WO2012136016A1 - Hydrogels qui peuvent former rapidement une réticulation covalente en conditions douces et leur procédé de préparation - Google Patents

Hydrogels qui peuvent former rapidement une réticulation covalente en conditions douces et leur procédé de préparation Download PDF

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WO2012136016A1
WO2012136016A1 PCT/CN2011/075117 CN2011075117W WO2012136016A1 WO 2012136016 A1 WO2012136016 A1 WO 2012136016A1 CN 2011075117 W CN2011075117 W CN 2011075117W WO 2012136016 A1 WO2012136016 A1 WO 2012136016A1
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hydrogel
solution
component
hydrogels
components
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PCT/CN2011/075117
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Chinese (zh)
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胡碧煌
胡晓阳
胡天柱
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广州圣谕医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/335—Polymers modified by chemical after-treatment with organic compounds containing phosphorus
    • C08G65/3356—Polymers modified by chemical after-treatment with organic compounds containing phosphorus having nitrogen in addition to phosphorus
    • 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
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C08G65/33337—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C08G65/33337—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic
    • C08G65/33341—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic aromatic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C08J3/246—Intercrosslinking of at least two polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • C08J2371/02—Polyalkylene oxides

Definitions

  • the invention relates to a hydrogel and a preparation method thereof, in particular to a hydrogel capable of rapidly forming covalent cross-linking under mild conditions and a preparation method thereof.
  • Hydrogel It is a network of hydrophilic polymers, insoluble in water, but can absorb and retain a large amount of water, is highly expanded in aqueous solution, and has good biocompatibility and similarity. They are used in surgical biologics for surgical sealants and adhesives, drug release, tissue repair and tissue engineering.
  • hydrogel systems are typically formed by chemical or physical action. Gels that chemically crosslink to form water often involve the use of toxic crosslinkers and free radicals, and the resulting hydrogels are generally not biodegradable.
  • physical hydrogels are formed by the action of non-covalent bonds, such as hydrogen bonding, ionic interaction, hydrophobic interaction, and phase transformation. The physical hydrogel thus formed is relatively fragile. Therefore, to meet the clinical needs, hydrogels that form covalent crosslinks without using toxic reagents under mild conditions still face challenges.
  • Hydrogels have been used clinically as surgical sealants.
  • surgical sealants are used in surgery for hemostasis, anti-adhesion and plugging, and are widely used in brain surgery, cardiac surgery, chest, abdominal surgery, neurosurgery and the like.
  • surgical sealant products using hydrogels can be divided into three categories: one is fibrin based on fibrinogen extracted from mammalian blood (bovine blood, pig blood, or human blood).
  • a surgical sealant, or a gelatin protein of cattle is a blocking agent for the ingredients.
  • Fibrinogen extracted from the blood of mammals forms a fibrin gel, such as TisseelTM, catalyzed by thrombin (thrombin) extracted from mammalian blood.
  • Anke glue double embroidery.
  • FloSealTM Use bovine gelatin and thrombin.
  • Such products are products derived from blood and are at risk of being contaminated by pathogenic organisms.
  • proteins and thrombin derived from pigs and cattle are heterologous proteins, which may be used in the human body to develop a serious immune response.
  • Another type of surgical sealant product is the cross-linking of a protein of animal origin under the action of a small molecule aldehyde crosslinker to form a hydrogel, for example, cross-linking using gelain and bovine-derived gelatin to form a hydrogel.
  • a small molecule aldehyde crosslinker for example, cross-linking using gelain and bovine-derived gelatin to form a hydrogel.
  • US patent US5385606 A method of forming a hydrogel by crosslinking bovine blood-derived albumin and adipaldehyde is described.
  • the use of small molecular aldehyde crosslinkers is also toxic.
  • the third type of surgical sealant products are all composed of synthetic biocompatible polymer biomaterials. These products are not at risk of being contaminated by pathogenic organisms and allergic to foreign proteins.
  • No. 5,410,016 describes the preparation of linear block copolymers using polyethylene glycol and polylactic acid, followed by polymerization of the crosslinked acrylic acid moiety under excitation of light by ester linkage at both ends of the molecule.
  • An aqueous solution of a block copolymer containing acrylate at both ends of the molecule is applied to the site of use to rapidly form a hydrogel (FocalSeal ® ) in situ under catalyst and light.
  • FocalSeal ® hydrogel system as a surgical sealer is that it is somewhat difficult to control in practice.
  • a hydrogel consisting of two solutions is disclosed: a solution of an activated acid derivative of a tetra-branched polyethylene glycol and a short peptide trilysine (Lys-Lys-Lys) a surgical sealant formed by in-situ polymerization of the solution after mixing.
