle(s) typically comprise(s) water soluble polymers, such as polyvinyl alcohol, polyvinylpyrrolidone or polyvinyl acetate, sugars, or any mixture thereof.
  • the dissolvable needle(s) or microneedle(s) or tip(s) of needle(s) or microneedle(s) comprise(s) the herein described particles.
  • needle(s) or microneedle(s) insertion is that performed in the context of tattoo procedures, i.e., insertion is non-invasive (it does not imply a physical intervention on the human or animal body).
  • composition comprising herein described particles and a pharmaceutically acceptable carrier.
  • the particles are not located at a biological area of the subject corresponding to fingertips, mouth, lips and foot soles. This is to limit, ideally avoid, any interference with critical sensory biological areas of human body. In other words, the particles are localized/present on a biological area which is distinct of fingertips, mouth, lips and foot soles.
  • the particles are located on a biological area which corresponds to an acupoint of the subject.
  • the particles or the composition comprising the particles can be administered, simultaneously or in several times, at multiple biological areas of a subject, typically 2, 3, 4, 5, 6, 7, 8, 9 or 10 different biological areas, which are preferably distinct of mouth, lips, fingertips and foot soles.
  • the surface of a biological area represents typically about 0.5 cm 2 , about 1 cm 2 , about 2 cm 2 , about 3 cm 2 , about 4 cm 2 , about 5 cm 2 , about 6 cm 2 , about 7 cm 2 , about 8 cm 2 , about 9 cm 2 , about 10 cm 2 , about 15 cm 2 , or about 20 cm 2 of the skin of the subject.
  • Multiple administrations (targeting multiple administration/injection spots at one or multiple biological areas) of particles or composition comprising particles, typically more than one administration and up to typically 1000 administrations at one or multiple biological areas (each area comprising one or multiple spots) of the subject are typically performed.
  • multiple administrations at one or several administration/injection spots
  • particles or composition comprising the particles are performed per biological area.
  • the distance between two adjacent administrations is typically of less than about 100 ⁇ m, or of about 100 ⁇ m, about 200 ⁇ m, about 300 ⁇ m, about 400 ⁇ m, about 500 ⁇ m, about 600 ⁇ m, about 700 ⁇ m, about 800 ⁇ m, about 900 ⁇ m or about 1000 ⁇ m.
  • Typical biological areas/injection spots where the particles can be valuably administered are for example areas where the subject is used to wear jewelry (such as a ring, a bracelet, a necklace) such as for example the subject’s arm, leg, neck or ankle.
  • jewelry such as a ring, a bracelet, a necklace
  • particles are to be administered once on a given site of implantation. In another particular aspect of the invention, particles are to be administered several times on a given site of implantation. Repeated/successive administrations of particles on a given site can typically be performed in order to increase the number of neural interfaces in the subject, the already administered particles being still usable on-demand when designed as non-biodegradable particles (i.e., used as “permanent” and “re-usable” neural interfaces which means that the conductor nano-objects remain conductor in the particle, and that the semiconductor nano-objects, if present in the particle, remain semiconductor).
  • biodegradable particles are preferably advantageously selected.
  • the volume occupied by the particles per administration/injection site/area is typically between about 0.001 mm 3 (i.e., 0.001 ⁇ L) and about 100 mm 3 (i.e., 100 ⁇ L), preferentially between about 0.005 mm 3 , about 0.01 mm 3 , about 0.05 mm 3 , about 0.1 mm 3 , about 0.2 mm 3 , about 0.5 mm 3 , about 1 mm 3 , about 2 mm 3 , or about 5 mm 3 as a minimum and about 10 mm 3 , about 20 mm 3 , or about 50 mm 3 as a maximum (if several administrations/injections are performed in a given biological area, the volume described in the present paragraph is that resulting from one administration/injection only).
  • the volume occupied by the particles corresponds to the minimum volume measured in vivo (typically using imaging technics well known by the skilled person) which includes all the administered, typically injected, particles. Because the particles remain at their administration site, the volume occupied by the particle corresponds to the administered volume (e.g., the volume of the injected/administered liquid or gel or the volume of the needle, microneedle or tip of the needle or microneedle which has dissolved).
  • the administered volume e.g., the volume of the injected/administered liquid or gel or the volume of the needle, microneedle or tip of the needle or microneedle which has dissolved.
  • the total volume of the particles at the biological area/administration spot corresponds to the sum of the volumes occupied by the particles after each single administration step.
  • Needle(s) or microneedle(s) which can be used to administer/inject the particles has(have) typically the following dimensions: a diameter typically between about 0.10 mm, preferably more than about 0.10 mm, and about 0.50 mm, and a length typically between about 1 mm, about 1.5 mm, about 2 mm, or about 5 mm, and about 100 mm or about 50 mm.
  • the concentration of particles per administration/injection site/area is typically between about 1 mg/100 g (expressed in weight of particles by weight of biological medium) and about 40 g/100 g, preferably between about 0.1 g /100 g or about 1 g/lOOg, and about 20 g /100 g.
  • the concentration of particles at their implantation site corresponds to the concentration of particles which is present in the suspension to be administered in vivo (e.g., the concentration of particles in the liquid or gel or the concentration of particles in the needle, microneedle or tip of the needle or microneedle).
  • the present invention advantageously allows spatiotemporal control of the stimulation of primary afferents (also herein identified as primary sensory neurons or LTMRs) through particles’ activation by (exposition to) external electrical signals and/or (artificial) light signals.
  • primary afferents also herein identified as primary sensory neurons or LTMRs
  • LTMRs primary sensory neurons
  • the electrical stimulation (i.e., the signal) intensity i.e., current intensity
  • the electrical stimulation frequency is typically between 1 Hz and 500 Hz
  • the electrical stimulation pulse width is typically between 5 ps and 500 ms
  • the electrical stimulation waveform is typically a square, a rectangle or a triangle waveform, said square, rectangle or triangle waveform being monophasic, biphasic-charge balanced or biphasic-charge imbalanced, or a pulson (i.e., a square pulse divided in short bursts of square pulses) waveform.
  • the source of energy used to activate the particles is an artificial light source (i.e., a source delivering artificial external light signals)
  • the light stimulation (i.e., the signal) wavelength is typically within the infrared or near infrared, because of its ability to penetrate deeper into the tissue.
  • the incoming light input source is typically selected based on the particle composition (i.e., the composition of the semiconductor nano-objects at least partially embedded in the insulating biocompatible matrix) to optimize the conversion of the signal emitted by the light source into an electrical signal.
  • the energy source to activate the particles is a light source
  • the light stimulation (i.e., the signal) irradiance rate is typically between 0.1 mW/mm 2 and 1000 mW/mm 2
  • the light stimulation frequency is typically between 1 Hz and 500 Hz
  • the light stimulation pulse width is typically between 5 ps and 500 ms
  • the light stimulation waveform is typically a square, a rectangle or a triangle waveform, or a pulson (i.e., a square pulse divided in short bursts of square pulses) waveform.
  • Removable device for particles external activation by electrical or light signals
  • the particles are intended to work through an “on” / “off’ mode of action, meaning that when they are administered at an acupoint of a subject, under the skin of a subject, typically in the dermis (in particular in the context of non-invasive administration) or both in the dermis and hypodermis, and then activated with an external means, typically an external source of electrical or light energy (i.e., when they are activated by external electrical signals and/or artificial light signals), preferably an external manmade source of energy, as described herein above, the particles of the invention act as transducers and convert an incoming signal (i.e., typically a signal emitted by a removable device) into an output signal of different nature, or modulate/relay locally an incoming signal (i.e. typically a signal emitted by a removable device), thereby acting on peripheral nerves to convey an information to the brain, for example for neural coding (i.e., processing of information).
  • an external means typically an external source of electrical or light energy (i.e.
  • the external source of electrical or light energy comes from a removable device.
  • the removable device is a wearable device typically included in a jewelry, in a clothing or in a medical device.
  • a jewelry When included in a jewelry, it may be included for example in a ring, in a bracelet or in a necklace.
  • a clothing When included in a clothing it may be included for example in a tee-shirt, in a sweatshirt, in a sock, in a mitt or in a glove, provided that it delivers reliable external stimulation to the particles administered/implanted under the subject’s skin.
  • a medical device it may be included for example in an artificial skin (for example an ‘electronic skin’), in a patch or in a bandage.
  • the removable device is a bracelet, a ring, a necklace, an artificial skin, a patch, a bandage, a mitt or a glove.
  • the removable device comprises a collector module (cl) the function of which is to collect an input signal.
  • the input signal is typically selected from a physical signal, a chemical signal and a biological signal, and is used to activate the particles.
  • the collector module (cl) is capable of processing the signal when required (cf. Figure 4).
  • a particular removable device of the invention thus collects an input signal which is, optionally processed and, used to activate the particles.
  • the removable device is preferably wearable by a subject.
  • a typical removable device of the invention comprises a collector module (cl) collecting an input signal which is typically a physical signal, a chemical signal or a biological signal, and capable of processing the signal when required, and a stimulator module (c2).
  • the collector module (cl) comprises a module (cl’) collecting an input signal and a processing module (cl”) encoding/converting the input signal into an output signal readable by the stimulator module (c2).
  • the stimulator module (c2) comprises a source of energy which is an external electrical source and/or an external (artificial) light source, said source using the output signal to activate the particles.
  • the collector module (cl) collects a signal which is typically a physical signal, a chemical signal or a biological signal or several signals, e.g., physical, chemical and/or biological signals.
  • a physical signal is for example an electromagnetic signal such as a radio wave signal, a microwave signal, a visible light signal, an infrared signal, an ultraviolet (UV) signal, an X-ray signal, a gamma- ray signal, etc.; a thermal radiation/heat signal; an electric signal; a magnetic signal; or a mechanic signal such as for example an ultrasound signal, a pressure signal or a strain signal.
  • an electromagnetic signal such as a radio wave signal, a microwave signal, a visible light signal, an infrared signal, an ultraviolet (UV) signal, an X-ray signal, a gamma- ray signal, etc.
  • a thermal radiation/heat signal such as for example an electric signal, a magnetic signal; or a mechanic signal such as for example an ultrasound signal, a pressure signal or a strain signal.
  • the collector module can be a sensor module.
  • a “physical sensor module” i.e., a sensor module collecting a physical phenomenon (i.e., a physical signal).
  • a physical sensor module can be an “image sensor module” detecting information in the form of light.
  • An image sensor module typically consists of integrated circuits that sense the information and convert it into an equivalent current or voltage which can be later converted into digital data.
  • a physical sensor module can also be an “ultrasonic sensor module”.
  • An ultrasonic sensor module is typically used to measure the distances between the sensor and an obstacle object.
  • the ultrasonic sensor module generally works on the principle of the Doppler Effect and includes an ultrasonic transmitter and a receiver.
  • the ultrasonic transmitter transmits the signal in one direction and this transmitted signal is then reflected back whenever there is an obstacle and is received by the receiver.
  • the total time required for the signal to be transmitted and then received back is generally used to calculate the distance between the ultrasonic sensor and the obstacle.
  • a physical sensor module or physical sensor can also be for example an “infrared” sensor module; a “tactile” sensor module; a “pressure” sensor module; a “strain” sensor module; a “temperature” sensor module; a “magnetic-based” sensor (magnetometer) module; an “optical” sensor module; an “acoustic- based” sensor module; a “gravity” sensor (accelerometer) module; an “angular rate” sensor (gyroscope) module or a “deep pressure” sensor (barometer) module.
  • the sensor module (cl) can also be a “chemical sensor module” or “chemical sensor”, i.e., a module collecting a chemical phenomenon (i.e., a chemical signal).
  • a chemical sensor module it is typically a liquid or gas sensor module detecting the composition or the concentration of a chemical agent in a medium such as for example an organic molecule or an ion.
  • the sensor module (cl) can also be a “biological sensor module” or “biosensor”, i.e., a module collecting a biological phenomenon (i.e., a biological signal), such as a heart rate sensor.
  • a biological sensor module i.e., a module collecting a biological phenomenon (i.e., a biological signal), such as a heart rate sensor.
  • the sensor module is a biosensor, it typically detects the composition or concentration of a biological agent such as for example a protein a nucleic acid a cell, a bacterium or a virus, in a medium;
  • Each sensor module is capable of processing the signal (if and when required) and typically combines sensing, computation, communications and power means into a very small volume typically below 100 mm 3 , below 10 mm 3 , or even below 1 mm 3 .
  • a sensor module or several sensor modules, typically two or three sensor modules, or even a network of sensor modules can be combined in the device to increase its sensing ability.
  • an optical sensor module can be coupled with an ultrasound sensor module to increase its sensing ability.
  • the collector module collecting the input signal can also be any other suitable means capable of collecting an input signal from one or several sensors (physical, chemical and/or biological sensors), or from one or several computing systems, for example any data generated by a computing system and transmitted in the form of a digital electrical signal, the sensor(s) or computing system(s) being external to the device.
  • the input signal received by the collector module can be any input signal sent by remote sensor(s) and/or remote computing system(s), through wired (such as for example a HDMI or USB connector) or wireless connection, preferentially via a wireless connection such as for example Bluetooth and WIFI.
  • the collector module (cl) comprises a module (cl’) collecting an input signal and a processing module (cl”) encoding/converting the input signal into an output signal readable by a stimulator module (c2)
  • the processing module (cl”) preferably contains a deep learning framework determining the parameters required to generate an output signal readable by the stimulator module.
  • Machine learning can typically be used to encode information and implement a neuronal network method or system capable of determining the required parameters.
  • the module (c G) transmits signals to the processing module (cl”) which uses ADC (Analog-to-Digital Converter) or an equivalent converter, to perform the digitization of (digitalize) the acquired analog signals and generate an output signal which is then sent to a stimulator module (c2).
  • ADC Analog-to-Digital Converter
  • the signal processing can be an image analysis, a text analysis (i.e., data analysis) or a speech analysis.
  • the signal is captured by a module (cl’) of the collector module and sent to a processing module (cl”), for example for color segmentation, radiance segmentation, hue segmentation, sentence segmentation, or word segmentation.
  • the processing module converts this input signal into an output signal and sends it to the stimulator module (c2).
  • a sensor module can sense a change of a measured parameter using a module (cl’) and transfer the information corresponding to this change to a processing module (cl”) (which can typically be a microcontroller) that calculates and converts the change into an output signal (containing all information from the input signal) readable by a stimulator module (c2).
  • a processing module cl
