[go: up one dir, main page]

WO2025144993A1 - Capteurs à micro-aiguilles de soie optique transdermique pour surveillance continue d'analytes physiologiques dans un fluide interstitiel - Google Patents

Capteurs à micro-aiguilles de soie optique transdermique pour surveillance continue d'analytes physiologiques dans un fluide interstitiel Download PDF

Info

Publication number
WO2025144993A1
WO2025144993A1 PCT/US2024/062043 US2024062043W WO2025144993A1 WO 2025144993 A1 WO2025144993 A1 WO 2025144993A1 US 2024062043 W US2024062043 W US 2024062043W WO 2025144993 A1 WO2025144993 A1 WO 2025144993A1
Authority
WO
WIPO (PCT)
Prior art keywords
silk fibroin
microneedle
chromophore
interest
suspension
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/062043
Other languages
English (en)
Inventor
David L. Kaplan
Sawnaz SHAIDANI
Jack LY
Thomas FALCUCCI
Kayla PRESLEY
Tod GRUSENMEYER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tufts University
United States Department of the Air Force
Original Assignee
Tufts University
United States Department of the Air Force
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tufts University, United States Department of the Air Force filed Critical Tufts University
Publication of WO2025144993A1 publication Critical patent/WO2025144993A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685—Microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4261—Evaluating exocrine secretion production
    • A61B5/4266—Evaluating exocrine secretion production sweat secretion
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles

