WO2020016476A1 - Matière injectable pour la régénération du cartilage articulaire - Google Patents

Matière injectable pour la régénération du cartilage articulaire Download PDF

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Publication number
WO2020016476A1
WO2020016476A1 PCT/ES2019/070505 ES2019070505W WO2020016476A1 WO 2020016476 A1 WO2020016476 A1 WO 2020016476A1 ES 2019070505 W ES2019070505 W ES 2019070505W WO 2020016476 A1 WO2020016476 A1 WO 2020016476A1
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WO
WIPO (PCT)
Prior art keywords
microspheres
prp
injectable material
material according
preparing
Prior art date
Application number
PCT/ES2019/070505
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English (en)
Spanish (es)
Inventor
José Luis GÓMEZ RIBELLES
Gloria GALLEGO FERRER
Carmen ANTOLINOS TURPÍN
María SANCHO-TELLO VALLS
Carmen CARDA BATALLA
Original Assignee
Universitat Politècnica De València
Fundación Incliva
Universitat De València
Consorcio Centro de Investigación Biomédica en Red, M.P.
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Application filed by Universitat Politècnica De València, Fundación Incliva, Universitat De València, Consorcio Centro de Investigación Biomédica en Red, M.P. filed Critical Universitat Politècnica De València
Publication of WO2020016476A1 publication Critical patent/WO2020016476A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • 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
    • 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
    • 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
    • A61L27/58—Materials at least partially resorbable by the body

