WO2018056937A2 - Barrière d'adhérence nano-fibreuse - Google Patents

Barrière d'adhérence nano-fibreuse Download PDF

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WO2018056937A2
WO2018056937A2 PCT/TR2017/050302 TR2017050302W WO2018056937A2 WO 2018056937 A2 WO2018056937 A2 WO 2018056937A2 TR 2017050302 W TR2017050302 W TR 2017050302W WO 2018056937 A2 WO2018056937 A2 WO 2018056937A2
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solution
hyaluronic acid
nanofibrous
electrospinning
carboxymethyl cellulose
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PCT/TR2017/050302
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WO2018056937A3 (fr
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Esra KARACA
Gozde Rabia OZALP
Serife SAFAK
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Karaca Esra
Ozalp Gozde Rabia
Safak Serife
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Publication of WO2018056937A2 publication Critical patent/WO2018056937A2/fr
Publication of WO2018056937A3 publication Critical patent/WO2018056937A3/fr

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the invention relates to adhesion barriers used in the biomedical field.
  • the invention relates in particular to a nanofibrous mat suitable for use as an adhesion barrier in biomedical field obtained by electrospinning method from a mixture of hyaluronic acid (HA), sodium alginate (NaAlg) and carboxymethyl cellulose (CMC) polymer solutions.
  • HA hyaluronic acid
  • NaAlg sodium alginate
  • CMC carboxymethyl cellulose
  • Adhesions are described as abnormal adhesions that are not normally associated with each other in the intra-abdominal region, and that the organs surrounded by the serous membrane are involved with each other's and / or adjacent organs following injury or surgical operations.
  • the main causes of adhesions are surgical procedures. Adhesions are common after thoracal, heart and abdominal operations. Postoperative intraabdominal adhesion formation rates are between 64% and 97%.
  • Abdominal adhesions which are one of the most important problems of both surgeons and patients, lead to chronic abdominal and pelvic pain, organ obstructions (bowel, ovarian tubule, kidney drainage channels, etc.) and functional disorders. As a result, it causes new operations to be performed.
  • adhesions are responsible for one third of all intestinal obstructions and two-thirds of small intestinal obstructions [1 - 5].
  • Adhesion opening operations are long-running operations. During these operations, anesthesia and the length of stay at the hospital are prolonged. Therefore, prevention of intra-abdominal adhesion is a very important issue during surgical interventions [6, 7].
  • the main approaches proposed in the literature to prevent or reduce adhesion are divided into three categories: the development of surgical techniques, the use of anti-adherence drugs, and the separation of tissues in the healing process.
  • the basic surgical principles that all surgeons must apply in order to prevent adhesion are to reduce surgical trauma as much as possible, to avoid unnecessary and excessive manipulations, to remove foreign bodies and dead tissues, to prevent dryness due to inadequate blood supply and loss of water in the tissues and to keep bacterial invasion to a minimum level.
  • the therapies and technological developments to be made with the surgical technique may not prevent adhesion formation but only reduce it [3, 4].
  • Adhesion barriers allow the surfaces in the injured intraabdominal region to be separated from each other and freely heal and thus prevents the formation of adhesion.
  • physical barriers used as adhesion inhibitors are divided into two main groups as liquid barriers and membrane barriers. These barriers are often used with a mesh material.
  • Composite mesh structures consisting of a combination of mesh and adhesion barriers are also available. However, these materials are very expensive and cannot be used in any part of the body [4, 5].
  • Adhesion barriers which have recently been developed and found to be the most widely used in clinical practice are the oxide regenerated cellulose membrane (Interceed®), e- polytetrafluoroethylene membrane (Gore-tex®) and carboxymethyl cellulose / hyaluronic acid membrane (Seprafilm®). The first two are used only in gynecology, and the latter are widely used both in general surgery and in gynecology.
  • HA hyaluronic acid
  • NaAlg sodium alginate
  • CMC carboxymethyl cellulose
  • the patent with the publication number EP2598180B1 relates to "Hyaluronic acid based hydrogel and its use in surgery".