Definitions

  • Disclosed herein is technology for monitoring hydration and electrolyte levels, identifying a metabolic status, real-time minimally invasive monitoring of tissue oxygenation, providing data on environmental conditions, monitoring food and/or beverage conditions such as acidity or oxygen levels, or the like.
  • this disclosure provides loading chromophores into silk nanoparticles (SNPs) prior to inclusion in MNs.
  • the system can be configured into additional modes depending on the needs, e.g., hollow MNs to facilitate fluid sampling or integration with electronics to provide readouts.
  • Transdermal MN patches are a method of drug delivery that has gained traction in recent years as an alternative, painless, and thus minimally invasive route of administration when compared to standard injections or implantable drug delivery devices. MN patches can penetrate the skin and deliver peptides, vaccines, proteins, and other small molecules. However, in MN formulations using non-degradable systems or synthetic materials, issues of thermal processing of polymers, harsh chemical conditions, ultraviolet light, or other factors used in the fabrication process can negatively impact the functionality of the loaded cargo.
  • silk fibroin films and sponges that maintained real-time oxygen-sensing functions throughout physiological states, and the loaded chromophore retained functionality in silk fibroin substrates in vivo.
  • SNPs were either utilized to fortify MNs, or they were loaded with chromophores and subsequently localized or stacked in specific portions of the MN array or needles themselves.
  • transdermal MN arrays may be exposed to atmospheric oxygen, we loaded oxygen sensing chromophores inside nanoparticles, which we specifically positioned only in the tip of the needles to avoid atmospheric influence.
  • By loading chromophores into nanoparticles prior to casting them into the microneedles there is also loaded multiple chromophores in the same needles or different chromophores within different needles (arrays).
  • Optical sensing via MNs could employ a wide variety of analyte- sensing dyes and sensing strategies. Most demonstrated analyte-sensing dyes operate in the ultraviolet (UV) or visible (400- 700 nm) regime, precluding their use in implantable sensors. However, such dyes are compatible with a transparent MN approach. Optical sensing strategies for MNs could monitor changes in phosphorescence lifetime, fluorescence intensity, or absorption (i.e., change in color). Note that lifetime-sensing is also possible with implantable technologies as we previously demonstrated in rodent studies with bioresorbable tissue oxygen (O2) sensors.
  • UV ultraviolet
  • 400- 700 nm visible
  • Optical sensing strategies for MNs could monitor changes in phosphorescence lifetime, fluorescence intensity, or absorption (i.e., change in color). Note that lifetime-sensing is also possible with implantable technologies as we previously demonstrated in rodent studies with bioresorbable tissue oxygen (O2) sensors.
  • Analytes of interest include tissue oxygenation, electrolytes (Na + , K + , Ca 2+ , Cl ) from the Chem 8 basic metabolic panel, as well as additional biomarkers such as lactate, pH, and other metabolites relevant to physiological and metabolic monitoring.
  • the system may be adaptable to utilize different particle sizes, different centrifuge times/forces to produce a “gradient” effect of SNPs loaded with chromophores, thus controlling particle location/chromophore concentration. It is contemplated that blank nanoparticles could be used with chromophores in the silk solution/matrix, the blank silk nanoparticles could be concentrated in a certain region (e.g., the tip), and then a higher concentration of chromophore could be present everywhere except the certain region (e.g., the tip).
  • a method of making a microneedle including a base, a tip, and a tapered section connecting the base of the tip may comprise the following steps a)-f).
  • a concentrated silk fibroin solution may be added to the second suspension to produce a third suspension having a final silk fibroin solution concentration and a final silk fibroin nanoparticle concentration, wherein the final silk fibroin concentration by weight is between 5% and 10% and the final silk fibroin nanoparticle concentration by weight is between 0.05% and 1.0%.
  • the third suspension may be casted into a mold defining a volumetric shape to produce a casted suspension having the volumetric shape.
  • the casted solution may be dried at a drying temperature of between 4 °C and 90 °C (e.g., preferred ambient conditions) for a drying length of time of between 2 hours and 24 hours, thereby producing a dried article having the volumetric shape.
  • a silk microneedle may have chromophores distributed throughout the microneedle or concentrated at a tip of the microneedle such that the presence of the chromophore allows for the sensing of a physiological analyte.
  • a functionalizing agent may be any compound or molecule that facilitates the attachment to and/or development (e.g., growth) of one or more endothelial cells on a silk membrane.
  • a functionalizing agent may be any compound or molecule that facilitates the attachment and/or development (e.g., growth) of one or more megakaryocytes and/or hematopoietic progenitor cells on a silk matrix and/or silk membrane.
  • a functionalizing agent may be or comprise an agent suitable for facilitating the production of one or more of white blood cells and red blood cells.
  • a functionalizing agent may be embedded or otherwise associated with a silk membrane and/or silk matrix such that at least a portion of the functionalizing agent is surrounded by a silk membrane and/or silk matrix as contrasted to a functionalizing agent simply being positioned along the surface of a silk membrane and/or silk matrix.
  • a functionalizing agent is distributed along and/or incorporated in substantially the entire surface area of a silk membrane/silk wall.