Definitions

  • the present invention falls within the biomedical and pharmaceutical sector, more specifically, in the field of tissue regeneration, and refers to an injectable material whose implantation in the place of a cartilage defect can be combined with a technique of stimulation of the subchondral bone
  • articular cartilage pathologies are one of the main causes of disability in the elderly.
  • various subchondral bone stimulation techniques are used. These surgical techniques are based on damaging, by different procedures, the bone below the site of damage to the cartilage so that bleeding occurs that opens the way to the migration of pluripotential, mesenchymal cells, with the ability to produce new cartilaginous tissue .
  • the tissue formed does not have the structure or properties of articular cartilage (hyaline cartilage) but is more like fibrocartilage, softer, which is not functional and degenerates over time.
  • One of the reasons why the cells that reach the defect site are not able to generate the correct tissue is that the biomechanical environment they find is not adequate.
  • Different implants have been developed that are intended to protect the cells and make the dynamic compression loads to which the joint is subjected to transfer to the cells in a similar way as in healthy tissue.
  • Platelet rich plasma is a product currently used in regenerative therapies. It is obtained from an extraction of the patient's own blood, which by centrifugation is separated into different components usually used in the clinic. In the lower part of the centrifuge tube the phase rich in red blood cells is obtained and on it a layer that contains the blood plasma where most of the platelets remain and which has been called in the scientific literature and in the clinical application rich plasma in platelets or PRP. On it are different layers of blood plasma with lower platelet content and is called “platelet poor plasma” or PPP. Both PRP and PPP coagulate in the presence of calcium ions, to form a gel Fortier et al.
  • biocompatible materials are disclosed in WO2013116791 A1, which describes a composition comprising a synthetic and biodegradable biomaterial, and a blood extract.
  • the biomaterial can be a polymer and also comprises a hydrogel.
  • the blood extract can be platelet rich plasma.
  • This composition is used in the treatment of skin wounds, osteoarthritis, heart muscle damage, bone defects, traumatic and dental damage.
  • Document W00200272A2 also refers to a polymeric gel composition that, mixed with whole blood, promotes the regeneration of tissues such as cartilage, meniscus, ligament or tendon among others.
  • W02006023803A2 discloses an implant formed by the combination of microparticles of a polymer as polylactic acid and an autologous component of the patient as blood plasma. This implant can be used to repair articular cartilage by injection.
  • document W02011150328A1 describes a matrix that promotes cell growth, formed by a biodegradable polymer together with a physiological solution that can be platelet rich plasma.
  • Gelatin Hydrogel Prepared by Photo-initiated Polymerization and Loaded with TGF-bI for Cartilage Tissue Engineering, Macromolecular Bioscience 2009: 9 (12): 1194-201; Oss- Ronen and Seliktar, Polymer-conjugated Albumin and Fibrinogen Composite Hydrogels as Cell Scaffolds Designed for Affinity-based Drug Delivery, Acta Biomaterialia 2011; 7 (1): 163-70; Dikovsky et al. The effect of Structural Alterations of PEG-fibrinogen Hydrogel Hcaffolds on 3-D Cellular Morphology and Cellular Migration, Biomaterials 2006; 27 (8): 1496-506). In the document Pradhan et al.
  • the present invention relates to an injectable material comprising a mixture of synthetic microspheres and platelet-rich blood plasma microspheres for the regeneration of cartilaginous tissue.
  • the presence of plasma microspheres rich in platelets and microspheres of a biodegradable synthetic polymer facilitates the penetration of stem cells from the microfracture of the subchondral bone, which can make their way between the support microspheres, something that does not occur when the components are not in the form of microspheres, but as a gel, since it cannot be penetrated by the cells until they degrade it.
  • platelet-rich plasma or PRP refers to blood plasma samples with platelet concentrations of double or more than the basal levels that on average supposes 5 x 10 5 or more platelets / pL (platelets per microliter ).
  • platelet poor plasma or PPP refers to blood plasma samples with a lower concentration of platelets than platelet rich plasma.
  • support microspheres refers to the injectable material, that is, the mixture of platelet rich plasma microspheres and synthetic microspheres.
  • a first aspect of the present invention relates to an injectable material comprising a mixture of:
  • microspheres of a biodegradable polymer - synthetic microspheres -
  • the synthetic microspheres are composed of at least one bio-absorbable polymer:
  • the synthetic microspheres comprise a polymer selected from polylactic acid, polylactic and polyglycolic acid copolymers, polycaprolactone, polyhydroxybutyrate, polyhydroxivalerate, copolymers of the two above, polypeptides, biodegradable polyanhydrides, biodegradable polyurethanes, chitosan, alginate, chondroitin sulfate, hyaluronic acid, starch, dextran and, gelatin, collagen, biodegradable derivatives of cellulose, fibrin, fibrinogen and mixtures of microspheres of several of the above materials.
  • synthetic microspheres are manufactured by emulsion or microfluidic using methods that have been published in the scientific literature (De la Vega et al. (Uniform polymer microspheres: monodispersity criteria, methods of formation and applications, Nanomedicine 2013 : Vol 8, pp 265-285); DL Elbert, Liquid-liquid two-phase systems for the production of porous hydrogels and hydrogel microspheres for biomedical applications: A tutorial review, Acta Biomaterialia 2011: Vol 7 pp31-56) and M Anindita , P Vilkas, (Drug delivery: Techniques for polymeric microsphere preparation, Research Journal of Biotechnology 2007: Vol 2 pp 58-63)) and are sterilized by the most appropriate method for each material, for example, gamma ray irradiation.