  • c2 which can typically be a microcontroller
  • the herein described stimulator module (c2) typically comprises a source of energy which is selected from an electrical source and a light source, said source using the signal to activate the particles.
  • Each collector module encodes an input signal into an output signal readable by a stimulator module, typically encodes/converts the input signal into an output signal readable for example by a light source of energy or an electric source of energy.
  • the output signal can be an electrical signal to be sent to a stimulator module (c2) comprising (micro)electrodes acting as an electrical source of energy to activate the particles (i.e., delivering external electrical signals).
  • the output signal can be an electrical signal to be sent to a stimulator module (c2) comprising (micro)LEDs acting as a light source of energy to activate the particles (i.e., delivering artificial external light signals).
  • Several stimulator modules typically two or three stimulator modules, or a network of stimulator modules, can be combined in the device to increase its sensing ability. Several devices can also be used in parallel to increase sensing ability.
  • a system comprising particles as herein described and a removable device as herein described, wherein the particles are located at an acupoint of a subject, in the dermis and/or hypodermis of a subject, or are non-invasively administered to (typically in the dermis of) a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to activate the particles by external signal(s), the removable device being wearable by a subject.
  • the spikes generated in response to input signal(s) from the collector module(s), confirm the successful reading of the output signal by the stimulator module(s) as well as the successful stimulation of the particles by the source of energy and consecutive induced stimulation of the peripheral nerves which will then convey/transmit a signal to the central nervous system which it can interpret.
  • These spikes can be recorded as electrophysiological signals and observed and/or decoded.
  • the removable device is preferably powered by an external source or by a battery which is part of the device. Use of the particles or of the composition comprising the particles.
  • the particle or the composition comprising the particles is for use for treating a subject suffering of a disease, disorder or dysfunctional state, typically suffering of an inflammatory or an infection disease, via an acupuncture effect.
  • the therapeutic effect is obtained via an acupuncture effect if i) the particle or the composition comprising the particles is administered to at least one acupoint of the subject and then ii) the particle(s) is/are activated by external electrical and/or light signals.
  • a particle is thus herein described for use for treating a subject via an acupuncture effect.
  • the particle is typically administered to the subject at an acupoint, and then activated by:
  • the description also relates to a method for delivering / providing / generating acupuncture effect to/in a subject in need thereof.
  • This method typically comprises a step of administering the particle, or a composition comprising the particles, to at least one acupoint of the subject, and a step of activating the particle(s) and/or of stimulating the particle(s) by external electrical signals and/or external (artificial) light signals, thereby triggering an acupuncture effect in the subject.
  • the particle or the composition comprising the particles is for use for sensory restoration, preferably for use for 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.
  • a particle of the invention for use for sensory restoration in a subject when the particle(s) is/are administered in the dermis and/or hypodermis of the subject, and then activated by:
  • a particle of the invention for use for sensory substitution in a subject when the particle(s) is/are administered in the dermis and/or hypodermis of the subject, and then activated by:
  • Inventor also herein describe the use of a particle of the invention or of a composition comprising such particles, for sensory enhancement in a (healthy) subject, or for creating new sensory means in a (healthy) subject, said new sensory means allowing the perception of external signals which are not perceived by a natural sense of the subject, for example by a human natural sense.
  • inventor herein describes the use of a particle of the invention, or of a composition comprising such particles, for sensory enhancement of a subject, in particular a healthy subject, the particle being for example non-invasively administered to the subject, and then activated by:
  • the particle of the invention for creating new sensory perception in a subject, in particular a healthy subject, the particle being for example non-invasively administered to the subject, and then activated by:
  • people suffering from mental, emotional and/or behavioral disorder/ihness such as psychotic disorder, obsessive-compulsive disorder, eating disorder, conduct disorder, learning disorder, anxiety disorder, bipolar disorder, etc.
  • AMI any mental illness
  • people who are followed (or are eligible for being followed) by a psychiatrist i.e., eligible for undergoing a psychotherapy
  • a psychiatrist i.e., eligible for undergoing a psychotherapy
  • who are taking (or are eligible for taking) medication as part of a treatment protocol at some point in their life (i.e., people who may be eligible for receiving, or receiving mental health services)
  • the present invention may typically benefit from the present invention to overcome their current disorders, as the invention typically allows sensory enhancement and/or the creation of new sensory perception.
  • the particle(s) of the invention, or composition comprising such particles is for use for sensory augmentation or for creation of new sensory perception in a subject suffering from mental, emotional and/or behavioral disorder.
  • the particle(s) is/are typically administered in the dermis and/or hypodermis of the subject, and then activated by:
  • the description further relates to a method for sensory restoration to a subject in need thereof, or for sensory substitution in a subject at least partially deprived of taste, smell, hearing, balance and/or vision, or for sensory enhancement in a subject, or for creating new sensory means in a subject.
  • the method typically comprises a step of administering the particle, or a composition comprising the particles, in the dermis and/or hypodermis of a subject, in particular in a non-invasive way (i.e., typically in the dermis of at least one biological area of a subject) or in an invasive way (i.e., typically in the hypodermis of at least one biological area of a subject), and a step of activating the particle(s) and/or of stimulating the particle(s) by external electrical signals and/or by external (artificial) light signals, thereby triggering sensory restoration, sensory substitution, sensory enhancement, or the creation of new sensory means allowing a (potentially new) perception of the environment, in the subject.
  • any of the herein described particles or composition comprising such particles create, when the particle(s) are stimulated by (i.e. exposed to) external electrical and/or (artificial) light signals, spatiotemporal electrical patterns at the level of the peripheral nervous system which can be efficiently read by the brain and are able to restore a perception, for example touch perception, in a subject who is deprived of it, to substitute a perception means to another in a subject suffering of an altered perception (for example of an altered vision or an altered hearing), to enhance perception in a subject, and/or to create a new perception means in a subject.
  • a perception for example touch perception
  • an altered perception for example of an altered vision or an altered hearing
  • the particle(s) of the invention when activated (or stimulated) by external electrical and/or (artificial) light signals, also enable(s) for the first time the brain of a subject, for example of a human subject, to perceive beyond the reality the subject is used to perceiving thanks to his (natural) senses.
  • a particular herein described advantageous system is a system comprising particles of the invention, for example a composition comprising such particles, and a removable device as herein described, wherein the particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of a subject, or are non-invasively administered (typically at the dermis level) to a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to (externally) activate the particles by (external) signal(s) (as herein described), the removable device being wearable by a subject.
  • the sensory restoration, sensory substitution, sensory enhancement, or new sensory perception system preferably comprises a sufficient number “X” of dimensions or parameters and, in each dimension, a sufficient level “N” of features to build a robust information that will create or re-create sensory perception.
  • Coding signal (corresponding to the signal emitted by the source of energy, typically from the stimulator module of the removable device) can typically have dimensions expressed for example as intra-signals frequency, inter-signals frequency, signals amplitude, signals intensity, signals waveform, signals repetition, signals repetition frequency, signals total time, and any combination thereof.
  • N features can be implemented to (i) reconstitute a well-known perception such as a sound, a melody, colors, hue and luminance of a landscape, distance and direction, etc. and/or to (ii) create a new perception such as for example infrared vision or ultrasound vision.
  • Machine learning can typically be used by the skilled person for such neural coding, or for implementing neuronal network methods to handle, typically transmit and/or record, information.
  • neural data of a subject such as data obtained from BOLD signal using functional Magnetic Resonance Imaging (fMRI) or electroencephalography (EEG) signals, may be recorded to assess the efficacy of sensory restoration, sensory substitution, sensory enhancement, or the creation of a new sense in the subject.
  • Neural data can also be recorded at the peripheral nerve system level (typically via a sensor, such as electrode(s)). These neural data can then be used as a feedback loop in order to “train” the system of the invention and/or to “train” the subject him/herself.
  • the information transmitted to the brain thanks to the system of the invention can be recorded (on a memory) and then processed by a processor, and then decoded (using the recorded/processed neural data and typically machine learning for neural decoding).
  • the processed data can then advantageously be sent back to the subject in the form a signal perceivable by any one of the five natural senses of the subject in order to accelerate the learning process and facilitate any sensory restoration process, sensory substitution process, sensory enhancement process, or new sensory perception process.
  • the decoded information obtained from a given subject can be used by said subject (i.e., transmitted to the subject and perceived by the subject) to facilitate learning and exploitation of information.
  • the decoded information can be sent to the wearable/removable device to update and improve output signal transmission.
  • such record(s) may be used to lock the system (A) of the invention by specifically associating the removable device (C) of the invention with the particles (B) of the invention.
  • kits comprising at least the herein described particles, optionally together with a tool (such as needle(s), microneedle(s), patch(es), injector(s), etc.) designed to appropriately deposit and/or position the particles in an adequate site of the subject’s body.
  • a tool such as needle(s), microneedle(s), patch(es), injector(s), etc.
  • the present description also encompasses a kit comprising in addition to the particles, a herein described system, and one or several tools selected from a sensor such as an electrode (for capturing neural data from the nervous system of a subject), a memory (for recording the captured neural data) and a processor (for processing the recorded neural data before sending the processed data back to the subject in the form of a signal perceivable by any one of the five natural senses of the subject).
  • a sensor such as an electrode (for capturing neural data from the nervous system of a subject), a memory (for recording the captured neural data) and a processor (for processing the recorded neural data before sending the processed data back to the subject in the form of a signal perceivable by any one of the five natural senses of the subject).
  • FIGURE 1 Schematic representation of a particle comprising conductor nano-objects or (both) conductor and semiconductor nano-objects at least partially embedded (A) of fully embedded (B) in an insulating biocompatible matrix.
  • FIGURE 2 Schematic representation of directly (in contact), or indirectly (via a linker), connected conductor and semiconductor nano-objects embedded in an insulating biocompatible matrix.
  • FIGURE 3 Schematic representation of a nanoparticle (A), a nanofiber (B) and a nanoplate (C).
  • FIGURE 4. System comprising particles of the invention and a removable device.
  • the particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of a subject, or are non-invasively administered (typically at the dermis level) to a subject, and are activated by a signal emitted by the removable device.
  • the removable device collects an input signal which is, optionally processed and, used to activate the particles, the removable device being wearable by a subject.
  • the device typically comprises:
  • a collector module (cl) 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 (cl’) collecting an input signal and a processing module (cl”) encoding the input signal into an output signal readable by the stimulator module (c2);
  • a stimulator module comprising a source of energy which is selected from an external electrical source and/or an external (artificial) light source, said source using the output signal to activate the particles.
  • 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 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.
  • FIGURE 5 Scanning Electron microscopy (SEM) images of particles of the invention acting as a neural interface.
  • Figure 5 shows representative images of particles of the invention synthesized as described in the Examples section.
  • Samples i.e., particles in aqueous suspensions
  • the samples were deposited onto a carbon adhesive by adding a small volume of suspension followed by a drying step at room temperature.
  • the samples were observed without any surface treatment (i.e., metallization).
  • the median size of the particles is above 1 ⁇ m and the particles are spherical in shape.
  • Particles can be manufactured/synthesized according to synthesis methods well-known by the skilled person in the art.
  • conductor for example gold or graphene
  • semiconductor for example CuInSe2 quantum dot or CdS/CdSe core/shell quantum dot
  • PMMA used as the insulating biocompatible matrix
  • PMMA Polymethylmethacrylate
  • Conductor nano-objects and optionally semiconductor nano-objects in a powder form are dispersed in dichloromethane and subsequently added to the PMMA solution (see below Table 1).
  • Carbon-based nano-objects are obtained by adding graphene nanoplatelets in powder form in Water For Injection (WFI) and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for at least 2 hours, the as-obtained suspension being dried at temperature between about 30°C and 100°C.
  • Graphene nanoflakes are obtained by adding graphene nanoplatelets in powder form in WFI and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for at least 2 hours, the as- obtained suspension being dried at temperature between about 10°C and 25 °C.
  • Reduced graphene oxide nano-objects are obtained by adding WFI to graphene oxide sheets powder and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for about 1 hour.
  • the as- obtained suspension is subsequently adjusted to a basic pH using basic aqueous solution.
  • Ascorbic acid is then added to the suspension under magnetic stirring.
  • the resulting suspension is stirred for about 3 hours using a magnetic stirrer, washed thoroughly with WFI using centrifugation, re-dispersed in WFI, and then let dried at temperature between about 10°C and 25°C.
  • the particles of the invention are administered on at least one biological area of a subject (preferably at an acupoint of a subject, or in the dermis and/or hypodermis of a subject).
  • a subject preferably at an acupoint of a subject, or in the dermis and/or hypodermis of a subject.
  • the administration is considered as non-invasive (as would be the administration of ink particle during a tattooing procedure).
  • Particles are subsequently activated by an appropriate external source of energy (i.e., artificial electrical and/or light signals).
  • 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.
  • external electrical signals and/or external artificial light signals i.e., different from the signals generated by natural light
  • the peripheral nerves convey the information to the brain of the subject typically for triggering an acupuncture effect, for touch sensory restoration, sensory substitution, sensory enhancement or new sense(s) perception.
  • 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).

