WO2011058208A1 - Hydrophilic polymers as systems for releasing bioactive compounds in meshes for surgical use - Google Patents
Hydrophilic polymers as systems for releasing bioactive compounds in meshes for surgical use Download PDFInfo
- Publication number
- WO2011058208A1 WO2011058208A1 PCT/ES2010/070725 ES2010070725W WO2011058208A1 WO 2011058208 A1 WO2011058208 A1 WO 2011058208A1 ES 2010070725 W ES2010070725 W ES 2010070725W WO 2011058208 A1 WO2011058208 A1 WO 2011058208A1
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- WIPO (PCT)
- Prior art keywords
- bioactive
- acrylic copolymer
- mesh
- mesh prosthesis
- monomers
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/0063—Implantable repair or support meshes, e.g. hernia meshes
-
- 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
- A61L27/28—Materials for coating prostheses
- A61L27/34—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
Definitions
- HYDROPHILE POLYMERS AS BIOACTIVE COMPOUND RELEASE SYSTEMS IN SURGICAL APPLICATION BADS.
- the present invention relates to the development of bioactive agent release systems, preferably antibiotics, based on hydrophilic polymers to be used as prosthetic coatings in the form of polymer mesh with special interest in abdominal surgical applications. Therefore the present application falls within the field of medicine.
- the infection can alter the integration of the biomaterial in the tissue and therefore the healing process of the patient who may suffer another hernia and therefore another operation.
- the adhesion of a bacterium to the surface of a biomaterial is the determining step in the pathogenesis of the infection.
- Some microorganisms are capable of forming a biofilm or biofilm on the mesh that protects them from the immune system and the action of antibiotics.
- the bacterium is wrapped and protected, thereby achieving strong and irreversible adhesion to the surface of the implant surviving on it.
- AMPS is an anionic monomer, carrier of an ionized sulfonic group (strong acid) in virtually the entire pH range [Tong Z., LX, Swelling equilibria and volume phase transition in hydrogels with strongly dissociating electrolytes. Macromolecules, 1994. 27].
- HEMA polymers and copolymers have wide applications in surgery and medicine, among which are: contact lenses [Rostoke M.V., L.L., Hema copolymers having high oxygen permeability., N.P.D. Corp, Editor. 1977: USA.], Healing, hemocompatible coatings, drug delivery systems, surgical prostheses, dialysis membranes, artificial corneas ... etc. [López G.P., R.B.D., Rapoza R.J., Horbett T.A., Plasma deposition of ultrathin films of poly (hydroxyethylmethacrylate): Sur ⁇ ace Analysis and protein adsorption measurements. Macromolecules, 1993. 26 (13): p. 3247-3253].
- a first object or aspect of the present invention is to provide a mesh prosthesis comprising a medical mesh impregnated with a bioactive acrylic copolymer, characterized in that the amount of bioactive acrylic copolymer is between and 40% w / w (weight / weight) with respect to the total and the bioactive acrylic copolymer comprises: between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; Y between 0.01% and 50% w / w of a bioactive agent.
- a second aspect of the present invention is a process for the manufacture of these mesh prostheses of the first aspect comprising at least the following steps: i) the bioactive acrylic copolymer is dissolved in ethanol;
- the solvent is evaporated, preferably at room temperature.
- stage (ii) is as homogeneous as possible, so that it can be carried out by deposition of the solution dropwise to the total coating or by simple immersion in the ethanolic solution.
- Ethanol is important for its practically Zero toxicity, and its characteristics that reduce the formation of lumps during drying compared to other solvents.
- a third aspect is the use of a bioactive acrylic copolymer comprising between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; and between 0.01% and 50% w / w of a bioactive agent for impregnating medical meshes, preferably abdominal mesh.
- a preferred embodiment of the invention are mesh prostheses characterized in that the monomer with hydroxyl groups comprises at least one hydroxyalkyl acrylate or a hydroxyalkyl methacrylate of the general formula (I):
- n is from 0 to 4.
- n is from 0 to 1;
- Ri is a hydrogen or a methyl radical.
- 2-hydroxyethyl methacrylate is the preferred hydroxyl group monomer.
- monomers with preferred sulfonic groups are those of the general formula (II):
- Ri is a hydrogen or methyl radical
- R2 and R3 are the same or different from each other and represent a hydrogen or a (C1-C3) alkyl radical
- n is a value from 1 to 6.
- the most preferred sulfonic group monomer is 2-acrylamido-2-methylpropane sulfonic.