  • the present invention relates to hydrogels based on hyaluronic acid-based derivatives which are more resistant to chemical and enzymatic degradation than hyaluronic acid alone.
  • Hyaluronic acid based hydrogel in various surgeries, has an optimal use for example for injection into bone fractures or cavities and for the production of prosthetic coatings in orthopedic surgery, as fillers in cosmetic and maxillofacial surgery, and as an anti-adhesion barrier in abdominal and abdominal / pelvic surgery and in the general surgery with the prevention of postoperative adhesions.
  • the patent with the publication number EP1975284B1 relates to "the electrospinning apparatus for serial production of nanofibers".
  • the invention refers to an electrophotographic apparatus having electrical stability and an improved nozzle blocks.
  • the patent with the publication number TR 2013 1341 7 relates to "Coaxial nanofibrous mats with plant extract".
  • mats are produced from coaxial biopolymer nanofibers trapped in plant extracts in their own regions.
  • Biologically compatible and degradable nanofibrous mats capable of releasing antioxidant and antimicrobial plant extracts, are produced by coaxial electrophoresis.
  • the present invention is concerned with a nanofiber adhesion barrier which meets the above-mentioned requirements, removes all disadvantages and adds some additional advantages.
  • the primary object of the invention is to obtain a nanofibrous mat from a mixture of hyaluronic acid (HA), sodium alginate (NaAlg) and carboxymethyl cellulose (CMC) polymer solutions suitable for use as an adhesion barrier in biomedical field.
  • HA hyaluronic acid
  • NaAlg sodium alginate
  • CMC carboxymethyl cellulose
  • the invention aims to provide a nanofibrous mat by means of electrospinning from a mixture of hyaluronic acid (HA), sodium alginate (NaAlg) and carboxymethyl cellulose (CMC) polymer solutions.
  • HA hyaluronic acid
  • NaAlg sodium alginate
  • CMC carboxymethyl cellulose
  • One object of the invention is to provide an alternative product that is easier and more efficient to use than commercial adhesion barriers used in the market.
  • Another object of the invention is to provide a nanofibrous product produced by electrospinning from carboxymethyl cellulose, sodium alginate and hyaluronic acid polymers, having the potential to inhibit / reduce adhesion by being used during intraabdominal surgery, thus reducing post-operative complications and providing less costly alternatives to commercially available products.
  • the invention is a nanofibrous mat obtained from the hyaluronic acid and carboxymethyl cellulose polymer mixture, suitable for using as an adhesion barrier in the biomedical field in order to fulfill the above-mentioned purposes.
  • Said polymer mixture also comprises sodium alginate.
  • the method of producing said nanofibrous mat to realize the objects of the invention comprises the steps of; ⁇ The preparation of the hyaluronic acid solution in the solvent,
  • an aqueous sodium alginate solution is prepared and mixed with the previously prepared hyaluronic acid solution and carboxymethyl cellulose solution.
  • betaine or Triton X-100 as surfactant NaOH/Dimethyl sulfoxide or NaOH/Dimethylformamide as solvent are used.
  • NaOH/Dimethyl sulfoxide or NaOH/Dimethylformamide solvent the mixing ratio between NaOH and Dimethyl sulfoxide or Dimethylformamide is 4/1 by volume
  • the concentration of hyaluronic acid solution prepared in the solvent is in the range of 8-15% by mass/volume %.
  • the concentration of carboxymethyl cellulose solution prepared in purified water is in the range of 1 -4% mass/mass %.
  • the concentration of sodium alginate solution prepared in pure water is in the range of 1 -4% by mass/mass %.
  • said hyaluronic acid solution, carboxymethyl cellulose solution and sodium alginate solution are mixed at a ratio of 3/1 /1 to 5/1 /1 by volume.
  • the mixture of the hyaluronic acid solution, the carboxymethyl cellulose solution and the sodium alginate solution is mixed with the surfactant in a ratio of 5/1 to 9/1 by volume.