Abstract

The present invention relates to the field of human machine interface. Inventors more particularly describe advantageous particle(s) for use as a neural interface(s) and composition(s) comprising such particles. The longest dimension of a typical particle of the invention is of at least 1 µm and below 100 µm and comprises conductor nano-objects or conductor and semiconductor nano-objects, the conductor, and optionally the semiconductor (if present), nano-objects being at least partially embedded in an insulating biocompatible matrix. The present description further relates to a system comprising such particles and a removable device wearable by a subject.

Description

PARTICLES AS NEURAL INTERFACES
FIELD OF THE INVENTION
The present invention relates to the field of human machine interface(s). Inventors more particularly describe advantageous particle(s) which may be used as neural interface(s), and composition(s) comprising such particles. The longest dimension of a typical particle as herein described is of at least 1 μm and below 100 μm. The particle typically comprises conductor nano-objects or (both) conductor and semiconductor nano-objects, the conductor, and semiconductor (if present), nano-objects being at least partially embedded in an insulating biocompatible matrix. The present description further relates to a system comprising such particles and a removable device wearable by a subject. The particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of the subject. The particles may also be non-invasively administered to the subject (i.e., administered at the dermis level of the subject, like a tattoo). The removable device collects an input signal which is, optionally processed and, used to activate the particles.
BACKGROUND
When searching for interfacing the human body with machine(s), typically for reading or recording neural signals from (generated by) the nervous system (typically to decode information circulating in the brain) and/or for sending or modulating neural signals to/in the nervous system (typically to code information in the brain), the design of a neural interface is crucial.
As a matter of fact, to achieve an optimal benefit / risk ratio of the neural interface, its design should precisely address the two following topics (technical problems): (i) be adapted to/compatible with the location/site/position where the neural interface will be positioned in a subject (more or less invasive); and (ii) be capable of triggering both efficient and robust/reliable (i.e. reproducible on demand) neural signals.
Today, the design of a neural interface remains a major challenge to the skilled person working in the field of human machine interfaces. Addressing all needs with an object as simple as possible has not yet been achieved by the skilled person, notably:
(i) the efficiency for coding and/or decoding information in the brain of a subject, which includes in particular the ability for the interface(s) to achieve high spatial and temporal resolutions to efficiently stimulate/modulate and/or detect neural signals, remains to be improved; (ii) the robustness/reliability of the neural interface, which depends in particular of the permanency and biocompatibility (i.e., safety) of the interface(s) at the most relevant location/site/position in a subject, remains to be improved.
BRIEF DESCRIPTION OF THE INVENTION
Inventors herein describe a particle, wherein: i) the longest dimension of the particle is of at least 1 μm and below 100 μm, ii) the particle comprises:
- a volume fraction of at least about 0.005% of conductor nano-objects based on the total volume of the particle, or
- a volume fraction of at least about 0.005% of conductor nano-objects and a volume fraction of at least about 0.1 % of semiconductor nano-objects, based on the total volume of the particle, and iii) the conductor nano-objects, and optionally the semiconductor nano-objects if present in the particle, are at least partially embedded in an insulating biocompatible matrix.
The particle of the invention is the simplest object usable to date as an efficient neural interface. Among other qualities it is small, i.e., not bulky, and it can be used non-invasively and efficiently in any mammal, in particular in a human being.
WO2019/204468 (“ Magnetic nanoparticles embedded in polymer microparticles ”) describes hybrid magnetic materials comprising typically nanoparticles (in particular iron oxide (FesCU) nanoparticles) embedded in non-magnetic microparticles (in particular polymer microparticles). These materials can be used to directionally orient and impart an ordered structure to a variety of materials in the context of user-friendly methods to manufacture filled plastic parts and composites via, for example, compression molding. The resulting microparticles are magnetic microparticles, i.e., they respond to/can be stimulated by a magnetic signal and thus, can be oriented in a magnetic field to construct structures that have tailored mechanical and physical properties as a result of the magnetically controlled orientation and morphology of its building blocks. However, contrary to the herein described particles, they cannot be used as neural interface since they are not designed to be activated on demand by an electrical signal or an artificial light signal. WO2019/204468 does not relate to human machine interface and does not describe particles capable of generating on demand both efficient and robust/reliable neural signals.
A particular particle comprises several nano-objects, the nano-objects being:
- nanoplate(s), each nanoplate having one dimension between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, - nanofiber(s), each nanofiber having two dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, and/or
- nanoparticle(s), each nanoparticle having three dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm.
In a particular aspect, the particle is for use for treating a subject via an acupuncture effect when the particle is administered to the subject at an acupoint, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e. is present in the particle), or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e. are present in the particle).
In another particular aspect, the particle is for use for sensory restoration in a subject when the particle is administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e. is present in the particle), or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e. are present in the particle).
In another particular aspect, the particle is for use for sensory substitution in a subject when the nanoparticle is administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e. is present in the particle), or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e. are present in the particle).
Also herein described is the use of such a particle for sensory enhancement of a subject, in particular a healthy subject, the particle being non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e. is present in the particle), or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e. are present in the particle).
Further herein described is the use of such a particle for creating new sensory perception in a subject, in particular a healthy subject, the particle being non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e. is present in the particle), or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e. are present in the particle). Inventor also describes such a particle for use for recording internal electrical signals. A preferred particle comprises semiconductor nano-objects made with a direct bandgap material (such particles are emitting light). In a preferred aspect, the particle is non-invasively administered to the subject.
Also, herein disclosed is a composition comprising particles as herein described and a pharmaceutically acceptable carrier.
Inventor also herein describe a system comprising particles as herein described and a removable device, wherein the particles are located at an acupoint of a subject, in the dermis and/or hypodermis of a subject, or are non-invasively administered to a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to activate the particles by external signal(s), the removable device being wearable by a subject.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
In the context of the invention, the term “dimension” (also identified in the art as the “external dimension”) is used in its usual sense and designates in particular the length, width, height or thickness of an object. A dimension typically follows an “axis” x, y or z in a volume.
In the context of the invention, the term “nano-object” designates any object having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm. Of note, the second and third dimensions are orthogonal to the first dimension and to each other.
A nano-object also herein designates an aggregate of nano-objects, said aggregate having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm.
In the context of the invention, the term “nanoparticle” designates any object having three dimensions (along the perpendicular x, y and z axes) above about 0.3 nm, or preferably above about 0.5 nm or about 1 nm, and below about 1000 nm, about 500 nm, about 100 nm or about 50 nm, and where the lengths of the longest and the shortest axes of the nano-object do not differ by more than three. In the context of the invention, the term “nanofiber” (also named “nanorod”, “nanotube” or “nanowire”) designates any object having two dimensions above about 0.3 nm, for example above about 0.5 nm or about 1 nm, and below about 100 nm or about 50 nm, and the third dimension being larger, for example having a third dimension at least three times larger than the other two, and not necessarily below 100 nm.
In the context of the invention, the term “nanoplate” (also named “nanoplatelet”, “nanolayer”, “nanosheet” or “nanoflake”) designates any object having one dimension (its thickness) above about 0.3 nm, for example above about 0.5 nm or about 1 nm, and below about 100 nm or about 50 nm, and the two other dimensions being larger, for example having the two other dimensions at least three times larger than the other one, and not necessarily below 100 nm. The term “nanolayer” or “nanosheet” is typically used when the object is made of a monolayer of material; The term “nanoflake” is typically used when the object is made of more than one layer and up to ten (10) layers of material(s); The term “nanoplatelet” is typically used when the object is made of more than ten (10) layers of material(s).
Carbon-based nano-objects are typically carbon nanotubes (single-wall or multi-walls nanotubes), carbon ball, carbon black, graphite, or graphene-related nano-objects which differ by their structures (e.g., graphene-related nanosheets, graphene -related nanoflakes, graphene-related nanoplates) or by their compositions (e.g., pristine graphene, graphene oxide, reduced graphene oxide).
Electrical percolation in the particle of the invention refers to the electrical conductivity (also herein identified as “conductivity”) allowed by the presence of conductor nano-objects at least partially embedded in an insulating biocompatible matrix. The presence of conductor nano-objects at least partially embedded in the insulating biocompatible matrix creates an increase of the electrical conductivity of the particle, typically by several orders of magnitude (when compared to the same particle which would have been made with the insulating biocompatible matrix only, i.e., without any conductor nano-objects). A conducting network occurs at a specific conductor nano-objects loading (i.e., at a specific volume fraction of conductor nano-objects within the particle), which corresponds to the percolation threshold. A conductive particle, in particular a conductive particle of the invention, can be obtained by adding conductor nano-objects to an insulating biocompatible matrix. When the conductor nano-objects loading reaches the percolation threshold, the conductivity of the particle rises suddenly. The conductivity of the particle evolves from insulating to percolating and conducting when the volume fraction of conductor nano-objects within the particle reaches and increases above the percolation threshold. An intermediary conductivity typically exists thanks to the tunneling effect when conductor nano-objects (at least partially embedded in an insulating biocompatible matrix) are closed to each other but not in direct contact. In a preferred aspect, the material the particles are made of is not magnetic (i.e., the orientation or motion of particles of the invention is not influenced by exposition to a magnetic field, contrary to what is observed for example with ferrimagnetic particles). Indeed, and without wishing to be bound by any particular theory, it is inventor’s belief that magnetism may be detrimental to the efficient technical effect allowed by the invention (i.e., the coding effect). Thus, in a preferred embodiment, the particles are neither ferrimagnetic nor ferromagnetic particles.
In the context of the present invention, the “aspect ratio” of a nano-object corresponds to the ratio of the longest dimension over the shortest dimension of the nano-object.
A nanosphere is a nanoparticle having typically an aspect ratio of about 1. A nanoparticle with a spheroid shape or an ellipsoid shape has typically an aspect ratio of about 2 or less than about 3. A nanorod, a nanotube, a nanofiber, a nanoplate, a nanosheet or a nanoflake has typically an aspect ratio above about 3, preferably above about 5, even more preferably above about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, up to for example 1 000, 10000 or 100000.
In this context, the selection of a conductor nano-object with a large aspect ratio is preferred when the nano-object is at least partially embedded in the insulating biocompatible matrix in order to reach the percolation threshold at a low volume fraction (of nano-objects). Typically, a conductor nano-object with an aspect ratio above about 2, 3, 4 or 5, preferably above about 10, 20, 30, 40, 50 or with an aspect ratio of about 100 or more, about 1 000 or more, or about 10000 or more.
The percolation criterion is classically supported in the art by the following equation: s = so(f - fo)' (only when f > fe), wherein s and so are respectively the conductivities of the particle and of the insulating biocompatible matrix; f is the volume fraction of conductor nano-objects and fe is the volume fraction of conductor nano-objects at the percolation threshold. When the conductor nano-objects are nanoparticles, the exponential factor “t” (which corresponds to the critical power law exponent and depends on the dimensionality of the network) is generally set about 2.
The conductive behavior in the insulating, percolating and conductive regimes can be identified from the microstructure of the particle: if there is no electric conductive path through the conductor nanoobjects which are at least partially embedded in an insulating biocompatible matrix, no charge can flow, and the particle remains insulating. On the other hand, if the conductor nano-objects form a directly connected network within the insulating biocompatible matrix, electrons can move through this network, and the particle is conductive. Between these two extremes, conduction takes place when the conductor nano-objects are not in contact but are connected via electrons tunneling through an interface formed between the nano-objects and the matrix; in this case, the conductivity is lower than that observed where a direct network has been formed. This tunneling conduction/effect is a quantum phenomenon. In the context of the present description, the expressions “action potential”, “evoked potential” or “evoked action potential”, refer to the electrical response from a tissue to stimulation. In the context of the present Invention the stimulation comes typically from (artificial) external electric signals and/or from artificial external light signals.
External electric or artificial external light signals are signals which are not natural (i.e., which are different from signals coming from the nature), but on the contrary are generated by external manmade device(s), typically removable/wearable device(s) which are in contact with (typically touch) the surface of the skin of a subject. When herein employed in relation with “light signals” the term “artificial” means that the light signals used to stimulate the tissue (typically a tissue comprising the herein described particles) is not generated by natural light (i.e., light coming from or generated by the sun).
The subject in the context of the invention, is typically a mammal subject, preferably a human being.
When the particle or the composition comprising the particles, is “non-invasively administered” to a subject, the particle or the composition comprising the particles is typically administered in the skin at a depth corresponding to that of a tattoo procedure (typically at the dermis level of the subject, in particular not deeper in the skin such as at the hypodermis level), i.e., the administration is non-invasive and is not to be considered as a physical intervention on the human or animal body.
Acupuncture points (also named acupoints) are located on the surface of a human body and are quantified as 361 classical acupoints by the World Health Organization (WHO) [WHO Standard Acupuncture Point Locations in the western pacific region, World Health Organization, 2008; A proposed standard international acupuncture nomenclature, Report of a WHO scientific Group, World Health Organization 1991]. The proposed nomenclature for the 361 classical acupoints is listed under 14 meridians as follows: (1) lung meridian (LU) with 11 acupoints; (2) large intestine meridian (LI) with 20 acupoints; (3) stomach meridian (ST) with 45 acupoints; (4) spleen meridian (SP) with 21 acupoints; (5) heart meridian (HT) with 9 acupoints; (6) small intestine meridian (SI) with 19 acupoints; (7) bladder meridian (BL) with 67 acupoints; (8) kidney meridian (KI) with 27 acupoints; (9) pericardium meridian (PC) with 9 acupoints; (10) triple energizer meridian (TE) with 23 acupoints; (11) gallbladder meridian (GB) with 44 acupoints; (12) liver meridian (LR) with 14 acupoints; (13) governor vessel (GV) with 28 acupoints; (14) conception vessel (CV) with 24 acupoints.
There is also 48 extra points. The proposed nomenclature for the 48 extra points consists of a prefix “EX” denoting “extra point” followed by an alphabetical code indicating the region (HN for head and neck, CA for chest and abdomen, B for back, UE for upper extremity and LE for lower extremity). Moreover, the WHO has presented methodologies for precisely locating the 361 acupuncture points (acupoints) on the surface of a human body | WHO Standard Acupuncture Point Locations in the Western Pacific Region, 2008]. Three methods are described and typically used by the acupuncturist for locating acupuncture points: The anatomical landmark method, the proportional bone (skeletal) measurement method (using the B-cun as standard measuring unit) and the finger-cun measurement method (using the F-cun as standard measuring unit). Complementary literature regarding acupoint location in human body can be found in the AACP Acupuncture Point Reference Manual 2015 [Evidence Based Acupuncture Training, Acupuncture in Physiotherapy, Western Medical Acupuncture for Musculoskeletal Pain Conditions, Course Handbook ]. When the particle, or the composition comprising the particles, is administered at an acupoint of a subject, the particle or the composition comprising the particles is typically administered in the skin at a depth corresponding to that of the dermis and/or hypodermis of the subject, and may even been administered deeper, typically at a depth corresponding to the muscle located below the skin of the subject.