  • a functionalizing agent is distributed and/or incorporated only at one or more discrete portions of a silk membrane/wall and/or silk matrix.
  • a functionalizing agent is distributed in and/or along at least one of the lumenfacing side of a silk wall and the matrix-facing side of a silk wall.
  • any application- appropriate amount of one or more functionalizing agents may be used.
  • the amount of an individual functionalizing agent may be between about 1 pg/ml and 1,000 pg/ml (e.g., between about 2 and 1 ,000, 5 and 1 ,000, 10 and 1 ,000, 10 and 500, 10 and 100 pg/ml).
  • the amount of an individual functionalizing agent may be at least 1 pg/ml (e.g., at least 5, 10, 15, 20 25, 50, 100, 200, 300 400, 500, 600, 700, 800, or 900 pg/ml ).
  • the amount of an individual functionalizing agent is at most 1,000 pg/ml (e.g., 900, 800, 700, 600, 500, 400, 300 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 pg/ml ).
  • the composition comprises one or more sensing agents, such as a sensing dye.
  • the sensing agents/sensing dyes are environmentally sensitive and produce a measurable response to one or more environmental factors.
  • the environmentally- sensitive agent or dye may be present in the composition in an effective amount to alter the composition from a first chemical -physical state to a second chemical -physical state in response to an environmental parameter (e.g., a change in pH, light intensity or exposure, temperature, pressure or strain, voltage, physiological parameter of a subject, and/or concentration of chemical species in the surrounding environment) or an externally applied stimulus (e.g., optical interrogation, acoustic interrogation, and/or applied heat).
  • an environmental parameter e.g., a change in pH, light intensity or exposure, temperature, pressure or strain, voltage, physiological parameter of a subject, and/or concentration of chemical species in the surrounding environment
  • an externally applied stimulus e.g., optical interrogation, acoustic interrogation, and/or applied heat.
  • the sensing dye is present to provide one optical appearance under one given set of environmental conditions and a second, different optical appearance under a different given set of environmental conditions.
  • Suitable concentrations for the sensing agents described herein can be the concentrations for the colorants and additives described elsewhere herein.
  • a person having ordinary skill in the chemical sensing arts can determine a concentration that is appropriate for use in a sensing application of the inks described herein.
  • the first and second chemical-physical state may be a physical property of the composition, such as mechanical property, a chemical property, an acoustical property, an electrical property, a magnetic property, an optical property, a thermal property, a radiological property, or an organoleptic property.
  • exemplary sensing dyes or agents include, but are not limited to, a pH sensitive agent, a thermal sensitive agent, a pressure or strain sensitive agent, a light sensitive agent, or a potentiometric agent.
  • Exemplary pH sensitive dyes or agents include, but are not limited to, cresol red, methyl violet, crystal violet, ethyl violet, malachite green, methyl green, 2-(p- dimethylaminophenylazo) pyridine, paramethyl red, metanil yellow, 4-phenylazodiphenylamine, thymol blue, metacresol purple, orange IV, 4-o-Tolylazo-o-toluindine, quinaldine red, 2,4- dinitrophenol, erythrosine disodium salt, benzopurpurine 4B, N,N-dimethyl-p-(m-tolylazo) aniline, p- dimethylaminoazobenene, 4,4'-bis(2-amino-l-naphthylazo)-2,2'-stilbenedisulfonic acid, tetrabromophenolphthalein ethyl ester, bromophenol blue, Congo red, methyl orange, ethyl orange, 4-
  • Exemplary light responsive dyes or agents include, but are not limited to, photochromic compounds or agents, such as triarylmethanes, stilbenes, azasilbenes, nitrones, fulgides, spiropyrans, napthopyrans, spiro-oxzines, quinones, derivatives and combinations thereof.
  • photochromic compounds or agents such as triarylmethanes, stilbenes, azasilbenes, nitrones, fulgides, spiropyrans, napthopyrans, spiro-oxzines, quinones, derivatives and combinations thereof.
  • Exemplary potentiometric dyes include, but are not limited to, substituted amiononaphthylehenylpridinium (ANEP) dyes, such as di-4-ANEPPS, di-8-ANEPPS, and N-(4- Sulfobutyl)-4-(6-(4-(Dibutylamino)phenyl)hexatrienyl)Pyridinium (RH237).
  • ANEP substituted amiononaphthylehenylpridinium
  • Exemplary temperature sensitive dyes or agents include, but are not limited to, thermochromic compounds or agents, such as thermochromic liquid crystals, leuco dyes, fluoran dyes, octadecylphosphonic acid.
  • chemi-sensitive dyes or agents include, but are not limited to, antibodies such as immunoglobulin G (IgG) which may change color from blue to red in response to bacterial contamination.
  • IgG immunoglobulin G
  • the compositions comprise one or more additive, dopant, or biologically active agent suitable for a desired intended purpose.
  • the additive or dopant may be present in the composition in an amount effective to impart an optical or organoleptic property to the composition.
  • Exemplary additives or dopants that impart optical or organoleptic properties include, but are not limited to, dyes/pigments, flavorants, aroma compounds, granular or fibrous fillers.
  • the additive, dopant, or biologically active agent may be present in the composition in an amount effective to "functionalize” the composition to impart a desired mechanical property or added functionality to the composition.
  • exemplary additive, dopants, or biologically active agent that impart the desired mechanical property or added functionality include, but are not limited to: environmentally sensitive/sensing dyes; active biomolecules; conductive or metallic particles; micro and nanofibers (e.g., silk nanofibers for reinforcement, carbon nanofibers); nanotubes; inorganic particles (e.g., hydroxyapatite, tricalcium phosphate, bioglasses); drugs (e.g., antibiotics, small molecules or low molecular weight organic compounds); proteins and fragments or complexes thereof (e.g., enzymes, antigens, antibodies and antigen-binding fragments thereof);