  • the cross-linking process comprises the steps that,
  • said 1 -ethyl-3-(3-imethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide or divinyl sulfone is 50-100 imM. Ethanol or methanol is used as the solvent.
  • the invention is a nanofibrous mat obtained by electrospinning from a mixture of hyaluronic acid and carboxymethyl cellulose polymer suitable for use as an adhesion barrier in biomedical field. Said polymer mixture also comprises sodium alginate.
  • FIG. 1 Is the Scanning Electron Microscopy (SEM) views of the nanofibrous mats ((a)
  • FIG. 3 Is the EDC/NHS cross-linking process views, ((a) the samples given to the
  • Figure-4 Is the view of the water resistance test of the nanofibrous mat before cross- linking process.
  • Figure-5 Is the view of the water resistance test of the nanofibrous mat after cross- linking process.
  • Figure-6 Is the view of Scanning Electron Microscopy (SEM) views of the nanofibrous mat after the cross-linking process with EDC/NHS. ((a) 50 mM/100 imM, (b)
  • Figure-7 It is a schematic view showing the insertion of the adhesion barrier (such as mesh) into the tissue [81 ].
  • the adhesion barrier such as mesh
  • Figure-8 It is a schematic view of the electrospinning process. Description of Parts Reference
  • inventive nanofibrous adhesion barrier and its preferred embodiments are described only for a better understanding of the subject and without forming any restrictive effect.
  • the invention relates to a nanofibrous mat obtained by electrospinning a mixture of hyaluronic acid (HA), sodium alginate (NaAlg) and carboxymethyl cellulose (CMC) polymer, suitable for use as an adhesion barrier in the biomedical field.
  • HA hyaluronic acid
  • NaAlg sodium alginate
  • CMC carboxymethyl cellulose
  • CMC Carboxymethyl cellulose
  • Hyaluronic acid is a high molecular weight, highly water-absorptive, antitoxic, biocompatible and biodegradable polymer. It is used in cosmetics, biomedical and food industries. Its ability to absorb water, high viscoelasticity and non-toxic properties due to high molecular weight and negatively charged nature make it possible to use HA in cosmetic, biomedical and food industries. Due to its biocompatibility and biodegradability, HA polymer has been especially found in tissue engineering applications in gel and/or film [26, 28-31 ]. Due to the water retention properties of the HA polymer, it is not possible to produce nanofibers in a conventional electrospinning unit. There are various studies in the literature regarding the usability of HA nanofibrous mats produced by different methods as tissue scaffolds and wound covers [32-38].
  • the hyaluronic acid (HA) from the glucose aminoglycan polymer is a long chain polysaccharide first isolated from the transparent fluid of the retina in the eye. It is composed of repeating disaccharide units occurred by glycosidic linkage ⁇ -1 ,3 and ⁇ -1 ,4 of the N-acetyl-D-glucosamine and D-glucuronic acid.
  • the molecular structure of hyaluronic acid is given below.
  • Hyaluronic acid is one of the major components of the extracellular space between cells in various living organisms such as cartilage, joint fluid, skin and umbilical cord. It can be purifed from rooster swallow, baby cord and some other animal sources. In addition, it can be obtained from bacteria by fermentation and isolation methods. It has been noted that hyaluronic acid does not cause any allergic reaction in any way [25-27].
  • Carboxymethyl cellulose is an inert, water-soluble, biocompatible polymer with high water retention capacity, resistant to bacterial growth. This polymer is used as a binder, blowing agent, gelling agent, adhesive and stabilizer agent in textile, paper, pharmaceutical, paint, cosmetic, ceramic and food industries.
  • the main reasons for preferring CMC as an additive in the fields of use are that it is physiologically inert, its solubility in water, resistance to certain pH, high water-holding capacity, compatibility with other colloids and resistance to bacterial growth due to high sodium content. It is also known that carboxymethyl cellulose is transparent, flexible and forms films resistant to oils and organic solvents [39-42].