An acupuncture effect is typically generated when acupoints are stimulated: neuroactive components at acupoints are non-neuronal tissues and biological cells as well as the various mediators capable of modulating afferent signals via local biochemical reactions which are released by these tissues and cells upon activation. In addition, biophysical reactions at acupoints are triggered by the activation of mechanoreceptors. Multiple central neural pathways convey afferent impulses from stimulated acupoints. A distributed network of widespread brain regions that respond to acupuncture provides the neural substrate for broad therapeutic effects of acupuncture. Clinical studies have revealed that acupuncture treatment was capable of normalizing abnormal neuroimaging activity in patients with Alzheimer’s disease, major depressive disorder, etc. Typically, neuroimaging approaches such as functional magnetic resonance imaging (fMRI) and positron emission topography (PET) have been widely introduced into acupuncture research. Normalization of neuroimaging signals was correlated with clinical improvement. Moreover, acupuncture has broad effects on normalizing neurochemical and behavioral abnormalities in neuropsychiatric disorders as well as on regulating autonomic activities in visceral disorders. [Z.-J. Zhang etal. Neural Acupuncture Unit: A New Concept for Interpreting Effects and Mechanism of Acupuncture. Evidence-Based Complementary and Alternative Medicine, 2012; Article ID 429412],
The skin comprises the epidermis, the dermis and the hypodermis. 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, 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. 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. The hypodermis comprises lipocytes. It also comprises the following appendages: loose connective tissue (lipocytes, collagen, elastin fibers), blood vessels, nerves and muscle spindles.
Low Threshold Mechanoreceptors (LTMRs), also identified as primary afferents or primary sensory neurons, detect innocuous mechanical stimuli acting on the skin. These cutaneous sensory neurons may be classified as either Ab, Ad or C based on their cell body sizes, axon diameter, degree of myelination and axonal conduction velocities. In addition, their firing pattern to sustain mechanical stimuli is variable, ranging from slow (SA) to intermediate (IA) and to rapidly adapting (RA). LTMRs associated cutaneous end-organs encode touch stimuli and this encoding is then integrated and processed within the central nervous system. Both hairy and hairless (also named non-hairy or glabrous) skin areas contain discrete sets of LTMRs and associated end-organs (also named endings), and these different sets of LTMRs detect specific tactile modalities. In glabrous skin, four types of LTMRs with fast conduction velocity (Ab LTMRs) have been defined more particularly, each with a distinct terminal morphology (“endings”) and tuning property: (i) Ab SAl-LTMRs (also herein identified as SAI-LTMRs) innervate Merkel cells in the basal epidermis, (ii) Ab SA2-LTMRs (also herein identified as SAII-LTMRs) are hypothesized to terminate in Ruffini corpuscles in the dermis, (iii) Ab RAl-LTMRs (also herein identified as RAI-LTMRs) innervate Meissner’s corpuscles in dermal papillae, and (iv) Ab RA2- LTMRs (also herein identified as RAII-LTMRs) terminate in Pacinian corpuscles deep in the dermis. In hairy skin, apart from the SA1-LTMR / Merkel cell complex (touch dome), hair follicles are for example innervated by LTMR termination collars located just below the level of sebaceous gland. Despite their differences in sensitivity and encoding’ ability, the 3 types of lanceolate-ending LTMRs have identical terminal structures [A. Zimmerman et al. The gentle touch receptors of mammalian skin. Science, 2014; 346(6212), 940-954; A. Handler et al. The mechanosensory neurons of touch and their mechanisms of activation. Nature Review Neuroscience, 2021; 22, 521-537].
In the context of the present description, when the conductor and semiconductor nano-objects are connected, it means that bonds exist between the conductor and semiconductor nano-objects (cf. Figure 2). Bonds are typically direct (i.e., the particles are in contact) or indirect (i.e., the particles are in contact via a linker) covalent bonds, direct or indirect complexing bonds, or direct or indirect ionic bonds, which hold the nano-objects together within the particle. Linkers are typically used when indirect bonds connect the nano-objects together. Linkers from the groups of organosilanes, organothiols, organophosphates and/or cyclic or linear oligomers or polymers of phosphates are preferably used to connect the nano-objects.
In the context of the invention, an ‘insulating biocompatible matrix or material’ is a matrix or a material which does not conduct (or conduct very poorly) electricity and is compatible with living tissues or a living system in that it is not toxic, injurious, or physiologically reactive and does not cause immunological rejection.
In the context of the invention, “stimulating” or “activating” the particle by an (artificial) external source of energy (i.e., by artificial external electric and/or light signals) also means “exposing” the particle to an external source of energy, the exposition being typically through the subject’s skin where the particle is located.
Particle comprising conductor nano-objects or (both) conductor and semiconductor nano-objects, said nano-objects being at least partially embedded in an insulating biocompatible matrix.
Composition of the conductor nano-objects
According to an aspect herein described, the particle comprises conductor nano-objects with an electrical bulk conductivity s of at least lxlO4 S/m at 20°C, preferably of at least lxlO5 S/m at 20°C, typically of at least lxlO6 S/m at 20°C, or lxlO7 S/m at 20°C, the electrical bulk conductivity corresponding to the electrical conductivity of the bulk material.
A preferred conductor nano-object can be selected from a metal nano-object, a crystallized metal oxide nano-object, an amorphous oxide nano-object, a transition metal dichalcogenide nano-object, a carbon- based nano-object, an organic nano-object, and any mixture thereof.
In a particular aspect, the conductor nano-object is made of material(s) selected from the group consisting of metal, crystallized metal oxide, amorphous oxide, transition metal dichalcogenide, carbon- based, and any mixture thereof.
When the nano-object is a metal, it is typically made of gold (Au) element (“gold nano-object”), Copper (Cu) element (“copper nano-object”), Silver (Ag) element (“silver nano-object”), Molybdenum (Mo) element (“molybdenum nano-object”), Aluminum (AI) element (“aluminum nano-object”), Palladium (Pd) element (“palladium nano-object”), platinum (Pt) element (“platinum nano-object”), or any mixture thereof. Preferably, it is made of gold (Au) element, Silver (Ag) element, platinum (Pt) element or a mixture thereof, even more preferably of Au and/or Pt elements. When the nano-object is a crystallized metal oxide particle, it typically comprises rhenium element. The nano-object can typically be a rhenium (VI) trioxide (RcOd nano-object or a rhenium (IV) dioxide nanoobject (ReCh, also named rhenium oxide nano-object).
When the nano-object is an amorphous oxide, it typically consists of a mixture of at least two metal elements, typically indium and tin to form the indium-tin oxide (ITO) nano-object, indium and zinc to form the indium-zinc oxide (IZO) nano-object, or aluminum and zinc to form the aluminum-zinc oxide (AZO) nano-object.
When the nano-object is a transition metal dichalcogenide, it is typically a FeS nano-object, a FeSe nano-object, a FeTe nano-object, a TaS nano-object, a TaSe nano-object, a TaTe nano-object or a NbSe nano-object.
When the nano-object is made of carbon-based material, it has typically a graphene structure, a singlewall carbon nanotube structure, a multi-wall carbon nanotube structure, a reduced graphene oxide structure, a graphite structure or a carbon black structure.
When the nano-object is made of an organic material, it is typically made of polypyrrole, polyaniline, polythiophene or a derivative thereof such as Poly(3,4-ethylenedioxythiophene) or Poly(3,4- ethylenedioxythiophene)-poly(styrenesulfonate).
Also herein described are nano-objects comprising a mixture of any one of the herein above described conductor materials as well as nano-objects having a core-shell structure, the core and the shell being prepared from distinct conductor materials, each material being selected from any one of the herein above described conductor materials, and their uses in the context of the present invention, for example in a method as herein taught.
In a preferred aspect herein described, the particle of the invention comprises conductor nano-objects, wherein the conductor nano-object is made of material(s) selected from the group consisting of gold, silver, platinum, Poly(3,4-ethylenedioxythiophene), transition metal dichalcogenide, carbon-based material and any mixture thereof. Such a particle has an electrical conductivity of at least 104 S/m.
Composition of the semiconductor nano-objects
The particle of the invention can, in addition to the conductor nano-objects, comprises semiconductor nano-objects having an electrical bulk conductivity s of at least 1x103 S/m at 20°C, preferably between lxlO 3 S/m and lxlO2 S/m at 20°C, even more preferably below lxlO2 S/m at 20°C, even more preferably of at least 1x102 S/m at 20°C, between 1x102 S/m and lxlO2 S/m at 20°C, or below lxlO2 S/m at 20°C, the electrical bulk conductivity corresponding to the electrical conductivity of the bulk material. A preferred semiconductor nano-object can be selected from a metal oxide nano-object, an organic nanoobject, a silicon or a germanium nano-object, a transition metal dichalcogenide nano-object, a quantum dot, a perovskite nano-object, and any mixture thereof.
In a particular aspect, the semiconductor nano-object is made of material(s) selected from the group consisting of metal oxide, silicon, germanium, transition metal dichalcogenide, perovskite, a ternary I-III-VI2 nanocrystal wherein I is selected from Cu+ and Ag+; III is selected from Al3+, Ga3+, and In3+; and VI is selected from S2_, Se2_, and Te2_, and any mixture thereof.
In a particular aspect, the mixture is in the form of a quantum dot, in particular in the form of a carbon- based quantum dot such as graphene quantum dot.
When the nano-object is a metal oxide, it typically consists of a mixture of at least two metal elements, typically of three metal elements such as indium, gallium and zinc to form an indium-gallium-zinc oxide (a-IGZO) nano-object. The metal oxide may also be prepared with a single metal element, typically the zinc element to form a zinc oxide (ZnO) nano-object, the titanium element to form a titanium dioxide (also named titanium oxide) (T1O2) nano-object, the tin element to form a tin oxide (SnO) nano-object. When the nano-object is made from an organic material, it typically consists in, or comprises, small molecules or polymers, for example pentacene, poly(3-hexylthiophene) (P3HT), poly(diketopyrrolopyrrole-terthiophene) (PDPP3T), 5, 50-bis-(7-dodecyl-9H-fluoren-2-yl)-2, 20- bithiophene (DDFTTF) and/or polyisoindigobithiophene-siloxane (PiI2T-Si).
When the nano-object is made of silicon, it typically has an amorphous (a-Si) structure, a polycrystalline structure or a crystalline structure.
When the nano-object is made of germanium, it typically has an amorphous structure or a crystalline structure.
When the nano-object is a transition metal dichalcogenide, it is typically a M0S2 nano-object, a MoSe2 nano-object, a MoTe2 nano-object, a WS2 nano-object, a WSe2 nano-object, a ReS2 nano-object, a ReSe2 nano-object, a FeSe nano-object or a FlfS2 nano-object.
When the nano-object is a quantum dot (also named a semiconductor nanocrystal), it is typically a carbon-based quantum dot, a GaN quantum dot, a InN quantum dot, a SnO quantum dot, a ZnO quantum dot, a ZnS quantum dot, a SnS quantum dot, a SnSe quantum dot, a FeSe quantum dot, a CdS quantum dot, a CdSe quantum dot, a ZnSe quantum dot, a CdTe quantum dot, a ZnTe quantum dot, a InSb quantum dot, a GeSe quantum dot, a InAs quantum dot, a GaAs quantum dot, a InP quantum dot, a GeTe quantum dot, a GaSb quantum dot, a Germanium quantum dot, a Silicon quantum dot, a SnTe quantum dot, a ternary I-III-VI2 quantum dot where I is typically the copper (Cu) element or the Silver (Ag) element, III is typically the Aluminum (Al) element, the gallium (Ga) element, the indium (In) element or the bismuth (Bi) element, preferably the Al, Ga or In element, and VI is typically the sulfur (S) element, the selenium (Se) element or the tellurium (Te) element. Ternary quantum dots are typically CuInSe2, AgBiTe2 or AgBiSe2. When the nano-object is a perovskite, it has typically the following structures ABX3, ABCX3, or ABCDX6 (corresponding to a double perovskite structure), where A is an organic or an inorganic element, B, C and D are inorganic elements, and X is an halide ion or oxygen. Typically, the nano-object is KBaTeBiOi, or Ba^AglOf,.
Also herein described are nano-objects comprising a mixture of any one of the herein above described semiconductor materials as well as nano-objects having a core-shell structure, the core and the shell being prepared from distinct semiconductor materials, each material being selected from any one of the herein above described semiconductor materials, preferably each material being selected from any one of the herein above described quantum dots, and their uses in the context of the present invention, for example in a method as herein taught.
In a preferred aspect herein described, the particle comprises semiconductor nano-objects, wherein the semiconductor nano-object is made of material(s) selected from the group consisting of a ternary I-III-VI2 nanocrystal wherein I is selected from Cu+ and Ag+; III is selected from Al3+, Ga3+, and In3+; and VI is selected from S2_, Se2_, and Te2_, a transition metal dichalcogenide, and any mixture thereof. In a particular aspect, the mixture is in the form of a quantum dot, in particular of a core-shell quantum dot. In another particular aspect, the particle comprises semiconductor nano-objects, wherein the semiconductor nano-object is made of carbon-based quantum dot.
In another preferred aspect, the semiconductor nano-object is made of semiconductor material(s) with direct bandgap.
In a particular aspect, the conductor and semiconductor nano-objects are connected directly or indirectly and are at least partially embedded within an insulating biocompatible matrix (cf. Figure 2).
Shape and size of the conductor and semiconductor nano-objects
In a typical aspect herein described, the nano-objects are objects having one dimension (ID), two dimensions (2D), or three dimensions (3D) above about 0.3 nm, in particular above about 0.5 nm or about 1 nm and below aboutlOOO nm, about 500 nm, about 100 nm or about 50 nm, preferably above about 0.5 nm or about 1 nm and below about 100 nm or about 50 nm.
The size and the aspect ratio of the conductor and semiconductor nano-objects are typically measured using electron microscopy (EM) such as transmission electron microscopy (TEM) or Cryo-TEM, and/or Atomic Force Microscopy (AFM).
At least 100 nano-objects of a population are measured in both their longest dimensions and their shortest dimensions. The aspect ratio of the nano-objects of the population comprising at least 100 nano-objects is obtained by calculating the ratio of the longest dimension over the shortest dimension for each nano-object of the population.
Nano-objects having an aspect ratio typically between about 1 and less than about 3, and having 3 dimensions above about 0.3 nm and below about 1000 nm, about 500 nm, about 100 nm, are typically defined as ‘nanoparticles’ (i.e., they belong to the nanoparticle category of nano-objects (cf. Figure 3.A)).
Nano-objects having an aspect ratio of more than about 3, preferably of more than about 5, or of more than about 10, and having two dimensions above about 0.3 nm and below about 100 nm, are typically defined as ‘nanofibers’ (i.e., they belong to the nanofiber category of nano-objects (cf. Figure 3.B)). Of note, the third dimension of objects that fall in the nanofiber category is typically larger, typically more than three times, larger than the two other dimensions.
Nano-objects having an aspect ratio of more than about 3, preferably of more than about 5 or of more than about 10, and having one dimension above about 0.3 nm and below about 100 nm (i.e., corresponding to its thickness) are defined as ‘nanoplates’ (i.e., they belong to the nanoplate category of nano-objects (cf. Figure 3C)). Of note, objects that fall in the nanoplate category have two dimensions larger, typically more than three times, larger than the third dimension, i.e., than the thickness of the nano-object.
In an aspect herein described wherein the nano-objects are nanoparticles, said nano-objects have three dimensions (along the perpendicular x, y and z axes). Each dimension is typically above about 0.3 nm, in particular above about 1 nm, and below about 1000 nm, about 500 nm, about 100 nm, preferably above about 1 nm, and below about 100 nm.
In another aspect of the invention wherein the nano-objects are nanofibers, said nano-objects have two dimensions (along the perpendicular x and y, x and z, or y and z axes) over three which are typically above about 0.3 nm, preferably above about 1 nm, and below about 100 nm.
In another aspect of the invention wherein the nano-objects are nanoplates, said nano-objects have one dimension (along the x, y or z axis) over two which is typically above about 0.3 nm, preferably above about 1 nm, and below about 100 nm.
In a particular and preferred aspect, the particle of the invention comprises several nano-objects. In a given particle, these nano-objects are: nanoplates, each nanoplate having one dimension between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, nanofibers, each nanofiber having two dimensions, each dimension being between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, and/or nanoparticles, each nanoparticle having three dimensions, each dimension being between about 0.3 nm and about 1000 nm, about 500 nm, about 100 nm, even more preferably between about 0.5 nm and about 50 nm.
Surface coating of the conductor and semiconductor nano-object
In an aspect herein described, the surface of the conductor and semiconductor nano-object is functionalized using a surface coating agent. The surface coating agent is preferably selected based on its ability to establish strong bonds/links with the surface of the nano-object, typically on its ability to establish complexing or covalent bonds. Typical covalent bonds are found between silane-based compounds (i.e., the coating agents) and the surface of the oxide material. Other very strong bonds (i.e., bonds considered as exhibiting a strength intermediate between the strength exhibited by covalent bonds and that exhibited by complexing bonds) are found between phosphate-based or phosphonate-based compounds (i.e., the coating agents) and the surface of the oxide material, or between thiol-based compounds (i.e., the coating agents) and the surface of the metal (metallic material).
Insulating biocompatible matrix
The insulating biocompatible matrix is typically made of a biodegradable or non-biodegradable insulating inorganic material, a biodegradable or non-biodegradable insulating organic material, or a mixture thereof.
In the context of the invention, an insulating biocompatible inorganic material is typically an insulating biocompatible polymer such as polydimethylsiloxane (PDMS) or an insulating biocompatible oxide such as zirconium oxide (ZrCP).