  • the volume ratio of synthetic microspheres to PRP microspheres is between 0.1 and 80%, more preferably it is in a range between 0.2 and 70%.
  • Another aspect of the present invention relates to a process for preparing the injectable material defined above, which comprises the following steps:
  • obtaining the PRP microspheres comprises: a) centrifuging blood taken from a patient,
  • the process for preparing the injectable material may comprise: d) extracting the PRP microspheres by removing the oily medium by adding a saline medium and centrifuging to separate the aqueous phase containing the PRP microspheres from the oily one,
  • the PRP microspheres obtained in step c) have diameters between 30 and 400 microns, more preferably between 50 and 200 microns.
  • the saline medium used in step d) is a phosphate buffered saline, PBS (an aqueous saline solution containing sodium chloride, sodium phosphate, potassium chloride, potassium phosphate).
  • PBS an aqueous saline solution containing sodium chloride, sodium phosphate, potassium chloride, potassium phosphate.
  • step c) the PRP microspheres can be formed with platelet activation.
  • the PRP microspheres in step c), can be formed without platelet activation.
  • step c) the formation of PRP microspheres with platelet activation in step c) comprises the following steps:
  • step b) an aqueous solution of a calcium salt, or an aqueous solution of a mixture of the calcium salt and a fibrinogen coagulant enzyme, capable of inducing platelet activation to initiate coagulation of the fibrinogen contained in the plasma and allow the mixture obtained to drip in an oily medium,
  • the salt used is calcium chloride.
  • the enzyme used is thrombin.
  • the oily medium is selected from a mineral oil and a vegetable oil.
  • the mineral oil can be a paraffinic oil, a naphthenic oil, an aromatic oil or a silicone oil.
  • Vegetable oil can be olive, sunflower, soy or corn oil.
  • the formation of PRP microspheres without platelet activation in step c) further comprises obtaining a hydrogel from a precursor of said hydrogel by chemical or enzymatic means.
  • the growth factors they contain are not released before implanting them at the site of regeneration, which could cause them to be lost, in part, during process.
  • the PRP is mixed with a precursor of a hydrogel and the microspheres are formed by a chemical or enzymatic reaction of the hydrogel that does not alter the viability of the PRP platelets. In this way, the PRP is retained in the microspheres containing all its components.
  • the hydrogel precursor may be hyaluronic acid, gelatin, fibrinogen, chondroitin sulfate, dextran or the PPP extracted in step b).
  • the formation of the hydrogel by chemical means comprises the following steps:
  • the oily medium in which the emulsion is formed can be a mineral oil (paraffinic oil, a naphthenic oil, an aromatic oil or a silicone oil), or a vegetable oil (olive, sunflower, soy or corn oil).
  • the formation of the hydrogel via enzymatic comprises the following steps:
  • the preparation of the solution of a hydrogel precursor with tyramine can be carried out following the method described in the document Poveda-Reyes et al. (Reinforcing an Injectable Gelatin Hydrogel with PLLA Microfibers: Two Routes for Short Fiber Production, Macromolecular Materials and Engineering 2015; 300 (10): 977-88);
  • the hydrogel precursor solution comprises tyramine modified macromolecules that are selected from tyramine conjugates of: gelatin, hyaluronic acid, chondroitin sulfate, dextane and mixture thereof.
  • the PRP microspheres Before mixing the PRP microspheres and synthetic microspheres, the PRP microspheres can be cryopreserved. Prior to mixing both microspheres (synthetic and biodegradable), a process of thawing said cryopreserved PRP microspheres is necessary.
  • the process further comprises the following steps after obtaining the PRP microspheres in saline medium, after step e):
  • step b) transfer the PRP microspheres to a dimethylsulfoxide solution and the PPP obtained in step b) and freeze the obtained microsphere suspension in liquid nitrogen to cryopreserve until later use,
  • the PRP microspheres are transferred to a solution of dimethylsulfoxide and the PPP obtained in step b) in which the latter is present in up to 10%, and is frozen in liquid nitrogen, inside cryotubes.
  • the suspension of the microspheres is cooled at a speed of up to 2 ° C / min to reach -80 ° C and after 24 hours of stabilization at this temperature, they are introduced into a thermally insulated container, Dewar, containing the liquid nitrogen.
  • microsphere suspension is thawed in a 37 ° C water bath for approximately 2 minutes
  • Conditioning is carried out by centrifugation at rotation speeds of between 600 and 1000 rpm for 5 minutes to recover the PRP microspheres, adding PPP to the PRP microspheres and centrifuging again between 600 and 1000 rpm for 5 minutes. Finally all the supernatant will be removed.
  • the suspension of defrosted PRP microspheres is mixed with the synthetic microspheres in the saline medium, allowed to decant and the excess liquid is removed.
  • a final aspect of the present invention relates to the use of the injectable material for the regeneration of articular cartilage.
  • the injectable material described in this invention has advantages (Figure 7) in comparison with each of the other therapies currently applied in clinical phases or in the market:
  • microspheres described herein once injected, leave migration paths of the stem cells from the subchondral bone. This is an advantage over the implantation of an injectable gel that fills the cartilage defect where regeneration is to occur because in this case the gel structure blocks the passage of new cells from the subchondral bone.