  • This in-situ hydrogel system requires a pH of 9.5 (pH) of the solution. Left and right to form a hydrogel quickly. Under such alkaline conditions, it is easy to produce an effect on local stimuli and an inflammatory reaction.
  • US 6312725 discloses a hydrogel surgical sealant product (CoSeal ® ) formed by mixing two solutions in situ.
  • the two solutions are respectively a solution of a tetra-branched polyethylene glycol having a terminal acid group as an activated acid derivative and a solution of a tetra-branched polyethylene glycol having a terminal group of a thiol group, which are mixed and formed by in-situ polymerization by forming a sulfur ester.
  • Hydrogels Hydrogels.
  • the disadvantages of this hydrogel CoSeal ® are that in addition to the pH of the solution at pH 9.6, the hydrogel can form a hydrogel with local irritations and inflammatory reactions, due to the easy hydrolysis of sulphur bonds in aqueous solution. However, it is unstable, and the hydrogel formed by cross-linking of thioester bonds has a poor stability and a short period of time.
  • the thioester compound and the N -terminal half-photo-acid compound are mixed under mild conditions (phosphate buffer solution, pH 7-8) to form a new amide bond.
  • This chemical reaction is called natural chemical bonding.
  • WO 2008/131325 describes the formation of hydrogels using a natural chemical linkage as a crosslinking reaction.
  • a solution of a tetra-branched polyethylene glycol having a thiol end group and a solution of a tetra-branched polyethylene glycol having a cysteine end group are used.
  • the two solutions are mixed and in situ polymerized under mild conditions (pH 7-8) by formation of an amide bond to form a hydrogel.
  • a hydrogel containing two components, A and B, and the structural formula of component A is as shown in formula I
  • component B is as shown in formula II.
  • Y is a linking atom or a linking group
  • X is a carbon or a molecular mother core having a branch number of not less than 2
  • n is 0 to 200
  • An integer between , m is an integer between 2 and 32.
  • the structural formula of component B is as shown in formula III.
  • R -H , -CH 2 CH 2 COOH or -(CH 2 ) 3 NH(NH)CNH 2
  • Y is a linking atom or a linking group
  • X is a carbon or a molecule having a branch number of not less than 2 Nucleus
  • n is an integer between 0 and 200
  • m is an integer between 2 and 32.
  • n is an integer between 4 and 16.
  • the connecting atom is O , N or C .
  • the preparation method of the above hydrogel comprises the following steps:
  • the mixed solution of the components A and B has a mass volume concentration of 5% to 20%.
  • the components A and B are mixed in a molar ratio of 4:1 to 1:4.
  • the solution having a pH of from 7 to 8 is a sodium phosphate buffer.
  • the hydrogel of the present invention after mixing the aqueous solutions of the A and B components, can rapidly react under mild conditions to form a new amide bond, which is not mixed.
  • a covalently crosslinked hydrogel is obtained in 10 seconds.
  • the hydrogel of the present invention is structurally stable, has excellent viscoelasticity, and can be used as a surgical sealant.
  • 1 and 2 are rheological behavior diagrams of the hydrogel of the present invention.
  • a hydrogel containing two components, A and B, and the structural formula of component A is as shown in formula I
  • component B is as shown in formula II.
  • Y is a linking atom or a linking group
  • X is a carbon or a molecular mother core having a branch number of not less than 2
  • n is 0 to 200
  • An integer between , m is an integer between 2 and 32.
  • the structural formula of component B is as shown in formula III.
  • R -H , -CH 2 CH 2 COOH or -(CH 2 ) 3 NH(NH)CNH 2
  • Y is a linking atom or a linking group
  • X is a carbon or a molecule having a branch number of not less than 2 Nucleus
  • n is an integer between 0 and 200
  • m is an integer between 2 and 32.
  • the number of branches of the multi-branched molecular nucleus is at least 2, preferably at least 3, so that the A and B components can form a three-dimensional network by living cross-linking reaction.
  • the molecular mother core is preferably those which are degradable in the body and which are not toxic to the human body.
  • n is an integer between 4 and 16.
  • each branch can form a hydrogel more uniformly.
  • the connecting atom is O, N or C .
  • it can also be other divalent linking groups which can be degraded in the body and have no toxic effect on the human body. The choice of these groups is a routine choice for those skilled in the art.
  • the preparation method of the above hydrogel comprises the following steps:
  • the mixed solution of the components A and B has a mass volume concentration of 5% to 20%.
  • the components A and B are mixed in a molar ratio of 4:1 to 1:4.
  • the solution having a pH of from 7 to 8 is a sodium phosphate buffer.
  • a sodium phosphate buffer can also be used.
  • Component B can be protected by a cysteine such as Boc-Cys(Trt)-OH, or L- Thioproline is obtained by reacting a polymer containing an amino group, a hydroxyl group, or a functional group, and removing a protecting group.
  • a cysteine such as Boc-Cys(Trt)-OH
  • L- Thioproline is obtained by reacting a polymer containing an amino group, a hydroxyl group, or a functional group, and removing a protecting group.