  • DNA/RNA e.g., siRNA, miRNA, mRNA
  • cells and fractions thereof viruseses and viral particles; prokaryotic cells such as bacteria; eukaryotic cells such as mammalian cells and plant cells; fungi).
  • the additive or dopant comprises a flavoring agent or flavorant.
  • Exemplary flavorants include ester flavorants, amino acid flavorants, nucleic acid flavorants, organic acid flavorants, and inorganic acid flavorants, such as, but not limited to, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, ethylvanillin, methyl salicylate, manzanate, glutamic acid salts, glycine salts, guanylic acids salts, inosinic acid salts, acetic acid, ascorbic acid, citric acid, fumaric acid, lactic acid, malic acid, phosphoric acid, tartaric acid, derivatives, and mixtures thereof.
  • diacetyl acetylpropion
  • the additive or dopant comprises an aroma compound.
  • aroma compounds include ester aroma compounds, terpene aroma compounds, cyclic terpenes, and aromatic aroma compounds, such as, but not limited to, geranyl acetate, methyl formate, metyl acetate, methyl propionate, methyl butyrate, ethyl acetate, ethyl butyrate, isoamyl acetate, pentyl butrate, pentyl pentanoate, octyl acetate, benzyl acetate, methyl anthranilate, myrecene, geraniol, nerol, citral, cironellal, cironellol, linalool, nerolidol, limonene, camphor, menthol, carone, terpineol, alpha-lonone, thujone, eucalyptol, benzaldehy
  • the additive or dopant comprises a colorant, such as a dye or pigment.
  • the dye or pigment imparts a color or grayscale to the composition.
  • the colorant can be different than the sensing agents and/or sensing dyes below. Any organic and/or inorganic pigments and dyes can be included in the inks.
  • Exemplary pigments suitable for use in the present disclosure include International Color Index or C.I. Pigment Black Numbers 1 , 7, 1 1 and 31 , C.I. Pigment Blue Numbers 15, 15 : 1 , 15 :2, 15 :3, 15 :4, 15 :6, 16, 27, 29, 61 and 62, C.I. Pigment Green Numbers 7, 17, 18 and 36, C.I.
  • the classes of dyes suitable for use in present invention can be selected from acid dyes, natural dyes, direct dyes (either cationic or anionic), basic dyes, and reactive dyes.
  • the acid dyes also regarded as anionic dyes, are soluble in water and mainly insoluble in organic solvents and are selected, from yellow acid dyes, orange acid dyes, red acid dyes, violet acid dyes, blue acid dyes, green acid dyes, and black acid dyes.
  • European Patent 0745651 incorporated herein by reference, describes a number of acid dyes that are suitable for use in the present disclosure.
  • Exemplary yellow acid dyes include Acid Yellow 1 International Color Index or C.I. 10316); Acid Yellow 7 (C.I. 56295); Acid Yellow 17 (C.I.
  • compositions provided herein can contain ETV fluorophores that are excited in the ETV range and emit light at a higher wavelength (typically 400 nm and above).
  • ETV fluorophores include but are not limited to materials from the coumarin, benzoxazole, rhodamine, napthalimide, perylene, benzanthrones, benzoxanthones or benzothia- xanthones families.
  • a UV fluorophore such as an optical brightener for instance
  • the amount of colorant, when present, generally is between 0.05% to 5% or between 0.1% and 1% based on the weight of the composition.
  • a bioactivity can refer to the ability of a compound to produce a toxic effect in a cell.
  • exemplary cellular responses include, but are not limited to, lysis, apoptosis, growth inhibition, and growth promotion; production, secretion, and surface expression of a protein or other molecule of interest by the cell; membrane surface molecule activation including receptor activation; transmembrane ion transports; transcriptional regulations; changes in viability of the cell; changes in cell morphology; changes in presence or expression of an intracellular component of the cell; changes in gene expression or transcripts; changes in the activity of an enzyme produced within the cell; and changes in the presence or expression of a ligand and/or receptor (e.g., protein expression and/or binding activity).
  • a ligand and/or receptor e.g., protein expression and/or binding activity
  • Methods for assaying different cellular responses are well known to one of skill in the art, e.g., western blot for determining changes in presence or expression of an endogenous protein of the cell, or microscopy for monitoring the cell morphology in response to the active agent, or FISH and/or qPCR for the detection and quantification of changes in nucleic acids.
  • Bioactivity can be determined in some embodiments, for example, by assaying a cellular response.
  • bioactivity includes, but is not limited to, epitope or antigen binding affinity, the in vivo and/or in vitro stability of the antibody, the immunogenic properties of the antibody, e.g., when administered to a human subject, and/or the ability to neutralize or antagonize the bioactivity of a target molecule in vivo or in vitro.
  • the aforementioned properties or characteristics can be observed or measured using art-recognized techniques including, but not limited to, scintillation proximity assays, ELISA, ORIGEN immunoassay (IGEN), fluorescence quenching, fluorescence ELISA, competitive ELISA, SPR analysis including, but not limited to, SPR analysis using a BIAcore biosensor, in vitro and in vivo neutralization assays (see, for example, International Publication No. WO 2006/062685), receptor binding, and immunohistochemistry with tissue sections from different sources including human, primate, or any other source as needed.
  • the “bioactivity” includes immunogenicity, the definition of which is discussed in detail later.
  • the “bioactivity” includes infectivity, the definition of which is discussed in detail later.
