The present invention relates to particles and compositions comprising such particles for use for treating a subject suffering of a disease via an acupuncture effect when particles stably interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors of at least one acupoint or Neural Acupuncture Unit (NAU) of the subject. The particles used in the context of the present invention are preferably below 100 pm and are preferably prepared from a material selected from a piezoelectric material, a pyroelectric material and a far-infrared radiation-emitting material.

BACKGROUND

Characteristic features of immunity, innate and/or adaptive, encompass the detection of immunogenic stimuli, the generation of protective responses and the formation of immunological memory. In this context, the activation of macrophages, dendritic cells, neutrophils, natural killers and other immune cells is pivotal in inflammation to restore tissue homeostasis. Macrophages and dendritic cells function as antigen-presenting cells and bridge innate and adaptive immune response. Upon antigen exposure, T and B lymphocytes undergo cell division and maturation and play key roles in antigen- specific adaptive immunity. The release of cytokines, chemokines and other inflammatory mediators amplifies the inflammatory process. This pro-inflammatory release is accompanied by the release of anti-inflammatory molecules, including IL-10 and soluble cytokine receptors and inflammation is classically resolved by the coordinated action of these pro-resolving mediators. In some conditions, however, excessive and unresolved inflammation can mediate tissue damage and lead to lethal and debilitating inflammatory diseases. In addition, unbalanced T- and B-cell-mediated processes associated with defects in antigen recognition, effector activity and immunologic memory may result in aberrant immune responses [Pavlov V.A. et al. Neural regulation of immunity: molecular mechanisms and clinical translation. Nature Neuroscience 2017, 20(2), 156-166]

Interestingly, researches have revealed that pattern-recognition receptors and cytokine receptors are expressed on neurons. As well, receptors for acetylcholine and other neurotransmitters are expressed on macrophages, dendritic cells and other immune cells. Peripheral immune cells also synthesize and release acetylcholine, catecholamines and other molecules classically identified as neurotransmitters [Menna R. Clatworthy et al. The nervous spleen. Immunology and Cell Biology, 2008, 86, 1-2]

It has been discovered that neuronal circuits operate reflexively and regulate innate and adaptive immunity. A neural reflex (i.e., a neuronal circuit operating reflexively) is defined by three components: first, a sensory receptor capable of responding to a change in the environment; second, a sensory afferent arc that transmits action potentials into the nervous system; and third, a motor efferent arc that sends action potentials from the nervous system back to the periphery to modulate environment. Known neural reflex circuitry involved in immunity are the inflammatory reflex, the vagus nerve-adrenal reflex, the enteric-neural reflex, the neural reflex in cancer, the gateway reflex, the nociceptive reflex in the lung, the axon-axon reflex [S.S. Chavan et al. Essential Neuroscience in Immunology. The Journal of Immunology. 2017; 198:3389-3397; K.J. Tracey. Reflexes in Immunity. Cell 164, January 28, 2016; 343]

One particularly well-characterized neuronal circuit regulating innate immunity is the inflammatory reflex, a neural reflex circuit of action potentials traveling in the sensory and motor vagus nerves that regulate cytokine production in the spleen. The efferent action potentials traveling down the vagus nerve culminate in the celiac ganglion, the site of origin of adrenergic splenic nerve. The splenic nerve is adrenergic, producing norepinephrine in the vicinity of lymphocytes in the spleen. A discreet subset of lymphocytes regulated by splenic nerve signal express choline acetyltransferase, the rate limiting enzyme in the biosynthesis of acetylcholine. Acetylcholine released by lymphocytes under the control of adrenergic splenic nerve signals inhibits macrophage cytokine release and shifts them toward an M2 anti-inflammatory tissue protective phenotype. Acetylcholine-induced signal transduction in monocytes and macrophages is mediated by a-7 nicotinic acetylcholine receptors which inhibit the nuclear translocation ofNF-kB, activate the JAK2/STAT3 pathway, stabilize mitochondrial membranes, and downregulate the activity of the inflammasome. The net-effect of vagus nerve-mediated signals within the spleen is the inhibition of cytokine release by the red pulp and marginal zone macrophages, which together account for 90% of the TNF and IF-1 produced during typically acute endotoxemia [Kevin J. Tracey. The inflammatory reflex. Nature, 2002. 420, 853-859; Valentin A. Pavlov etal. Neural regulation of immunity: molecular mechanisms and clinical translation. Nature Neuroscience. 2017, 20(2), 156-166; Sangeeta S. Chavan et al. Essential Neuroscience in Immunology. The Journal of Immunology. 2017, 198, 3389-3397; J.M. Huston et al. The inflammatory reflex and neural tourniquet: harnessing the healing power of the vagus nerve. Bioelectron. Med., 2018; 1(1); 29-38]

In this context, the bioelectronic medicine that stimulate the peripheral nervous system has been used to treat injury and disease. The bioelectronic medicine utilize tools to interface with the nervous system to modulate and control the immune response and the physiological state of organs and systems. In fact, communication within the neural network occurs via electrical signals that travel rapidly and specifically along nerves. Upon reaching their intended cellular and molecular targets, these electrical signals cause the release of neurotransmitters. Through targeted manipulation of the neural signals (i.e., communication within the neural network), bioelectronic medicine harnesses endogenous pathways for therapeutic purposes.

Invasive vagus nerve stimulation is currently approved for the treatment of medically refractory epilepsy and depression and clinical trials are ongoing for the treatment of sepsis and inflammatory disorders, including rheumatoid arthritis and Crohn’s disease. [D. Fox. The electric Cure, Nature 2017; 545; 20-22] Opportunities of treatment when stimulating the vagus nerve using invasive vagus nerve stimulation encompasses inflammatory disorder including appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, pneumonitis, pneumonoultramicroscopicsilicovolcanoconiosis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, herpes virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, bums, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasculitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillaume-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget' s disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome and Hodgkin's disease (W02006073484).

However, invasive neurostimulation requires surgical implantation which may trigger unwanted side effects. Therefore, non-invasive approaches seem particularly advantageous as they can be administered more easily, and tolerated better [Huston J.M. et al. The inflammatory reflex and neural tourniquet: harnessing the healing power of the vagus nerve. Bioelectron. Med. (2018) 1(1), 29-38] Among them, transcutaneous electrical nervous stimulation (TENS) emerged as a promising approach, notably the transcutaneous vagus and trigeminal nerve stimulation through the ear (tVNS and TNV respectively) [B. Mercante et al. Auricular Neuromodulation: the Emerging Concept beyond the Stimulation of Vagus and Trigeminal nerves. Medicines, 2018; 5, 10; 3-12] However, skin represents an electrical barrier for transcutaneous electrical stimulation. Also, selectivity for stimulating specific nerve fibers and enhancing spatial resolution may be improved.

Therefore, transdermal nerve stimulation represents another alternative strategy which is minimally invasive for nerve stimulation. The percutaneous electrical nerve stimulation (PENS) is delivered by insertion of electrodes near the peripheral nerves which is to be stimulated. Wireless PENS has also been proposed. The Stimwave system, used for pain relief, typically involves an implant which comprises a stimulator and a micro-receiver, an electronic device (i.e., Wearable Antenna Assembly: WAA) used to power the receiver, the implanted receiver and stimulator only accepting power and parameter settings from a specific WAA, personalized for each patient, and a programmer (Apple watch, Apple Touch, IPad programmer). PENS represents a useful alternative for subjects who may not support transcutaneous electrical stimulation or when wanting to avoid skin resistance. PENS is sometimes assimilated to electroacupuncture when the stimulation is given at an acupoint.

