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64 results about "Neuroregeneration" patented technology

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially the extent and speed. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

Devices and methods for delivering neuroregenerative therapy

Systems, devices and methods are disclosed for the treatment of injured peripheral nerves or other tissue using electrical stimulation. The systems can be used either in intraoperative or peri-operative settings and incorporate the use of either a plurality of monopolar electrodes with a patch used as return or a plurality of bipolar electrodes such as a cuff. The systems can provide hands-free delivery of electrical stimulation therapy over a predetermined set of time.
Owner:EPINEURON TECH INC

Devices and methods for delivering neuroregenerative therapy

Systems, devices and methods are disclosed for the treatment of injured peripheral nerves or other tissue using electrical stimulation. The systems can be used either in intraoperative or peri-operative settings and incorporate the use of either a plurality of monopolar electrodes with a patch used as return or a plurality of bipolar electrodes such as a cuff. The systems can provide hands-free delivery of electrical stimulation therapy over a predetermined set of time.
Owner:EPINEURON TECH INC

Systems and methods for gel-based neuromodulation

Methods, devices and systems are described for gel-based modulation of neural tissue, including prevention of nerve regeneration and neuroma formation. The gel can be delivered to selected target locations within or proximate nerves, including interfascicularly and intrafascicularly. Gel delivery associated with an operative procedure for the treatment of pain and other indications is also disclosed.
Owner:TULAVI THERAPEUTICS INC

Nerve growth factor functionalized exosome as well as preparation method and application thereof

The invention provides a nerve growth factor functionalized exosome as well as a preparation method and application thereof. The functionalized exosome can activate a Wnt / beta-catenin signal channel to maintain dryness of corneal limbal stem cells (LSCs) so as to promote corneal epithelium repair, can activate a cAMP signal channel to relieve inflammatory response and promote corneal nerve regeneration, and can be used for treating or relieving corneal chemical burns, including relieving inflammatory response, reducing stromal scar formation and inhibiting corneal neovascularization. Corneal epithelium repair and nerve regeneration are promoted.
Owner:EYE INST OF SHANDONG FIRST MEDICAL UNIV

Multifunctional bionic hydrogel as well as preparation and application thereof in traumatic brain injury treatment

The invention provides multifunctional bionic hydrogel as well as preparation and application thereof in traumatic brain injury treatment, and belongs to the field of biomedical materials. The preparation method comprises the following steps: combining polydopamine modified hemoglobin nanoparticles with curcumin-based carbon quantum dots with anti-inflammatory activity, and embedding into bionic hyaluronic acid-collagen double-network hydrogel, so as to prepare the multifunctional bionic hydrogel. The hydrogel can effectively relieve neuron hypoxia, reduce apoptosis, promote the polarity of microglial cells to be converted into anti-inflammatory phenotype, and significantly down-regulate the expression of S100A8, thereby inhibiting pathological neural immune crosstalk. In a traumatic brain injury model, hydrogel implantation improves the pathological microenvironment, enhances endogenous nerve regeneration, and ultimately results in significant neurological function and cognitive recovery. The multifunctional bionic hydrogel prepared by the invention has a good application prospect in preparation of materials for preventing and / or treating traumatic brain injury.
Owner:SICHUAN UNIV

Genetically engineered mesenchymal stem cells and uses thereof

Therefore, this disclosure provides a genetically engineered mesenchymal stem cell (MSC) population, including an expression vector containing the Akt or HGF gene and the PD-L1 gene. It also provides a method for synergistically improving the survival status and immunomodulatory capacity of mesenchymal stem cells or enhancing their proliferation, including transfecting mesenchymal stem cells with the Akt or HGF gene and the PD-L1 gene; and a method for preventing, improving, and / or treating ischemic conditions, enhancing neurogenesis, or reducing neuronal death, including administering an effective amount of the genetically engineered mesenchymal stem cell population of this disclosure to individuals in need.
Owner:洪明奇

Boron-containing rho kinase inhibitors

The present invention provides boron-containing isoquinoline compounds as protein kinase-modulating compounds. These compounds are useful as neuroprotective and neuro-regenerative agents for the amelioration of glaucoma and other ocular neuropathies.
Owner:PERCIPIAD INC