  • the “bioactivity” refers to the ability of a contrast agent when administered to a subject to enhance the contrast of structures or fluids within the subject’s body.
  • the bioactivity of a contrast agent also includes, but is not limited to, its ability to interact with a biological environment and/or influence the response of another molecule under certain conditions.
  • small molecule can refer to compounds that are “natural productlike,” however, the term “small molecule” is not limited to “natural product-like” compounds. Rather, a small molecule is typically characterized in that it contains several carbon — carbon bonds, and has a molecular weight of less than 5000 Daltons (5 kDa), preferably less than 3 kDa, still more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases it is preferred that a small molecule have a molecular weight equal to or less than 700 Daltons.
  • Exemplary therapeutic agents include, but are not limited to, those found in Harrison’ s Principles of Internal Medicine, 13th Edition, Eds. T.R. Harrison et al. McGraw-Hill N.Y., NY; Physicians’ Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, ETSP XII NF XVII, 1990, the complete contents of all of which are incorporated herein by reference.
  • Therapeutic agents include the herein disclosed categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will recognize also numerous other compounds that fall within the categories and that are useful according to the present disclosure. Examples include a radiosensitizer, a steroid, a xanthine, a beta- 2-agonist bronchodilator, an anti-inflammatory agent, an analgesic agent, a calcium antagonist, an angiotensin-converting enzyme inhibitors, a beta-blocker, a centrally active alpha- agonist, an alpha- 1 -antagonist, an anticholinergic/antispasmodic agent, a vasopressin analogue, an anti arrhythmic agent, an antiparkinsonian agent, an antiangina/antihypertensive agent, an anticoagulant agent, an antiplatelet agent, a sedative, an ansiolytic agent, a peptidic agent, a biopolymeric agent, an antineoplastic agent,
  • the pharmaceutically active agent can be coumarin, albumin, steroids such as betamethasone, dexamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, budesonide, hydrocortisone, and pharmaceutically acceptable hydrocortisone derivatives; xanthines such as theophylline and doxophylline; beta-2- agonist bronchodilators such as salbutamol, fenterol, clenbuterol, bambuterol, salmeterol, fenoterol; antiinflammatory agents, including antiasthmatic anti-inflammatory agents, antiarthritis antiinflammatory agents, and non-steroidal antiinflammatory agents, examples of which include but are not limited to sulfides, mesalamine, budesonide, salazopyrin, diclofenac, pharmaceutically acceptable diclofenac salts, nimesulide, naproxene, acetaminophen,
  • steroids such as beta
  • Antihistamines include pyrilamine, chlorpheniramine, and tetrahydrazoline, among others.
  • Anti-inflammatory agents include corticosteroids, nonsteroidal anti-inflammatory drugs (e.g., aspirin, phenylbutazone, indomethacin, sulindac, tolmetin, ibuprofen, piroxicam, and fenamates), acetaminophen, phenacetin, gold salts, chloroquine, D-Penicillamine, methotrexate colchicine, allopurinol, probenecid, and sulfinpyrazone.
  • nonsteroidal anti-inflammatory drugs e.g., aspirin, phenylbutazone, indomethacin, sulindac, tolmetin, ibuprofen, piroxicam, and fenamates
  • acetaminophen phenacetin
  • gold salts chloroquine
  • Muscle relaxants include mephenesin, methocarbomal, cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, and biperiden.
  • Anti-spasmodics include atropine, scopolamine, oxyphenonium, and papaverine.
  • Analgesics include aspirin, phenybutazone, idomethacin, sulindac, tolmetic, ibuprofen, piroxicam, fenamates, acetaminophen, phenacetin, morphine sulfate, codeine sulfate, meperidine, nalorphine, opioids (e.g., codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide, morphine sulfate, noscapine, norcodeine, normorphine, thebaine, nor- binaltorphimine, buprenorphine, chlomaltrexamine, funaltrexamione, nalbuphine, nalorphine, naloxone, naloxonazine, naltrexone, and naltrindole), procaine, lidocain, tetracaine and dibucaine
  • Ophthalmic agents include sodium fluorescein, rose bengal, methacholine, adrenaline, cocaine, atropine, alpha-chymotrypsin, hyaluronidase, betaxalol, pilocarpine, timolol, timolol salts, and combinations thereof.
  • Prostaglandins are art recognized and are a class of naturally occurring chemically related long-chain hydroxy fatty acids that have a variety of biological effects.
  • Anti-depressants are substances capable of preventing or relieving depression.
  • Trophic factors are factors whose continued presence improves the viability or longevity of a cell trophic factors include, without limitation, platelet-derived growth factor (PDGP), neutrophilactivating protein, monocyte chemoattractant protein, macrophage- inflammatory protein, platelet factor, platelet basic protein, and melanoma growth stimulating activity; epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet- derived endothelial cell growth factor, insulin-like growth factor, glial derived growth neurotrophic factor, ciliary neurotrophic factor, nerve growth factor, bone growth/cartilage- inducing factor (alpha and beta), bone morphogenetic proteins, interleukins (e.g., interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10), interferons (e.g., interferon alpha, beta and gamma), hematopoietic factors, including erythropoietin,
  • Hormones are commonly employed in hormone replacement therapy and / or for purposes of birth control. Steroid hormones, such as prednisone, are also used as immunosuppressants and anti-inflammatories.
  • the additive is an agent that stimulates tissue formation, and/or healing and regrowth of natural tissues, and any combinations thereof.