Alternatively, acupuncture (including manual acupuncture, electroacupuncture, pressure acupuncture, laser acupuncture and heat acupuncture) is an interesting approach performed by an acupuncturist for transdermal nerve stimulation. Clinical studies showed that acupuncture can improve post-operative recovery, osteoarthritis, migraine, joint pain, stroke, post-traumatic stress disorder and drug addiction [L. Ulloa et al. Nerve Stimulation: Immunomodulation and Control of Inflammation. Trends Mol. Med. 2017; 23(12); 1103-1120] Neuromodulation with acupuncture or electroacupuncture is endorsed by the WHO and NIH and it is used by millions of people to control pain, inflammation and to reestablish physiological homeostasis during illness. [L. Ulloa et al. Nerve Stimulation: Immunomodulation and Control of Inflammation. Trends Mol. Med. 2017; 23(12); 1103-1120] Vagus nerve stimulation via acupuncture has also been used to alter bowel function, gastric acidity and heart rate [K.J. Tracey. The Inflammatory Reflex. Nature, 2002; 420; 853-859] Activation of an anti inflammatory reflex involving the vagus nerve was described in endotoxemic rats using electroacupuncture at a point located at the junction of the first and the second metacarpal bones. In this reflex, somatosensory stimulation via unknown mechanism reaches the brain and triggers activation of muscarinic acetylcholine receptor-mediated signaling. This activation is linked with efferent vagus nerve activity and catecholaminergic signaling to the spleen, which results in suppression of serum TNF, IL-ip and IL-6 and in improved survival in lethal endotoxemia. Electroacupuncture at another acupuncture point causes stimulation of sciatic nerve activity in a voltage dependent manner. Signals arising in the sciatic nerve culminate on efferent vagus nerve signals. The efferent vagus nerves signals terminate on the release of dopamine in the adrenal medulla. Dopamine induced by sciatic nerve stimulation targets dopaminergic type 1 (Dl) receptors and suppresses systemic inflammation through D1 -receptor-mediated mechanism and results in improved survival of mice with cecal ligation and puncture-induced polymicrobial sepsis [V.A. Pavlov et al. Neural regulation of immunity: molecular mechanisms and clinical translation. Nature Neuroscience, 2017; 20(2); 156-166; S. S. Chavan et al. Regulating innate immunity with dopamine and electroacupuncture. Nature medicine 2014; 20(3); 239- 241; R. Torres-Rosas et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nature Medicine. 2014, 20, 291-295]

The world health organization (WHO) has published a report indicating diseases or disorders for which acupuncture therapy has been tested in controlled clinical trials reported in the recent literature and has produced a classification comprising the four following categories [Acupuncture: review and analysis of reports on controlled clinical trials. WHO, 2003]:

I Diseases, symptoms or conditions for which acupuncture has been proved - through controlled trials - to be an effective treatment. In this category, treatment for depression (including depressive neurosis and depression following stroke) and Rheumatoid arthritis are listed. 2_Diseases, symptoms or conditions for which the therapeutic effect of acupuncture has been shown but for which further proof is needed. In this category, treatment for Diabetes mellitus, non-insulin- dependent, osteoarthritis and schizophrenia are listed.

3_Diseases, symptoms or conditions for which there are only individual controlled trials reporting some therapeutic effects, but for which acupuncture is worth trying because treatment by conventional and other therapies is difficult. In this category, Pulmonary heart disease, Chronic (CCS) and Irritable (ICS) Colon Syndrome are listed.

4_Diseases, symptoms or conditions for which acupuncture may be tried provided the practitioner has special modem medical knowledge and adequate monitoring equipment. In this category, Coronary heart disease (angina pectoris) and Breathlessness in chronic obstructive pulmonary disease are listed. Furthermore, according to the 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], 14 meridians, 361 classical acupuncture points, 8 extra meridians, 48 extra points, and scalp acupuncture lines (also identified in the literature as “acupoints” or “APs”) are located on the surface of a human body. 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. 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).

The World Health Organization (WHO) has presented a methodology for locating acupuncture points on the surface of a human body, as well as the location of 361 acupunctures points (acupoints) [WHO Standard Acupuncture Point Locations in the Western Pacific Region, 2008] Three methods are described 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] . Nerves, at the acupoints (APs), can be stimulated with different technique including pressure (acupressure), massage, heat (moxibustion for example), sound (sonopuncture) or electricity (electroacupuncture) .

Acupoints are specific points of the human body that have demonstrated mechanical hypersensitivity and have high electrical conductance. Sensory nerve endings are distributed unevenly over the body and acupoints have a higher density of sensory nerve endings than surrounding areas. Early studies in animals and human autopsies revealed that (the biological medium of) most acupoints contained abundant free nerve endings, encapsulated cutaneous mechanoreceptors (Merkel cells, Meissner, Ruffini and/or Pacinian corpuscles), sarcous sensory receptors (muscles spindles and tendon organs), and their afferent fibers. Many examined acupoints had relatively dense neural component, particularly nerves fibers, with a ratio nearly 1.4:1 compared to non-acupoint areas. The ratio of local myelinated to nonmyelinated fibers was found to be nearly 4-fold higher in human Zusanli (ST36) acupoint than in surrounding areas. Specific acupuncture points are also identified as Neural Acupuncture Unit (NAU) when stimulated with acupuncture needles. “NAU” designates the collection of local neural and neuroactive components distributed in the skin, muscle and collective tissues activated i) by an acupuncture needle that is inserted into a designated point on the body (an acupoint) and ii) exposed to a mechanical or electrical stimulation [Z.-J. Zhang et al. Neural Acupuncture Unit: A New Concept for Interpreting Effects an Mechanism of Acupuncture. Evidence-Based Complementary and Alternative Medicine, 2012; Article ID 429412] The legend of figure 1 indicates the biological components and biological cells which are typically present at an acupoint and/or NAU.

Recent studies have also suggested that acupoints associated with internal organs can be identified as neurogenic inflammatory spots occurring on the skin that are associated with visceral disorders. These cutaneous “neurogenic spots” function as therapeutic acupoints (i.e., electroacupuncture at neurogenic spots generates therapeutic effects like acupuncture effects), and are characterized by plasma extravasation and vasodilation in the postcapillary venules of the skin arising from release of calcitonin gene-related peptide (CGRP) and substance P (SP) from activated small diameter sensory afferents. These neurogenic spots can be visualized experimentally in the skin by systemic injection of Evans blue dye. Authors suggest that these “neurogenic spot” can be identified by non-invasive methods, such as infrared thermal imaging or electrodermal measurement [Do-Hee Kim et al. Acupuncture points can be identified as cutaneous neurogenic inflammatory spots. Scientific Report (2017) 7: 15214; Yu Fan etal. Enhanced spinal neuronal responses as a mechanism for increased number and size of active acupoints in visceral hyperalgesia. Scientific Report (2020) 10:10312 ].

