WO2012175563A1 - Colle biocompatible ainsi que procédé de fabrication de ladite colle - Google Patents

Colle biocompatible ainsi que procédé de fabrication de ladite colle Download PDF

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Publication number
WO2012175563A1
WO2012175563A1 PCT/EP2012/061856 EP2012061856W WO2012175563A1 WO 2012175563 A1 WO2012175563 A1 WO 2012175563A1 EP 2012061856 W EP2012061856 W EP 2012061856W WO 2012175563 A1 WO2012175563 A1 WO 2012175563A1
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WO
WIPO (PCT)
Prior art keywords
adhesive
collagen
weight
aqueous
hyaluronate
Prior art date
Application number
PCT/EP2012/061856
Other languages
German (de)
English (en)
Inventor
Michael Sittinger
Jochen Ringe
Tilo Dehne
Boris Habermann
Rafael Valbuena
Günter Westphal
Original Assignee
Charité - Universitätsmedizin Berlin
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 Charité - Universitätsmedizin Berlin filed Critical Charité - Universitätsmedizin Berlin
Publication of WO2012175563A1 publication Critical patent/WO2012175563A1/fr

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Classifications

    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J105/00—Adhesives based on polysaccharides or on their derivatives, not provided for in groups C09J101/00 or C09J103/00
    • C09J105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J189/00—Adhesives based on proteins; Adhesives based on derivatives thereof
    • C09J189/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C09J189/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin

Definitions

  • Biocompatible adhesives or adhesives are used in many areas of medicine. It is not only important that the adhesive has a high adhesive effect, but it is also important that the adhesive is well-tolerated and thus biocompatible. For this reason, efforts are made to provide adhesives, which preferably consist of well-tolerated components. For example, from US 5,209,776, US 2005/02081 14A1 or US 4,280,954 adhesives are known which may contain the components collagen and hyaluronic acid.
  • a problem with these adhesives is e.g. in that these adhesives either contain denatured collagen, a covalent bond between collagen and hyaluronic acid is produced and / or catalysts or other constituents are used which bring about an increased allergy potential.
  • the object of the present invention is to provide improved adhesives and processes for their preparation.
  • the object is achieved by providing a method for producing an adhesive, characterized in that an aqueous collagen solution having a dissolved collagen concentration of 0.01 to 5% (w / v) and a pH of 2 to 5 with an aqueous hyaluronate solution having a hyaluronate or hyaluronic acid concentration of 0.02 to 5% (w / v) and a pH of 5 to 7, preferably 6 to 7, mixed and the resulting precipitate is separated from the liquid phase , Preferably, the mixture of the aqueous collagen solution and the aqueous hyaluronate solution is stirred until the precipitate has formed.
  • the inventive method is characterized in particular by the fact that the preparation of the adhesive requires no addition of a catalyst.
  • the resulting precipitate is a biocompatible adhesive with good adhesion, high biocompatibility and low allergy potential.
  • the adhesive according to the invention contains or consists of 1 to 20% by weight of collagen, 0.5 to 15% by weight of hyaluronic acid or hyaluronate and 65 to 98.5% by weight of water; the data in% by weight relate to the total weight of the adhesive.
  • the starting polymers are structured as a polyionic complex (PIK) of positively charged collagen and negatively charged hyaluronic acid. Between the polymers arise ionic interactions and no covalent bonds. By means of a polyion complex, an improved sustainability of the adhesive properties is achieved via the interaction mechanism.
  • the functional groups of the polymers are reversibly associated with each other via ionic interactions and are therefore fully reactive again after a temporary separation. The interaction of the two polymers results in a liquid phase and a gelatinous, sticky solid phase as a precipitate (also referred to herein as a coprecipitate or adhesive).
  • the biocompatible adhesive that is the solid, sticky phase, precipitate or coprecipitate, is recovered by separation from the liquid phase.
  • various methods such as centrifugation, filtration or simple decanting can be used.
  • the formed PIKs of the precipitate further possess functional, in particular nucleophilic groups, which can ensure a continuous interaction with surrounding cellular systems or tissues.
  • the free functional groups of the polymers in the precipitate can thus bonds with the environment, eg. B. in the form of tissues or frameworks, received.
  • the adhesive is particularly suitable for use in the medical field.
  • an aqueous collagen solution which has a concentration of dissolved collagen of 0.01% to 5% (w / v), based on the total volume of the aqueous collagen solution.
  • the aqueous collagen solution preferably has a concentration of dissolved collagen of from 0.1% to 1% (w / v), in each case based on the total volume of the aqueous collagen solution.
  • the aqueous collagen solution has a pH in the acidic range of from pH 2 to pH 5, preferably a pH of from 2.3 to pH 4.5.
  • dissolved collagen is understood as meaning collagen which is present dissolved in the aqueous collagen solution and is substantially non-hydrolyzed and / or non-denatured.
  • the collagen can be used as a natural collagen or renatured.
  • the dissolved collagen is present in the aqueous collagen solution in native triple helical structure. The recovery of such collagen is known to those skilled in principle.
  • the collagen can be obtained from the skin, especially from the skin of animals such as pigs.
  • the collagen used according to the invention contains or consists preferably of type I collagen or of a mixture of different types of collagen, with type I collagen in the mixture preferably making up the largest proportion by mass in comparison to every other type of collagen.
  • Other collagen types may be, for example, Type II, III, V collagen. However, other types of collagen may also be present in the mixture.
  • the collagen according to the invention is preferably collagen type I in substantially pure form or a mixture of different types of collagen, type I collagen making up at least 30%, particularly preferably at least 50%, of the total collagen mass.
  • the collagen may contain or consist of atelocollagen and / or tropocollagen. Atelocollagen is characterized by the fact that it is dissolved collagen without telopeptides.
  • the aqueous collagen solution is mixed in the process according to the invention with an aqueous hyaluronate solution.
  • Hyaluronic acid or hyaluronate is preferably used here, which has an average molecular weight of from 1, 400 to 2,400 kDa.
  • the aqueous hyaluronate solution has a hyaluronic acid concentration or a hyaluronate concentration of from 0.02% to 5% (w / v), preferably from 0.2% to 1% (w / v), in each case based on the total volume of the aqueous hyaluronate solution.
  • the hyaluronate used is a salt of hyaluronic acid with various cations, preferably the sodium salt of hyaluronic acid.
  • the aqueous hyaluronate solution Before being mixed with the aqueous collagen solution, the aqueous hyaluronate solution has a pH of from pH 5 to 7 or pH 6 to pH 7, preferably from pH 5.5 to 6.5, more preferably from pH 6.3 to pH 6.5.