Application of high taurine in inhibiting macrophage aging after spinal cord injury

The invention discloses application of high taurine in inhibiting macrophage senescence after spinal cord injury. Comprising application of homotaurine in preparation of drugs for inhibiting aging of macrophages after spinal cord injury, drugs for inhibiting mitochondrial dysfunction of the macrophages after spinal cord injury, drugs for promoting repair of spinal cord injury, drugs for inhibiting neuroinflammation after spinal cord injury and drugs for increasing the expression quantity of SHMT2 protein in the macrophages. The invention relates to application of the compound in preparation of drugs for reducing mtDNA / cGAS / STING pathway activation in macrophages and drugs for reducing nuclear DNA damage mediated by reactive oxygen species in macrophages, in particular to application of the compound in preparation of drugs for reducing mtDNA / cGAS / STING pathway activation in macrophages. The invention reveals for the first time that high taurine significantly promotes spinal nerve regeneration, improves neurological functions, alleviates inflammatory response and protects spinal cord tissues by regulating immune cell mitochondrial metabolism-cell aging axis. The high taurine synergistically intervenes in secondary neurodegenerative diseases after spinal cord injury through a metabolism and immune dual-channel, and a brand new direction is provided for SCI treatment.
Owner:THE FIRST PEOPLES HOSPITAL OF NANTONG

Spinal cord injury repairing method based on four-dimensional multifunctional hydrogel

The invention relates to a spinal cord injury repair method based on four-dimensional multifunctional hydrogel, which comprises the following steps: firstly, encapsulating NT-3 in PLGA (poly (lactic-co-glycolic acid)) microspheres through a microsphere technology, and integrating HCT (Hydroxycycline Computed Tomography) into SilMA hydrogel, so as to construct four-dimensional multifunctional hydrogel 4DMSH with time specificity; the hydrogel shows a remarkable anti-inflammatory effect in an in-vivo experiment, can effectively inhibit the inflammatory reaction at the early stage of spinal cord injury, promotes eNSCs to differentiate into neurons by improving a microenvironment and inhibits formation of glial scars, so that the nerve repair efficiency is improved; the four-dimensional multifunctional hydrogel has time specificity and can create an anti-inflammatory and neuroactive microenvironment, so that effective spinal cord injury repair and nerve regeneration are realized; the hydrogel can be widely applied to SCI treatment, and a brand new strategy is provided for repairing nervous system injury.
Owner:SHANDONG UNIV

Injectable nutrient solution

The present invention relates to a customizable injectable solution comprising Human Growth Hormone (HGH), Insulin-like Growth Factor 1 (IGF-1), or a growth hormone secretagogue such as sermorelin or ipamorelin, combined with a blend of nutrients including amino acids, vitamins, electrolytes, functional mushroom extracts, and optionally mushroom mycelium. The solution is delivered via a dual-chamber syringe to preserve component stability, with mixing occurring immediately before administration. The formulation is suitable for subcutaneous, intramuscular, or intravenous injection and may be tailored for muscle growth, cognitive performance, immune support, or neuroregeneration. The invention also contemplates injectable formulations of functional mushrooms alone, as well as alternative delivery methods such as sublingual troches containing GH-inducing peptides, functional mushrooms, and ketamine. This system provides a versatile, bioavailable, and clinically adaptable approach to personalized health optimization.
Owner:MARULIS NIKOLAS CARMELO

A neurotrophic protein peptide composition and its application

This invention discloses a neurotrophic brain protein peptide composition and its applications, belonging to the field of food technology. The components of the composition provided by this invention have synergistic effects. On the one hand, they reduce the damage of oxidative stress to the nervous system, improve sleep quality, and create a favorable environment for the repair and regeneration of the nervous system. On the other hand, they provide the raw materials needed for the maintenance, repair, and regeneration of nerve cells, as well as the synthesis of neurotransmitters, ensuring energy supply and the activity of the required enzyme systems, thereby achieving the effect of effectively nourishing / repairing nerves and / or promoting nerve regeneration. The provided composition does not use organic reagents, is environmentally friendly, and has high safety; it has low preparation cost and a good taste.
Owner:HAINAN YUTIDE BIOPHARMACEUTICAL CO LTD