Acupoint reflects the status of a visceral organ, and visceral disorders can be treated by manipulating acupoints. Acupoints or NAUs for which a large portion of surrounding biological components is made of muscle fibers include among other Zusanli (ST36), Hegu (LI4) and Huantiao (GB30). Acupuncture at the Zusanli (ST36) or at the Hegu (LI4) acupoint are typically shown to modulate inflammatory responses in internal organs [H.-D. Lim el al. Anti-inflammatory effects of acupuncture stimulation via the vagus nerve. PLOS ONE, DOI: 10.1371/joumal.pone.0151882, 2016; V.A. Pavlov etal. Neural regulation of immunity: molecular mechanisms and clinical translation. Nature Neuroscience 20(2), 2017] Acupoints or NAUs for which a large portion of surrounding biological components is made of cutaneous receptors include acupoints located in the finger pads, palms, plantar area, and the surrounding lips such as Shaoshang (LU11) and Shuigou (GV26). Acupoints or NAUs for which a large portion of surrounding biological components is made of tendons organs, Ruffini corpuscles and Pacinian corpuscles include acupoints located around elbow, wrist, and ankle joints such as Chize (LU5), Daling (PC7), Dubi (ST35) and Jiexi (ST41).

Neuroactive components of NAUs are non-neuronal tissues and biological cells as well as the various mediators capable of modulating NAU afferent signals via local biochemical reactions which are released by these tissues and cells. In addition, biophysical reactions of NAUs are triggered by the activation of mechanoreceptors. Multiple central neural pathways convey NAU afferent impulses. 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 el al. Neural Acupuncture Unit: A New Concept for Interpreting Effects and Mechanism of Acupuncture. Evidence-Based Complementary and Alternative Medicine, 2012; Article ID 429412]

The following Table 1 lists the main existing bioelectronic medical technologies used to treat diseases in relation with inflammation and infection. In this Table, the invasiveness of each of the herein above described technologies, its spatial and temporal resolution, its safety risk as well as its ability to offer autonomy to the subject receiving the treatment (i.e. ability of the subject to receive treatment without impact on daily activities), are criteria evaluated/estimated as follows: © (high negative impact on one or more criteria), © (moderate negative impact on one or more criteria), © (no negative impact on criteria). Table 1:

*Manual acupuncture or electroacupuncture

**Heat acupuncture, sonopuncture, acupressure, laser acupuncture Table 1 illustrates the need to optimize the modulation of neural signals in order to mobilize the body immunity for therapeutic purposes.

The present invention provides a solution to this unmet need which advantageously satisfies all of the criteria listed above. Indeed, the herein below described invention is moderately invasive (similar to acupuncture’s invasiveness) and safe, offers optimal spatial and temporal resolution, and allows the subject to manage the therapeutic treatment without the physical help of a practitioner, typically of an acupuncturist.

SUMMARY OF THE INVENTION Inventors herein describe particles for use for treating a subject suffering of a disease via an acupuncture effect when particles stably interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors (present in the biological medium) of at least one acupoint or NAU of the subject, and to a composition for use for treating a subject suffering of a disease, wherein the composition comprises particles and the therapeutic effect is obtained via an acupuncture effect when particles interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors (present in the biological medium) of at least one acupoint or NAU of the subject. Particles are preferably below 100 pm and are preferably prepared from a material selected from a piezoelectric material, a pyroelectric material and a far-infrared radiation-emitting material.

The description further relates to a method for delivering acupuncture to a subject in need thereof. When the particles are prepared from a material selected from a far-infrared radiation emitting-material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, thereby triggering an acupuncture effect in the subject.

When the particles are prepared from a piezoelectric material, the method for treating a subject suffering of a disease via an acupuncture effect / for delivering acupuncture to a subject in need thereof typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by a skin massage on the at least one acupoint or NAU, thereby triggering an acupuncture effect in the subject.

When the particles are prepared from a pyroelectric material, the method for treating a subject suffering of a disease via an acupuncture effect / for delivering acupuncture to a subject in need thereof typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by heating the surface of the skin of the subject above the acupoint or NAU, thereby triggering an acupuncture effect in the subject.

The description also relates to a method for treating a subject in need thereof via an acupuncture effect. When the particles are prepared from a material selected from a far-infrared radiation emitting-material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, thereby treating the subject.

When the particles are prepared from a piezoelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by a skin massage on the at least one acupoint or NAU, thereby treating the subject.

When the particles are prepared from a pyroelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by heating the surface of the skin of the subject above the acupoint or NAU, thereby treating the subject. DETAILED DESCRIPTION OF THE INVENTION

Inventors herein describe particles for use for treating a subject suffering of a disease via an acupuncture effect when particles stably interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors (present in the biological medium) of at least one acupoint or Neural Acupuncture Unit (NAU) of the subject. Preferred therapeutic particles are below 100 pm, and are prepared from a material selected from a piezoelectric material, a pyroelectric material and a far-infrared radiation-emitting material.

The present invention optimizes the efficacy of treatments involving peripheral nerve stimulation while minimizing the detrimental effects/risk compared to existing treatments using bioelectronic approaches. In addition, it facilitates patient’s autonomy.

THERAPEUTIC PARTICLES: TEMPORAL AND SPATIAL RESOLUTIONS

The material constituting the particles of the invention as well as their structure are key to obtain the desired therapeutic efficacy. Indeed, the particle’s efficacy directly depends on the specific intrinsic property of the material constituting the particle. A careful selection of the composition and structure (i.e., an amorphous structure, a semi-crystalline structure or a crystalline structure) of the particles therefore optimizes the temporal energy input signal transduction and/or the temporal energy input signal modulation.

Piezoelectric particle

The particle of the invention can be a piezoelectric particle, typically a piezoelectric particle having a structure and/or composition capable of converting in vivo an external mechanical input signal into an internal electrical output signal.

When the particle is a piezoelectric particle, it typically consists of a quartz (S1O2) particle, a barium titanate (BaTiO,) particle, a AIN particle, a GaN particle, a ZnO particle, a boron nitride (BN) particle or a particle comprising or consisting in polyvinylidene fluoride polymer or a derivative thereof, polymeric L-lactic acid, polymeric D-lactic acid, DNA or M13 bacteriophage.

These piezoelectric particles, in contact with the peripheral nervous system on at least one acupoint and/or NAU, stimulate the peripheral nerves when activated by a skin massage on the acupoint or NAU. This stimulation of the nerve’s internal electrical signal is rendered possible by the intrinsic piezoelectric property of the particles selected for use in the context of the present invention which are “activated” when a skin massage is performed on the acupoint or NAU where the piezoelectric particles are located. Pyroelectric particle

The particle of the invention can be a pyroelectric particle. When the particle is a pyroelectric particle, it is typically a UiTaCri particle or it is a particle comprising or consisting in PVDF polymer.

These pyroelectric particles, in contact with the peripheral nervous system on at least one acupoint and/or NAU, stimulate in vivo the peripheral nerves when activated. The activation is obtained by heating the surface of the skin of the subject above the acupoint or NAU where the pyroelectric particles are located. This stimulation of the nerve’s internal electrical signal is rendered possible by the intrinsic pyroelectric property of the particles selected for use in the context of the present invention which are “activated” when a step of heating the surface of the skin of the subject above the acupoint or NAU where the pyroelectric particles are located is performed.