- the bioactive acrylic copolymer comprises 2-hydroxyethyl monomers and 2-acrylamido-2-methylpropane sulfonic monomers.
- Bioactive agents may be of a different nature, but for biomedical applications the most important are antibiotics, antithrombogens, antiangiogenic, proangiogenic and any of their mixtures. Antibiotics are the most preferred to avoid post implantation operations. Different antibiotics are known that can be useful for the present invention such as quinolones, glycopeptides, tetracyclines, oxazolidinones, macrolides, lycosamides, streptogramins, sulfonamides, polypeptides, penicillins, ansamycins or any of their mixtures. Glycopeptides are the preferred antibiotics.
- Glycopeptides they include vancomycin, erythromycin, neomicin streptomycin, daptomycin, rifamycin, puromycin, lincomycin or any combination thereof, preferably it is vancomycin.
- the amount of bioactive acrylic copolymer is between 15 and 30% w / w. These percentages allow the incorporation of an adequate amount of bioactive agent, correctly coating the device, without exposed areas and without blocked pores.
- the bioactive acrylic copolymer shows good release profiles of the bioactive agent when this copolymer comprises between 45 and 75% w / w of one or more monomers with hydroxyl groups.
- the bioactive agent may preferably be between 5 and 30% w / w relative to the total bioactive acrylic copolymer.
- the bioactive acrylic copolymer may additionally comprise polyethylene glycol, preferably between 10 and 30% w / w, which is a suitable range to achieve a homogeneous coating without lumping.
- the medical mesh may have different natures, but preferably it is selected from the following types: Low molecular weight polypropylene monofilament; High molecular weight polypropylene monofilament; High molecular weight double filament polypropylene; Polypropylene large pore multifilament; High molecular weight multifilament polyester; Polytetrafuoroethylene (Gore-Tex®).
- step (i) preferably in step (i) the bioactive acrylic copolymer is dissolved in a proportion between 1 and 5% w / v in ethanol, obtaining suitable viscosities for the coating of the medical mesh .
- Viscosity is a critical parameter because if low viscosity solutions were obtained the coating could be low and, on the other hand, very high viscosities would encourage lump formation.
- step (iii) The evaporation of step (iii) must be carried out in a way that the product obtained is homogeneous. This can be achieved simply by evaporating the solvent at room temperature.
- the process for obtaining the bioactive acrylic copolymer comprises: i ') the bioactive agent is dissolved, preferably together with polyethylene glycol, in distilled water;
- the mixture is frozen and lyophilized.
- step (i ') the concentration of preferably bioactive agent in the aqueous solution is between 5 mg / mL and 40 mg / mL.
- step (i ') the concentration of preferably polyethylene glycol in the aqueous solution is between 5 mg / mL and 40 mg / mL.
- the process for obtaining the Acrylic copolymer comprises the following steps: i ") dissolve the monomers with a radical polymerization initiator in a mixture of water: isopropanol;
- the radical polymerization initiator may be any of those known to those skilled in the art, preferably being azobis-isobutyronitrile (AIBN), and preferably being in a proportion between 0.25 and 2% w / w.
- AIBN azobis-isobutyronitrile
- the mixture is deoxygenated and this can be carried out with a stream of nitrogen.
- step (iii ) the heat treatment can be carried out at a temperature between 60 and 80 ° C.
- mesh in the context of the present invention refers to a woven or interwoven polymer network of biocompatible and biostable polymers: polyolefins, polyesters, polyethers, polyurethanes or biodegradable polymers: polyhydroxyalkanoates, polylactic, polybutyrates, polyglycolics used in various surgical procedures such as abdominal, dental or orthopedic for the purpose of insulating tissues or organs.
- the mesh is abdominal, among other things because of the great relevance of infections to patients.
- FIG. 1 - Standardized ATR-FTIR spectra of HA80, HA80rec and HA80recV copolymers. Transmittance vs. wavelength is represented.
- Figure 3 Vancomycin release curve from HA70recV, HA80recV systems.
- Figure 5. Death curve for a) S.aureus and b) S.epidermidis.
- Figure 7 Macroscopic photos of rabbits treated with the different systems and infected with a) S. aureus and b) S. epidermidis.
- Figure 8. Microscopic photos of rabbits treated with the different systems and infected with a) nothing, b) S. aureus and c) S. epidermidis.
- Example 1 Preparation of systems based on copolymers of 2-hydroxyethyl methacrylate-2-acrylamido-2-methylpropanesulfonic acid and vancomycin.