  • CMC carboxymethyl cellulose
  • cellulose contains hydrophilic carboxymethyl groups and the hydrogen bonds are very weak due to not the homogeneous settling of these groups. These two conditions cause the CMC polymer to absorb too much water [39].
  • CMC molecules have a flat structure at low concentrations. Due to their ionic carboxyl groups, they have negatively charged (anionic), long and rigid molecules and these molecules push each other in solution. For this reason, CMC solutions show a highly viscous stable structure [39-42].
  • Carboxymethyl cellulose is a cellulose-derived polysaccharide formed by the attachment of carboxymethyl groups (CH2-COOH) to hydroxyl groups of glucopyranose monomers which constitute the cellulose chain, resulting from the reaction of alkali groups and chloroacetic acid. In other words, it's produced with carboxylation of the cellulose and enters to the group of cellulose ethers.
  • the re-unit that forms the CMC molecule chains consists of ⁇ -(1 - 4) -D-glucopyranose linked to the cellulose group [39-42].
  • the molecular structure of carboxymethyl cellulose is given below.
  • CMC nanofibrous mats Because of its rigid structure and high surface tension it does not allow chain complexity and therefore the aqueous solutions cannot form a stable jet, the electrospinning of CMC polymer is quite hard. For this reason, in the limited studies in the literature, it has been possible to produce CMC nanofibrous mats by using co-polymers such as polyvinyl alcohol (PVA) and polyethylene oxide (PEO) or by adding additives such as aluminum and lithium [43-45]. The CMC nanofibrous mats produced in this way were used in lithium ion batteries [45-49] and drug delivery systems [50].
  • PVA polyvinyl alcohol
  • PEO polyethylene oxide
  • Sodium alginate is a biocompatible polymer that has the ability to absorb wounds, stop the bleeding, and have high moisture absorption and gelling ability.
  • the specific properties of sodium alginate that facilitate wound healing, high moisture absorption and ion exchange abilities, excellent biocompatibility and bleeding inhibitor properties make it a unique raw material in the production of high absorbent wound dressing [54].
  • Alginates have been used in food, pharmaceutical, medical, textile and paper industries for many years. Recently, its use has increased, especially in biomedical and medical fields.
  • Alginate is a natural polysaccharide derived from brown seaweed and on the cell walls of these mosses it is present as calcium, magnesium and sodium salts of alginic acid. While the calcium and magnesium salts of alginate are insoluble in water, the sodium salt is soluble in water.
  • Sodium alginate is defined as a block copolymer because its polymeric structure is formed by the incorporation of two types of monomeric acids as blocks into a-L-guluronic acid (G) and ⁇ -D-mannuronic acid (M). The molecular structure of sodium alginate is given below.
  • alginate which is structurally similar to cellulose, unlike cellulose, the COOH group is replaced by the CH2OH group [51 , 52].
  • the most important feature of alginates is the reaction with polyvalent cations to convert them into hydrogels resulting in ion exchange.
  • a three-dimensional networked gel structure is formed, in which the Ca+2 ions are replaced by Na+1 ions in the alginate molecule and attached to the carboxylate groups [54].
  • the alginate polymer has a long and rigid chain structure. Due to rigid chain structure and high electrical conductivity, it is quite difficult to subject aqueous sodium alginate solutions to electrocution alone.
  • alginate nano particles produced by electrospinning in the presence of ancillary polymers are used as wound dressing [55- 57], tissue scaffold [58-60] and drug release system [61 ], there are some studies about its use.
  • Nanofibrous mats are the materials proven in tissue engineering due to its flexibility, large surface area, nano-porous structure, oxygen permeability, non-bacterial permeability, similarity to natural tissue, favorable cell growth and be inexpensive of its production.
  • nanofiber refers to fibers with diameters less than one micron.
  • Biomedical applications are one of the most applied areas of nanofibers.