  • the cells in this case must be injected together with the gel precursors, which adds the complexity described in the previous paragraph.
  • scaffolds in the scientific literature, as a support for regeneration we have found in the animal model that the microspheres move easily during the growth of the new tissue, which allows it to organize itself in a similar way to the natural one. In the scaffolding pores, growth is restricted by the pores walls. The displacement of the microspheres leaves free space for the newly formed tissue before the synthetic material is bioabsorbed, in this way, materials with long degradation times can be used.
  • Figure 1 Samples of synthetic and PRP microspheres and their handling or mixing thereof: a) polylactic acid microspheres, PLA, b) mixture of chitosan microspheres with PLA microspheres, c) PRP microspheres and d) mixture of microspheres of PRP with PLA microspheres.
  • Figure 2 FESEM micrograph (field emission scanning electron microscopy) of PLA microspheres with 50 pm scale bar. b) Micrograph performed under an optical microscope of lyophilized and hydrated chitosan microspheres (20x magnification). c) Micrograph performed under an optical microscope of the PRP microspheres after 12 days of cryopreservation (10x magnification). d) SEM micrograph (scanning electron microscopy), with 40 pm scale bar, of the PLA membranes obtained by electro-spinning.
  • FIG. 3 Diagram of the surgery with the implant or (material) of support microspheres injected into a defect of articular cartilage and microfracture of the subchondral bone and a synthetic membrane covers the defect and is attached to the clot covering the defect. Migration of mesenchymal cells (MSC) is shown.
  • MSC mesenchymal cells
  • PLA membranes a) PLA membrane before sterilizing and die-cutting and b) sterilized, die-cut PLA membranes prior to implantation.
  • FIG. 1 Femoral condyles in a rabbit knee model 3 months after surgery a) PLA; b) PLA + PRP; c) surgery control; d) native control.
  • Rabbit blood from the New Zealand breed was centrifuged for 8 minutes at 1800 rpm, separating the PPP and PRP phases.
  • 250 mL of olive oil was introduced into a beaker and a four-blade rod was introduced from a mechanical stirrer. The temperature was controlled at 37 ° C and stirred at 360 rpm.
  • To the PRP was added 5 pL of a 10% aqueous solution of calcium chloride for every 100 pL of PRP and the mixture was dripped onto the oil, maintaining the stirring by controlling the flow of PRP solution by a syringe pump at a rate 0.5 mL / min. Stirring was maintained for 5 hours after finishing adding the PRP solution.
  • microspheres were allowed to settle and the oil was aspirated.
  • a 5 minute acetone wash was performed with stirring followed by another 5 minute rest and aspirate of the acetone.
  • the obtained microspheres have diameters between 50 and 150 microns ( Figure 2c).
  • a solution of the hydrogel precursor was prepared consisting of a 4% solution of gelatin or hyaluronic acid modified with tyramine or mixtures of both containing 50% by mass of each of them in the Krebs Ringer Buffer buffer (formed by 115 mM sodium chloride, 5 mM potassium chloride, 1 mM potassium dihydrogen phosphate and 25 Mm HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid);
  • the emulsion microspheres were formed in medium consisting of olive oil and the emulsion was maintained 10 minutes (gelation occurs in 5 minutes) for the formation of microspheres,
  • the microspheres were removed by removing the oil with successive steps that included: adding a phosphate buffered saline, PBS (an aqueous saline solution containing sodium chloride, sodium phosphate, potassium chloride, potassium phosphate), centrifuge to separate the aqueous phase containing the PRP microspheres of the oil, aspirating the oil, the operation was repeated once more;
  • PBS an aqueous saline solution containing sodium chloride, sodium phosphate, potassium chloride, potassium phosphate
  • the surgeon causes bleeding at the site of the defect by microfracture, nanofracture or drilling of the subchondral bone.
  • the injectable material of the invention is injected and soaked into the blood and is embedded in the blood clot.
  • the defect is covered with a synthetic membrane that is attached to the clot covering the defect ( Figures 2d and 4).
  • the membrane can be produced by electro-spinning of the same polymers used to produce the microspheres.
  • the entire surgical procedure can be performed by arthroscopy.
  • PRP microspheres The role of PRP microspheres is to release chemotactic and growth factors, which act as a stimulus for the migration and differentiation of mesenchymal cells from the bone to the site of the defect.
  • the role of synthetic, rigid microspheres is to create the appropriate biomechanical environment. In the tests carried out in an animal model of the rabbit knee, it has been shown that, within three months, the PRP microspheres have been reabsorbed while both the membrane and the synthetic microspheres have moved from the implant site to the bone (where they will end up being bio-absorbed), leaving in the place where the cartilage defect was performed a functional tissue with all the characteristics of the articular cartilage ( Figures 5 and 6).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne une matière injectable pour la régénération du cartilage articulaire et porte sur une matière injectable dont l'implantation à l'emplacement du défaut de cartilage peut être combinée avec une technique de stimulation de l'os sous-chondral, plus particulièrement la matière est une matière injectable de microsphères de plasma riche en plaquettes obtenues à partir d'un prélèvement de sang du patient lui-même et d'autres microsphères synthétiques, de préférence, d'un polymère biorésorbable et son utilisation comme support de la régénération du cartilage.
PCT/ES2019/070505 2018-07-19 2019-07-18 Matière injectable pour la régénération du cartilage articulaire WO2020016476A1 (fr)