- HEMA / AMPS copolymers were prepared from 80/20 and 70/30% -p feed compositions (named HA80 and HA70 respectively. The reaction was carried out in solution, using water: isopropanol (50 : 50) as solvent, at 50 ° C and AIBN as initiator in concentration 1.5x10-2 M.
- Isopropanol was used as solvent in order to obtain copolymers of controlled molecular weight due to its low toxicity (classified by Food and Drugs Administration (FDA) as class 3)
- Guidance for the Industry Q3C Impurities Residual Solvents International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 62 FR67377 (1997) and high transfer constant [Brandrup J., IEH, Grulke EA, Polymer Handbook, ed. IEH Brandrup J., Grulke EA (ed.).
- the antibiotic was incorporated into the corresponding copolymer for which vancomycin (20% -p) was dissolved together with polyethylene glycol (20% -p) in distilled water and then the corresponding copolymer (HA80) was added. This mixture was left under magnetic stirring for 24 h and subsequently frozen and lyophilized. The system was named as HA80recV.
- the control polymer was prepared in the absence of vancomycin (HA80rec).
- the structural characterization of the copolymers was carried out by infrared spectroscopy with Fourier transform by Attenuated Total Reflectance, ATR-FTIR, in a Perkin-Elmer Spectrum One device. To this end, a sample of the corresponding copolymer was deposited on the window of the equipment exerting a pressure controlled on it in order to ensure a good window-copolymer contact (figure 1). The thermal stability of the copolymers was evaluated using a thermobalance (TA Instruments TGAQ500). For this, the weight loss of the sample subjected to a constant heating rate of 10 ° C / min between 50 and 500 ° C, in an atmosphere of N 2, was recorded. Each trial was performed in duplicate (figure 2).
- Example 2 Study of the in vitro release of vancomycin from prostheses coated with polymer plus antibiotic.
- prostheses coated with polymer-antibiotic of 1 cm 2 in size were used, which were immersed in 10 ml of phosphate buffer (composition detailed in the previous section) and incubated at 37 ° C. During certain periods of time (Table I) samples of the release medium (0.5 ml) were taken and replaced by fresh medium (0.5 ml).
- Example 3 Bactericidal activity of the prostheses coated in liquid medium.
- the experimental phase in vitro in liquid medium consists in the realization of a death curve.
- the death curve is a microbiological method to know the concentrations in which an antibiotic kills a known bacterial strain. It is a protocol described by the NCCLS (National Committee for Clinical Laboratory Standards), so that the results are reproducible and comparable.
- a known concentration of antibiotic is tested in death curve studies and viable colony forming units (CFU / ml) are quantified at each time. These studies consider that a decrease of 3logioUFC / ml compared to the control group (without antibiotic) indicates an adequate bactericidal response. The dose that achieves this decrease in CFU is considered bactericidal.
- bare polypropylene mesh (PP), which was the control group, polymer coated polypropylene mesh without antibiotic (POL) and polymer coated mesh with vancomycin (VC). Each group had three meshes. A sterility control was also used. All meshes were sterilized by ethylene oxide.
- the mesh that was used in the different examples herein was the low molecular weight monofilament polypropylene (Parietene®, K991400 Sofradim, Trevoux (France))
- MIC 1 mg / L.
- a bacterial suspension equivalent to a standard of 0.5 McFarland 1.5 x 108 CFU / ml was previously prepared by nephelometry. For each 10-ce tube, 100 microliters of the 0.5 McFarland bacterial suspension was inoculated.
- the tubes were incubated at 37 0 C and samples were collected at 0, 3, 6, and 24 hours for S. aureus and 0, 2, 4, 6, and 24 hours for S. epidermidis. For each time the microbiological count, previously vortexing, with the serial dilution method in Mueller Hinton Agar, with a sample of 100 microliters, the detection limit being 10 CFU / mi.
- Vancomycin levels were measured using an automated fluorescent polarization immunoassay technique (Tdx / Flx®, from Abbott laboratories), with a minimum detection threshold of 2 ⁇ g / ml.
- Example 4 Bactericidal activity of coated prostheses. Agar test
- the bactericidal activity of the coated prosthesis is determined by the diffusion method on agar plate commercial blood agar plates were used and cultured at 37 0 C for twenty four hours and fourteen days.
- the Staphylococcus aureus (ATCC 25923) and Staphylococcus epidermides strains of a sample from a patient's vascular catheter are used as model cultures. Both cultures are preserved by storing them at -80 ° C in glycerin / water mixtures (20% v / v).