Far-infrared radiation emitting particle

The particle of the invention can be a far-infrared radiation-emitting particle. When the particle is a far-infrared radiation emitting particle, it is typically an inorganic particle, preferentially a metal oxide particle with an emissivity level of more than 50%, preferably more than 60%, more than 70%, more than 80%, or more than 90%, and emitting between 4 microns and 200 microns, preferably between 4 microns and 50 microns, or between 4 microns and 20 microns. The inorganic particle capable of emitting far-infrared radiation is typically an AI ₂ O ₃ particle, a Fe ₂ C> ₃ particle, a MgO particle, a ZrC particle or a Y ₂ O ₃ particle.

These far-infrared radiation emitting particles, in contact with the peripheral nervous system on at least one acupoint and/or NAU, stimulate/modulate in vivo the electrical signal. This signal is then conducted by said nerves up to the central nervous system (CNS). This stimulation/modulation of the nerve’s internal electrical signal is rendered possible by the intrinsic far-infrared radiation emitting property of the particles selected for use in the context of the present invention (i.e., an increase of the temperature at acupoint or NAU is obtained by converting radiation emitted by the particle into heat).

Particles have been selected by inventor for their ability to stably interact with biological entities present on at least one acupoint and/or NAU and to efficiently stimulate the peripheral nerves. The expression “stably interacting” indicates that particles (i) do not move after injection/administration on at least one acupoint or NAU, i.e. at least, preferably more than 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, even more preferably more than 80% or 90%, of the injected dose of particles remain at the site of injection, the particles interacting with elements of the biological medium present on the at least one acupoint or NAU and/or with the biological cells, i.e. they interact in particular with the membranes of the biological cells and/or are up taken by the biological cells, and (ii) do not degrade after injection/administration on the at least one acupoint or NAU unless expressly designed to experience in vivo degradation (for example via dissolution of the particle). By stably interacting with the biological entities present on at least one acupoint and/or NAU, the particles ensure a high spatial resolution for signal transmission.

The biological cells of interest the particles are directly or indirectly stably interacting with at the site of injection (i.e., on the at least at one acupoint or NAU) typically comprise keratinocytes, melanocytes, Merkel cells, Langerhans cells, fibroblasts, mast cells, macrophages, lymphocytes, platelets and/or lipocytes. Particles also directly or indirectly stably interact with the other elements typically present in the biological medium of at least one acupoint or NAU, i.e., with free nerve endings, nerves fibers, sarcous sensory receptors and/or end-organs, the end-organs being typically Meissner corpuscles, Ruffini corpuscles, Pacinian corpuscles and/or longitudinal lanceolate endings.

To allow the required “stable interaction” state between the particles and the elements of the biological medium, for example the biological cells, at acupoint(s) or NAU(s), the two following particles’ features are to be properly selected: (i) the size of the particles and (ii) the composition of the particles’ core and/or of the particles’ surface coating.

(i) The size of the particles

In the context of the present invention, the particles’ size is typically below about 100 pm. A threshold limit of the particles’ size of about 200 nm has been observed regarding uptake and retrograde transport of particles following axonal delivery in cortical neuronal cells [Anna Uesniak el al. Rapid growth cone uptake and dynein-mediated axonal retrograde transport of negatively charged nanoparticles in neurons is dependent on size and cell type. Small, 2018, 1803758] Uptake and retrograde transport were observed for particles having a size up to 100 nm whereas they were hardly observed for particles having a size typically above about 200 nm. In the context of the present invention wherein the stable interaction between particles and elements of the biological medium including biological cells is required, the size of the particles is preferably between about 200 nm and about 100 pm.

The size of the particles is typically measured using well-known electron microscopic (EM) tools or light scattering tools.

When the particles are hydrophobic or hydrophilic and the size of the particles is at the microscale, i.e., between about 1 pm and about 100 pm, the size is typically measured using an electron microscopic technic, typically scanning electron microscopy. The longest dimension of the core of a particle (the core of the particle being the particle without any surface coating) measured in the electron microscopy image is reported. At least 100 particles of a population are measured in their longest dimension and the median size of the considered population of particles is calculated. In this context, the “size” of the particles designates the median size of the particles of a population comprising at least 100 particles. When the particles are hydrophilic and the size of the particles is at the nanoscale, i.e., between about 1 nm and about 1000 nm, and when the particle size is monodisperse, i.e., the polydispersity index of the suspension of particles is found typically below 0.2, the size is typically measured using the Dynamic Light Scattering (DLS) technique. In the context of the DLS technic, the size of the particle is typically measured when the particles are in aqueous suspension (i) at a pH between about 6.5 and about 7.5, (ii) at a particles’ concentration between 0.5 g/kg and 10 g/kg (weight/weight), the particles’ concentration being typically measured by dry extract (i.e. the suspension containing the particles is typically placed at a temperature between 100°C and 250°C for a duration period typically comprised between 15 minutes and overnight) or by ICP-MS or by ICP-OES and (iii) at an ionic strength presenting an electrical conductivity typically comprised between about 0.01 pS/cm and about 2000 pS/cm at a temperature between about 15°C and about 25°C. When measured by DLS, the size of the particles corresponds to the size of the particles given in intensity.

Alternatively, the electron microscopy technique (EM), typically the transmission electron microscopy (TEM) or Cryo-TEM can be used to measure the size of the particles at the nanoscale. In this case, the longest dimension of a particle measured in the electron microscopy image is reported. At least 100 particles are measured in their longest dimension and a median size of the particles of the population comprising at least 100 particles is calculated. In this context, the “size” of the particles designates the median size of the particles of a population comprising at least 100 particles.

When the particle size is polydisperse (i.e., the polydispersity index of the suspension of particle is found typically above 0.2 when measured by DLS), a fractionation technique can be used to separate the populations of particles in different monodisperse particles’ size populations. Typically, a field flow fractionation tool can be used to reach this goal. The size of the particles in each population/fraction is determined as described herein-above using DLS or EM tools. In addition, in each population/fraction the quantity of particles is estimated. This estimation can typically be done by quantification of at least one element constituting the particle. The “size” of the particles represents in this context the average weight of the sizes of the particles obtained in each population of particles or fraction thereof.

The shape of particle is not critical for the invention. Typically, the particle can have an “inhomogeneous shape”. The expression “inhomogeneous shape” designates particle the sizes of which have been measured in the 3 dimension (x, y, z) and present one or two dimensions larger than the other(s), typically one or two dimensions more than about three times larger than the other(s). 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 present a ratio which does not exceed a factor 3 between each dimension (i.e., x/y < 3, y/z < 3 and z/x < 3).

