WO2012085609A1 - Traitement de l'ostéoarthrite par injection intra-articulaire continue de gel alginate - Google Patents

Traitement de l'ostéoarthrite par injection intra-articulaire continue de gel alginate Download PDF

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Publication number
WO2012085609A1
WO2012085609A1 PCT/IB2010/003303 IB2010003303W WO2012085609A1 WO 2012085609 A1 WO2012085609 A1 WO 2012085609A1 IB 2010003303 W IB2010003303 W IB 2010003303W WO 2012085609 A1 WO2012085609 A1 WO 2012085609A1
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WO
WIPO (PCT)
Prior art keywords
alginate
alginate gel
gel
osteoarthritis
treatment
Prior art date
Application number
PCT/IB2010/003303
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English (en)
Inventor
Abbas Mirshafiey
Original Assignee
Dept. Of Pathobiology
Dorkoosh, Farid, Abedin
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 Dept. Of Pathobiology, Dorkoosh, Farid, Abedin filed Critical Dept. Of Pathobiology
Priority to PCT/IB2010/003303 priority Critical patent/WO2012085609A1/fr
Publication of WO2012085609A1 publication Critical patent/WO2012085609A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A61L27/3843—Connective tissue
    • A61L27/3852—Cartilage, e.g. meniscus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/10—Materials for lubricating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