  • Nanofiber materials are used in many places such as medical prostheses, artificial veins and organ applications, wound covers, drug distribution systems, tissue scaffolds, skin care products.
  • the large surface area and nano-porous structure of the nanofibrous mats provide oxygen and air permeability while exhibiting barrier properties against bacteria [9-15].
  • Morphologically, the mats obtained by electrospinning are very similar to the natural human extracellular matrix (ECM). Therefore, it can be used as a tissue scaffold in cell culture and tissue engineering applications. Electrospinning method is the most studied nanofiber production technique in recent years.
  • Nanofibrous mats obtained by the electrospinning method are very convenient for cell growth and for the formation of three-dimensional cellular colonies because of the attainment of very low fiber diameters.
  • nanofibrous mats produced by electrospinning from various polymers are used as wound covers [16, 17], drug release systems [18-20], tissue scaffolds [21 -24].
  • the electrospinning process is based on the principle that the electrically charged liquid polymer (15) is positioned in continuous fiber form on a grounded surface [62, 63]. There are basically 4 main elements in an electrospinning mechanism.
  • Feeding unit (jet, syringe, metal needle, etc.) (5)
  • the liquid polymer (15) in melt or solution is fed from a capillary tube.
  • a high voltage power supply (1 ) very high voltages are applied to the polymer solution.
  • the surface of the solution droplet suspended at the tip of the needle is electrically charged.
  • the polymer droplet receives the cone form (Taylor cone) (20).
  • the voltage reaches a critical value and the push forces of the charges in the droplet absorb the surface tension forces a thin jet is launched from the tail of the Taylor cone (20) and the jet travels from one end of the same electrical charge to the next to the grounded collector (10).
  • this polymer jet follows prior stable then unstable (spiral) track path.
  • the solvent in it evaporates and leaves behind a charged polymeric fiber having diameters in the nano scale.
  • the resulting continuous nanofibers are randomly positioned on the collector plate (10) and form a nonwoven mat [65-67].
  • Electrospinning is an inexpensive and simple method of producing nanofibres, while controllability is a very difficult process. Because there are many technical parameters affecting the process [9].
  • the electrospinning process and the structure and morphology of the nanofibers obtained from this process are directly related to the parameters collected in the three main headings as solution properties, process conditions and ambient conditions.
  • the properties of the polymer solution are the most important parameters affecting the electrospinning process and the morphology of the formed fiber.
  • Surface tension plays an important role in the formation of beads, one of the most common problems on nanofibrous mats.
  • the solution viscosity and electrical properties are influential on the formation and movement of the polymer jet. All have an effect on the diameter of electrospinning fibers [68].
  • Another important parameter that affects the electrospinning process is the various external factors that influence the electrospinning jet. These factors include the voltage applied, the feed rate, the solution temperature, the collector type, the nozzle diameter and the distance between the nozzle and the collector. Although not as much as the solution parameters, process parameters also have a significant effect on the resulting fiber diameter and morphology [69, 70].
  • surface tension may cause beads to form along the jet as the polymer jet travels toward reservoir plate (10).
  • High viscosity means more interaction between solvent and polymer molecules, so that when the solution is stretched by the action of the charge, the solvent molecules will diffuse into the complex polymer molecules, thereby reducing the tendency of the solvent molecules to aggregate under the influence of surface tension [67-69].
  • the polymer jet is stretched by pushing the loads on the surface together. If the electrical conductivity of the solution is increased, more charge may be carried in the electrospinning jet. If the solution is not fully stretched, pilling will occur. Another effect of the increased load is to increase the collection area of the fibers to produce finer fibers.
  • the electrical conductivity is advantageous for the electrospinning process, it has a decisive effect, which makes the process more difficult, even after a certain limit.