Recombinant adeno-associated virus vector

The present invention provides adeno-associated virus (rAAV) vectors, in particular rAAV vectors comprising gene constructs carrying genes encoding tyrosine receptor kinase B (TrkB) and brain derived neurotrophic factor (BDNF). The invention also extends to pharmaceutical compositions comprising said rAAV vectors, and the use of these vectors and compositions in gene therapy for the prevention or treatment of a range of optic nerve and cochlear disorders or for promoting nerve regeneration and / or survival. The invention also provides a method of producing the rAAV vector.
Owner:QUETHERA

Methods and compositions to promoting retinal regeneration using prox1 migration inhibitor as active ingredient

ActiveUS12624357B2Organic active ingredientsSenses disorderNeurophysinsRetinal regeneration
The present invention relates to a technique capable of treating a retinal neurodegenerative disease through regeneration of a retinal nerve by targeting Prox1 in the mammalian retina using an inhibitor which inhibits Prox1 expression or migration. According to the present invention, inducing the regeneration of the damaged retina in mammals, and thus can be commonly applied to the treatment of various retinal neurodegenerative diseases causing vision loss, and furthermore, when combining with a selective retinal nerve differentiation method or the like, it is expected that the method can be used for the development of an innovative retinal regeneration method capable of selectively regenerating only specific degenerating retinal neurons.
Owner:KOREA ADVANCED INST OF SCI & TECH

Application of AAV overexpression of macrophage MCT1 in the treatment of corneal nerve injury repair in mice

The present application relates to the technical field of biological medicine, and particularly relates to application of a nucleic acid vector encoding a macrophage monocarboxylate transporter MCT1 in preparation of a pharmaceutical composition for promoting corneal nerve regeneration and recovery of corneal sensitivity after corneal nerve injury. The present application finds that after corneal nerve injury, increasing the level of macrophage MCT1 can drive the change of the metabolic mode of macrophages to the direction of enhanced oxidative phosphorylation and reduced glycolysis, reduce the expression of local pro-inflammatory related factors, and increase the level of pro-regeneration factors and neurotrophic factors, thereby improving the regeneration of corneal nerve structure and the recovery of sensory function. Therefore, a macrophage-targeted or macrophage-biased expression vector containing a nucleic acid sequence encoding MCT1 can be used for preparation of a pharmaceutical composition for treating corneal nerve injury.
Owner:THE THIRD MEDICAL CENT OF THE CHINESE PEOPLES LIBERATION ARMY GENERAL HOSPITAL

Preparation method of carboxylated silk fibroin hydrogel composite nerve conduit

The application discloses a preparation method of a carboxylated silk fibroin hydrogel composite nerve conduit. The carboxylated silk fibroin is chemically crosslinked with chitosan amino groups, the crosslinking is carried out in an aqueous solution, and no organic solvent such as ethanol is contained, so that the cell activity is not inhibited, the safety hazard to the human body is avoided, and the temperature and pH do not need to be additionally controlled, which is beneficial to the stability of vascular endothelial growth factor, and the hydrogel can be formed in a very short time, and the VEGF with the function of blood vessel regeneration is rich in the application, so that the neuroangiogenesis is enhanced, and the nerve regeneration is promoted.
Owner:WUHAN UNIV OF TECH

Use of an inhibitor of METTL1 in the preparation of a medicament for treating inflammation after central nervous system injury

The present invention relates to the use of an inhibitor of METTL1 in the preparation of a medicament for treating inflammation after central nervous system injury, belonging to the technical field of biomedicine. The present invention has confirmed that central nervous system injury can lead to an increase in the expression level of METTL1; compared with the mice in the sham operation group, the mice with specific knockdown of METTL1 in astrocytes significantly reduced the inflammatory response caused by central nervous system injury and promoted nerve regeneration, and significantly improved motor function. The present invention has found that METTL1 plays a key role in the inflammation of central nervous system injury, and reduces the secondary pathological changes of central nervous system injury by regulating the level of m 7 6G methylation, and this discovery provides a new target for the treatment of central nervous system injury, with important clinical application potential and broad market prospects.
Owner:JINAN CENTER HOSPITAL