Definitions

  • the embodiments herein generally relate to a method of treating osteoarthritis using a viscoelastic material.
  • the embodiments herein more particularly relate to a novel protocol for treating osteoarthritis by continuous injections of the viscoelastic material into the osteoarthritic joint.
  • Osteoarthritis also known as osteoarthrosis
  • osteoarthrosis is a chronic and progressive degenerative joint disease which is associated with significant pain and disability. It is established by a complex process involving mechanical and biological alterations of the musculoskeletal system which are generated by a great variety of interactions between genetic factors and extrinsic injuries.
  • the pathogenesis of OA is related to an increased and divergent production of inflammatory mediators and proteolytic enzymes that promote the degradation and destruction of the extracellular matrix of articular and periarticular tissues (Wells et al., 2005; Brizuela et al., 2008).
  • the capacities of synovial fluids in lubrication and in shock absorption are typically reduced.
  • hyaluronic acid hyaluronan
  • the conventional therapy for treating osteoarthritis is based on improvement in the factional function of joints and pain relief in order to delay the time for surgery intervention.
  • a new therapeutic approach to OA, especially osteoarthritis of the knee is to inject hyaluronan or its derivatives such as, sodium hyaluronate (Hyalgan and Supartz) and hylan G-F 20 (Synvisc) as viscosupplement into the joint (Hammesfahr et al., 2003; van den Bekerom et al., 2008).
  • hyaluronan or its derivatives such as, sodium hyaluronate (Hyalgan and Supartz) and hylan G-F 20 (Synvisc) as viscosupplement into the joint (Hammesfahr et al., 2003; van den Bekerom et al., 2008).
  • hyaluronan preparations is a popular treatment for osteoarthritis of the knee however the clinical reports have recently described acute inflammatory reactions in joints following these injections (Ottaviani et al., 2007).
  • Alginates are natural copolymers comprising of ⁇ -D-mannuronate (M-block) and a-L-guluronate (G-block) linked by 1 ⁇ 4 glycosidic linkages. Alginates are synthesized by bacteria belonging to the genera Pseudomonas and Azotobacter and brown sea-weeds, and the M-residues of the bacterial, but not sea-weed polymers, are to a variable extent acetylated at positions 0-2 and/or 0-3 (Skjak-Braek et al., 1986; Bucke, 1987; Rehm, 1998).
  • alginate gels are well known as biocompatible, degradable and nontoxic.
  • alginic acid has anti-anaphy lactic effects and inhibits inflammatory cytokine expression via suppression of nuclear factor- kappa B activation (Jeong et al., 2006).
  • kits and compositions for producing an alginate gel were disclosed and filed under the title of "Self- gelling alginate systems and uses thereof (United States patent, US 2006/0159823 Al).
  • a method of modifying salts of alginic acid in situ for preventing adhesions in situ between tissues after surgery comprising the steps of: injecting a water soluble alginate into the intra-articular space prior to or after closing the surgical site and injecting a complexing solution of water soluble cations into said intra-articular space was filed, entitled “In situ modification of alginate” (United States patent, US005266326A).
  • the primary object of the embodiments herein is to provide a novel therapeutic protocol for treatment of osteoarthritis using the continuous intra-articular injections of an alginate gel.
  • Another object of embodiments herein is to provide a method which can alleviate the degenerative process of articular cartilage in osteoarthritis.
  • Yet another object of the embodiments herein is to provide a method which leads to an improvement in the movement of joints thereby reducing swelling and relieving pain.
  • Yet another object of the embodiments herein is to provide a safe and non-toxic method of treatment of osteoarthritis.
  • Yet another object of the embodiments herein is to provide a viscoelastic material with anti-inflammatory properties for the treatment of osteoarthritis.
  • the various embodiments herein provide a method of treatment of osteoarthritis comprising of injecting a preset amount of alginate gel continuously into a joint of a subject for a preset period.
  • the preset period is atleast six months and the alginate gel is injected 3-5 times per week continuously for the atleast six months.
  • the alginate gel is selected from a group comprising of alginic acid, sodium alginate, potassium alginate, magnesium alginate, calcium alginate and combinations thereof.
  • the preset amount of the alginate gel to be injected to the subject is 40mg/2ml/syringe.
  • the alginate gel has a molecular weight of 20 to 240 KDa.
  • the alginate gel has a preferred molecular weight of more than 200 KDa.
  • the alginate gel has a concentration of 0.5% w/v to 3% w/v in an aqueous solution.
  • the alginate gel has a preferred concentration of 2% w/v.
  • the alginate gel has a viscosity of 20 to 200 mPa.s.
  • the alginate gel preferably has a viscosity of 200 mPa.s.
  • the alginate gel has a pH of 4 to 10.
  • the alginate gel has a preferred pH of 7.2.
  • the alginate gel is injected intra-articularly.
  • a method of treatment of osteoarthritis comprises injecting a preset amount of alginate solution continuously into a joint of a subject for a preset period; wherein the preset period is atleast six months and wherein the alginate solution is injected 3-5 times per week continuously for the atleast six months.
  • the embodiments herein provide a new method of treatment of osteoarthritis involves continuously injecting a composition containing a therapeutically effective amount of alginate gel or solution into a joint of a subject in need thereof.
  • the alginate is selected from a group consisting of alginic acid, sodium alginate, potassium alginate, magnesium alginate, calcium alginate and combinations thereof.
  • the alginate has a molecular weight spectrum of 20 to 240 KDa, wherein the preferred molecular weight for getting more therapeutic efficacy is more than 200 KDa.
  • the concentration of alginate solution is in the range of 0.5% w/v to 3% w/v. More therapeutic effect is provided by the alginate solution in the concentration of 2% w/v.
  • a therapeutically effective amount of alginate gel to be given continuously for three to five times per week intra-articularly for at least six months or more is 40mg/2ml/lSyr, depending on the patient's clinical status.
  • the alginate gel has a viscosity in the range of 20 to 200 mPa.s, wherein the preferred viscosity is 200 mPa.s.
  • the pH of alginate gel is in a range of 4 to 10 wherein the preferred pH is 7.2.
  • the joint is any small and/or large osteoarthritic joint of the body of the patient in need thereof.
  • the embodiments herein provide a novel therapeutic protocol using continuous intra-articular injections of alginate gel as a new viscoelastic material with anti-inflammatory properties for treatment of osteoarthritis and joint pain relief.
  • the various embodiments herein provide a new method of treatment of osteoarthritis comprising continuously injecting into a joint of a subject in need thereof a composition containing a therapeutically effective amount of alginate gel or solution.
  • the alginate is selected from a group consisting of alginic acid, sodium alginate, potassium alginate, magnesium alginate, calcium alginate and combinations thereof.
  • the alginate with a molecular weight spectrum of 20-240 KDa can be used for preparing the alginate gel wherein the preferred molecular weight for more therapeutic efficacy in osteoarthritis (OA) is >200 KDa.
  • the viscosity of alginate gel for administration in osteoarthritis can be in a complete range of minimum to maximum of ⁇ 20 to >200 mPa.s and the optimum viscosity for more therapeutic effect in OA is the viscosity >200 mPa.s.
  • the effective concentration of the alginate gel to be injected for getting the more therapeutic effect in OA is 2% w/v aqueous solution of alginate.
  • a range of aqueous solution of alginate with concentration of about 0.5% to about 3% w/v of alginate can be used for treating the osteoarthritis.
  • the optimum dose of 40mg/2ml/lSyr of alginate gel given intra-articularly is considered effective for treating osteoarthritis.
  • the dose is to be given continuously for atleast three to five times per week for at least six months depending on the patient's clinical status.
  • the total number of intra-articular injection can be varied on the basis of clinical status of patients.
  • the alginate gel can be prepared at pH range of 4 to 10 with optimum pH of 7.2 for getting more therapeutic effect in OA.
  • the joint is any small and/or large osteoarthritic joint of the patient.
  • a pyrogen- free sterile alginate gel was prepared using sodium alginate solution (2%) with a medium viscosity of approximately 3500 cP keeping the temperature at 25°C [A2033, Sigma- Aldrich. Com].
  • To induce the experimental model of osteoarthritis sixty mature New Zealand white rabbits were used. They were randomly divided into various groups A, B and C (20 per group). Ten were selected for histopathology assessment and ten for PCR analysis.
  • mice in group B were given 0.3 ml of intra-articularl% sodium hyaluronate (HA) injection and group C was given the same volume of 2% sodium alginate solution, once a week for 5 weeks.
  • Group A was considered as control (patient) group.
  • the animals were checked daily for activity, body weight, food consumption, rectal temperature and wound healing in the first postoperative week.
  • the macroscopic osteoarthritic lesions included osteophytes, cartilage erosion (ulceration and fissures) and loss of cartilage luster (softening and fibrillation).
  • the evaluation of these lesions was based on the following three macroscopic parameters: the location, the type and the size of the osteoarthritic changes.
  • the histological sections were performed in the above- mentioned sites and were stained with haematoxyline/eosin (H/E) and saffranin.
  • the following four histological parameters were taken into consideration: the morphology of the articular cartilage, the morphology of the subchondral bone, the thickness of the cartilage by comparing the normal and the affected sites and the arrangement of chondrocytes into the hyaline cartilage.
  • the first two microscopic parameters were indicative of degeneration.
  • MMP-2 Matrix Metalloproteinase Type 2
  • MMPs Matrix metalloproteinases
  • MMPs are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand) and chemokine/cytokine in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis and host defense.
  • VEGF Vascular Endothelial Growth Factor
  • alginate could inhibit the expression of MMP-1 in cartilage whereas hyaluronic acid has no effect on it. None of alginate and hyaluronic acid has effect on the expression of MMP-3 in cartilage.
  • Alginate can enhance TIMP-1 expression in cartilage whereas hyaluronic acid has no effect on it. None of alginate and hyaluronic acid had effect on TIMP-2 expression in cartilage. None of alginate and hyaluronic acid had effect on the expression of VEGF in cartilage indicating that alginate has no effect on angiogenesis process as one of the important parameters in inflammation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les différents modes de réalisation de la présente invention concernent une nouvelle méthode de traitement de l'ostéoarthrite comprenant l'injection continue d'une composition contenant une quantité thérapeutiquement efficace de gel alginate ou de solution d'alginate dans une articulation d'un sujet en ayant besoin. L'alginate est choisi dans un groupe comprenant l'acide alginique, l'alginate de sodium, l'alginate de potassium, l'alginate de magnésium, l'alginate de calcium et leurs combinaisons. Le gel alginate est injecté 3-5 fois par semaine en continu pour les au moins six mois. La quantité préfixée du gel alginate à injecter dans le sujet est de 40 mg/2 ml/seringue en fonction de l'état clinique du patient.
PCT/IB2010/003303 2010-12-20 2010-12-20 Traitement de l'ostéoarthrite par injection intra-articulaire continue de gel alginate WO2012085609A1 (fr)