- the inoculum was done by planting a colony, twenty-four hours old, for each quadrant. Each plate was divided into 4 quadrants, of which one was free and in each of the other 3 a 1 cm 2 fragment of each mesh was studied: Polypropylene monofilament reticular prosthesis (PP), polypropylene with polymeric coating (Pol) and Polypropylene with polymer and vancomycin (Vaneo). In each group, 5 plates were used for each of the study times, which were established at 24 hours and 14 days.
- PP Polypropylene monofilament reticular prosthesis
- Polypropylene with polymeric coating Polypropylene with polymer and vancomycin
- the halo area is measured by the ImageJ morphometric program, in photos of the blood agar plates, and statistically processed with the U-Mann Whitney statistical test for the average of paired data independent of the halo of the plates with Staphylococcus aureus and Staphylococcus epidermididis
- bactericidal activity of the polymer is measured by evaluating the inhibition or retardation of the development of colonies just in the areas of direct contact with the surface of the prosthesis.
- halo of inhibition can be seen in the polypropylene mesh covered with polymer with vancomycin, compared to the bare mesh or with polymer without vancomycin, in which its quadrant in the plate is Germ cover.
- the mean halo for Staphylococcus aureus was 1.75 square centimeters (0.59 standard deviation) and for Staphylococcus epidermidis it was 1.84 square centimeters (0.12 standard deviation). There were no statistically significant differences in halo size for epidermidis or aureus. (Figure 4).
- Example 5 In vivo experimental model: Rabbit abdominal wall defects.
- the white New Zealand male rabbit was used as an experimental animal.
- the weight of the animals was between 3,200 and 3,500 kg at the beginning of the study.
- the animals were divided into 3 study groups, in total 84 rabbits were used, 12 from the control group, 36 rabbits at 14 days and 36 rabbits at 30 days.
- the study groups are the following: - Control Group, without bacterial inoculum: The same rabbit was used for the control subgroups of PP and POL, implanting each mesh on one side of the alba line.
- the animals Prior to surgery, the animals were anesthetized with a mixture of ketamine hydrochloride, 70 mg / kg, diazepam, 1.5 mg / kg and chlorpromazine, administered intramuscularly. In some of the animals it was necessary to administer an additional dose intraperitoneally during the intervention.
- the skin and subcutaneous cellular tissue were sectioned. Defects were created in the anterior muscular wall of the abdomen (right and left lateral flank in the control group and right flank in the infected groups), which included the external and internal oblique, retaining the transverse muscle, the transversalis fascia and the parietal peritoneum to avoid contact of microorganisms with the visceral peritoneum.
- the final surface of the defect was 15 cm 2 , corresponding to a rectangular defect of 5 cm of longitudinal axis and 3 cm of transverse axis. This defect was repaired by one of the meshes under study (PP, Pol, or Vaneo).
- the biomaterial was fixed to the edges of the defect (prosthetic interface - anchor fabric) by means of a continuous 4/0 polypropylene suture interrupted only at the corners.
- the skin incision was closed with a 3/0 silk. The technique can be seen in the surgical technique photos.
- the defect bed was inoculated with 0.5 ml of 108 CFU / ml suspension of Staphylococcus aureus (Sa) or Staphylococcus epidermidis (Se), before placing the biomaterial.
- the concentration of microorganisms was obtained by nephelometry (0.5 McFarland).
- the animals were sacrificed at 14 and 30 days and the abdominal wall pieces were divided into three and processed for histological study with scanning and scanning electron microscopy, and for immunohistochemical study.
- the pieces were fixed in solution F13, included in paraffin, cut into sections of 5 ⁇ and stained with hematoxylin-eosin or Masson's trichrome (Goldner-Gabe variety). Finally, they were observed under a Zeiss Axiophot microscope (Cari Zeiss, Oberkochen, Germany).
- the immunohistochemical study was carried out using a monoclonal antibody specific for Staphylococcus aureus (Abcam, ab8067, Cambridge, UK) and Staphylococcus epidermidis (Abcam, ab20942, Cambridge, UK). After rehydration of the samples in saline phosphate buffer solution (PBS) pH 7.4 and specific blocking with 3% bovine serum albumin (BSA), the samples were incubated with the primary antibody for 12 h at 4 o C. Then the preparations were washed with PBS-BSA, and incubated with a biotinylated anti-mouse antibody (IgG, Sigma, St.