Whatever the surface of the particles, they will most certainly end up within biological cells when their size is below about 20 pm or 10 pm. On the contrary, whatever the surface of the particles, they will be localized preferentially outside biological cells, typically in the biological medium surrounding the cells when their size is typically above about 10 pm or 20 pm. Indeed, when the size of the particles is typically below 20 pm, the particles can enter cells by different mechanisms: through endocytosis-dependent pathways or direct cytoplasmic delivery [Nathan D. Donahue, et al. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Advanced Drug Delivery Reviews 143 (2019) 68-96] Endocytic -dependent pathways encompass five mechanistically distinct classes: (a) clathrin-dependent endocytosis for particles’ size typically between about 100 nm and about 500 nm; (b) caveolin-dependent endocytosis for particles’ size typically between about 50 nm and about 100 nm; (c) clathrin- and caveolin-independent endocytosis; (d) phagocytosis, typically used by immune cells, including macrophages, dendritic cells, neutrophils, and B lymphocytes, for particles’ size typically up to about 20 pm, preferentially up to about 10 pm; and (e) micropinocytosis for particles’ size typically between about 0.5 pm and about 1.5 pm [Nathan D. Donahue, et al. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Advanced Drug Delivery Reviews 143 (2019) 68-96]

Alternatively, direct injection of particles into the cytoplasm of biological cells present on at least one acupoint may be performed in the context of the present invention, the biological cells being preferably selected from keratinocytes, melanocytes, Merkel cells, Langerhans cells, fibroblasts, mast cells, macrophages, lymphocytes, platelets, lipocytes and any combination thereof. For this, several technics may be used via biochemical or physical means, including electroporation or microinjection [Nathan D. Donahue, et al. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Advanced Drug Delivery Reviews 143 (2019) 68-96]

In any case, the size of the particles below about 100 pm will ensure relevant (i.e., stable) interaction between the particles of the invention and the biological medium where the particles have been injected. A direct interaction of the particle with the cell is possible, and the particle can even operate from within the cell. The particles having the same size-scale as a cell, they are capable of significantly enhancing smooth interactions both with the biological cells and with the biological medium compared to current implants (typically needles used for electroacupuncture have a much larger diameter than the size of a cell).

(ii) The composition of the particles and/or of the particles ’ surface coating agent

When the composition of the particles’ core presents potential safety issues for the subject (i.e. a potential dissolution process triggering direct release of potentially toxic metal elements in the biological medium, and/or a potential redox phenomenon at the surface of the particle triggering oxidation of proteins or biological moieties or generation of reactive oxygen species (ROS), and/or a potential catalytic property of the particles), a surface coating is preferably applied using a surface coating agent.

This surface coating is preferably an inorganic surface coating limiting, ideally preventing, any potential degradation of the organic surface coating agent (such as bond breaking) upon time, ex-vivo (i.e., upon storage of the particles prior use) or in vivo (i.e., upon injection of the particles in vivo). Indeed, the surface coating agent should ideally not contain carbon-carbon bonds or any bonds susceptible of being broken ex vivo or in vivo (typically due to oxidation phenomenon). Also, when an organic coating agent is selected, precaution regarding sterilization and storage of the particles are to be taken to prevent potential degradation of the surface coating agent, typically due to oxidation reactions. In any case, the surface coating agent should be selected so that potential residues or moieties typically resulting from oxidation reactions and/or bond breaking of the surface coating agent do not triggered in vivo toxicity.

Also, when a surface coating agent is applied to the particles in a particular aspect of the description, this surface coating agent should not desorb from the particles’ core. Therefore, it is key to consider coating agent able to establish strong bonds/links with the surface of the particles, typically able to establish complexing or covalent bonds. Typical covalent bonds are found between silane-based compounds (i.e., coating agents) and the surface of oxide particles. 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., coating agents) and the surface of oxide particles, or between thiol-based compounds and the surface of metal particles, quantum dots or semiconductor particles.

In any configuration (i.e., whatever the selection of the core of the particle and/or of the surface coating agent), the particles should be stable (i.e., physically and chemically stable) prior their injection in a subject (unless specified that the particles should degrade in vivo). When the particles are in suspension (i.e., dispersed in solution), typically prior injection, they should form a stable suspension. A suspension is considered as stable in the absence of observed sedimentation of the particles (i.e., the appearance of the suspension is homogeneous) within typically 1 minute, 2 minutes or 3 minutes following manual agitation of the suspension. Also, when the particles are in suspension, the supernatant solution collected by any means and free of particles, should present no or a very low amount of elements constituting the particles and/or constituting the particles’ surface coating (i.e. the detected amount of elements should be in the limit of resolution of the technic selected for quantifying these elements which are well-known by the skilled person in the art such as the ICP-MS (inductively coupled plasma - mass spectrometry) or the ICP-OES (inductively coupled plasma - optical emission spectrometry) technics).

The surface of the particles is typically hydrophilic or hydrophobic. An hydrophilic surface ensures the wettability of the particles in aqueous medium and the possibility to obtain a water suspension. Alternatively, an hydrophobic surface is not wet by water. However, a particle with an hydrophobic surface can be wet by biological entities (such as proteins absorption on the surface of the hydrophobic particles), present in the biological medium. Particles contact angles with water measurement represents a typical wettability measurement to assess particles’ hydrophobicity. In such measurement, particles are dispersed in ultrapure water and left to dry on a substrate to create a homogeneous layer of particles. The contact angle measurement is performed with water as probe liquid, at room temperature. Typical hydrophobic particles have a contact angle with water above about 50°, preferably above about 60°, 70°, 80° or 90°. Typical hydrophilic particles have a contact angle with water below about 30°, preferably below about 25°, 20° or 10°. Quantification of nanoparticle surface’s hydrophobicity is also proposed by comparing nanomaterial binding affinity to two or more engineered collector [Andrea Valsesia et al. Direct quantification of nanoparticle surface hydrophobicity. Communications Chemistry, 2018, 1:53]

When the particles are hydrophilic and have a size typically below about 20 pm, preferably below about 10 pm, they have typically a surface charge below about +30 mV to avoid any potential in vivo toxicity triggered by the surface charge. In this context, the surface charge is typically measured through the so-called zeta potential of the particles, the particles being in a water solution (i) at pH between about 6.5 and about 7.5, (ii) at a particles’ concentration between 0.5 g/kg and 10 g/kg (weight/weight), the particles concentration being typically measured by dry extract (i.e. the suspension containing the particles is typically placed at a temperature between 100°C and 250°C for a period typically comprised between 15 minutes and overnight) or by ICP-MS or ICP-OES and (iii) at an ionic strength presenting an electrical conductivity typically between about 0.01 pS/cm and about 2000 pS/cm at a temperature between about 15°C and about 25°C.

DISEASES AND RELATED ACUPOINTS OR NA US

In a particular and preferred aspect, inventors herein describe particles for use for treating a subject suffering of a disease, disorder or dysfunctional state as herein described via an acupuncture effect, when particles stably interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors of at least one acupoint or NAU of the subject. As explained herein above, preferred particles have a size below 100 pm and are prepared from a material selected from a piezoelectric material, a pyroelectric material and a far-infrared radiation emitting -material.

The term “Treatment” refers to both therapeutic and prophylactic or preventive treatment or measures able to alleviate or cure a disease, disorder or dysfunctional state. Such a treatment is intended for a mammal subject, preferably a human subject, in need thereof, whatever its age or sex. Are considered as such, the subjects suffering from a disease, disorder or dysfunctional state, or those considered “at risk of developing” such a disease, disorder or dysfunctional state, in which this has to be prevented.

In the context of the present invention, diseases encompasses inflammatory and infection diseases, disorders or dysfunctional state, for example inflammatory bowel disease, appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, chronic obstructive pulmonary disease, bronchitis, emphysema, rhinitis, pneumonitis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, herpes virus infection disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, bums, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasculitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillaume-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, psoriatic arthritis, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcet’s syndrome, allograft rejection, graft- versus-host disease, Type I diabetes, Type II diabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome, depression, Hodgkin's disease and cancer.

In a preferred embodiment, treatment is performed in a subject suffering from type 2 diabetes, inflammatory bowel diseases including typically ulcerative colitis and Crohn’s disease, chronic obstructive pulmonary disease, depression, rheumatoid arthritis or psoriatic arthritis.