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ES201830730A ES2690392B2 (es) 2018-07-19 2018-07-19 Material inyectable para la regeneracion del cartilago articular
ESP201830730 2018-07-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4445905A1 (fr) * 2023-04-14 2024-10-16 Santxa Research S.L.U. Plasma enrichi en plaquettes et molécules de plasma

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Publication number Priority date Publication date Assignee Title
WO2002000272A2 (fr) * 2000-06-29 2002-01-03 Biosyntech Canada Inc. Composition et procede de reparation et de regeneration de cartilage et d'autres tissus
WO2006023803A2 (fr) * 2004-08-20 2006-03-02 Artes Medical, Inc. Methodes d'administration de microparticules combinees a des composants corporels autologues
WO2011150328A1 (fr) * 2010-05-27 2011-12-01 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Echafaudage biodégradable électrofilé humide et utilisations associées
EP2591812A1 (fr) * 2011-11-14 2013-05-15 University of Twente, Institute for Biomedical Technology and Technical Medicine (MIRA) Petit tissu à base de dextrane contenant un lysat à plasma riche en plaquettes pour la réparation des cartilages
WO2013116791A1 (fr) * 2012-02-02 2013-08-08 Mosaic Biosciences, Inc. Biomatériaux destinés à l'administration d'extraits sanguins et procédés les utilisant

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Publication number Priority date Publication date Assignee Title
WO2002000272A2 (fr) * 2000-06-29 2002-01-03 Biosyntech Canada Inc. Composition et procede de reparation et de regeneration de cartilage et d'autres tissus
WO2006023803A2 (fr) * 2004-08-20 2006-03-02 Artes Medical, Inc. Methodes d'administration de microparticules combinees a des composants corporels autologues
WO2011150328A1 (fr) * 2010-05-27 2011-12-01 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Echafaudage biodégradable électrofilé humide et utilisations associées
EP2591812A1 (fr) * 2011-11-14 2013-05-15 University of Twente, Institute for Biomedical Technology and Technical Medicine (MIRA) Petit tissu à base de dextrane contenant un lysat à plasma riche en plaquettes pour la réparation des cartilages
WO2013116791A1 (fr) * 2012-02-02 2013-08-08 Mosaic Biosciences, Inc. Biomatériaux destinés à l'administration d'extraits sanguins et procédés les utilisant

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Title
MEHEUX CARLOS J ET AL.: "Efficacy of Intra-articular Platelet-Rich Plasma Injections in Knee Osteoarthritis: A Systematic Review", ARTHROSCOPY MAR 2016, vol. 32, no. 3, 29 February 2016 (2016-02-29), pages 495 - 505, XP029451066, ISSN: 0749-8063, DOI: 10.1016/j.arthro.2015.08.005 *
SAITO M ET AL.: "Intraarticular administration of platelet-rich plasma with biodegradable gelatin hydrogel microspheres prevents osteoarthritis progression in the rabbit knee.", CLINICAL AND EXPERIMENTAL RHEUMATOLOGY ITALY, vol. 27, no. 2, 28 February 2009 (2009-02-28), pages 201 - 207, XP055172009, ISSN: 0392-856X *
SANCHO-TELLO M ET AL.: "Poly(l-lactic acid) microspheres induce ''in vivo'' articular cartilage regeneration in rabbits", ARTIFICIAL ORGANS 20170901 BLACKWELL PUBLISHING INC. NLD., vol. 41, no. 9, 1 September 2017 (2017-09-01), pages A79, ISSN: 1525-1594 *
SANCHO-TELLO MARIA ET AL.: "Human platelet-rich plasma improves the nesting and differentiation of human chondrocytes cultured in stabilized porous chitosan scaffolds.", JOURNAL OF TISSUE ENGINEERING ENGLAND, vol. 8, January 2017 (2017-01-01), pages 1 - 6, XP055678237, ISSN: 2041-7314 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4445905A1 (fr) * 2023-04-14 2024-10-16 Santxa Research S.L.U. Plasma enrichi en plaquettes et molécules de plasma
WO2024213714A1 (fr) * 2023-04-14 2024-10-17 Santxa Research S.L.U. Plasma enrichi en plaquettes et en molécules de plasma

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