Composition for enhancing memory and improving cognitive function and application

The invention discloses a composition for enhancing memory and improving cognitive function and application. The composition disclosed by the invention comprises acanthopanax, ginseng, Chinese wolfberry fruits, gastrodia elata, spina date seeds, poria cocos, Chinese yams, lotus seeds, gordon euryale seeds, mulberries, longan pulp, fresh ginger, walnut powder, egg protein powder, blueberry powder, raspberry powder, pumpkin seed powder, oat powder, spirulina powder, dark chocolate powder, a vitamin B group compound, gamma-aminobutyric acid, galactooligosaccharide and citric acid. According to the invention, a multi-channel and multi-target collaborative network is constructed by taking acanthopanax senticosus as a core, through multiple channels such as nerve regeneration, energy metabolism, oxidative stress, signal transduction, endocrine regulation and the like, different nodes such as neurons, neuroglial cells, cerebrovascular endothelium and the like are targeted, the overall optimization of the memory function is realized on the system level, and the memory function is optimized. The core idea of systematic biology of overall regulation and control is reflected, and the composition prepared from the composition has the effects of improving memory, learning ability and cognitive ability.
Owner:HARBIN INST OF TECH +2

Magnetic-control electric three-layer composite nerve scaffold for nerve regeneration microenvironment stage adaptation and preparation method of magnetic-control electric three-layer composite nerve scaffold

The invention discloses a magnetic control electric three-layer composite nerve scaffold for nerve regeneration microenvironment stage adaptation and a preparation method thereof. The outer layer of the stent is a PLLA-IAA membrane responding to inflammation microenvironment stimulation, the middle of the stent is an SPIONs-doped piezoelectric layer, and the inner layer of the stent is an Nrg-1-loaded neurotrophic factor sustained release layer. In the initial stage of stent implantation, reactive oxygen species (ROS) stimulates a responsive chain segment to break, and IAA is quickly released to inhibit an inflammatory microenvironment; then, an alternating magnetic field is applied to cause vibration of the SPIONs, formation of an electric signal in the piezoelectric layer is triggered, and a favorable electrophysiological microenvironment is provided for promoting neuronal differentiation and axon regeneration; under the action of environmental degradation, the spinning membrane structure disintegrates slowly and continuously releases the neurotrophic factor Nrg-1 so as to promote myelin sheath formation. The stent innovatively integrates the requirements of three stages of a nerve regeneration microenvironment, and realizes accurate, dynamic and multi-dimensional regulation and control of high-efficiency regeneration.
Owner:FUZHOU UNIV

Use of chchd2 in the preparation of a product for promoting proliferation and differentiation of neural stem cells

The application belongs to the field of biomedical science and neurology, and particularly relates to application of CHCHD2 gene and a protein coded by the CHCHD2 gene in preparation of a product for promoting proliferation and differentiation of neural stem cells. The application proves that the CHCHD2 gene and the protein coded by the CHCHD2 gene are highly expressed in in-vivo neural development and in-vitro neural differentiation process; and that knocking down or over-expressing the CHCHD2 gene or the protein coded by the CHCHD2 gene has a certain regulating effect on proliferation and differentiation of neural stem cells. The application provides a new scheme for preparation of a product for promoting proliferation and differentiation of neural stem cells, and provides a new target for drug research and development of neural regeneration and repair treatment of central nervous system development deficiency diseases, neurodegenerative diseases, cerebrovascular diseases, craniocerebral and spinal cord injuries.
Owner:THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV

Programmed controllable slow-release bionic spinal cord graft as well as preparation method and application thereof

The invention discloses a programmed controllable slow-release bionic spinal cord graft and a preparation method and application thereof, and belongs to the field of medical biomaterials.The preparation method comprises the steps that a micro-nano oriented fiber scaffold with a groove is synthesized on the basis of recombinant NT3, silk fibroin, bovine collagen and a neurotrophic factor NGF; the programmed controllable slow-release bionic spinal cord graft is jointly constructed by combining an acellular matrix and an exosome derived from human umbilical cord mesenchymal stem cells with a programmed slow-release system of GelMA drug-loaded microspheres containing cyclosporine a; multiple technologies such as bionic tissue engineering, a micro-fluidic technology, a drug-loaded microsphere controllable slow-release technology, an acellular matrix and exosome are combined, spinal cord injury repair is facilitated, good biocompatibility is achieved, nerve axons are promoted to grow in an oriented mode, immune regulation can be given in the early stage of spinal cord injury, the nerve regeneration microenvironment after spinal cord injury is improved, and the nerve regeneration effect is improved. The method is beneficial to nerve regeneration and functional reconstruction after spinal cord injury.
Owner:NANTONG UNIV