  • Agents that increase formation of new tissues and/or stimulates healing or regrowth of native tissue at the site of injection can include, but are not limited to, fibroblast growth factor (FGF), transforming growth factor-beta (TGF-beta, platelet-derived growth factor (PDGF), epidermal growth factors (EGFs), connective tissue activated peptides (CTAPs), osteogenic factors including bone morphogenic proteins, heparin, angiotensin II (A-II) and fragments thereof, insulin-like growth factors, tumor necrosis factors, interleukins, colony stimulating factors, erythropoietin, nerve growth factors, interferons, biologically active analogs, fragments, and derivatives of such growth factors, and any combinations thereof.
  • FGF fibroblast growth factor
  • TGF-beta transforming growth factor-beta
  • PDGF platelet-derived growth factor
  • EGFs epidermal growth factors
  • CTAPs connective tissue activated peptides
  • osteogenic factors
  • the silk composition can further comprise at least one additional material for soft tissue augmentation, e.g., dermal filler materials, including, but not limited to, poly(methyl methacrylate) microspheres, hydroxylapatite, poly(L-lactic acid), collagen, elastin, and glycosaminoglycans, hyaluronic acid, commercial dermal filler products such as BOTOX® (from Allergan), DYSPORT®, COSMODERM®, EVOLENCE®, RADIESSE®,RESTYLANE®, JUVEDERM® (from Allergan), SCULPTRA®, PERLANE®, and CAPTIQEIE®, and any combinations thereof.
  • dermal filler materials including, but not limited to, poly(methyl methacrylate) microspheres, hydroxylapatite, poly(L-lactic acid), collagen, elastin, and glycosaminoglycans, hyaluronic acid, commercial dermal filler products such as BOTOX® (from
  • the additive is a wound healing agent.
  • a wound healing agent is a compound or composition that actively promotes wound healing process.
  • Exemplary wound healing agents include, but are not limited to dexpanthenol; growth factors; enzymes, hormones; povidon-iodide; fatty acids; anti-inflammatory agents; antibiotics; antimicrobials; antiseptics; cytokines; thrombin; angalgesics; opioids; aminoxyls; furoxans; nitrosothiols; nitrates and anthocyanins; nucleosides, such as adenosine; and nucleotides, such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP); neutotransmitter/neuromodulators, such as acetylcholine and 5 -hydroxy tryptamine (serotonin/5- HT); histamine and catecholamines, such as adrenalin and noradrenalin; lipid molecules, such as 5 sphingosine- 1 -phosphate and lysophosphatidic acid;
  • the active agents provided herein are immunogens.
  • the immunogen is a vaccine.
  • Most vaccines are sensitive to environmental conditions under which they are stored and/or transported. For example, freezing may increase reactogenicity (e.g., capability of causing an immunological reaction) and/or loss of potency for some vaccines (e.g., HepB, and DTaP/IPV/FQB), or cause hairline cracks in the container, leading to contamination. Further, some vaccines (e.g., BCG, Varicella, and MMR) are sensitive to heat.
  • compositions and methods provided herein also provide for stabilization of vaccines regardless of the cold chain and/or other environmental conditions.
  • the additive is a cell, e.g., a biological cell.
  • Cells useful for incorporation into the composition can come from any source, e.g., mammalian, insect, plant, etc.
  • the cell can be a human, rat or mouse cell.
  • cells to be used with the compositions provided herein can be any types of cells.
  • the cells should be viable when encapsulated within compositions.
  • cells that can be used with the composition include, but are not limited to, mammalian cells (e.g.
  • exemplary cells that can be used with the compositions include platelets, activated platelets, stem cells, totipotent cells, pluripotent cells, and/or embryonic stem cells.
  • exemplary cells that can be encapsulated within compositions include, but are not limited to, primary cells and/or cell lines from any tissue.
  • cardiomyocytes myocytes, hepatocytes, keratinocytes, melanocytes, neurons, astrocytes, embryonic stem cells, adult stem cells, hematopoietic stem cells, hematopoietic cells (e.g. monocytes, neutrophils, macrophages, etc.), ameloblasts, fibroblasts, chondrocytes, osteoblasts, osteoclasts, neurons, sperm cells, egg cells, liver cells, epithelial cells from lung, epithelial cells from gut, epithelial cells from intestine, liver, epithelial cells from skin, etc., and/or hybrids thereof, can be included in the silk/platelet compositions disclosed herein.
  • Cells listed herein represent an exemplary, not comprehensive, list of cells.
  • Cells can be obtained from donors (allogenic) or from recipients (autologous). Cells can be obtained, as a non-limiting example, by biopsy or other surgical means known to those skilled in the art.
  • Differentiated cells that have been reprogrammed into stem cells can also be used.
  • human skin cells reprogrammed into embryonic stem cells by the transduction of Oct3/4, Sox2, c-Myc and Klf4 (Junying Yu, et. ah, Science, 2007, 318 , 1917-1920 and Takahashi K. et. ah, Cell, 2007, 131 , 1-12).
  • the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.”
  • the terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims.
  • the terms “consist” and “consisting of’ should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims.
  • the term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.
  • needles should be maximally loaded throughout the needle to increase the intensity of colorimetric readouts for accurate quantification.
  • This is controlled by incorporating chromophore-loaded SNPs in the silk solution used to create the microneedle arrays (which upon centrifugation of the silk solution and the SNPs into the microneedle mold would cause the SNPs to pellet to the tips of the needles (Fig 1A, Fig. 1C ), or by incorporating the chromophore in the silk solution itself, with blank, unloaded SNPs used as just a structural component (Fig IB, Fig. 1G, and Fig. 1 J).
  • SNPs which are included for either chromophores to be loaded into and/or for structural integrity