  • the applied high voltage ensures that the polymer solution with a certain electrical conductivity is electrically charged and the electrostatic forces which cause the solution to travel in a thin jet towards a grounded collector (10). Electrospinning processes start when the electrostatic forces acting on the resistors absorb the surface tension forces of the solution. When voltage is applied, the resulting electric field affects the jet tension and acceleration. That is, both the voltage and the electric field obtained have an influence on the morphology of the fiber obtained. When a higher voltage is applied, due to the higher Coulomb power in the jet and the stronger electric field, the solution will stretch further. As this situation leads to a reduction in fiber diameter at the same time it causes the solvent to evaporate more rapidly, resulting in more dry fibers [69, 74].
  • the feed rate defines the amount of solution available for electrospinning. To keep the Taylor cone (20) stable, there is a corresponding feed rate for a given voltage. As the feed rate increases, the volume of the solution coming from the gland increases, resulting in an increase in fiber diameter or bead size. Due to the greater volume of solution coming out of the nozzle, the drying of the jet takes longer. As a result, the solvent in the fibers collected during the same flight does not have enough time to evaporate. Some solvent remaining after evaporation will evaporate after the fibers are placed on the collector (10), so that sticking can occur at points where the fibers are in contact with each other [69, 70].
  • the distance between the collector (10) and the nozzle is the area where the jetting occurs, the jet is incinerated and the solvent evaporates and forms solid fibers. That is, the electrospinning process takes place at this distance.
  • the flight time and the electric field strength of the polymer jet in the air until reaching the collector (10) are factors affecting the electrospinning process and formed fibers.
  • both the flight time and the electric field strength are changed.
  • the distance is shortened, this time will be shortened and since the solvent does not evaporate completely, the sticks and bead formations will be seen at the contact points of the fibers.
  • the electric field strength will increase and the jet speed will increase and the fiber diameters will decrease [69, 71 ].
  • CMC, HA and NaAlg used to form the nanofibrous mat subject of the invention are water- soluble polymers.
  • the resulting nanofibrous mats have low resistance to water and water vapor. This would lead to problems in practical applications of nanofibrous mats that are planned to be used as adhesion barriers it is necessary to make an appropriate cross- linking treatment on the produced mats to increase the water resistance.
  • Cross-linking is the process of attaching two or more molecules together by covalent bonding with a chemical method.
  • Cross-linking of the adhesion zone nanofibrous mat is carried out in the presence of 1 -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS).
  • EDC is a water-soluble, biocompatible and non-toxic cross-linking agent used to couple carboxyl groups to primary amines.
  • the non-inclusion of EDC in the cross-linked structure, i.e., not binding to polymer molecules, is particularly recommended for materials used in the biomedical field [75, 76].
  • the chemical structure of EDC is given below.
  • EDC binds by activating carboxyl groups on polysaccharide molecules and forming ester bonds between hydroxyl and carboxyl groups.
  • the carboxyl groups of the HA polymer are activated with carbodiimide and form an O-acylurea labile intermediate product. This unstable intermediate product is shortlived and breaks down to link the hydroxyl and carboxyl groups of the HA polymer [78, 79].
  • NHS is a cross-linking agent used to activate carboxylic acid groups.
  • carboxylic acid forms a salt with amines
  • the acids which are activated in the presence of NHS react with amines to give amides [79].
  • the chemical structure of NHS is given below.
  • NHS is a homo-bifunctional crosslinker. This cross-linker is used in conjunction with EDC to inhibit the formation of irreversible N- acylic compounds.
  • EDC and NHS provides intermediate formulations that are hydrolytically resistant and cannot be regenerated.
  • NHS has no toxic properties and imparts properties such as biocompatibility to the material, resistance to enzymatic degradation.
  • NHS provides cross-linking by activating the esters of the glucuronic acid moiety present in the HA polymer [80]. Below, the EDC/NHS cross-linking reaction mechanism of HA is given.
  • the method of producing the nanofibrous mat of the present invention comprises;
  • HA solutions were prepared in 2% aqueous CMC, 2% aqueous NaAlg, 1 0% and 1 2% NaOH/DMSO.
  • the measured properties of the prepared solutions are given in Table 2-4.