In a particular aspect, the acupoint or the scalp acupuncture line is selected from LU1, LU2, LU3, LU4, LU5, LU6, LU7, LU8, LU9, LU10, LU11, LI1, LI2, LI3, LI4, LI5, LI6, LI7, LI8, LI9, LI10, LI11, LI 12, LI13, LI14, LI15, LI16, LI17, LI18, LI19, LI20, ST1, ST2, ST3, ST4, ST5, ST6, ST7, ST8, ST9, ST10, ST11, ST12, ST13, ST14, ST15, ST16, ST17, ST18, ST19, ST20, ST21, ST22, ST23, ST24, ST25, ST26, ST27, ST28, ST29, ST30, ST31, ST32, ST33, ST34, ST35, ST36, ST37, ST38, ST39, ST40, ST41, ST42, ST43, ST44, ST45, SP1, SP2, SP3, SP4, SP5, SP6, SP7, SP8, SP9, SP10, SP11, SP12, SP13, SP14, SP15, SP16, SP17, SP18, SP19, SP20, SP21, HT1, HT2, HT3, HT4, HT5, HT6, HT7, HT8, HT9, SI1, SI2, SI3, SI4, SI5, SI6, SI7, SI8, SI9, SI10, Sil l, SI12, SI13, SI14, SI15, SI16, SI 17, SI18, SI 19, BL1, BL2, BL3, BL4, BL5, BL6, BL7, BL8, BL9, BL10, BL11, BL12, BL13, BL14, BL15, BL16, BL17, BL18, BL19, BL20, BL21, BL22, BL23, BL24, BL25, BL26, BL27, BL28, BL29, BL30, BL31, BL32, BL33, BL34, BL35, BL36, BL37, BL38, BL39, BL40, BL41, BL42, BL43, BL44, BL45, BL46, BL47, BL48, BL49, BL50, BL51, BL52, BL53, BL54, BL55, BL56, BL57, BL58, BL59, BL60, BL61, BL62, BL63, BL64, BL65, BL66, BL67, KI1, KI2, KI3, KI4, KI5, KI6, KI7, KI8, KI9, KI10, Kil l, KI12, KI13, KI14, KI15, KI16, KI17, KI18, KI19, KI20, KI21, KI22, KI23, KI24, KI25, KI26, KI27, PCI, PC2, PC3, PC4, PC5, PC6, PC7, PC8, PC9, TE1, TE2, TE3, TE4, TE5, TE6, TE7, TE8, TE9, TE10, TE11, TE12, TE13, TE14, TE15, TE16, TE17, TE18, TE19, TE20, TE21, TE22, TE23, GB1, GB2, GB3, GB4, GB5, GB6, GB7, GB8, GB9, GB10, GB11, GB12, GB13, GB14, GB15, GB16, GB17, GB18, GB19, GB20, GB21, GB22, GB23, GB24, GB25, GB26, GB27, GB28, GB29, GB30, GB31, GB32, GB33, GB34, GB35, GB36, GB37, GB38, GB39, GB40, GB41, GB42, GB43, GB44, LR1, LR2, LR3, LR4, LR5, LR6, LR7, LR8, LR9, LR10, LR11, LR12, LR13, LR14, GV1, GV2, GV3, GV4, GV5, GV6, GV7, GV8, GV9, GV10, GV11, GV12, GV13, GV14, GV15, GV16, GV17, GV19, GV20, GV21, GV22, GV23, GV24, GV25, GV26, GV27, GV28, CV1, CV2, CV3, CV4, CV5, CV6, CV7, CV8, CV9, CV10, CV11, CV12, CV13, CV14, CV15, CV16, CV17, CV18, CV19, CV20, CV21, CV22, CV23, CV24, EX-HN1, EX-HN2, EX-HN3, EX-HN4, EX-HN5, EX-HN6, EX-HN7, EX-HN8, EX-HN9, EX-HN10, EX-HN11, EX-HN12, EX-HN13, EX-HN14, EX-HN15, EX-CA1, EX- Bl, EX-B2, EX-B3, EX-B4, EX-B5, EX-B6, EX-B7, EX-B8, EX-B9, EX-UE1, EX-UE2, EX-UE3, EX-UE4, EX-UE5, EX-UE6, EX-UE7, EX-UE8, EX-UE9, EX-UE10, EX-UE11, EX-LEI, EX-LE2, EX-LE3, EX-LE4, EX-LE5, EX-LE6, EX-LE7, EX-LE8, EX6LE9, EX-LE10, EX-LE11, EX-LE12, MSI, MS2, MS3, MS4, MS5, MS6, MS7, MS8, MS9, MS10, MS11, MS12, MS13 and MS14.

In another particular aspect, several acupoints or scalp acupuncture lines are activated during a protocol/method as herein described such as at least 2 acupoints or scalp acupuncture lines, for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 acupoints or scalp acupuncture lines, said lines being selected from MSI, MS2, MS3, MS4, MS5, MS6, MS7, MS8, MS9, MS10, MS11, MS12, MS13 and MS14.

The following acupoints are preferred (i.e., a preferred acupoint may be selected from): BL10, BL11, BL13, BL14, BL15, BL18, BL20, BL22, BL23, BL36, BL40, BL54, BL56, BL60, BL62, CV4, CV6, CV12, CV17, EX-B1, EX-LE2, EX-LE4, EX-LE5, EX-UE4, EX-UE9, GB12, GB20, GB21, GB25, GB30, GB31, GB33, GB34, GB39, GB40, GV4, GV14, GV20, HT5, HT7, KI3, KI6, KI10, KI13, LI4, LI5, LI11, LI15, LI18, LR3, LU1, LU9, PC6, SI3, SI4, SI9, SI11, SP4, SP6, SP9, SP10, ST5, ST25, ST28, ST34, ST35, ST36, ST37, ST41, TE4, TE5 and TE14.

In the context of rheumatoid arthritis, the following acupoints are preferred (i.e., a preferred acupoint may be selected from): BL11, BL18, BL20, BL23, BL36, BL54, BL56, BL60, BL62, CV4, CV6, CV12, EX-LE2, EX-LE4, EX-LE5, EX-UE4, EX-UE9, GB20, GB25, GB30, GB31, GB33, GB34, GB39, GB40, GV4, GV14, GV20, HT7, KI3, KI6, KI10, KI13, LI4, LI5, LI11, LI15, LR3, PC6, SI3, SI4, SI9, Sill, SP6, SP9, SP10, ST5, ST25, ST34, ST36, ST41, TE4, TE5 and TE14 [Pei-Chi Chou et al. Clinical efficacy of acupuncture on rheumatoid arthritis and associated mechanisms: a systemic review. Evidence-Based Complementary and Alternative Medicine 2018, ID8596918]

In the context of osteoarthritis, the following acupoints are preferred (i.e., a preferred acupoint may be selected from): ST35, EX-LE5, GB34, SP9, GB39 and SP6 [X. Chen et al. The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients. Mol Pain (2015) 11:67]

In the context of inflammatory bowel disease, the following acupoints are preferred (i.e., a preferred acupoint may be selected from): BL18, BL20, BL21, BL23, BL25, CV4, CV12, GV4, GV20, GV26, LI4, LI11, LR3, PC6, SP4, SP9, SP14, SP15, ST21, ST25, ST36, ST37, ST39 and TE5 [Gengqing Song et al. Acupuncture in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2019, 25(7), 1129-1139] In particular, in the context of Crohn’s disease, the following acupoints are preferred (i.e., a preferred acupoint may be selected from): CV6, CV12, KI13, LI4, LI11, LR3, SP4, SP6, ST25, ST36 and ST37 [Chun-Hui Bao et al. Randomized controlled trial: Moxibustion and acupuncture for the treatment of Crohn’s disease. World J Gastroenterol 2014 August 21; 20(31): 11000-11011]

In the context of diabetes type II, the following acupoints are preferred (i.e., a preferred acupoint may be selected from): BL13, BL14, BL20, BL22, BL23, CV4, CV12, KI13, LI4, LI11, SP6, ST28, ST36 and TE5 [ClinicalTrials.gov Study NCT04076800 ; Acupuncture and Insulin Doses in Insulin- treated Type 2 Diabetes (ACUDIA)] .