In the context of the invention an insulating biocompatible organic material is typically an insulating biocompatible polymer, such as an acrylate polymer or co-polymer, a polyurethane, a polycarbonate or a polytetrafluoroethylene. When the insulating biocompatible organic material is an acrylate polymer or co-polymer, it is typically prepared from acrylate monomers such as ethyl acrylate monomers, ethylene- methyl acrylate monomers, methyl methacrylate monomers, 2-chloroethyl vinyl ether monomers, 2- hydroxyethyl acrylate monomers, hydroxyethyl methacrylate monomers, etc. A typical insulating biocompatible acrylate polymer usable in the context of the present invention is the polymethylmethacrylate (PMMA) or the poly(2 -hydroxy ethyl methacrylate).
In a preferred aspect, the particle comprises an insulating biocompatible matrix made of a material selected from the group consisting of polymethylmethacrylate, polycarbonate, non-biodegradable polyurethane and any mixture thereof. Conductor and semiconductor nano-objects partially embedded in an insulating biocompatible matrix.
In a particular aspect herein described, the conductor nano-objects, or the conductor and semiconductor nano-objects, are at least partially embedded in an insulating biocompatible matrix as herein described (cf. Figure 1A). In the context of the invention ‘partially embedded’ means that at least 20%, 30% or 40%, preferably at least 50%, of the surface of the particle is covered with the insulating biocompatible material. Typically, the surface of the particle is analyzed using for example Atomic Force Microscopy (AFM): about 5 particles are typically observed, and a map of their surface’s electric property is established. The relative ratio (in %) of insulating biocompatible material present at the surface of the particle can be established easily with such a method.
In another aspect herein described, the conductor nano-objects, or the conductor and semiconductor nano-objects, are fully/ completely embedded in an insulating biocompatible matrix as herein described (i.e., about 100% of the particle’s surface is constituted of the insulating biocompatible material (as shown for example on Figure IB).
Volume fraction of conductor and semiconductor nano-objects in the particle.
To determine the volume fraction of conductor and semiconductor nano-objects in the particle, a two- step process is typically performed.
First, the particle is typically submitted to a thermogravimetric analysis (TGA) under a nitrogen atmosphere, with a heating rate typically between 2°C/min and 10°C/min to determine the weight fraction (wt.%) of conductor and semiconductor nano-objects, based on the total weight of the particle. Second, the quantitative analysis of the ratio (in weight) of semiconductor and conductor nano-objects (r semiconductor/conductor) is calculated in the particle using typically the inductively coupled plasma mass spectrometry (ICP-MS) or the inductively coupled plasma optical emission spectroscopy (ICP-OES). These techniques are suitable to quantify anyone of the following elements: magnesium (Mg), aluminum (Al), silicon (Si), phosphorus (P), sulfur (S), chlorine (Cl), potassium (K), calcium (Ca), scandium (Sc), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), gallium (Ga), germanium (Ge), arsenic (As), selenium (Se), bromine (Br), rubidium (Rb), strontium (Sr), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), ruthenium (Ru), palladium (Pd), silver (Ag), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), tellurium (Te), iodine (I), cesium (Cs), barium (Ba), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thullium (Tm), ytterbium (Yb), lutetium (Lu), hafnium (Hf), tantalum (Ta), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), gold (Au), lead (Pb) or bismuth (Bi), that can be present in the particle. Therefore, knowing the chemical composition of the conductor and semiconductor nano-objects, and having quantified at least one element from the conductor and semiconductor nano-objects, the weight fractions of the conductor (wt.%COnductor) and semiconductor (wt.% semiconductor) nano-objects within the particle is deduced from the following equations:
Figure imgf000019_0001
, wherein r semiconductor/conductor correspond to the weight ratio of semiconductor over conductor material.
Finally, the volume fraction of the conductor and semiconductor nano-objects within the particle is deduced from the following equations:
Figure imgf000019_0002
, wherein pConductor, Psemiconductor, and Pmatrix are the (theoretical) bulk density of the conductor, the semiconductor, and the insulating biocompatible matrix, respectively.
The volume fraction of the conductor nano-objects in the particle is typically of at least about 0.005%, at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.25%, at least about 0.5% and typically below 100%, for example below about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, preferably below about 35%, based on the total volume of the particle. The volume fraction of the conductor nano-objects in the particle is typically of at least about 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%. In another aspect, the volume fraction of the conductor nano-objects in the particle is for example of at least about 40, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
The volume fraction of the semiconductor nano-objects in the particle is typically of at least about 0.005%, at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.25%, at least about 0.5% and typically below about 40%, preferably below about 35%, based on the total volume of the particle. The volume fraction of the semiconductor nano-objects in the particle is typically of at least about 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%.
Mixture of particles can be used wherein the volume fraction of the conductor nano-objects in each particle constituting the mixture is typically of at least 0.005% and typically below 100%.
In a preferred aspect herein described, the particle comprises:
- a volume fraction of at least about 0.005% of conductor nano-objects, based on the total volume of the particle, or
- a volume fraction of at least about 0.005% of conductor nano-objects and a volume fraction of at least about 0.1 % of semiconductor nano-objects, based on the total volume of the particle.
A particular and preferred object is a particle, wherein i) the longest dimension of the particle is of at least 1 μm and below 100 μm, ii) the particle comprises:
- a volume fraction of at least about 0.005% of conductor nano-objects, based on the total volume of the particle, or
- a volume fraction of at least about 0.005% of conductor nano-objects and a volume fraction of at least about 0.1 % of semiconductor nano-objects, based on the total volume of the particle, and iii) the conductor and, optionally the semiconductor nano-objects, if present in the particle, are at least partially embedded in an insulating biocompatible matrix.
Size and shape of the particle
The size of the particle is typically measured using electron microscopy (EM), such as the scanning electron microscopy (SEM), and/or Atomic Force Microscopy (AFM).
When using EM, the size of the particle is measured as follows: using the electron microscopy images, the longest dimension of the particle is measured and reported. At least 100 particles of a population are taken, and the measurement of their longest dimension is reported. The median size (which corresponds to the median longest dimension) of the particles of the population is calculated. The “size” (also corresponding to the “longest dimension”) of the particles designates the median size (i.e., the median longest dimension) of the particles of a population comprising at least 100 particles.
According to the invention the longest dimension of the particle is preferably of at least 1 μm, or of at least 5 μm, and below 100 μm. The longest dimension of the particle is for example of at least 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 pm or 40 pm, and below 100 pm.
In another preferred aspect herein described, the longest dimension of the particle is of at least 20 pm, preferably of at least 40 pm, and below 100 pm.
The shape of the particle is not critical for the invention. However, a particle with a homogeneous shape is preferred. The expression “homogeneous shape” designates particle the sizes of which have been measured in the 3 dimension (x, y, z) and presenting a ratio which does not exceed a factor 3 between each dimension (i.e., x/y < 3, y/z < 3 and z/x < 3).
Electrical conductivity of the particle
The electrical conductivity of the particle is typically measured on a specimen of millimeter-size range. In a typical aspect, the specimen of millimeter-size range is prepared from pressed pellet of pure powder of particles.
A four-probe station and a source meter in Direct Current (DC) regime is typically chosen for conductivity measurement and silver paste electrodes are typically deposited on the specimen to eliminate the contact resistance between the probe and the specimen.
Alternatively, the material used to press the particles is used as electrode and the electrical conductivity of the specimen is measured using a LCR meter (i.e., an equipment which measures the inductance (L), the capacitance (C), and the resistance (R) of the specimen).
The (electrical) conductivity of the specimen results from the combination of the respective conductivity of the particles themselves and of the boundaries between the particles. Said conductivity of the specimen is assimilated to the electrical conductivity of the particle. The electrical conductivity of the particle is typically of at least 104 S/m (Siemens per meter), and for example of at least 104 S/m and below 10s S/m, preferably of at least 103 S/m and below 107 S/m, or of at least 102 S/m and below 106 S/m, even more preferably of at least 10° S/m and below 107 S/m.
Alternatively, the electrical conductivity of the particles can be measured in suspension (see for instance Robert Gloukhovski et al. Measurements of the Electric Conductivity of MWCNT Suspension Electrodes with Varying Potassium Bromide Electrolyte Ionic Strength. Journal of The Electrochemical Society, 2020 167020528).
In a preferred aspect, the particle of the invention has an electrical conductivity of at least 104 S/m. In a particular aspect of the invention, the particle has an electrical conductivity of at least 104 S/m and the conductor nano-object is made of material(s) selected from the group consisting of metal, crystallized metal oxide, amorphous oxide, transition metal dichalcogenide, carbon elements, and any mixture thereof.
The following particle characterization methods can be performed in the context of the present invention with for example the following purposes: (1) the Fourier-transform infrared (FTIR) spectroscopy or Raman spectroscopy to study the interactions between the nano-objects and the insulating biocompatible matrix; (2) the electron microscopy (EM), such as scanning EM (SEM) or transmission EM (TEM) to study the dispersion and the percentage (%) of the nano-objects embedded in an insulating biocompatible matrix; (3) the energy-dispersive X-ray spectroscopy (EDX) to identify (i.e. to learn on the chemical composition of) the nano-objects within an insulating biocompatible matrix.
Methods for the preparation of a particle as herein described
The preparation of the particle typically relies on physical dispersion of the nano-objects within an insulating biocompatible matrix. Physical dispersion typically uses ultrasonic agitation (such as the ultrasonic bath or the ultrasonic probe), or shear mixing (such as the use of an Ultra-Turrax®) [cf. Nanoparticle-doped electrically-conducting polymers for flexible nano-microsystems. A. Khosla. The Electrochemical Society Interface. Fall-Winter 2012, pp 67-70; Electrical percolation in graphene- polymer Composites A J Marsden et al 2018 2D Mater. 5 032003].
In a particular aspect, the particle is prepared by ‘melt compounding’: the nano-objects are added to an insulating biocompatible matrix, typically made of an organic material (i.e., such as an organic polymer), and the resulting compound is compounded typically at temperature above the insulating biocompatible matrix’s Tg (Glass Transition Temperature), extruded, molded and subsequently annealed at a temperature sufficiently above the insulating biocompatible matrix’s Tg for enough time.
In another aspect, the particle is prepared by the ‘solvent casting method’: an insulating biocompatible matrix, typically made of an organic material (i.e., such as an organic polymer), is dissolved in an appropriate solvent. A dispersion of nano-objects using a solvent compatible with the insulating biocompatible matrix solution is then added to the insulating biocompatible matrix solution under vigorous stirring. The resulting compound is poured into a mold and the solvent is evaporated.
In another aspect, the particle is prepared by ‘oil-in-water emulsion followed by solvent evaporation’ : an insulating biocompatible matrix, typically made of organic material, and the nano-objects are dissolved/dispersed in an appropriate solvent, typically an organic solvent (non-miscible with aqueous solution). The resulting organic suspension is then added to an aqueous solution and an emulsion is formed by vigorous mixing. The solvent is evaporated typically by further stirring. The resulting suspension is centrifugated and the particles are recovered.
In another aspect, the particle is prepared by ‘in situ polymerization’ of an insulating biocompatible matrix, typically made of an organic polymer: a vigorous mixing of nano-objects with organic monomers is performed and followed by polymerization of the monomers using typically a bulk polymerization method with a free radical initiator.
In another aspect, the particle is prepared by ‘in situ precipitation’ of the nano-objects in an insulating biocompatible matrix: a vigorous mixing of the precursors of the nano-objects and the insulating biocompatible matrix is performed and followed by precipitation of the precursors and formation in situ of the nano-objects, using typically heat to triggers the formation of the nano-objects.
In a preferred aspect, conductor and semiconductor nano-objects are connected directly (i.e., are in contact) or indirectly (i.e., via a linker) prior mixing with an insulating biocompatible matrix. In a particular aspect, the conductor and semiconductor nano-objects remain connected when at least partially embedded in the insulating biocompatible matrix. The connection may typically be observed using electron microscopy.
Particles’ formulation and composition
The particles are typically formulated in a liquid or in a gel. In a particular example, the particles are formulated in a liquid that turns into a gel when administered to a subject.
When the transition from a liquid to a gel is triggered by a change of temperature, the liquid-to-gel transition typically occurs between 30°C and 40°C. Poly(D,L-lactic acid-co-glycolic acid)-/?- poly(ethylene glycol)-Z?-poly(D,L-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers typically are materials which exhibit a sol-gel transition upon heating. The liquid-to-gel transition temperature is typically affected by the following parameters: the concentration of copolymer, the chain length of PEG, the chain length of PLGA, the molar ratio between PEG and PLGA, or the lactic acid/glycolic acid (LA:GA) ratio within the PLGA. All these parameters can be easily adjusted by the skilled person to trigger a liquid-to-gel transition at a temperature typically comprised between 30°C and 40°C, for example at the human body temperature.
The herein defined particles are typically part of a composition which is a liquid or a gel, in particular a liquid having a liquid-to-gel transition temperature between 30°C and 40°C. When using a liquid that turns into a gel when administered to a subject, a controlled release of the particles at the site of administration can be obtained by an adaptation of the gel according to methods well-known by the skilled person in the art. Depending on the affinity between the particles and the gel, a controlled release of the particles, typically between few seconds (for example at least 2 seconds) and 1 week, can be obtained. Alternatively, according to the kinetic of degradation of the gel, a controlled release of the particles, typically between 1 hour and 1 week, can be obtained.
The affinity between the particles and the gel is typically characterized by the type of bonding existing between the particles and the material constituting the gel. The bonding can typically be a hydrogen bonding, a bonding resulting from electrostatic interactions, a complexing bonding or a chemically cleavable covalent bonding.
The degradation of the gel typically consists in the swelling (i.e., expansion) of the gel or the breaking of bonds in the material(s) constituting the gel. The gel is ideally biodegradable. A biodegradable gel can typically comprises hydrolytic degradable polyesters blocks, such as poly(e-caprolactone) (PCL) blocks and poly(D,L-lactide- co -glycolide) (PLGA), blocks. Alternatively, the biodegradable gel can comprise polymer blocks with enzymatically degradable peptides, such as poly(L-alanine) (PA) blocks and chitosan blocks.
The particles or composition comprising such particles herein described can be directly administered to the subject at an acupoint, in the dermis or both in the dermis and in the hypodermis, or non-invasively (i.e., in the dermis), using typically syringe(s) and needle(s) when particles are in suspension (i.e., when they are formulated as a liquid, for example as a liquid that turns into a gel when administered in a subject).
Alternatively, the particles can be directly stuck to the surface of a needle (or microneedle), the particles being released in the biological medium typically between few seconds (for example at least 2 seconds) and 10 minutes following needle insertion into the skin typically at an acupoint, in the der is or both in the der is and hypodermis, or non-invasively in a subject. Also, the particles can be formulated as a gel which stuck to the surface of a needle, the gel being released in the biological medium typically between few seconds and 10 minutes upon needle(s) insertion in vivo. To stick the particles or the gel containing the particles to the surface of a needle in a way allowing the (possibly rapid) release of the particles or of the gel containing the particles from the needle once in vivo, a linker agent containing a chemical cleavable bond, or a UV cleavable bond can typically be used. This linker agent binds the particle or the gel containing the particles to the surface of the needle. The linker agent is typically a linker agent containing a chemical cleavable bond such as a cleavable disulphide bond, a cleavable ester bond, or a cleavable hydrazone bond. The particles can become the principal component of the needle(s), microneedle(s), or of the tip(s) of the needle(s) or microneedle(s). In such case, the needle(s), microneedle(s), or the tip(s) of the needle(s) or microneedle(s) is(are) inserted in vivo and remain(s) there. The erosion (such as degradation or dissolution) of the needle(s) or microneedle(s), or of the tip(s) of the needle(s) or microneedle(s), triggers the release of the particles, typically within seconds (for example about 2 seconds), hours or days following needle(s) or microneedle(s) insertion/implantation. The needle(s) or microneedle(s) are left in the skin for a pre-determined period and can be removed at any time typically by extracting the part(s) of the needle(s) or microneedle(s) that has/have not been dissolved. Dissolvable needle(s) or microneedle(s) or dissolvable tip(s) of the needle(s) or microneedle(s) typically comprise(s) water soluble polymers, such as polyvinyl alcohol, polyvinylpyrrolidone or polyvinyl acetate, sugars, or any mixture thereof. The dissolvable needle(s) or microneedle(s) or tip(s) of needle(s) or microneedle(s) comprise(s) the herein described particles.