  • the concentration data for collagen and hyaluronic acid or hyaluronate and the pH ranges for the aqueous collagen solution and the aqueous hyaluronate solution before the mixture of the two aqueous solutions are essential components for the fact that the precipitate and thus the desired adhesive can form without the use of a catalyst.
  • the allergy potential of the resulting adhesive can be further reduced if, for example, hyaluronate or hyaluronic acid of non-animal origin, preferably of bacterial origin, is used. This can be obtained, for example, biotechnologically. It has proven particularly favorable when the hyaluronate or hyaluronic acid is peptide-free.
  • the aqueous collagen solution and the hyaluronate aqueous solution are mixed together to produce a precipitate which, separated from the aqueous phase, is an adhesive of the present invention.
  • Particularly favorable results are achieved when the aqueous collagen solution and the aqueous hyaluronate solution are mixed with each other in a fixed mass ratio.
  • the aqueous collagen solution and the aqueous hyaluronate solution are mixed together in a mass ratio of 1: 0.5 to 1: 1, 5, more preferably in a mass ratio of 1: 0.7 to 1: 1.2.
  • the efficiency of the preparation of the adhesive with the method according to the invention can be further increased by stirring the mixture until a precipitate is formed.
  • the precipitate is separated from the aqueous phase and can be used as the adhesive of the present invention.
  • the separation of the precipitate from the aqueous phase of the mixture can be achieved by conventional methods, for example by centrifugation, filtration and / or decantation.
  • aqueous collagen solution and / or aqueous hyaluronate solution may additionally comprise further constituents, in which case preferably biocompatible constituents are used.
  • biocompatible ions, salts, organic or inorganic acids and / or bases, sugars, proteins, amino acids, oligopeptides, telopeptides and / or gelatin and mixtures thereof can be used.
  • the process according to the invention may be provided in the process according to the invention to homogenize the precipitate obtained.
  • This homogenization can be carried out, for example, by treating the precipitate with shearing forces.
  • the optimum range for the peripheral speed of a rotor-stator arrangement for generating the shear forces is in the range of 2 to 25 m / s.
  • the resulting precipitate can be homogenized before, during or after separation from the liquid phase. Homogenization is preferably carried out after separation of the precipitate from the liquid phase.
  • an adhesive can be produced, which is characterized by a particularly favorable stability in higher pH ranges.
  • a particularly favorable stability is achieved.
  • This is achieved, for example, by adding arginine and calcium hydroxide in the process so that the resulting precipitate contains from 1 to 6% by weight of arginine and from 1 to 6% by weight of calcium hydroxide, the data in% by weight being based on the Total weight of the precipitate refer.
  • the arginine and / or calcium hydroxide may be added to the aqueous collagen solution and / or to the aqueous hyaluronate solutions prior to their mixing and / or to the separated precipitate.
  • the aqueous collagen solution is preferably arginine and the aqueous
  • Hyaluronate solution Calcium hydroxide added before mixing the aqueous collagen solution and the aqueous Hyaluronatives.
  • the arginine is preferably added in such a way that a concentration of from 1 to 6% by weight of arginine is achieved in the adhesive, the details in% by weight being based on the total weight of the adhesive.
  • the calcium hydroxide can be added in such a way that a concentration of 1 to 6 wt .-% calcium hydroxide is achieved in the adhesive, wherein the data in wt .-% based on the total weight of the adhesive.
  • the calcium hydroxide is added as an aqueous solution.
  • the addition of arginine and / or calcium hydroxide takes place during the homogenization of the precipitate.
  • the present invention also relates to an adhesive comprising or consisting of: 1 to 20% by weight of collagen,
  • the data in% by weight relate to the total weight of the adhesive.
  • the adhesive according to the invention contains or consists of:
  • the data in% by weight relate to the total weight of the adhesive.
  • a particular embodiment of the adhesive according to the invention which has improved stability at higher pH ranges, contains arginine and calcium hydroxide.
  • the adhesive according to the invention contains or consists of: 1 to 15% by weight of collagen,
  • the data in% by weight relate to the total weight of the adhesive.
  • the adhesive according to the invention can be distinguished, in particular, in that it contains no other sticking or adhesion-promoting substances ("tackifying agent”)
  • tacky or adhesion-promoting substances can be understood to mean, for example, dextran, polyglucosides, polyvinylpyrrolidone, bioresorbable starch or derivatives thereof and / or bioresorbable cellulose or derivatives thereof, such as, for example, cellulose ethers and salts thereof
  • the arginine and / or the calcium hydroxide can be added to the corresponding aqueous collagen or hyaluronic acid or hyaluronate solutions prior to their mixing and / or directly to the separated one
  • the calcium hydroxide is preferably metered in as an aqueous solution, and the precipitate is homogenized in order to obtain a homogeneous product and to further improve the adhesive properties of the precipitate (polyionic complex) For example, by using preselected shear forces.
  • the homogenization can already take place during the addition of the arginine and / or the calcium hydroxide.
  • the adhesive according to the invention is distinguished by a particularly favorable adhesive effect if collagen and hyaluronic acid or hyaluronate are present in a weight ratio of 0.5: 1 to 5: 1 in the adhesive.