  • silk solution tend to become more gel-like. This can cause needle deformation as well as nonuniform loading of hydrogel-like chromophore aggregates within the MNs.
  • i) the order in which the stock silk solution used to form the MNs is added ii) the DMSO content; and iii) the temperature at which the MNs are dried after centrifugation.
  • ambient processing conditions, a 5% DMSO content, and order #7 in Table 1 resulted in reproducibly uniform needles as shown in Fig. 1.
  • Table 1 Addition of silk solution components prior to casting into MNs, performed with all components scaled down to 25% of their original quantities to conserve materials. Parenthesis denote order of addition. Original volumes were decided based on: 5% DMSO content (10 mg/mL chromophore stock soln), 2 mg of SNPs, 7% silk (diluted from 10% silk, with volumes of other components accounted for to bring the solution to 7% silk).
  • Silk fibroin were isolated from Bombyx mori cocoons as previously described (Yavuz B,engage L, Harrington K, Kluge J, Valenti L, Kaplan DL. Silk Fibroin Microneedle Patches for the Sustained Release of Levonorgestrel. ACS Applied Bio Materials. 2020;3(8):5375-82. doi: 10.1021/acsabm.0c0067). Briefly, B. mori cocoons (Tajima Shoji Co., Japan) were boiled in a 0.02 M sodium carbonate solution for 30 minutes to remove sericin.
  • Nanoprecipitated silk nanoparticles were prepared as previously described, with modifications (Xiao L, Lu G, Lu Q, Kaplan DL. Direct Formation of Silk Nanoparticles for Drug Delivery. ACS Biomaterials Science & Engineering. 2016;2(l l):2050-7. doi: 10.1021/acsbiomaterials.6b00457). Briefly, a 5-6% w/v silk solution was added dropwise to acetone to generate a turbid solution that is >75% v/v acetone using a 60 nil addition funnel (Fisherscientific CG170401), while stirring (200 rpm, Cole Palmer UX-84003-80) in a 20 mL scintillation vial.
  • the nanoparticle solution was stirred for >3 hours to evaporate the acetone. Once evaporated, the nanoparticle solution was sonicated with a Branson Ultrasonic Cell Disruptor for 30 seconds at 30% amplitude to yield particles of -150 nm, confirmed using dynamic light scattering (DLS).
  • DLS dynamic light scattering
  • Blank, unloaded particles were incorporated into microneedles to fortify the MNs, or particles were loaded with chromophore via coatings or pre-mixing the chromophore with the silk solution prior to conducting the nanoprecipitation protocol (entrapment), and then ultracentrifuged at -180,000 x G for 30 minutes at 4 °C to remove unbound chromophore, similar to drug loading methods previously published (Wongpinyochit T, Johnston BF, Seib FP. Manufacture and Drug Delivery Applications of Silk Nanoparticles. J Vis Exp. 2016(116). Epub 20161008. doi: 10.3791/54669. PubMed PMID: 27768078; PMCID: PMC5092179).
  • chromophore was dissolved in DMSO at a concentration of 10 mg/mL. Per 100 mg of silk solution needed for the nanoprecipitation process, 0.1, 0.5 or 1 mg of chromophore was added to the silk solution from the stock solution. After adding the chromophore to the silk, and ensuring proper mixing, the nanoprecipitation process was conducted.
  • MNs were prepared using poly(dimethylsiloxane) (PDMS) molds as previously described (Yavuz B,engage L, Harrington K, Kluge J, Valenti L, Kaplan DL. Silk Fibroin Microneedle Patches for the Sustained Release of Levonorgestrel. ACS Applied Bio Materials. 2020;3(8):5375- 82. doi: 10. 102 l/acsabm.0c00671). The molds were patterned with a 11 x 11 array of MNs, each MN with a 700 pm height, with a dose area of 1 cm 2 .
  • PDMS poly(dimethylsiloxane)
  • a stock solution of the chromophore dissolved in DMSO was added to the silk solution and accounted for in the total volume and concentration of the silk solution (2 mL and 7%, respectively).
  • the 50 mL tube, containing the insert, silk fibroin chromophore solution, and microneedle mold, was then centrifuged at 3,220 ref for 20 minutes (10 minutes 2x, reversing the direction of the tube in the centrifuge after 10 minutes) at 4 °C, to allow silk solution to fill the microneedle molds fully (Fig. 4).
  • microneedle molds were removed from the 3D printed insert and allowed to dry for 8 hours in ambient conditions in the dark, followed by another 8 hours of being placed in a vapor annealer (Fig. 4). This process crystallizes the silk to maintain insolubility in aqueous systems.
  • a backing was pipetted onto the mold, either using silk solution or another optically translucent material, and left to dry for 8 hours in ambient conditions.
  • extra silk solution loaded with or without chromophore could be vacuumed into the molds using the vapor annealer immediately following the centrifugation step and prior to the ambient drying step.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Nanotechnology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Physiology (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Manufacturing & Machinery (AREA)
  • Endocrinology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des capteurs à micro-aiguilles (MN) à base optique pour détecter des analytes dans un fluide interstitiel dermique d'une manière mini-invasive. Par rapport aux stratégies de MN électrochimiques, la détection optique est largement inexplorée mais présente de nombreux avantages potentiels, notamment une durée de conservation améliorée, l'évitement d'une dérive, l'impact réduit de l'encrassement biologique, et un facteur de forme réduit lorsqu'il n'est pas en utilisation active. Cette stratégie évite également les défis considérables associés à la fois aux capteurs optiques implantables et aux capteurs qui utilisent un effet de mèche/la collecte de fluide interstitiel cutané pour analyse en aval.
PCT/US2024/062043 2023-12-27 2024-12-27 Capteurs à micro-aiguilles de soie optique transdermique pour surveillance continue d'analytes physiologiques dans un fluide interstitiel Pending WO2025144993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363615081P 2023-12-27 2023-12-27
US63/615,081 2023-12-27