In an aspect of the invention, needle(s) or microneedle(s) insertion is that performed in the context of tattoo procedures, i.e., insertion is non-invasive (it does not imply a physical intervention on the human or animal body).
Also herein described is a composition comprising herein described particles and a pharmaceutically acceptable carrier.
Localization, administration, volume and concentration of particles
In a preferred aspect of the description, the particles are not located at a biological area of the subject corresponding to fingertips, mouth, lips and foot soles. This is to limit, ideally avoid, any interference with critical sensory biological areas of human body. In other words, the particles are localized/present on a biological area which is distinct of fingertips, mouth, lips and foot soles.
In a particular and preferred aspect, the particles are located on a biological area which corresponds to an acupoint of the subject.
The particles or the composition comprising the particles can be administered, simultaneously or in several times, at multiple biological areas of a subject, typically 2, 3, 4, 5, 6, 7, 8, 9 or 10 different biological areas, which are preferably distinct of mouth, lips, fingertips and foot soles. The surface of a biological area represents typically about 0.5 cm2, about 1 cm2, about 2 cm2, about 3 cm2, about 4 cm2, about 5 cm2, about 6 cm2, about 7 cm2, about 8 cm2, about 9 cm2, about 10 cm2, about 15 cm2, or about 20 cm2 of the skin of the subject. Multiple administrations (targeting multiple administration/injection spots at one or multiple biological areas) of particles or composition comprising particles, typically more than one administration and up to typically 1000 administrations at one or multiple biological areas (each area comprising one or multiple spots) of the subject are typically performed.
In other words, multiple administrations (at one or several administration/injection spots) of particles or composition comprising the particles are performed per biological area. For example, 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300,
400 or 500 administrations are performed per biological area.
When multiple administrations of particles or composition comprising particles are performed, the distance between two adjacent administrations is typically of less than about 100 μm, or of about 100 μm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm or about 1000 μm.
Typical biological areas/injection spots where the particles can be valuably administered are for example areas where the subject is used to wear jewelry (such as a ring, a bracelet, a necklace) such as for example the subject’s arm, leg, neck or ankle.
In a particular aspect of the invention, particles are to be administered once on a given site of implantation. In another particular aspect of the invention, particles are to be administered several times on a given site of implantation. Repeated/successive administrations of particles on a given site can typically be performed in order to increase the number of neural interfaces in the subject, the already administered particles being still usable on-demand when designed as non-biodegradable particles (i.e., used as “permanent” and “re-usable” neural interfaces which means that the conductor nano-objects remain conductor in the particle, and that the semiconductor nano-objects, if present in the particle, remain semiconductor).
In another particular aspect where transient effect is sought, biodegradable particles are preferably advantageously selected.
The volume occupied by the particles per administration/injection site/area is typically between about 0.001 mm3 (i.e., 0.001 μL) and about 100 mm3 (i.e., 100 μL), preferentially between about 0.005 mm3, about 0.01 mm3, about 0.05 mm3, about 0.1 mm3, about 0.2 mm3, about 0.5 mm3, about 1 mm3, about 2 mm3, or about 5 mm3 as a minimum and about 10 mm3, about 20 mm3, or about 50 mm3 as a maximum (if several administrations/injections are performed in a given biological area, the volume described in the present paragraph is that resulting from one administration/injection only). The volume occupied by the particles corresponds to the minimum volume measured in vivo (typically using imaging technics well known by the skilled person) which includes all the administered, typically injected, particles. Because the particles remain at their administration site, the volume occupied by the particle corresponds to the administered volume (e.g., the volume of the injected/administered liquid or gel or the volume of the needle, microneedle or tip of the needle or microneedle which has dissolved).
When multiple administrations/injections of particles per biological area/administration spot are performed, the total volume of the particles at the biological area/administration spot corresponds to the sum of the volumes occupied by the particles after each single administration step.
Needle(s) or microneedle(s) which can be used to administer/inject the particles, has(have) typically the following dimensions: a diameter typically between about 0.10 mm, preferably more than about 0.10 mm, and about 0.50 mm, and a length typically between about 1 mm, about 1.5 mm, about 2 mm, or about 5 mm, and about 100 mm or about 50 mm.
The concentration of particles per administration/injection site/area (in a given biological area, if several administrations/injections are performed, the concentration described in the present paragraph is that resulting from one administration/injection only) is typically between about 1 mg/100 g (expressed in weight of particles by weight of biological medium) and about 40 g/100 g, preferably between about 0.1 g /100 g or about 1 g/lOOg, and about 20 g /100 g. Because the particles remain at their administration site, the concentration of particles at their implantation site corresponds to the concentration of particles which is present in the suspension to be administered in vivo (e.g., the concentration of particles in the liquid or gel or the concentration of particles in the needle, microneedle or tip of the needle or microneedle).
External activation of the particles by electrical or light signals
In a particular aspect, the present invention advantageously allows spatiotemporal control of the stimulation of primary afferents (also herein identified as primary sensory neurons or LTMRs) through particles’ activation by (exposition to) external electrical signals and/or (artificial) light signals.
When the source of energy used to activate the particles is an electrical source (i.e., a source delivering artificial external electrical signals), the electrical stimulation (i.e., the signal) intensity (i.e., current intensity) is typically between 0.1 mA and 10 mA, the electrical stimulation frequency is typically between 1 Hz and 500 Hz, the electrical stimulation pulse width is typically between 5 ps and 500 ms, and the electrical stimulation waveform is typically a square, a rectangle or a triangle waveform, said square, rectangle or triangle waveform being monophasic, biphasic-charge balanced or biphasic-charge imbalanced, or a pulson (i.e., a square pulse divided in short bursts of square pulses) waveform.
When the source of energy used to activate the particles is an artificial light source (i.e., a source delivering artificial external light signals), the light stimulation (i.e., the signal) wavelength is typically within the infrared or near infrared, because of its ability to penetrate deeper into the tissue. However, the incoming light input source is typically selected based on the particle composition (i.e., the composition of the semiconductor nano-objects at least partially embedded in the insulating biocompatible matrix) to optimize the conversion of the signal emitted by the light source into an electrical signal. In addition, when the energy source to activate the particles is a light source, the light stimulation (i.e., the signal) irradiance rate is typically between 0.1 mW/mm2 and 1000 mW/mm2, the light stimulation frequency is typically between 1 Hz and 500 Hz, the light stimulation pulse width is typically between 5 ps and 500 ms, and the light stimulation waveform is typically a square, a rectangle or a triangle waveform, or a pulson (i.e., a square pulse divided in short bursts of square pulses) waveform.
Removable device for particles’ external activation by electrical or light signals
In a particular aspect of the invention, the particles are intended to work through an “on” / “off’ mode of action, meaning that when they are administered at an acupoint of a subject, under the skin of a subject, typically in the dermis (in particular in the context of non-invasive administration) or both in the dermis and hypodermis, and then activated with an external means, typically an external source of electrical or light energy (i.e., when they are activated by external electrical signals and/or artificial light signals), preferably an external manmade source of energy, as described herein above, the particles of the invention act as transducers and convert an incoming signal (i.e., typically a signal emitted by a removable device) into an output signal of different nature, or modulate/relay locally an incoming signal (i.e. typically a signal emitted by a removable device), thereby acting on peripheral nerves to convey an information to the brain, for example for neural coding (i.e., processing of information).
In a particular aspect of the invention, the external source of electrical or light energy (i.e., the external electrical signals or the external artificial light signals) comes from a removable device.
The removable device is a wearable device typically included in a jewelry, in a clothing or in a medical device. When included in a jewelry, it may be included for example in a ring, in a bracelet or in a necklace. When included in a clothing it may be included for example in a tee-shirt, in a sweatshirt, in a sock, in a mitt or in a glove, provided that it delivers reliable external stimulation to the particles administered/implanted under the subject’s skin. When included in a medical device, it may be included for example in an artificial skin (for example an ‘electronic skin’), in a patch or in a bandage.
In a particular aspect, the removable device is a bracelet, a ring, a necklace, an artificial skin, a patch, a bandage, a mitt or a glove.
In a preferred aspect of the invention, the removable device comprises a collector module (cl) the function of which is to collect an input signal. The input signal is typically selected from a physical signal, a chemical signal and a biological signal, and is used to activate the particles. The collector module (cl) is capable of processing the signal when required (cf. Figure 4). A particular removable device of the invention thus collects an input signal which is, optionally processed and, used to activate the particles. The removable device is preferably wearable by a subject. A typical removable device of the invention comprises a collector module (cl) collecting an input signal which is typically a physical signal, a chemical signal or a biological signal, and capable of processing the signal when required, and a stimulator module (c2).
In a particular aspect, the collector module (cl) comprises a module (cl’) collecting an input signal and a processing module (cl”) encoding/converting the input signal into an output signal readable by the stimulator module (c2).
In another typical aspect, the stimulator module (c2) comprises a source of energy which is an external electrical source and/or an external (artificial) light source, said source using the output signal to activate the particles.
As taught herein above, the collector module (cl) collects a signal which is typically a physical signal, a chemical signal or a biological signal or several signals, e.g., physical, chemical and/or biological signals.
A physical signal is for example an electromagnetic signal such as a radio wave signal, a microwave signal, a visible light signal, an infrared signal, an ultraviolet (UV) signal, an X-ray signal, a gamma- ray signal, etc.; a thermal radiation/heat signal; an electric signal; a magnetic signal; or a mechanic signal such as for example an ultrasound signal, a pressure signal or a strain signal.
The collector module can be a sensor module.
It is typically a “physical sensor module”, i.e., a sensor module collecting a physical phenomenon (i.e., a physical signal).
A physical sensor module can be an “image sensor module” detecting information in the form of light. An image sensor module typically consists of integrated circuits that sense the information and convert it into an equivalent current or voltage which can be later converted into digital data.
A physical sensor module can also be an “ultrasonic sensor module”. An ultrasonic sensor module is typically used to measure the distances between the sensor and an obstacle object. The ultrasonic sensor module generally works on the principle of the Doppler Effect and includes an ultrasonic transmitter and a receiver. The ultrasonic transmitter transmits the signal in one direction and this transmitted signal is then reflected back whenever there is an obstacle and is received by the receiver. The total time required for the signal to be transmitted and then received back is generally used to calculate the distance between the ultrasonic sensor and the obstacle.
A physical sensor module or physical sensor can also be for example an “infrared” sensor module; a “tactile” sensor module; a “pressure” sensor module; a “strain” sensor module; a “temperature” sensor module; a “magnetic-based” sensor (magnetometer) module; an “optical” sensor module; an “acoustic- based” sensor module; a “gravity” sensor (accelerometer) module; an “angular rate” sensor (gyroscope) module or a “deep pressure” sensor (barometer) module.
The sensor module (cl) can also be a “chemical sensor module” or “chemical sensor”, i.e., a module collecting a chemical phenomenon (i.e., a chemical signal). When the sensor module is a chemical sensor module, it is typically a liquid or gas sensor module detecting the composition or the concentration of a chemical agent in a medium such as for example an organic molecule or an ion.
The sensor module (cl) can also be a “biological sensor module” or “biosensor”, i.e., a module collecting a biological phenomenon (i.e., a biological signal), such as a heart rate sensor. When the sensor module is a biosensor, it typically detects the composition or concentration of a biological agent such as for example a protein a nucleic acid a cell, a bacterium or a virus, in a medium;
Each sensor module is capable of processing the signal (if and when required) and typically combines sensing, computation, communications and power means into a very small volume typically below 100 mm3, below 10 mm3, or even below 1 mm3. A sensor module or several sensor modules, typically two or three sensor modules, or even a network of sensor modules can be combined in the device to increase its sensing ability. For instance, an optical sensor module can be coupled with an ultrasound sensor module to increase its sensing ability.
The collector module collecting the input signal can also be any other suitable means capable of collecting an input signal from one or several sensors (physical, chemical and/or biological sensors), or from one or several computing systems, for example any data generated by a computing system and transmitted in the form of a digital electrical signal, the sensor(s) or computing system(s) being external to the device. The input signal received by the collector module can be any input signal sent by remote sensor(s) and/or remote computing system(s), through wired (such as for example a HDMI or USB connector) or wireless connection, preferentially via a wireless connection such as for example Bluetooth and WIFI.
When the collector module (cl) comprises a module (cl’) collecting an input signal and a processing module (cl”) encoding/converting the input signal into an output signal readable by a stimulator module (c2), the processing module (cl”) preferably contains a deep learning framework determining the parameters required to generate an output signal readable by the stimulator module. Machine learning can typically be used to encode information and implement a neuronal network method or system capable of determining the required parameters. In one aspect, the module (c G) transmits signals to the processing module (cl”) which uses ADC (Analog-to-Digital Converter) or an equivalent converter, to perform the digitization of (digitalize) the acquired analog signals and generate an output signal which is then sent to a stimulator module (c2). For instance, the signal processing can be an image analysis, a text analysis (i.e., data analysis) or a speech analysis. The signal is captured by a module (cl’) of the collector module and sent to a processing module (cl”), for example for color segmentation, radiance segmentation, hue segmentation, sentence segmentation, or word segmentation. Then, the processing module converts this input signal into an output signal and sends it to the stimulator module (c2).
In another context, a sensor module can sense a change of a measured parameter using a module (cl’) and transfer the information corresponding to this change to a processing module (cl”) (which can typically be a microcontroller) that calculates and converts the change into an output signal (containing all information from the input signal) readable by a stimulator module (c2).
The herein described stimulator module (c2) typically comprises a source of energy which is selected from an electrical source and a light source, said source using the signal to activate the particles.
Each collector module encodes an input signal into an output signal readable by a stimulator module, typically encodes/converts the input signal into an output signal readable for example by a light source of energy or an electric source of energy. Typically, the output signal can be an electrical signal to be sent to a stimulator module (c2) comprising (micro)electrodes acting as an electrical source of energy to activate the particles (i.e., delivering external electrical signals). Additionally, or alternatively, the output signal can be an electrical signal to be sent to a stimulator module (c2) comprising (micro)LEDs acting as a light source of energy to activate the particles (i.e., delivering artificial external light signals). Several stimulator modules, typically two or three stimulator modules, or a network of stimulator modules, can be combined in the device to increase its sensing ability. Several devices can also be used in parallel to increase sensing ability.
Also, herein disclosed is a system comprising particles as herein described and a removable device as herein described, wherein the particles are located at an acupoint of a subject, in the dermis and/or hypodermis of a subject, or are non-invasively administered to (typically in the dermis of) a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to activate the particles by external signal(s), the removable device being wearable by a subject.
The spikes, generated in response to input signal(s) from the collector module(s), confirm the successful reading of the output signal by the stimulator module(s) as well as the successful stimulation of the particles by the source of energy and consecutive induced stimulation of the peripheral nerves which will then convey/transmit a signal to the central nervous system which it can interpret. These spikes can be recorded as electrophysiological signals and observed and/or decoded.