  • the adhesive of the present invention may be prepared by the above-described process of the present invention for producing an adhesive.
  • the present invention also relates to the use of the adhesive of the invention in the medical field.
  • the adhesive according to the invention can be used as a surgical adhesive, for the local introduction of cells with or without cell carriers, for the local introduction of active ingredients and / or excipients, for the treatment of wounds (externally and / or in the body) and in the implantation of medical devices ,
  • Figure 1 shows results from the SDS-PAGE study of native collagen extracted with acid solutions, where in lane 1 a molecular weight standard (band at 64, 98, 148 and 250 kDa), in lane 2 a collagen standard
  • FIG. 2 shows the IR spectrum of a coprecipitate of atelocollagen
  • Figure 3 shows the results of a determination of adhesiveness in vital cartilage (A)
  • Bone tissue (B). Shown are the average values from 5 measurements with the standard deviation as error bars. Examples:
  • Pre-cleaning Separation of dirt and blood residues and, where appropriate, NaCI removal; for hydration and loosening of the tissue, the cut skin is washed with 5 times the amount of water three times with stirring (each 2 hours treatment time).
  • non-collagenous proteins are to be separated from the skin.
  • a solution containing 6% NaCl (w / v) and 1% formic acid (w / v) is prepared.
  • the swollen skin is extracted with this solution twice with stirring (each 24 hours treatment time, skin-to-solution ratio 1: 5 w / v).
  • the skin is separated from the extractant.
  • collagen extraction from the pigskin can be done in different ways.
  • acetic acid In the extraction by means of acetic acid, 20 g of the treated skin are mixed with 125 ml of acetic acid (0.1M to 1.0M, preferably 0.5M) and extracted with stirring for 48 hours at 25 ° C. Subsequently, the liquid phase (collagen solution) is separated from the solid phase (skin residue). The collagen solution is then purified by ultrafiltration (cross-flow filtration on a UF membrane of polyethersulfone, MWCO 50 kDa) and concentrated. The amount of collagen can be determined by an amino acid analysis or a hydroxyproline determination according to the method of Stegemann and Stalder. The determination of the proportion of native collagen can be determined by means of CD spectroscopy and SDS-PAGE Electrophoresis done. The collagen extracted in this way is present as tropocollagen (see Table 1 and Figure 1).
  • urea-based substance solution 4 M to 8 M, preferably 6 M
  • the collagen solution is separated from the skin residue and purified by dialysis (dialysis tube of regenerated cellulose, pore size 8 - 15 kDa) against 0.1 M acetic acid.
  • the collagen is also present as tropocollagen, here renatured before (see Table 1).
  • the pH is adjusted to 3 to 4 with acetic acid and the collagen is precipitated with NaCl (2.5 M NaCl in the total mixture) and then centrifuged off. There are two further cleaning steps. In each of these steps, the collagen is redissolved in 0.1 M acetic acid, reprecipitated with NaCl (1.8 M NaCl in the total mixture) and then removed by centrifugation. Finally, to remove NaCI, the purified collagen is finally dialyzed against 0.1 M acetic acid (dialysis tube made of regenerated cellulose, pore size 8 - 15 kDa). The collagen is present as atelocollagen (see Table 1).
  • Table 1 Amino acid composition of tropocollagen (Example 1) and atelocollagen
  • the coprecipitate contains 5.0 to 15.0% (w / w) collagen, 3.0 to 10.0% (w / w) hyaluronic acid and 75.0 to 92.0 % Water.
  • Example 4 Preparation of an adhesive of collagen and hyaluronic acid using atelocollagen
  • Example 4 describes the preparation of an adhesive based on atelocollagen.
  • Atelokollagenmoleküle contains (concentration of collagen 0.1 to 1, 0% w / v) and has a pH of 2.3 to 4.5, with an already prepared solution of Na-hyaluronate of biotechnological origin (pH 6.3 to 6.5, concentration 0.2 to 1, 0% w / v, mg of the
  • Hyaluronate 1 .400 to 2400 kDa in a mass ratio of 1: 1 (collagen solution to hyaluronate solution) mixed. The mixture is then stirred until a coprecipitate is formed. This is separated from the liquid phase by centrifuging or decanting.
  • Coprecipitate is highly adhesive and constitutes the adhesive.
  • the coprecipitate contains 5.0 to 15.0% (w / w) collagen, 3.0 to 10.0% (w / w) hyaluronic acid and 75.0 to 92.0%. Water.
  • Figure 2 shows the IR spectrum of a coprecipitate of atelocollagen and Na-hyaluronate of biotechnological origin.
  • Example 5 Preparation of an adhesive of collagen and hyaluronic acid using arginine, calcium hydroxide and shear forces
  • the arginine was dissolved in the collagen solution (0.9 g of arginine per 100 g of 0.8% strength
  • Femur bone made of pig This raw punch contains both bone and cartilage tissue.
  • This raw punch contains both bone and cartilage tissue.
  • the surface was cut flat using a microtome.
  • the cartilage layer was completely removed.
  • two cylinders (cartilage or bone) were vertically opposed, centered and placed at a distance of 5 mm in a Zwick force measuring stand (Z005) by means of a round sample holder. The course of the measurement was as follows.
  • an adhesion of on average 15.2 kN / m 2 with a standard deviation of 1.0 kN / m 2 could be measured for the adhesive produced according to the invention in comparison to cartilage tissue.
  • this value in the same tissue was only 5.2 kN / m 2 , with a standard deviation of 2.5 kN / m 2 ( Figure 3A).
  • an adhesion of 1 1, 8 kN / m 2 with a standard deviation of 1, 9 kN / m 2 was determined for the collagen hyaluronic acid adhesive.
  • fibrin glue it was significantly lower at 2.6 kN / m 2 and the standard deviation was 1.9 kN / m 2 (Fig. 3B).
  • the adhesive effect of the adhesives prepared according to Examples 3 and 4 does not differ, but the adhesive prepared on the basis of atelocollagen has a reduced allergy potential.