Neuropeptide S for promoting mouse spinal cord injury repair by regulating and controlling endogenous NSPCs to be differentiated into neurons and regenerated from axons

The invention discloses a neuropeptide S for promoting mouse spinal cord injury repair by regulating and controlling endogenous NSPCs to differentiate into neurons and perform axonal regeneration, and belongs to the field of biological medicine and nerve repair. According to the technical scheme of the invention, a complete T11 spinal cord injury mouse model is transplanted and treated by adopting a thermo-sensitive hydrogel stent loaded with NPS. In-vitro experiments show that NPS can significantly promote neural stem / progenitor cells to differentiate into neurons and prolong axons. In-vivo experiments show that the immune response of an injured area is relieved, endogenous nerve stem / progenitor cells migrate and are differentiated into functional neurons, axons extend, more synapses are formed, and the movement function of hind limbs is obviously recovered. NPS activates downstream Ca < 2 + > and cAMP signal channels through an NPS-NPSR axis, and regulates and controls polygene expression, so that nerve regeneration and functional recovery are promoted. The NPS provided by the invention provides an efficient and feasible treatment strategy for spinal cord injury repair, and has an important clinical application prospect.
Owner:JIANGNAN UNIV

VHH suitable to vectorize molecules intracellularly

The invention relates to a particular modified camelid single chain antibody called VHHNPX and uses of VHHNPX in new methods for the efficient delivery of molecular cargos inside target cells (in particular neurons and eye retina cells). The invention further relates to a Neurovita short interfering peptide suitable for neuroprotection and neuroregeneration and uses thereof, in particular a Neurovita peptide short fragment encoding a PDZ-binding motif (PBM) inhibiting the PDZ domain of the human MAST2 & MAST1 enzymes. The invention also relates to polypeptides comprising this Neurovita short peptide, notably peptides further comprising a cell-penetrating molecule (CPM), and uses thereof.
Owner:INST PASTEUR +1

Flavonoid derivatives, preparation methods, pharmaceutical compositions and applications thereof

The present invention relates to the field of pharmaceutical chemistry, and discloses flavonoid derivatives, preparation methods thereof, pharmaceutical compositions, and applications thereof. The general structural formula of the flavonoid derivatives is: wherein R2 and R'2 are independently selected from -H, -OH, or -OCH3; R3 and R'3 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2, or -CH(CH2)2; R5 and R'5 are independently selected from -H, -CH3, -OCH3, -CH(CH3)2, or -CH(CH2)2; R6 and R'6 are independently selected from -H, -OH, or -OCH3. The flavonoid derivatives have enhanced lipid solubility, facilitate BBB penetration, increase drug concentration in the brain, maintain pharmacokinetic levels, effectively retain neuroprotective effects such as anti-oxidative stress, anti-inflammatory, and neuroregeneration, and introduce propofol into the flavonoid skeleton to enhance the anesthetic effect under the synergistic effect of the two, making them a potential new antidepressant drug.
Owner:SHENZHEN PEOPLES HOSPITAL

A neurovita short interfering peptide suitable for neuroprotection and neuroregeneration and uses thereof

The invention relates to a Neurovita peptide short fragment encoding a PDZ-binding motif (PBM) inhibiting the PDZ domain of the human MAST2 & MAST1 enzymes. The invention also relates to polypeptides comprising this Neurovita short peptide, notably peptides further comprising a cell-penetrating molecule (CPM), and uses thereof.
Owner:INST PASTEUR +1