The removable device is preferably powered by an external source or by a battery which is part of the device. Use of the particles or of the composition comprising the particles.
In one aspect of the invention, the particle or the composition comprising the particles is for use for treating a subject suffering of a disease, disorder or dysfunctional state, typically suffering of an inflammatory or an infection disease, via an acupuncture effect. The therapeutic effect is obtained via an acupuncture effect if i) the particle or the composition comprising the particles is administered to at least one acupoint of the subject and then ii) the particle(s) is/are activated by external electrical and/or light signals.
A particle is thus herein described for use for treating a subject via an acupuncture effect. The particle is typically administered to the subject at an acupoint, and then activated by:
- external electrical signals if a conductor nano-object is used, or
- external electrical signals and/or (artificial) external light signals if (both) a conductor nano-object and a semiconductor nano-object are used.
The description also relates to a method for delivering / providing / generating acupuncture effect to/in a subject in need thereof. This method typically comprises a step of administering the particle, or a composition comprising the particles, to at least one acupoint of the subject, and a step of activating the particle(s) and/or of stimulating the particle(s) by external electrical signals and/or external (artificial) light signals, thereby triggering an acupuncture effect in the subject.
In another aspect, the particle or the composition comprising the particles is for use for sensory restoration, preferably for use for 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.
Also herein described is thus a particle of the invention, or composition comprising such particles, for use for sensory restoration in a subject when the particle(s) is/are administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e., is present in the particle), or
- external electrical signals and/or (artificial) external light signals if (both) a conductor nano-object and a semiconductor nano-object are used (i.e., are present in the particle).
Also described is a particle of the invention, or composition comprising such particles, for use for sensory substitution in a subject when the particle(s) is/are administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e., is present in the particle), or - external electrical signals and/or (artificial) external light signals if (both) a conductor nano-object and a semiconductor nano-object are used (i.e., are present in the particle).
Inventor also herein describe the use of a particle of the invention or of a composition comprising such particles, for sensory enhancement in a (healthy) subject, or for creating new sensory means in a (healthy) subject, said new sensory means allowing the perception of external signals which are not perceived by a natural sense of the subject, for example by a human natural sense.
Thus, inventor herein describes the use of a particle of the invention, or of a composition comprising such particles, for sensory enhancement of a subject, in particular a healthy subject, the particle being for example non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e., is present in the particle), or
- external electrical signals and/or (artificial) external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e., are present in the particle).
Herein also described is the use of the particle of the invention, or composition comprising such particles, for creating new sensory perception in a subject, in particular a healthy subject, the particle being for example non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e., is present in the particle), or
- external electrical signals and/or (artificial) external light signals if a conductor nano-object and a semiconductor nano-object are used (i.e., are present in the particle).
Moreover, people suffering from mental, emotional and/or behavioral disorder/ihness (such as psychotic disorder, obsessive-compulsive disorder, eating disorder, conduct disorder, learning disorder, anxiety disorder, bipolar disorder, etc.), also defined or identified in the art as “any mental illness” (“AMI”), typically people who are followed (or are eligible for being followed) by a psychiatrist (i.e., eligible for undergoing a psychotherapy) and/or who are taking (or are eligible for taking) medication as part of a treatment protocol at some point in their life (i.e., people who may be eligible for receiving, or receiving mental health services), may typically benefit from the present invention to overcome their current disorders, as the invention typically allows sensory enhancement and/or the creation of new sensory perception.
Therefore, in a particular aspect, the particle(s) of the invention, or composition comprising such particles, is for use for sensory augmentation or for creation of new sensory perception in a subject suffering from mental, emotional and/or behavioral disorder. In such a context, the particle(s) is/are typically administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used (i.e., is present in the particle), or - external electrical signals and/or (artificial) external light signals if (both) a conductor nano-object and a semiconductor nano-object are used (i.e., are present in the particle).
The description further relates to a method for sensory restoration to a subject in need thereof, or for sensory substitution in a subject at least partially deprived of taste, smell, hearing, balance and/or vision, or for sensory enhancement in a subject, or for creating new sensory means in a subject. The method typically comprises a step of administering the particle, or a composition comprising the particles, in the dermis and/or hypodermis of a subject, in particular in a non-invasive way (i.e., typically in the dermis of at least one biological area of a subject) or in an invasive way (i.e., typically in the hypodermis of at least one biological area of a subject), and a step of activating the particle(s) and/or of stimulating the particle(s) by external electrical signals and/or by external (artificial) light signals, thereby triggering sensory restoration, sensory substitution, sensory enhancement, or the creation of new sensory means allowing a (potentially new) perception of the environment, in the subject.
Any of the herein described particles or composition comprising such particles create, when the particle(s) are stimulated by (i.e. exposed to) external electrical and/or (artificial) light signals, spatiotemporal electrical patterns at the level of the peripheral nervous system which can be efficiently read by the brain and are able to restore a perception, for example touch perception, in a subject who is deprived of it, to substitute a perception means to another in a subject suffering of an altered perception (for example of an altered vision or an altered hearing), to enhance perception in a subject, and/or to create a new perception means in a subject. The particle(s) of the invention, when activated (or stimulated) by external electrical and/or (artificial) light signals, also enable(s) for the first time the brain of a subject, for example of a human subject, to perceive beyond the reality the subject is used to perceiving thanks to his (natural) senses.
A particular herein described advantageous system is a system comprising particles of the invention, for example a composition comprising such particles, and a removable device as herein described, wherein the particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of a subject, or are non-invasively administered (typically at the dermis level) to a subject, and wherein the removable device collects an input signal which is, optionally processed and, used to (externally) activate the particles by (external) signal(s) (as herein described), the removable device being wearable by a subject.
In a preferred aspect of the invention herein described, the sensory restoration, sensory substitution, sensory enhancement, or new sensory perception system, preferably comprises a sufficient number “X” of dimensions or parameters and, in each dimension, a sufficient level “N” of features to build a robust information that will create or re-create sensory perception. Coding signal (corresponding to the signal emitted by the source of energy, typically from the stimulator module of the removable device) can typically have dimensions expressed for example as intra-signals frequency, inter-signals frequency, signals amplitude, signals intensity, signals waveform, signals repetition, signals repetition frequency, signals total time, and any combination thereof. As well, in each of these dimensions, “N” features can be implemented to (i) reconstitute a well-known perception such as a sound, a melody, colors, hue and luminance of a landscape, distance and direction, etc. and/or to (ii) create a new perception such as for example infrared vision or ultrasound vision. Machine learning can typically be used by the skilled person for such neural coding, or for implementing neuronal network methods to handle, typically transmit and/or record, information.
In a particular aspect of the invention, neural data of a subject, such as data obtained from BOLD signal using functional Magnetic Resonance Imaging (fMRI) or electroencephalography (EEG) signals, may be recorded to assess the efficacy of sensory restoration, sensory substitution, sensory enhancement, or the creation of a new sense in the subject. Neural data can also be recorded at the peripheral nerve system level (typically via a sensor, such as electrode(s)). These neural data can then be used as a feedback loop in order to “train” the system of the invention and/or to “train” the subject him/herself. Indeed, the information transmitted to the brain thanks to the system of the invention can be recorded (on a memory) and then processed by a processor, and then decoded (using the recorded/processed neural data and typically machine learning for neural decoding). The processed data can then advantageously be sent back to the subject in the form a signal perceivable by any one of the five natural senses of the subject in order to accelerate the learning process and facilitate any sensory restoration process, sensory substitution process, sensory enhancement process, or new sensory perception process. In a particular aspect, the decoded information obtained from a given subject can be used by said subject (i.e., transmitted to the subject and perceived by the subject) to facilitate learning and exploitation of information. Alternatively, the decoded information can be sent to the wearable/removable device to update and improve output signal transmission.
These records can be used as herein above described thanks to the stable interaction existing (under activation) between the removable device and the implanted/injected particles.
In an aspect of the invention, such record(s) may be used to lock the system (A) of the invention by specifically associating the removable device (C) of the invention with the particles (B) of the invention.
The present description also encompasses any kit comprising at least the herein described particles, optionally together with a tool (such as needle(s), microneedle(s), patch(es), injector(s), etc.) designed to appropriately deposit and/or position the particles in an adequate site of the subject’s body.
The present description also encompasses a kit comprising in addition to the particles, a herein described system, and one or several tools selected from a sensor such as an electrode (for capturing neural data from the nervous system of a subject), a memory (for recording the captured neural data) and a processor (for processing the recorded neural data before sending the processed data back to the subject in the form of a signal perceivable by any one of the five natural senses of the subject).
The aspects of the invention described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of herein described specific materials, particles, compositions and systems as well as equivalents of herein described methods or procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
FIGURES
FIGURE 1. Schematic representation of a particle comprising conductor nano-objects or (both) conductor and semiconductor nano-objects at least partially embedded (A) of fully embedded (B) in an insulating biocompatible matrix.
FIGURE 2. Schematic representation of directly (in contact), or indirectly (via a linker), connected conductor and semiconductor nano-objects embedded in an insulating biocompatible matrix.
FIGURE 3. Schematic representation of a nanoparticle (A), a nanofiber (B) and a nanoplate (C). FIGURE 4. System comprising particles of the invention and a removable device.
The particles are typically located at the dermis and/or hypodermis level and in particular at an acupoint of a subject, or are non-invasively administered (typically at the dermis level) to a subject, and are activated by a signal emitted by the removable device. The removable device collects an input signal which is, optionally processed and, used to activate the particles, the removable device being wearable by a subject.
The device typically comprises:
- a collector module (cl) 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 (cl’) collecting an input signal and a processing module (cl”) encoding the input signal into an output signal readable by the stimulator module (c2);
- a stimulator module (c2) comprising a source of energy which is selected from an external electrical source and/or an external (artificial) light source, said source using the output signal to activate the particles.
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 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.
FIGURE 5. Scanning Electron microscopy (SEM) images of particles of the invention acting as a neural interface.
Figure 5 shows representative images of particles of the invention synthesized as described in the Examples section. Samples (i.e., particles in aqueous suspensions) were deposited onto a carbon adhesive by adding a small volume of suspension followed by a drying step at room temperature. The samples were observed without any surface treatment (i.e., metallization). The median size of the particles is above 1 μm and the particles are spherical in shape.
A) SEM representative image of particles of the invention where graphene nanoplatelets are at least partially embedded in PMMA insulating biocompatible matrix. Magnification x500 (top picture) and xlOOOO (bottom picture) were chosen for the observation of the sample.
B) SEM representative image of particles of the invention where carbon-based nano-objects and gold nanoparticles are at least partially embedded in PMMA insulating biocompatible matrix.
C) SEM representative image of particles of the invention where carbon-based nano-objects and graphene quantum dots are at least partially embedded in PMMA insulating biocompatible matrix.
D) SEM representative image of particles of the invention where graphene nanoflakes are at least partially embedded in PMMA insulating biocompatible matrix
E) SEM representative image of particles of the invention where reduced graphene oxide nano-objects are at least partially embedded in PMMA insulating biocompatible
EXAMPLES
Particles of the invention
Particles can be manufactured/synthesized according to synthesis methods well-known by the skilled person in the art.
As an example of oil-in- water emulsion/solvent evaporation technique, conductor (for example gold or graphene) nano-objects, or both conductor (for example gold or graphene) nano-objects and semiconductor (for example CuInSe2 quantum dot or CdS/CdSe core/shell quantum dot) nano-objects and PMMA (used as the insulating biocompatible matrix), are weighted and dissolved/dispersed in organic solvent, typically dichloromethane. This suspension is then added to an aqueous solution. The resulting suspension is emulsified under vigorous mixing and subsequently stirred to allow solvent to evaporate. The obtained particles are then centrifuged and washed several times with water for injection by centrifugation and supernatant removal. The resulting particles are re-suspended in water and characterized for their size and shape, typically by SEM and/or AFM. Figures 5A-E are representative SEM images of particles of the invention synthesized as followed:
1) Polymethylmethacrylate (PMMA) (average molecular weight about 120000) is dissolved in dichloromethane. Conductor nano-objects and optionally semiconductor nano-objects in a powder form are dispersed in dichloromethane and subsequently added to the PMMA solution (see below Table 1).
Table 1. Composition of the conductor nano-objects and optionally semiconductor nano-objects dispersed in dichloromethane and subsequently added to a dichloromethane solution containing dissolved PMMA.
Figure imgf000038_0001
Carbon-based nano-objects are obtained by adding graphene nanoplatelets in powder form in Water For Injection (WFI) and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for at least 2 hours, the as-obtained suspension being dried at temperature between about 30°C and 100°C. Graphene nanoflakes are obtained by adding graphene nanoplatelets in powder form in WFI and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for at least 2 hours, the as- obtained suspension being dried at temperature between about 10°C and 25 °C.
Reduced graphene oxide nano-objects are obtained by adding WFI to graphene oxide sheets powder and submitting the resulting suspension to ultrasound (using an ultrasonic bath) for about 1 hour. The as- obtained suspension is subsequently adjusted to a basic pH using basic aqueous solution. Ascorbic acid is then added to the suspension under magnetic stirring. The resulting suspension is stirred for about 3 hours using a magnetic stirrer, washed thoroughly with WFI using centrifugation, re-dispersed in WFI, and then let dried at temperature between about 10°C and 25°C.
2) PVA (1% w/v) solution is then added to the dichloromethane suspension containing the dissolved PMMA, the conductor nano-objects (dispersed powder) and optionally the semiconductor nano-objects (dispersed powder). 3) The resulting mixture is vigorously stirred using an UltraTurrax, followed by magnetic agitation to remove the solvent, and subsequently washed by centrifugation using WFI and dispersed in WFI for characterization by SEM (see Figure 5).
Protocol
In a typical experiment, the particles of the invention are administered on at least one biological area of a subject (preferably at an acupoint of a subject, or in the dermis and/or hypodermis of a subject). In particular examples where the administration is not performed in the hypodermis, in particular is performed in the dermis, the administration is considered as non-invasive (as would be the administration of ink particle during a tattooing procedure). Particles are subsequently activated by an appropriate external source of energy (i.e., artificial electrical and/or light signals).
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, external electrical signals and/or external artificial light signals (i.e., different from the signals generated by natural light) are converted into signals that stimulate the peripheral nerves, for example induce or modulate the signal (information) conveyed by the peripheral nerves. Then, the peripheral nerves convey the information to the brain of the subject typically for triggering an acupuncture effect, for touch sensory restoration, sensory substitution, sensory enhancement or new sense(s) perception.
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).