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

Abstract

L'invention concerne une colle contenant ou constituée de 1 à 20 % en poids de collagène, de 0,5 à 15 % en poids d'acide hyaluronique ou de hyaluronate et de 65 à 98,5 % en poids d'eau, les données en % en poids se rapportant au poids total de la colle. La présente invention concerne également un procédé pour la fabrication d'une telle colle.
PCT/EP2012/061856 2011-06-20 2012-06-20 Colle biocompatible ainsi que procédé de fabrication de ladite colle WO2012175563A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011077809.8 2011-06-20
DE102011077809A DE102011077809A1 (de) 2011-06-20 2011-06-20 Biokompatibles Klebemittel sowie Verfahren zu dessen Herstellung

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WO2012175563A1 true WO2012175563A1 (fr) 2012-12-27

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Cited By (1)

* Cited by examiner, † Cited by third party
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CN111420023A (zh) * 2020-04-30 2020-07-17 广州市红十字会医院（暨南大学医学院附属广州红十字会医院） 含i型胶原和透明质酸的复合物及制备和用途

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* Cited by examiner, † Cited by third party
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CN115645617B (zh) * 2022-09-09 2023-07-25 北京鑫康辰医学科技发展有限公司 一种具有生物活性的骨基质凝胶的制备方法

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US4280954A (en) 1975-07-15 1981-07-28 Massachusetts Institute Of Technology Crosslinked collagen-mucopolysaccharide composite materials
US5137875A (en) * 1988-04-19 1992-08-11 Shiseido Co., Ltd. Hyaluronic acid-containing aqueous solution or aqueous dispersion of collagen
CZ202591A3 (cs) * 1991-07-02 1993-01-13 Hypro Vyzkum Prostředek pro prevenci dekubitft a topickou terapii kožních lézt
US5209776A (en) 1990-07-27 1993-05-11 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5866165A (en) * 1997-01-15 1999-02-02 Orquest, Inc. Collagen-polysaccharide matrix for bone and cartilage repair
US20050208114A1 (en) 1998-03-24 2005-09-22 Petito George D Composition and method for healing tissues
US20110081701A1 (en) * 2009-10-02 2011-04-07 Timothy Sargeant Surgical compositions

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WO2008103997A2 (fr) 2007-02-23 2008-08-28 Bioject Inc. Dispositifs d'injection sans aiguille et systèmes d'administration de médicament pour ceux-ci

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US4280954A (en) 1975-07-15 1981-07-28 Massachusetts Institute Of Technology Crosslinked collagen-mucopolysaccharide composite materials
US5137875A (en) * 1988-04-19 1992-08-11 Shiseido Co., Ltd. Hyaluronic acid-containing aqueous solution or aqueous dispersion of collagen
US5209776A (en) 1990-07-27 1993-05-11 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
CZ202591A3 (cs) * 1991-07-02 1993-01-13 Hypro Vyzkum Prostředek pro prevenci dekubitft a topickou terapii kožních lézt
US5866165A (en) * 1997-01-15 1999-02-02 Orquest, Inc. Collagen-polysaccharide matrix for bone and cartilage repair
US20050208114A1 (en) 1998-03-24 2005-09-22 Petito George D Composition and method for healing tissues
US20110081701A1 (en) * 2009-10-02 2011-04-07 Timothy Sargeant Surgical compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111420023A (zh) * 2020-04-30 2020-07-17 广州市红十字会医院（暨南大学医学院附属广州红十字会医院） 含i型胶原和透明质酸的复合物及制备和用途
CN111420023B (zh) * 2020-04-30 2024-03-15 广州市红十字会医院（暨南大学医学院附属广州红十字会医院） 含i型胶原和透明质酸的复合物及制备和用途

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