  • Cross-linking Process 50, 70, 80, and 100 mM EDC and 100 mM NHS to provide cross-linking were dissolved in ethanol.
  • EDC/NHS mixture solutions prepared in a volume ratio of 1 /1 nanofibrous mat samples were immersed and allowed to stand at room temperature for 24 hours. After this time, the nanofiber cross-linked without any structural degradation, gelling or dissolution were removed from the solutions, rinsed in ethanol and allowed to dry for 12 hours at 37 Q C in the incubator.
  • Figure 3 shows the cross-linking images made with EDC/NHS.
  • the polymer, the polymer mixture solution and the production parameters are within the following ranges.
  • -HA concentration to be prepared in NaOH/DMSO; 8-15% (w/v %)
  • the invention includes a low cost nanofibrous product that can reduce postoperative complications and has an alternative to commercial products used in the prior art, having potency to inhibit / reduce adhesion by using electrospinning from carboxymethyl cellulose, sodium alginate and hyaluronic acid polymers during intra-abdominal surgical operations.
  • the natural polymers HA, NaAlg and CMC are used in mixture with different polymers or purely as a gel, film, membrane or fiber/nanofiber biomedical field.
  • no nanofibrous mat was produced by electrospinning from the HA/NaAlg/CMC polymer mixture.
  • no nanofibrous mat have been produced from these polymers, either alone or in admixture, for use as an adhesion barrier.
  • Nanofibrous mats are the materials proven in tissue engineering due to its flexibility, large surface area, nano-porous structure, oxygen permeability, non-bacterial permeability, similarity to natural tissue, favorable cell growth and be inexpensive of production. According to the invention, the adhesion barrier formed of a nanofibrous mat is an easier, cheaper and more effective alternative to commercial adhesion barriers used in the market.
  • the insertion of the adhesion barriers (mesh) into the tissue is carried out as follows.
  • Sahiner, i . T. 201 1 Comparison of Intraabdominal Adhesions in the Repair of Abdominal Wall Defects with Simvastatin Loaded Polypropylene Patch. Specialization Thesis, Kirikkale University, Kirikkale.
  • Carbohydrate Polymers 83(2), 101 1 -1015.

Abstract

L'invention concerne des barrières d'adhérence utilisées dans le domaine biomédical. L'invention concerne, en particulier, un mat nanofibreux approprié à une utilisation en tant que barrière d'adhérence dans le domaine biomédical et obtenu par procédé d'électrofilage à partir d'un mélange d'acide hyaluronique (HA), d'alginate de sodium (NaAlg) et de solutions polymères de carboxyméthylcellulose (CMC).
PCT/TR2017/050302 2016-07-29 2017-07-04 Barrière d'adhérence nano-fibreuse WO2018056937A2 (fr)

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Publication number Priority date Publication date Assignee Title
US11857701B2 (en) 2010-10-08 2024-01-02 Board Of Regents, The University Of Texas System Anti-adhesive barrier membrane using alginate and hyaluronic acid for biomedical applications
US11890344B2 (en) 2010-10-08 2024-02-06 Board Of Regents, The University Of Texas System One-step processing of hydrogels for mechanically robust and chemically desired features
US11771769B2 (en) 2017-11-10 2023-10-03 Cocoon Biotech Inc. Ocular applications of silk-based products
US20210030917A1 (en) * 2018-02-12 2021-02-04 Inovenso Teknoloji Limited Sirketi Nanofibrous adhesion barrier
KR20210120484A (ko) * 2020-03-27 2021-10-07 주식회사 원바이오젠 사용성이 개선된 유착방지막 및 그 제조방법
KR102380400B1 (ko) 2020-03-27 2022-03-30 주식회사 원바이오젠 사용성이 개선된 유착방지막 및 그 제조방법
WO2022138686A1 (fr) * 2020-12-25 2022-06-30 国立大学法人金沢大学 Composition de nanofibres de cellulose et son procédé de production

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