Extracellular vesicle loaded with neuropeptide and use thereof

The present invention relates to an extracellular vesicle loaded with a neuropeptide and, more specifically, to the use of an extracellular vesicle loaded with a neuropeptide for preventing, alleviating, or treating nervous system damage or nervous system diseases. The extracellular vesicle loaded with a neuropeptide according to the present invention was experimentally verified to have excellent effects in increasing brain-derived neurotrophic factor (BDNF) expression, promoting neuronal cell proliferation, and promoting neuronal cell differentiation. This means that the extracellular vesicle loaded with a neuropeptide of the present invention exhibits excellent neuroprotective and neuroregenerative effects and can thus be variously used in the field of treating nervous system damage or nervous system diseases.
Owner:S&E BIO CO LTD

Janus membrane with tissue adhesiveness, preparation method of Janus membrane and application of Janus membrane to neural restoration

The invention provides a Janus membrane with tissue adhesiveness, a preparation method of the Janus membrane and application of the Janus membrane to neural restoration. The Janus membrane with the tissue adhesiveness comprises an electrospun fiber layer and an oriented hydrogel fiber layer with the tissue adhesiveness. The electrospun fiber layer is used as a non-viscous isolation layer, has good mechanical properties and air permeability, and can effectively avoid adhesion and compression of surrounding tissues; the oriented hydrogel fiber layer has unique tissue adhesiveness and an oriented structure, the tissue adhesiveness characteristic of the oriented hydrogel fiber layer can ensure that the oriented hydrogel fiber layer is tightly attached to nervous tissues, and the oriented structure can guide directional regeneration of nerves, so that the nerve regeneration efficiency is remarkably improved, directional adhesion and migration of cells can be induced, axons are promoted to extend in a specific direction, and the nerve regeneration effect is improved. Therefore, the formation of neuroma is effectively prevented. The Janus membrane and a nerve broken end are bonded without tension and curled to form an exclusive catheter which is adaptive to various nerve diameters and complex branch structures.
Owner:WEST CHINA HOSPITAL SICHUAN UNIV

Compositions comprising neuregulin and methods of using the same to treat or prevent neurotrophic keratitis

PCT designated stage expiredWO2025122581A1Senses disorderPeptide/protein ingredientsNeuregulinPharmaceutical drug
Disclosed are pharmaceutical compositions comprising the growth factor neuregulin 1 (NRG1). Further disclosed herein are methods of using neuregulin 1, or pharmaceutical compositions comprising NRG1, to treat or prevent neurotrophic keratitis, methods to induce corneal headlining in an eye of a subject that has been denervated, and methods or preventing death of Schwann cells in the cornea of a subject that has suffered a corneal denervation.
Owner:THE TRUSTEES OF INDIANA UNIV

Neural regenerating cells with alterations in DNA methylation

Disclosed herein are cells, that are descendents of marrow adherent stem cells (MASCs), capable of rescuing and / or reversing various neural disorders after transplantation into sites of central nervous system (CNS) or peripheral nervous system (PNS) injury. The cells contain alterations in the methylation state of certain genes, compared to their methylation state in MASCs. Methods of making cells capable of rescuing and / or reversing various neural disorders after transplantation into sites of CNS or PNS injury, by alteration of the methylation status of certain genes, are also provided.
Owner:SANBIO INC

Injectable nutrient solution

PCT designated stageWO2026096310A1Organic active ingredientsPeptide/protein ingredientsBUTTON MUSHROOM EXTRACTSomatotropic hormone
The present invention relates to a customizable injectable solution comprising Human Growth Hormone (HGH), Insulin-like Growth Factor 1 (IGF-1), or a growth hormone secretagogue such as sermorelin or ipamorelin, combined with a blend of nutrients including amino acids, vitamins, electrolytes, functional mushroom extracts, and optionally mushroom mycelium. The solution is delivered via a dual-chamber syringe to preserve component stability, with mixing occurring immediately before administration. The formulation is suitable for subcutaneous, intramuscular, or intravenous injection and may be tailored for muscle growth, cognitive performance, immune support, or neuroregeneration. The invention also contemplates injectable formulations of functional mushrooms alone, as well as alternative delivery methods such as sublingual troches containing GH-inducing peptides, functional mushrooms, and ketamine. This system provides a versatile, bioavailable, and clinically adaptable approach to personalized health optimization.
Owner:MARULIS NIKOLAS CARMELO