In the context of chronic obstructive pulmonary disease (COPD), the following acupoints are preferred (i.e., a preferred acupoint may be selected from): LU1, LU9, LI18, KI3, GB12, BL13, BL20, BL23, CV4, CV12, CV17, EX-B1 and ST36 [Masao Suzuki et al. A Randomized, Placebo-Controlled Trial of Acupuncture in Patients With Chronic Obstructive Pulmonary Disease (COPD). Arch Intern Med. 2012; 172(l l):878-886; Ken SL Lau et al. A single session of Acu-TENS increases FEV1 and reduces dyspnoea in patients with chronic obstructive pulmonary disease: a randomised, placebo-controlled trial. Australian Journal of Physiotherapy 54: 179-184]

In the context of depression, the following acupoints are preferred (i.e., a preferred acupoint maybe selected from): HT7, LI4, ST36, SP6, LR3 andGV20 [ClinicalTrials.gov Study NCT01633996] In a preferred embodiment, particles interact with at least one, preferably several or all, of the following acupoints: BL23, GB34, KI3, LI4, LI11 and ST36.

In another preferred embodiment, the particles interact with at least one and up to ten acupoints, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 acupoints.

The description also relates to a composition for use for treating a subject suffering of a disease, disorder or dysfunctional state as herein described. The composition comprises particles and the therapeutic effect is obtained via an acupuncture effect when the particles stably interact with biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors present (in the biological medium of) at least one acupoint or NAU of the subject. As explained herein above, preferred particles have a size below 100 pm and are prepared from a material selected from a piezoelectric material, a pyroelectric material and a far-infrared emitting -material.

A particular composition comprises between about lmg/lOOg (particles weight/dispersion medium weight) and 40g/100g particles, preferably between about lg/lOOg and lOg/lOOg particles.

Also herein described is the use of such particles for preparing a composition of the invention for treating a subject suffering of a disease as herein described.

The description further relates to a method for delivering acupuncture to a subject in need thereof. When the particles are prepared from a material which is a far-infrared radiation emitting-material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, thereby triggering an acupuncture effect in the subject.

When the particles are prepared from a piezoelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by a skin massage on the at least one acupoint or NAU, thereby triggering an acupuncture effect in the subject.

When the particles are prepared from a pyroelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by heating the surface of the skin of the subject above the acupoint or NAU, thereby triggering an acupuncture effect in the subject.

The description also relates to a method for treating a subject in need thereof via an acupuncture effect.

When the particles are prepared from a material which is a far-infrared radiation emitting-material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, thereby treating the subject.

When the particles are prepared from a piezoelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating said particles by a skin massage on the at least one acupoint or NAU, thereby treating the subject.

When the particles are prepared from a pyroelectric material, the method typically comprises a step of administering the particles, or a composition comprising the particles, to at least one acupoint or Neural Acupuncture Unit (NAU) of the subject, and a step of stimulating particles by heating the surface of the skin of the subject above the acupoint or NAU, thereby treating the subject.

PARTICLES ’ FORMULATION AND ADMINISTRATION

Particles are typically formulated in a liquid or in a gel, in particular in a liquid that turns into a gel when administered on at least one acupoint or NAU of the subject. A particular composition of the invention comprising particles is in the form of a liquid or a gel, in particular in a liquid form that turns into a gel when administered on at least one acupoint or NAU of the 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)-A poly(ethylene glycol)-ft-poly(D,L-lactic acid-co-glycolic acid) (PUGA-PEG-PUGA) 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.

Thus, a preferred composition for use for treating a subject suffering of disease as herein described is in a liquid or gel form, in particular in the form of 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 on at least one acupoint or NAU, 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 about two 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 an 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(s- 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 can be directly administered on at least one acupoint or NAU using typically a syringe and a needle when particles are in suspension (i.e., when they are formulated as a liquid or as a gel, provided the viscosity of the gel remains compatible with such administration mode, for example as a liquid that turns into a gel when administered in a subject). When formulated as a gel, the particles can also be deposited on the surface of the skin. Particles will penetrate in the dermis and epidermis for example spontaneously or by massage. In this particular cases, hydrophobic particles are preferred.

Alternatively, the particles can be directly stuck to the surface of a needle and the particles are released in the biological medium typically between few seconds (typically at least two seconds) and 10 minutes following needle insertion into the skin typically up to the dermis and/or the hypodermis layer. 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 insertion in vivo. To stick the particles or the gel containing the particles to the surface of the needle while allowing the rapid release of the particles or of the gel containing the particles from the needle when 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), 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, days or weeks following needle(s) or microneedle(s) insertion/ implantation in the skin. The needle(s) or microneedle(s) are left in the skin for a selected period and can be removed at any time 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 a preferred aspect, needle insertion is that observed in the context of acupuncture.

VOLUME AND CONCENTRATION OF PARTICLES AT THE ACUPOINTS

The volume occupied by particles on at least one acupoint or NAU location is typically comprised between about 0.001 mm ³ (i.e., 0.001 pL) and about 100 mm ³ (i.e., 100 pL), 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 , and about 10 mm ³ , about 20 mm ³ , or about 50 mm ³ . The volume occupied by the particle 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 administered liquid or gel, or the volume of the needle, microneedle or tip of the needle or microneedle which has dissolved). Needle(s) or microneedle(s) which can be used to administer/inject the particles at the acupoint or NAU, have typically the following dimensions: a diameter typically between about 0.10 mm, or more than about 0.10 mm, and about 0.50 mm or about 0.40 mm, and a length typically between about 1 mm, about 1.5 mm, about 2 mm, or about 5 mm and about 100 mm.

The concentration of particles on at least one acupoint or NAU is typically between 1 mg/lOOg (weight of particles by weight of biological medium) and 40 g / lOOg. Because the particles remain at their administration site, the concentration of particles on at least one acupoint or NAU corresponds to the concentration of particles which is present in the suspension (i.e., the dispersion medium) 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).

COMBINATION

The present invention is typically for use for treating a subject suffering of an inflammatory or infection disorder via an acupuncture effect. In a particular aspect, particles can be combined with anti inflammatory agent(s), anti -infectious agent(s) and/or pain relief agent(s).

The anti-inflammatory agent is for example a nonsteroidal anti-inflammatory agent such as diclofenac, ibuprofen or aspirin. The anti-infectious agent is for example an agent from the cephalosporin, penicillin, fluoroquinolone, carbapenem or macrolide class.