Claims

1. A particle, wherein: i) the longest dimension of the particle is of at least 1 μm and below 100 μm, ii) the particle comprises: a volume fraction of at least about 0.005% of conductor nano-objects, based on the total volume of the particle, or a volume fraction of at least about 0.005% of conductor nano-objects and a volume fraction of at least about 0.1 % of semiconductor nano-objects, based on the total volume of the particle, and iii) the conductor nano-objects, and optionally the semiconductor nano-objects, if present in the particle, are at least partially embedded in an insulating biocompatible matrix.
2. A particle as described in claim 1, wherein the particle is for use for treating a subject via an acupuncture effect when the particle is administered to the subject at an acupoint, and then activated by:
- external electrical signals if a conductor nano-object is used/ present in the particle, or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used/ present in the particle.
3. A particle as described in claim 1, wherein the particle is for use for sensory restoration in a subject when the particle is administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used/ present in the particle, or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used/ present in the particle.
4. A particle as described in claim 1 , wherein the particle is for use for sensory substitution in a subject when the particle is administered in the dermis and/or hypodermis of the subject, and then activated by:
- external electrical signals if a conductor nano-object is used/ present in the particle, or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used/ present in the particle.
5. Use of a particle as described in claim 1 for sensory enhancement of a healthy subject, the particle being non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used/ present in the particle, or - external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used/ present in the particle.
6. Use of a particle as described in claim 1 for creating new sensory perception in a healthy subject, the particle being non-invasively administered to the subject, and then activated by:
- external electrical signals if a conductor nano-object is used/ present in the particle, or
- external electrical signals and/or artificial external light signals if a conductor nano-object and a semiconductor nano-object are used/ present in the particle.
7. The particle according to claim 1 , wherein the longest dimension of the particle is of at least 20 μm, preferably of at least 40 μm, and below 100μm.
8. The particle according to claim 1, wherein the particle has an electrical conductivity of at least 104 S/m and the conductor nano-object is made of material(s) selected from the group consisting of metal, crystallized metal oxide, amorphous oxide, transition metal dichalcogenide, carbon elements, and any mixture thereof.
9. The particle according to claim 1 , wherein the semiconductor nano-object is made of material(s) selected from the group consisting of metal oxide, silicon, germanium, transition metal dichalcogenide, perovskite, a ternary I-III-VU nanocrystal wherein I is selected from Cu+ and Ag+; III is selected from Al3+, Ga3+, and In3+; and VI is selected from S2_, Se2_, and Te2_, and any mixture thereof.
10. The particle according to claim 1, 8 or 9, wherein the particle comprises several nano-objects, the nano-objects being: nanoplate(s), each nanoplate having one dimension between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, nanofiber(s), each nanofiber having 2 dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm, and/or nanoparticle(s), each nanoparticle having 3 dimensions between about 0.3 nm and about 100 nm, preferably between about 0.5 nm and about 50 nm.
11. The particle according to claim 1 , wherein the insulating biocompatible matrix is made of a material selected from the group consisting of polymethylmethacrylate, polycarbonate, non- biodegradable polyurethane and any mixture thereof.
12. A composition comprising particles as described in anyone of claims 1, 7-11, and a pharmaceutically acceptable carrier.
13. A system comprising particles as described in anyone of claims 1, 7-11, and a removable device, wherein the particles are located at an acupoint of a subject, in the dermis and/or hypodermis of a subject, or are non-invasively administered to a subject, and wherein the removable device collects an input signal which is used to activate the particles by external signal(s), the removable device being wearable by a subject.
14. The system according to claim 13, wherein the input signal collected by the removable device is processed by the device before being used to activate the particles by external signal(s).
15. The particle for use according to anyone of claims 2-4, the use according to claim 5 or 6, or the system according to claim 13 or 14, wherein the subject is a mammal, preferably a human being.
PCT/EP2022/057395 2021-03-22 2022-03-22 Particles as neural interfaces WO2022200297A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21305348.1 2021-03-22
EP21305348 2021-03-22

Publications (1)

Publication Number Publication Date
WO2022200297A1 true WO2022200297A1 (en) 2022-09-29

Family

ID=76859578

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/057395 WO2022200297A1 (en) 2021-03-22 2022-03-22 Particles as neural interfaces

Country Status (1)

Country Link
WO (1) WO2022200297A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090011536A1 (en) * 2004-10-21 2009-01-08 Fengyan Zhang Optical device with irox nanostruture electrode neural interface
US20180369086A1 (en) * 2012-09-28 2018-12-27 Stelo Technologies Methods of making silver nanoparticles and their applications
WO2019204468A1 (en) 2018-04-18 2019-10-24 Sabic Global Technologies B.V. Magnetic nanoparticles embedded in polymer microparticles
WO2020081817A1 (en) * 2018-10-17 2020-04-23 University Of Florida Research Foundation Magnetically responsive composite microparticles for triggered delivery of biologically active agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090011536A1 (en) * 2004-10-21 2009-01-08 Fengyan Zhang Optical device with irox nanostruture electrode neural interface
US20180369086A1 (en) * 2012-09-28 2018-12-27 Stelo Technologies Methods of making silver nanoparticles and their applications
WO2019204468A1 (en) 2018-04-18 2019-10-24 Sabic Global Technologies B.V. Magnetic nanoparticles embedded in polymer microparticles
WO2020081817A1 (en) * 2018-10-17 2020-04-23 University Of Florida Research Foundation Magnetically responsive composite microparticles for triggered delivery of biologically active agents

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
A J MARSDEN ET AL.: "Electrical percolation in graphene-polymer Composites", 2D MATER, vol. 5, 2018, pages 032003
A. HANDLER ET AL.: "The mechanosensory neurons of touch and their mechanisms of activation", NATURE REVIEW NEUROSCIENCE, vol. 22, 2021, pages 521 - 537, XP037541268, DOI: 10.1038/s41583-021-00489-x
A. KHOSLA: "Fall-Winter", 2012, THE ELECTROCHEMICAL SOCIETY INTERFACE, pages: 67 - 70
A. ZIMMERMAN ET AL.: "The gentle touch receptors of mammalian skin", SCIENCE, vol. 346, no. 6212, 2014, pages 940 - 954
DERVISEVIC MUAMER ET AL: "Skin in the diagnostics game: Wearable biosensor nano- and microsystems for medical diagnostics", NANO TODAY, ELSEVIER, AMSTERDAM, NL, vol. 30, 20 December 2019 (2019-12-20), XP086041239, ISSN: 1748-0132, [retrieved on 20191220], DOI: 10.1016/J.NANTOD.2019.100828 *
ROBERT GLOUKHOVSKI ET AL.: "Measurements of the Electric Conductivity of MWCNT Suspension Electrodes with Varying Potassium Bromide Electrolyte Ionic Strength", JOURNAL OF THE ELECTROCHEMICAL SOCIETY, vol. 167, 2020, pages 020528
WHO STANDARD ACUPUNCTURE POINT LOCATIONS IN THE WESTERN PACIFIC REGION, 2008
WORLD HEALTH ORGANIZATION, WHO STANDARD ACUPUNCTURE POINT LOCATIONS IN THE WESTERN PACIFIC REGION, 2008
WORLD HEALTH ORGANIZATION: "A proposed standard international acupuncture nomenclature", REPORT OF A WHO SCIENTIFIC GROUP,, 1991
Z.-J. ZHANG ET AL.: "Neural Acupuncture Unit: A New Concept for Interpreting Effects and Mechanism of Acupuncture", EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE, 2012

Similar Documents

Publication Publication Date Title
Mathew et al. A review on real-time implantable and wearable health monitoring sensors based on triboelectric nanogenerator approach
Deng et al. Piezoelectric nanogenerators for personalized healthcare
Zhang et al. Electroactive electrospun nanofibers for tissue engineering
Liu et al. Electroactive biomaterials and systems for cell fate determination and tissue regeneration: design and applications
Wang et al. Applications of nanogenerators for biomedical engineering and healthcare systems
Mehrali et al. Blending electronics with the human body: A pathway toward a cybernetic future
Sun et al. Nanogenerator-based devices for biomedical applications
AU2016335931B2 (en) High-charge capacity electrodes to deliver direct current nerve conduction block
Li et al. Bioinspired prosthetic interfaces
Olvera et al. Electroactive material-based biosensors for detection and drug delivery
Lee et al. Nanomaterials for bioelectronics and integrated medical systems
Song et al. Nanogenerators for wearable bioelectronics and biodevices
Xu et al. Self‐powerbility in electrical stimulation drug delivery system
Ma et al. Highly permeable and ultrastretchable liquid metal micromesh for skin-attachable electronics
Sun et al. Hybrid nanogenerator based closed-loop self-powered low-level vagus nerve stimulation system for atrial fibrillation treatment
Lin et al. Soft–hard composites for bioelectric interfaces
Liang et al. Strategies for interface issues and challenges of neural electrodes
Gibney et al. Toward nanobioelectronic medicine: Unlocking new applications using nanotechnology
Sunwoo et al. Stretchable Low-Impedance Conductor with Ag–Au–Pt Core–Shell–Shell Nanowires and in Situ Formed Pt Nanoparticles for Wearable and Implantable Device
Radhakrishnan et al. Recent updates on triboelectric nanogenerator based advanced biomedical technologies: a short review
Zhang et al. A high-performance, biocompatible, and degradable piezoresistive-triboelectric hybrid device for cross-scale human activities monitoring and self-powered smart home system
Wu et al. Self-powered nanocomposites under an external rotating magnetic field for noninvasive external power supply electrical stimulation
Barshutina et al. PDMS-CNT composite for soft bioelectronic neuronal implants
Miao et al. Biology-guided engineering of bioelectrical interfaces
Zeng et al. Challenges and Opportunities of Implantable Neural Interfaces: From Material, Electrochemical and Biological Perspectives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22716936

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE