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WO2013176739A1 - Matières d'origine biologique à surface renouvelable - Google Patents

Matières d'origine biologique à surface renouvelable Download PDF

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Publication number
WO2013176739A1
WO2013176739A1 PCT/US2013/030543 US2013030543W WO2013176739A1 WO 2013176739 A1 WO2013176739 A1 WO 2013176739A1 US 2013030543 W US2013030543 W US 2013030543W WO 2013176739 A1 WO2013176739 A1 WO 2013176739A1
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composition
polycaprolactone
hyaluronan
poly
pcl
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PCT/US2013/030543
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English (en)
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Ron SIEGEL
Chun Wang
Wenshou WANG
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Regents Of The University Of Minnesota
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Publication of WO2013176739A1 publication Critical patent/WO2013176739A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/34—Shaped forms, e.g. sheets, not provided for in any other sub-group of this main group
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L101/00—Compositions of unspecified macromolecular compounds
    • C08L101/16—Compositions of unspecified macromolecular compounds the macromolecular compounds being biodegradable

Definitions

  • polymeric biomaterials are increasingly being used as implants in human body in the last decades.
  • the surface chemistry and morphology of a polymeric biomaterial are of critical importance when implanted in a living environment (see Ikada Y., Biomateirals, 1994, 15, 725-736).
  • physiological fluids such as proteins, oligopeptides, or polysaccharides, etc
  • cells such as platelets, macrophages, and fibroblasts
  • biomolecules and cells that bind nonspecifically typically have hydrophobic character and are inclined to be adsorbed onto
  • hydrophobic surfaces The surfaces of most polymers used to prepare implants are hydrophobic. Such fouling at the surface will usually reduce the material's functionality and cause undesirable effects. Examples include background interference, protein accumulation onto biosensor surfaces, bacterial colonization of contact lenses and indwelling catheters, thrombosis in cardiovascular implants, and foreign body responses leading to isolation or rejection of implants and devices (see Banerjee I, et al., Adv. Mater. , 2011, 23, 690-718). Therefore, an interface between biomaterial and physiological fluid, which attenuates or completely prevents the absorption of nonspecific molecules and cells, is usually necessary and important for implants and devices.
  • Baier demonstrated a correlation between relative adhesion of fouling organisms and the material's surface energy, called the Baier curve, which has been confirmed in several marine and biomedical environments (Baier RE., J Mater Sci: Mater Med, 2006, 17, 1057- 1062). Based on the Baier curve, minimal fouling is typically achieved at a surface tension of 22-24 mM/m, which is lower than the surface energy of most polymeric biomaterials.
  • the general principle of designing a bioresistant surface is to build a thin layer of hydrophilic material into the interface to decrease the surface energy of implants made from polymeric biomaterials.
  • Whitesides and coworkers systematically varied the surface energy of self-assembled monolayers to test resistance to protein adsorption, and concluded that surfaces that are hydrophilic, electrically neutral and contain hydrogen bond acceptors are most effective at resisting protein adhesion (see Ostuni E, et al., Langmuir, 2001, 17, 5605-5620).
  • Well-packed zwitterionic compounds were found to be very efficient as stable nonfouling surfaces as well (see Chang Y, et al., Langmuir, 2008, 24, 5453-5458).
  • Peptidomimetic polymers were synthesized by Statz et al and showed excellent protein resistance and long lasting ability (several months) (see Statz AR, et al., J Am Chem Soc, 2005, 127, 7972- 7973).
  • Jiang et al developed and demonstrated that poly(zwitterions) act as nonfouling surfaces that can prevent protein adsorption from complex biological media, and also provide resistance to nonspecific protein adsorption from blood serum and plasma (see Jiang SY, et al., Adv. Mater. , 2010, 22, 920-932; and Yang W, et al., Biomaterials, 2009, 30, 5617-5621).
  • Biodegradable polymeric materials have been widely been used as surgical implants and as scaffolds for tissue engineering (see Gunatillake PA, Adhikari R., European Cells and Materials, 2003, 5, 1-16). However, surface modification to provide persistent bioresistance remains challenging for numerous applications.
  • Hyaluronan (aka hyaluronic acid, HA) is a linear negatively charged polysaccharide consisting of repeating disaccharide units of N-acetyl-D-glucoamine and D-glucuronate, linked by ⁇ 1-4 and ⁇ 1 -3 glycosidic bonds.
  • the hydrophilic hyaluronan segment will spread on the surface of polymers and act as an antifouling layer in an aqueous environment; and the copolymer will dispersed uniformly in the polymer matrix and will not migrate to the surface because of its high molecular weight. Hence, as the bulk polymer degrades, the dispersed HA-amphiphile will become available to "coat" the dynamically evolving biointerface.
  • composition comprising 1) from about 0.1 to about 30 weight percent of the composition as one or more POLYMER conjugates that comprise A
  • HYDROPHILIC POLYMER SEGMENT linked to one or more HYDROPHOBIC POLYMER SEGMENTS and 2) at least about 70 weight percent of the composition as BULK POLYMERIC BIOMATERIAL.
  • the invention provides a composition comprising 1) from about 0.1 to about 30 weight percent of the composition as a hyaluronan copolymer conjugate, which conjugate comprises hyaluronan linked to one or more polycaprolactone segments, and 2) at least about 70 weight percent of the composition as bulk polycaprolactone.
  • compositions of the invention can be incorporated into a wide variety of materials and devices, including but not limited to medical, dental, and pharmaceutical implants, surgical devices and accessories, scaffolds for tissue engineering, container linings, antibacterial and antiseptic surfaces for households, and construction materials.
  • the compositions of the invention can also be incorporated into microspheres and nanoparticles that can be used in diagnostic, biosensing, and drug/protein/gene delivery systems.
  • Figure 1 Shows the structure and the proton NMR spectra of CTA-HA-g-PCL and CTA-HA.
  • Figure 7 Illustrated data from Example 1 showing antifouling property of a PCL/HA-g-PCL nanocomposite film.
  • Figure 8. Quantification of adherent cells on the surfaces of nanocomposite and pristine PCL films.
  • Figure 9 Quantification of adherent cells on the surfaces of nanocomposite films polished to different depth, in comparison with the surfaces of pristine PCL and tissue cultured plate (TCP).
  • compositions of the invention comprise POLYMER conjugates that comprise A
  • the HYDROPHILIC POLYMER SEGMENT linked to one or more HYDROPHOBIC POLYMER SEGMENTS.
  • the HYDROPHILIC POLYMER SEGMENT can be a water-soluble polymer known to the field, synthetic or natural, charged or non-charged, degradable or nondegradable, having at least one functional group (such as for example COOH, OH, or amine, or SH) through which the "hydrophobic segments" can be chemically conjugated.
  • glycosaminoglycans such as hyaluronan (HA), heparan sulfate, chondroitin sulfate, keratan sulfate; other natural polymers such as alginate, dextran, starch, chitosan and chitosan derivatives, carboxymethyl cellulose and other water-soluble cellulose derivatives; synthetic hydrophilic polymers such as PEG, polyvinylpyrrolidone, poly(alkyl)acrylic acid and their derivatives and copolymers containing carboxylic acid groups in the side-chains, polysialic acid, polyglutamic acid, poly(alkyl)arylates or poly(alkyl)acrylamides and their derivatives and copolymers containing amino groups in the side-chains.
  • HA hyaluronan
  • chondroitin sulfate keratan sulfate
  • other natural polymers such as alginate, dextran, starch, chi
  • the HYDROPHILIC POLYMER SEGMENT is hyaluronan.
  • the hyaluran that is incorporated into the compositions of the invention can be a linear polysaccharide consisting of repeating disaccharide units of N-acetyl-D-glucoamine and D- glucuronate, linked by ⁇ 1-4 and ⁇ 1-3 glycosidic bonds.
  • the hyaluronan has an average molecular weight in the range of from about 1 ,000 to about 2,000,000. In one embodiment of the invention the hyaluronan has an average molecular weight in the range of from about 10,000 to about 1,000,000.
  • the hyaluronan has an average molecular weight in the range of from about 700,000 to about 900,000.
  • Hyaluronan is readily available from a number of commercial suppliers in a variety of molecular weight ranges and grades.
  • the HYDROPHILIC POLYMER SEGMENT is alginate.
  • compositions of the invention comprise POLYMER conjugates that comprise A
  • HYDROPHILIC POLYMER SEGMENT linked to one or more HYDROPHOBIC POLYMER SEGMENTS are typically biodegradable, poorly water-soluble polymers known to the field, having at least one functional group (such as COOH, OH, amine, SH) through which the "hydrophilic component" can be covalently conjugated.
  • polylactide include but are not limited to polylactide, polyglycolide, polydioxanone, poly(trimethylene carbonate), polyanhydride, poly(ester anhydride) poly(anhydride-co-imide), poly(ortho ester), polyacetal, polyketal, tyrosine-derived polycarbonate, polyhydroxylalkanoates, polycaprolactone (PCL), polyurethane, poly(ester amide), poly(propylene fumarate), Pseudo poly(amino acids), poly(amino acids), poly(alkyl cyanoacrylate), polyphosphazene, polyphosphoester.
  • PCL polyurethane
  • poly(ester amide) poly(propylene fumarate)
  • Pseudo poly(amino acids) poly(amino acids), poly(alkyl cyanoacrylate
  • polyphosphazene polyphosphoester.
  • the HYDROPHOBIC POLYMER SEGMENT is polylactic acid (PLA). In one embodiment of the invention the HYDROPHOBIC POLYMER SEGMENT is a co-polymer of polylactic acid and poly glycolic acid (PLGA). In one embodiment of the invention the HYDROPHOBIC POLYMER SEGMENT is a co-polymer of polylactic acid and polycaprolactone (PLCA). Methods for preparing and derivatizing HYDROPHOBIC POLYMER SEGMENT are described in C.G. Pitt, "Poly-s-caprolactone and its copolymers," in Biodegrable Polymers as Drug Delivery Systems, edited by M. Chasin and R. Langer, Dekker, New York, 1990, and in references cited therein.
  • the HYDROPHOBIC POLYMER SEGMENT is polycaprolactone.
  • each polycaprolactone segment has an average molecular weight in the range of from about 500 to about 10,000.
  • each polycaprolactone segment has an average molecular weight in the range of from about 500 to about 5,000.
  • each polycaprolactone segment has an average molecular weight in the range of from about 500 to about 1 ,000.
  • the PCL segments can be attached to the HYDROPHILIC POLYMER SEGMENT through any acceptable means that does not interfere with the function of the copolymer conjugates in the compositions of the invention.
  • the PCL segments can be attached through one or more of the hydroxy groups on the HYDROPHILIC POLYMER SEGMENT through ether, ester, carbonate, or carbamate bonds.
  • the PCL segments can be attached through one or more of the hydroxy groups on the HYDROPHILIC POLYMER SEGMENT through ester bonds.
  • the PCL segments can be attached through one or more of the hydroxy groups on the HYDROPHILIC POLYMER SEGMENT through carbamate bonds.
  • a linker group can be disposed between the PCL segment and the hydroxy oxygen of the
  • the linker can comprise a linear, branched, or cyclic alkyl group or a 6-10 membered monocyclic or bicyclic aromatic group, or a combination thereof.
  • the linear or branched alkyl group comprises 2-18 carbon atoms and the cyclic alkyl group can comprise 3-18 carbon atoms.
  • the linker is derivable from an diisocyanate that comprises from 2-18 carbon atoms.
  • the linker is derivable from hexamethylene -1,6-diisocyanate.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 200 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 100 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 50 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 25 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 10 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to up to about 5 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to 1 polycaprolactone segment.
  • each HYDROPHILIC POLYMER SEGMENT is linked to at least about 100 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linkedo at least about 50 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linkedo at least about 25 polycaprolactone segments. In one embodiment of the invention each HYDROPHILIC POLYMER SEGMENT is linked to at least about 10 polycaprolactone segments.
  • each HYDROPHILIC POLYMER SEGMENT is linked to at least about 5 polycaprolactone segments.
  • d is an integer selected from 5-5000;
  • each PCL is independently a polycaprolactone chain having a molecular weight of from about 500 to 10,000;
  • Y is a suitable linker group.
  • compositions of the invention comprise POLYMER conjugates that comprise a
  • HYDROPHILIC POLYMER SEGMENT linked to one or more HYDROPHOBIC POLYMER SEGMENTS and 2) at least about 70 weight percent of the composition as BULK POLYMERIC BIOMATERIAL.
  • the BULK POLYMERIC BIOMATERIAL is typically a biodegradable, poorly water-soluble polymer known to the field. These include but not limited to polylactide,
  • polyglycolide polydioxanone, poly(trimethylene carbonate), polyanhydride, poly(ester anhydride) poly(anhydride-co-imide), poly(ortho ester), polyacetal, polyketal, tyrosine-derived polycarbonate, polyhydroxylalkanoates, polycaprolactone (PCL), polyurethane, poly(ester amide), poly(propylene fumarate), Pseudo poly(amino acids), poly( amino acids), poly(alkyl cyanoacrylate),
  • the BULK POLYMERIC BIOMATERIAL can be polycaprolactone (PCL).
  • PCL polycaprolactone
  • PCL is available from a number of commercial sources and it can be prepared as described in C.G. Pitt, "Poly-s-caprolactone and its copolymers," in Biodegrable Polymers as Drug Delivery Systems, edited by M. Chasin and R. Langer, Dekker, New York, 1990. Chapter 2, pp 71-120.
  • the bulk polycaprolactone has an average molecular weight in the range of from about 2,000 to about 1,000,000. In one embodiment of the invention the bulk polycaprolactone has an average molecular weight in the range of from about 5,000 to about 200,000. In another embodiment of the invention the bulk polycaprolactone has an average molecular weight in the range of from about 10,000 to about 20,000.
  • the hydrophilic component is an anionic polymer or neutral polymer
  • the surface coating will be antifouling, antiadhesive, and lubricious
  • the hydrophilic component is a cationic polymer
  • the surface coating will be bioadhesive, and potentially antimicrobial.
  • HA-g-PCL (Degree of grafting: 1.4%) (about 31 PCL grafts per HA chain)
  • HA-Na Medical grade hyaluronan sodium salt
  • Lifecore Biomedical Choski, MN
  • Cetyltrimethyl ammonium bromide CAB
  • ⁇ -caprolactone 1-butanol
  • stannous octoate DBTDL
  • toluene and hexamethylene -1 ,6-diisocyanate (HDI) were all purchased from Sigma Aldrich.
  • CAB cetyltrimethyl ammonium bromide
  • DBTDL dibutyltin dilaurate
  • HDI hexamethylene -1 ,6-diisocyanate
  • CTA-HA cetyltrimethyl ammonium HA salt
  • the method was adapted from the work of Laurent Pravata, et al. (see Pravata L, et al., New amphiphilic lactic acid oligomer-hyaluronan conjugates: synthesis and physicochemical characterization, Biomacromolecules 2008, 9, 340-348). Briefly, 0.55 g of CTAB was dissolved in 7.5ml of distilled water at 40°C. This solution was added dropwise to aqueous solution of 0.6 g HA- Na (1 wt %) at 40°C. The white precipitate that formed was collected and washed three times with hot water and then dried under vacuum.
  • the method of remove the CTA group from CTA-HA-g-PCL is adapted from to Pravata et al. (see Pravata L, et al., New amphiphilic lactic acid oligomer -hyaluronan conjugates: synthesis and physicochemical characterization, Biomacromolecules 2008, 9, 340-348).
  • PCL was dissolved in CHC1 3 .
  • a certain amount of HA-g-PCL was dispersed in CHCI 3 with the aid of ultrasonication. The two solutions were mixed and poured into a glass Petri dish, followed by evaporation of solvent to harvest a polymer film.
  • a smooth PCL/HA-g-PCL blend film was prepared by further compression molding at 100°C.
  • ⁇ NMR spectra were recorded on a Varian Unity spectrometer (300 MHz) with CDCI 3 or DMSO-d 6 as solvent.
  • Fourier transform infrared spectroscopy (FTIR) was conducted using a Nicolet Series II Magna-IR System 750 with OMNIC® software for data collection and analysis.
  • Particle sizes of the HA-g-PCL in both water and chloroform were measured by transmission electron microscopy (TEM: JEOL JEM-1210) with phosphotungstic acid as a staining agent.
  • DLS Dynamic laser scattering
  • Static mechanical tensile stress-strain measurements were performed on the samples using Rheometrics Minimat equipment and a MTS Testworks 4 computer software package for automatic control of test sequences and data acquisition and analysis. Dumbbell-shaped test specimens were cut from the synthesized films and tested at room temperature with a crosshead speed of 20 mm/min according to the ASTM D882-88 standard method.
  • Fluorescein-labeled bovine serum albumin (FITC-BSA) was dissolved in PBS at 10 mg/mL.
  • PCL and PCL/HA-g-PCL films (5 5 1mm, L W H) were soaked in the FITC -BS A/PBS solution and placed in a 37°C incubator. At specified time points, polymer films were removed and washed three times with DI water. Fluorescence micrographs of sample surfaces were recorded using an Olympus 1X70 inverted microscope equipped with an Olympus DP72 camera and CellSens software. All sample images were acquired using the same exposure time (10 s). The amount of protein adsorbed onto the surfaces was approximated by the green fluorescence intensity of each image.
  • PCL end-capped with hydroxyl group was synthesized through ring-opening polymerization with a yield of 90%.
  • the number average molecular weight (Mn) of PCL synthesized was 7300 Da calculated from the proton NMR spectrum with a yield of 90%.
  • the PCL end-capped with isocyanate was confirmed by FTIR. The peak at 2200 cm "1 corresponding to the vibration of isocyanate functional group clearly confirmed the success of end-capping reaction.
  • the synthesized CTA-HA-g-PCL was characterized by ⁇ -NMR with DMSO-d 6 as solvent, shown in Figure 1.
  • the degree of grafting of PCL was calculated from the following formula:
  • HA-g-PCL The particle size distribution of HA-g-PCL was measured by DLS in both water and chloroform, and the colloidal stability of these particles is shown as a function of incubation time ( Figure 2). This measurement was to confirm that self assembly of the HA-PCL conjugate can happen in both solvents. The average effective diameter of the particles is a little larger in
  • the particles size measured by TEM is around 50 nm in water and 60 nm in chloroform ( Figure 3). Compared with the sizes measured by DLS, they are much smaller. The possible reason is that DLS measures the particle size in solution, with particles swelled by solvent, while TEM measures the size of dry particles.
  • PCL/HA-g-PCL composites consisting of bulk PCL and HA conjugates were prepared, of which the weight content of HA conjugate HA-g-PCL was 1 wt% and 3 wt%. Thermal and mechanical properties of the PCL/HA-g-PCL composites
  • Pristine PCL film is highly hydrophobic and HA is hydrophilic, so the measurement of water contact angle of the nanocomposite films will give us clues on whether there is any HA on the surface.
  • the contact angle is around 80 °C, which dropped significantly to 58 °C after incorporation of HA-g-PCL, indicating that the HA on the surface of the nanocomposite films made the surface significantly hydrophilic.
  • PCL segment of the HA-g-PCL conjugate is a reliable anchor and that HA will not be lost with time in water
  • the invention provides a sustainable antifouling surface for the medical devices made from
  • FITC-BSA was used as a model protein to test the antifouling properties of the materials.
  • PCL/HA-g-PCL composites showed an obviously improvement of anti-absorption of BSA protein up to 32 h, as shown in Figure 7.
  • the antifouling property of the PCL/HA-g-PCL nanocomposite films was tested with mouse fibroblast NIH3T3 cells.
  • the anti-adhesion effect was very significant at both time points; there were almost no cells observed on the surfaces of PCL/HA-g-PCL composites compared with the large amount of cells attached and spread on the surfaces of pristine PCL and bare tissue culture plate (TCP) controls.
  • TCP bare tissue culture plate
  • the polished samples were also tested for cell adhesion also with PCL/HA-g-PCL- 3% as an example.

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Abstract

L'invention concerne des matières polymères ayant des surfaces antisalissures améliorées (par exemple continues). Les matières peuvent être incorporées dans diverses matières, notamment des dispositifs médicaux, des microsphères, des nanoparticules et des contenants. Ces matières combinent des conjugués de copolymère amphiphile ayant un hyaluronane comme composant hydrophile, dispersés à travers la matière d'origine biologique polymère en masse. Le composant hydrophobe du copolymère aura une bonne compatibilité avec le polymère en masse hôte, permettant une excellente dispersion du copolymère dans la masse, et un ancrage pour le composant hydrophile à la surface. Le segment d'acide hyaluronane hydrophile s'étalera sur la surface de polymères et agira comme couche antisalissure dans un environnement aqueux ; et le copolymère sera uniformément dispersé dans la matrice polymère et ne migrera pas à la surface à cause de sa masse moléculaire élevée. De ce fait, alors que le polymère en masse se dégrade, l'amphiphile à HA dispersé deviendra disponible pour « revêtir » l'interface biologique à changement dynamique.
PCT/US2013/030543 2012-05-25 2013-03-12 Matières d'origine biologique à surface renouvelable WO2013176739A1 (fr)

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JP2016141697A (ja) * 2015-01-29 2016-08-08 学校法人東京電機大学 修飾ヒアルロン酸及び／又はその塩、並びにその製造方法

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