The pain relief agent is for example an analgesic agent such as acetaminophen, or an opioid agent such as morphine.

These agents can be administered for example orally, topically, or by local administration, typically by injection, at the site of inflammation. These agents can be administered before, concomitantly or after a treatment method comprising a step of administering the herein described particles, or concomitantly or after particles’ activation/stimulation when a massage or heat treatment step is required by the material the selected particles are made of.

In a particular aspect, the agent(s) and particles are present in the same composition, typically in a composition as herein described, and administered simultaneously to the subject, for example topically. In another particular aspect of the description, particles are combined with an anti-cancer agent such as for example a chemotherapeutic agent or an immunotherapeutic agent, and/or are administered to a subject suffering of a cancer and treated locally by surgery or by radiotherapy. Such a combination may improve the prognosis of cancer patients by promoting anticancer immunity in the patients.

FREQUENCY OF PARTICLES ADMINISTRATION: INVASIVENESS & RISK

The particles can be administered on at least one acupoint or NAU more than once. However, they are preferably designed to be administered only once. In terms of invasiveness and detrimental effects/ risk linked to the administration procedure, a single administration of the particles of the invention is advantageous when compared to repeated needles implantation on at least one acupoint or NAU, which is typically required in the context of a treatment, especially in the context of chronic disorders.

TREATMENT SESSION FREQUENCY

When the particles are prepared from a piezoelectric material, or when the particles are prepared from a pyroelectric material, the treatment (via activation/stimulation of particles, typically, as taught herein above, by skin massage when particles are prepared from a piezoelectric material and by skin heating when the particles are prepared from a pyroelectric material) can be applied at least once per day, typically two-, three-, for-, five-, six-, seven-, eight-, nine- or ten-times per day, and during at least one day, typically two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. The treatment can be applied on a regular basis (i.e., every day or every week), or it can be sequenced in periods (typically days or weeks). For instance, the treatment period can last for one month, two months, three months, four months, five months, six month or seven months, where the input energy source is applied once a day, twice a day or three-times a day, 1 day, 2 days, 3 days, 4 days or five days per week.

When a stimulation/activation of the particles is required and performed, the stimulation duration (treatment session duration) is typically between 1 minutes and 60 minutes, preferably between 1 minute and 30 minutes, 1 minute and 15 minutes, 1 minute and 10 minutes, or 1 minute and 5 minutes, for example between 5 seconds, 10 seconds, 15 seconds or 30 seconds and 1 minute, 2 minutes, 3 minutes, 4 minutes or 5 minutes.

Treatment using a heating source to stimulate the particles

When the particles are prepared from a pyroelectric material, a heating step of the surface of the skin of the subject above the acupoint(s) or NAU(s) is performed to stimulate the particles located on said acupoint(s) or NAU(s). Typically, one or several cycle(s) of temperature is/are performed depending on the composition of the particles. The temperature during each cycle typically does not exceed about 40°C in order to avoid skin burning.

In a particular aspect, a cooling step is added to any protocol including a heating step in order to induce a thermic shock which will further enhance the effects of the following heating step applied to the particle, i.e., which will enhance the activation of the cooled particle when reheated.

PATIENT A UTONOMY

When the particles are prepared from a material selected from a piezoelectric material or a pyroelectric material, the number of times per day or per week the treatment should be applied, the frequency of stimulation, its duration, and possibly the intensity of stimulation are typically parameters that can be delivered to the subject according to a pre-established protocol. As such, the particles used in the context of the present invention facilitate the follow up of the treatment, and are in particular advantageously used in the context of chronic diseases.

The protocol may typically be adjusted upon measuring blood biomarkers (as detailed herein below) when these biomarkers are usable to monitor the disease status in a subject under treatment. The treatment/protocol can then be adjusted/modulated, for example increased or decreased, for example by increasing or reducing the number of times per day or per week the treatment is to be applied, and/or by increasing or reducing the treatment session duration.

BIOMARKERS

In the context of an inflammatory or infection disorder, a panel of serum cytokines can be advantageously measured, typically in the blood. The panel for example comprises IL-6, IL-10, IL- 12p70, IL-13, IL-la, IL-Ib, IL-2, IL-4, IL-8, IL-5, IL-17, IL-23 and/or TNF. Also, HMGB1, C-reactive protein (CRP), vascular endothelial growth factor (VEGF), white blood cell (WBC), platelet, or intercellular adhesion molecule 1 (ICAM-1) can be used each one independently, or in combination, as marker(s) of inflammation. Particularly, IL-6 serum level may be measured in a subject under treatment to assess/monitor the inflammatory or infection disorder evolution. A decreased IL-6 serum level in a patient who responds to therapy is typically correlated with a positive response to treatment of the treated subject.

The embodiments 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 compounds, materials, particles and compositions 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.

LEGENDS TO THE FIGURES

Figure 1: Biological components, i.e., biological cells, free nerve endings, end-organs, nerve fibers and/or sarcous sensory receptors at acupoint or Neural Acupuncture Unit (NAU).

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

Dermis (zone ID. 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.

Hvnodermis (zone III). The hypodermis comprises lipocytes. It also comprises the following appendages: loose connective tissue (lipocytes, collagen, elastin fibers), blood vessels, nerves and muscle spindles.

EXPERIMENTAL PART

Particles of the invention

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

Typical examples of particles synthesis protocols are described in the following publications:

-N. Lee etal. (Magnetosome-like ferrimagnetic iron oxide nanocubes for highly sensitive MRI of single cells and transplanted pancreatic islets. PNAS, February 15, 2011, vol. 108, no. 7, 2662-2667): Far- infrared radiation emitting particles made of FesCL; and

- A. Merlo et al. (Boron nitride nanomaterials: biocompatibility and bio-applications. Biomater. Sci., 2018, 6, 2298): Piezoelectric particles made of boron nitride (BN).

Treatment protocol

Each test treatment method comprises a step of administering the particles on least one acupoint or NAU of the subject to be treated and, when the particles are prepared from a material selected from a piezoelectric material or a pyroelectric material, a subsequent step comprising the stimulation of the particles by a skin massage or a skin heating respectively. The following groups/conditions are typically tested to assess the efficiency of the treatment:

Control group n° 1 : healthy / no treatment;

Control group n°2: healthy / particles’ injection on at least one acupoint but no activation; Control group n°3: diseased / treatment by acupuncture, typically electroacupuncture, transcutaneous electrical nervous stimulation (TENS), percutaneous electrical nervous stimulation (PENS), or any other bioelectronic medicine tool known to stimulate peripheral nerves such as the invasive vagus nerve stimulation;

Test Group n°l: diseased / injection of particles prepared from a far-infrared radiation-emitting material on at least one acupoint but no activation; - Test Group n°2: diseased / injection of particles on at least one acupoint and when the particles are prepared from a material selected from a piezoelectric material or a pyroelectric material, a subsequent step comprising the stimulation of the particles by a skin massage or a skin heating respectively. Particles of the invention for use for treatment of an infection

A LPS-induced cytokine release mouse model can typically be used as a mouse model of sepsis to monitor serum biomarkers under different conditions.

Particles of the invention for use for treatment of an inflammatory disorder Mice models of Rheumatoid Arthritis, diabetes, or Inflammatory Bowel Disease can typically be used to monitor biomarkers such as cytokines.