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PCT/IB2010/003303 WO2012085609A1 (fr) 2010-12-20 2010-12-20 Traitement de l'ostéoarthrite par injection intra-articulaire continue de gel alginate

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11406612B2 (en) 2018-02-26 2022-08-09 Rensselaer Polytechnic Institute Method of treatment via intra-articular application of potassium

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB189611538A (en) 1896-05-27 1896-08-29 Axel Krefting An Improved Method of Treating Sea Weed to Obtain Valuable Products therefrom.
JPS57167919A (en) 1981-04-07 1982-10-16 Hirozo Ohira Preventing agent for intraperitoneal adhesion
EP0251905A2 (fr) 1986-06-30 1988-01-07 FIDIA S.p.A. Esters d'acide alginique
US20050266326A1 (en) 2004-02-17 2005-12-01 Xerox Corporation Electrophotographic imaging members
US20060159823A1 (en) 2004-10-12 2006-07-20 Jan-Egil Melvik Self-gelling alginate systems and uses thereof
EP2127687A1 (fr) * 2007-02-21 2009-12-02 Mochida Pharmaceutical Co., Ltd. Composition pour le traitement d'une maladie de cartilage
EP2210621A1 (fr) * 2007-10-24 2010-07-28 Mochida Pharmaceutical Co., Ltd. Composition pour le traitement d'une affection articulaire

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB189611538A (en) 1896-05-27 1896-08-29 Axel Krefting An Improved Method of Treating Sea Weed to Obtain Valuable Products therefrom.
JPS57167919A (en) 1981-04-07 1982-10-16 Hirozo Ohira Preventing agent for intraperitoneal adhesion
EP0251905A2 (fr) 1986-06-30 1988-01-07 FIDIA S.p.A. Esters d'acide alginique
US20050266326A1 (en) 2004-02-17 2005-12-01 Xerox Corporation Electrophotographic imaging members
US20060159823A1 (en) 2004-10-12 2006-07-20 Jan-Egil Melvik Self-gelling alginate systems and uses thereof
EP2127687A1 (fr) * 2007-02-21 2009-12-02 Mochida Pharmaceutical Co., Ltd. Composition pour le traitement d'une maladie de cartilage
EP2210621A1 (fr) * 2007-10-24 2010-07-28 Mochida Pharmaceutical Co., Ltd. Composition pour le traitement d'une affection articulaire

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11406612B2 (en) 2018-02-26 2022-08-09 Rensselaer Polytechnic Institute Method of treatment via intra-articular application of potassium

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