  • Component B can also pass a fully protected cysteine-containing dipeptide, such as Boc-Cys(Trt)-Gly-OH, Boc-Cys(Trt)-Glu(OtBu)-OH and Boc-Cys(Trt)-Arg(Pbf)-OH It is reacted with a polymer containing an amino group, a hydroxyl group, or which can be converted into these functional groups, and a protective group is removed to obtain a reaction.
  • a fully protected cysteine-containing dipeptide such as Boc-Cys(Trt)-Gly-OH, Boc-Cys(Trt)-Glu(OtBu)-OH and Boc-Cys(Trt)-Arg(Pbf)-OH It is reacted with a polymer containing an amino group, a hydroxyl group, or which can be converted into these functional groups, and a protective group is removed to obtain a reaction.
  • a fully protected cysteine-containing dipeptide can be obtained by solid phase synthesis of the Fmoc polypeptide.
  • the reaction equation is as follows:
  • the residue was dissolved in methanol (50 ml), and the methanol solution was frozen overnight (-20 ° C) and centrifuged (-9 ° C, 6000 rpm, 20 minutes), remove the supernatant;
  • the ninhydrin test showed a dark blue color.
  • the Ellman reagent reacted bright yellow. Indicates that the protecting group has been removed.
  • the trifluoroacetic acid salt was dissolved in an ammonium hydrogencarbonate solution (0.1 M, 25 ml) and lyophilized to give component B1 ( Cys-PEG4A ).
  • the resin was washed three times with dimethylformamide (DMF) and methanol, and the resin was dried under vacuum, and the ninhydrin test was pale yellow;
  • DMF dimethylformamide
  • the polypeptide resin obtained above was added to a solution of 1% trifluoroacetic acid in dichloromethane, 30 ml, and shaken 20 Minute, collect the solution;
  • the precipitate was washed with water until the eluate was neutral and dried under vacuum to give a protected cysteine dipeptide.
  • Boc-Cys(Trt)-Gly-OH or Boc-Cys(Trt)-Glu(OBu)-OH , or Boc-Cys(Trt)-Arg(Pbf)-OH (0.25 mmol)
  • PEG4A 0.5g, amino 0.2 mmol
  • BOP (0.11 g, 0.25 mmol) dissolved in dichloromethane (2 ml)
  • DIEA 44 ⁇ L, 0.25 mmol
  • shake 2 Hour dry the solvent with nitrogen, add 50 ml of methanol to dissolve all solids, freeze the solution overnight (-20 ° C), remove the centrifugation (-9 ° C, 6000 rpm, 20 Minutes), remove the supernatant.
  • Boc-Cys(Trt)-Gly-PEG4A Dry the Boc-Cys(Trt)-Gly-PEG4A, or Addition of trifluoroacetic acid to Boc-Cys(Trt)-Glu-PEG4A, or Boc-Cys(Trt)-Arg(Pbf)-PEG4A samples (30 ML) containing 1 ml of triisopropylsilane (TIS) and 1 ml of 1,2-dimercaptoethane (EDT), stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure;
  • TIS triisopropylsilane
  • EDT 1,2-dimercaptoethane
  • the residue was dissolved in methanol (50 ml), and the methanol solution was frozen overnight (-20 ° C) and centrifuged (-9 ° C, 6000 rpm, 20 minutes), remove the supernatant;
  • the ninhydrin test showed a dark blue color.
  • the Ellman reagent reacted bright yellow. Indicates that the protecting group has been removed.
  • Comparative Example 1 Comparative Example 2, and Comparative Example 3 (US6566406, US6312725, and The hydrogel product disclosed in WO 2008/131325 was tested under the same conditions at the same concentration.
  • the component B1 of the present invention can form a hydrogel by crosslinking a thiol group to form a disulfide bond, but at a very slow rate.
  • the formed network structure may be broken due to the rotation of the stirrer, so that the recording time is longer than the actual hydrogel formation time.
  • the measured time should have a relative reference value.
  • Hydrogel dissolution test 1 Mix equimolar equal volume of component A in sodium phosphate buffer solution (0.1 M, pH 7.2 ) (10%) and component B sodium phosphate buffer solution (0.1 M, pH 7.2) (10%), take two 100 ⁇ l portions to two plastic tubules, 10 After minute, check for hydrogel. Add 100 ⁇ l of 0.1 M aqueous hydroxylamine solution and 100 ⁇ l of 200 mM 2- in two small tubes. a solution of mercaptoethanol, shaking, and the hydrogel is not dissolved;
  • the oscillatory mode measures the storage modulus (G') and the loss modulus (G'). Take one data point every 15 seconds. Longest measurement time to 300 minutes.
  • the hydrogel of the present invention has a very short formation time and is a covalently crosslinked hydrogel having excellent viscoelasticity.
  • the crosslinking mechanism of the hydrogel of the present invention is as follows:
  • A, B of the present invention After the aqueous solution of the components is mixed, the hydrogel can be rapidly formed.
  • components A and B are preferably 1 : 1
  • the molar ratio is mixed.
  • hydrogels represented by the following structural formulas can be obtained separately.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Polyethers (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des hydrogels qui peuvent former rapidement une réticulation covalente en conditions douces et leur procédé de préparation. Les hydrogels comprennent deux composants : un ester NHS de PEG et un groupe terminal N-cystéine contenant du PEG. Les deux composants sont dissous et mélangés, et les hydrogels sont obtenus. Les hydrogels peuvent former rapidement une réticulation covalente en conditions douces, et sont particulièrement appropriés pour un agent d'étanchéité chirurgical.
PCT/CN2011/075117 2011-04-07 2011-06-01 Hydrogels qui peuvent former rapidement une réticulation covalente en conditions douces et leur procédé de préparation WO2012136016A1 (fr)