Publications (1)

Publication Number Publication Date
WO2025144993A1 true WO2025144993A1 (fr) 2025-07-03

Family

ID=96219796

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/062043 Pending WO2025144993A1 (fr) 2023-12-27 2024-12-27 Capteurs à micro-aiguilles de soie optique transdermique pour surveillance continue d'analytes physiologiques dans un fluide interstitiel

Country Status (1)

Country Link
WO (1) WO2025144993A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102344686A (zh) * 2011-08-02 2012-02-08 北京汇亨创管理咨询有限公司 一种以聚乙烯醇为稳定剂的丝素蛋白纳米颗粒的制备方法
US20200171290A1 (en) * 2017-08-11 2020-06-04 Lts Lohmann Therapie-Systeme Ag Micro-needle array comprising a color change indicator
US20210244850A1 (en) * 2011-11-09 2021-08-12 Trustees Of Tufts College Injectable silk fibroin particles and uses thereof
US20210290829A1 (en) * 2010-10-19 2021-09-23 Trustees Of Tufts College Silk fibroin-based microneedles and methods of making the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210290829A1 (en) * 2010-10-19 2021-09-23 Trustees Of Tufts College Silk fibroin-based microneedles and methods of making the same
CN102344686A (zh) * 2011-08-02 2012-02-08 北京汇亨创管理咨询有限公司 一种以聚乙烯醇为稳定剂的丝素蛋白纳米颗粒的制备方法
US20210244850A1 (en) * 2011-11-09 2021-08-12 Trustees Of Tufts College Injectable silk fibroin particles and uses thereof
US20200171290A1 (en) * 2017-08-11 2020-06-04 Lts Lohmann Therapie-Systeme Ag Micro-needle array comprising a color change indicator

Similar Documents

Publication Publication Date Title
US20240082405A1 (en) Low Molecular Weight Silk Compositions and Stabilizing Silk Compositions
Battisti et al. Non-invasive production of multi-compartmental biodegradable polymer microneedles for controlled intradermal drug release of labile molecules
Zhao et al. An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery
Yin et al. Design of genipin-crosslinked microgels from concanavalin A and glucosyloxyethyl acrylated chitosan for glucose-responsive insulin delivery
Yin et al. Engineering synthetic artificial pancreas using chitosan hydrogels integrated with glucose-responsive microspheres for insulin delivery
US11376329B2 (en) Low molecular weight silk compositions and stabilizing silk compositions
Ding et al. Squid suckerin microneedle arrays for tunable drug release
Zheng et al. Incorporation of quantum dots into silk biomaterials for fluorescence imaging
US20210155812A1 (en) Silk ink compositions and methods of making and using the same
Jayant et al. In vitro and in vivo evaluation of anti-inflammatory agents using nanoengineered alginate carriers: Towards localized implant inflammation suppression
Srivastava et al. “Smart tattoo” glucose biosensors and effect of coencapsulated anti-inflammatory agents
WO2025144993A1 (fr) Capteurs à micro-aiguilles de soie optique transdermique pour surveillance continue d'analytes physiologiques dans un fluide interstitiel
Shkand et al. Assessment of alginate hydrogel degradation in biological tissue using viscosity-sensitive fluorescent dyes
WO2024158919A2 (fr) Bioplastiques en soie et leur procédé de production
US20250325495A1 (en) Silk nanoparticle synthesis: tuning size, dispersity, and surface chemistry for drug delivery
WO2025054426A1 (fr) Films comestibles à image holographique transférable et procédés associés
WO2024254604A1 (fr) Modele intestinal in vitro utilisant des analogues de mucine
WO2025193717A1 (fr) Assemblage de biopolymères provoqué par le son
WO2025155859A1 (fr) Matériaux à base de soie réticulée double pour dépôt ou impression in situ
WO2024145272A1 (fr) Support osseux modulaire
WO2025259801A2 (fr) Fabrication additive (fa) par dépôt pour crèmes fouettées à base de soie
WO2025231379A1 (fr) Adhésifs de coacervat à l'état solide et leurs procédés de fabrication et d'utilisation
WO2025091012A1 (fr) Cuir de soie amélioré et ses procédés de fabrication et d'utilisation
WO2024259420A2 (fr) Systèmes et procédés de bioimpression à sec avec des biopolymères
WO2025007132A2 (fr) Articles moulés par centrifugation et procédés

Legal Events

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

Ref document number: 24914342

Country of ref document: EP

Kind code of ref document: A1