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CN201110086407.7 2011-04-07
CN201110086407.7A CN102206409B (zh) 2011-04-07 2011-04-07 一种温和条件下快速形成共价交联的水凝胶及其制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015616A1 (fr) * 2015-07-22 2017-01-26 Envisia Therapeutics, Inc. Livraison de protéines dans l'oeil

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013191759A1 (fr) * 2012-06-21 2013-12-27 Northwestern University Adhésifs en hydrogel polymère formés par de multiples mécanismes de réticulation au ph physiologique
CN113181418B (zh) * 2021-04-09 2022-05-03 青岛大学附属医院 一种医用粘合剂及其制备方法

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US6312725B1 (en) * 1999-04-16 2001-11-06 Cohesion Technologies, Inc. Rapid gelling biocompatible polymer composition
US6566406B1 (en) * 1998-12-04 2003-05-20 Incept, Llc Biocompatible crosslinked polymers
US20080274980A1 (en) * 2007-04-19 2008-11-06 Northwsetern University Macromonomers and hydrogel systems using native chemical ligation, and their methods of preparation
CN101934089A (zh) * 2010-09-01 2011-01-05 北京大学人民医院 一种可眼内注射的原位交联水凝胶在制备人工玻璃体中的应用

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CN1660443A (zh) * 2005-01-19 2005-08-31 中国人民解放军军事医学科学院野战输血研究所 甲氧基聚乙二醇衍生物的用途、经化学修饰的通用型红细胞及其制备方法
CN101768263B (zh) * 2008-12-30 2012-04-04 上海医药工业研究院 一种可用于制备长循环脂质体的巯基化聚乙二醇的合成方法

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US6566406B1 (en) * 1998-12-04 2003-05-20 Incept, Llc Biocompatible crosslinked polymers
US6312725B1 (en) * 1999-04-16 2001-11-06 Cohesion Technologies, Inc. Rapid gelling biocompatible polymer composition
US20080274980A1 (en) * 2007-04-19 2008-11-06 Northwsetern University Macromonomers and hydrogel systems using native chemical ligation, and their methods of preparation
CN101934089A (zh) * 2010-09-01 2011-01-05 北京大学人民医院 一种可眼内注射的原位交联水凝胶在制备人工玻璃体中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015616A1 (fr) * 2015-07-22 2017-01-26 Envisia Therapeutics, Inc. Livraison de protéines dans l'oeil

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