- PBS saline phosphate buffer solution
- BSA bovine serum albumin
- the statistical analysis of the data was performed using the Graph Pad Prism 4 program. The results were expressed as mean values ⁇ the standard deviation. The Mann Withney U test was used to compare data from different study groups. The level of statistical significance was considered with p ⁇ 0.05. There were no signs of infection or other alterations in the animals of the control group. The animals of the PP group and the POL group infected with S. aureus in the first days after the intervention presented clinical signs of infection with loss of appetite and weight loss and a mortality rate of 16.67% in the PP group. , and 8.33% in the Pol group. In the VC group there was no clinical impact of weight loss and mortality was 0%.
- the neoformed tissue was arranged concentrically around the prosthetic filaments. It was made up of collagen fibers and inflammatory cells. In the biomaterials with polymer (Pol and Vaneo) this coating also appeared surrounded by macrophage cells and giant foreign body cells, being evident in some of the samples studied, signs of degradation (Figure 8)
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Abstract
The present invention relates to a mesh prosthesis which includes a medical mesh impregnated with a bioactive acrylic copolymer, characterised in that the amount of bioactive acrylic copolymer is between 5 wt % and 40 wt % of the total; and the bioactive acrylic copolymer includes 30 wt % to 95 wt % of one or more monomers with hydroxyl groups, 5 wt % to 55 wt % of one or more monomers with sulphonic groups, and 0.01 wt % to 50 wt % of a bioactive agent. The invention also relates to the use of said mesh prosthesis in surgical operations performed to repair hernia complaints.
Description
POLIMEROS HIDRÓFILOS COMO SISTEMAS DE LIBERACION DE COMPUESTOS BIOACTIVOS EN MALLAS DE APLICACIÓN QUIRURGICA. HYDROPHILE POLYMERS AS BIOACTIVE COMPOUND RELEASE SYSTEMS IN SURGICAL APPLICATION BADS.
D E S C R I P C I O N D E S C R I P C I O N
La presente invención se refiere al desarrollo de sistemas de liberación de agentes bioactivo, preferiblemente antibióticos, en base a polímeros hidrófilos para ser utilizados como recubrimientos de prótesis en forma de malla polimérica con especial interés en aplicaciones quirúrgicas abdominales. Por lo tanto la presente solicitud se engloba dentro del campo de la medicina. The present invention relates to the development of bioactive agent release systems, preferably antibiotics, based on hydrophilic polymers to be used as prosthetic coatings in the form of polymer mesh with special interest in abdominal surgical applications. Therefore the present application falls within the field of medicine.
ESTADO DE LA TECNICA ANTERIOR La reparación de procesos hemiarios es una de las intervenciones quirúrgicas más frecuentes en cirugía general por detrás de la de cataratas en EEUU. Cuando se intervienen grandes defectos de la pared abdominal: hernias incisionales, (generalmente secundarias a laparotomías previas), eliminación de tumores, etc. La colocación de un biomaterial de sustitución y/o refuerzo está hoy en día casi plenamente consensuado por parte de todos los cirujanos. La introducción por primera vez de una malla de polipropileno por Uscher en 1962 fue considerado uno de los mejores avances conseguidos en esta cirugía [Uscher, Hernia repair with marlex mesh. Arch Surg., 1962. 84: p. 325-8).]. Los efectos positivos derivados del uso de mallas abdominales ha estimulado la búsqueda de mallas óptimas con alta biocompatibilidad y baja adhesión celular. Existen en el mercado gran cantidad de mallas hechas de materiales sintéticos reabsorbibles, no reabsorbibles o de material orgánico derivado de humanos o de cerdo. Esta amplia variedad de sistemas implica importantes diferencias en la interacción de la malla con los microorganismos después de su implantación. Una de las más devastadoras consecuencias del uso de un material prostético es la aparición de una infección. En la reparación de grandes hernias donde el paciente se somete a varias intervenciones quirúrgicas, la incidencia de
infección puede alcanzar un 10%. Los microorganismos implicados en dichas infecciones corresponden a bacterias de la piel del paciente, concretamente a Staphylococcus aureus (Sa) y Staphylococcus epidermidis (Se). La infección puede alterar la integración del biomaterial en el tejido y por tanto el proceso de curación del paciente que puede sufrir otra hernia y por tanto otra operación. La adhesión de una bacteria a la superficie de un biomaterial es el paso determinante en la patogénesis de la infección. Algunos microorganismos son capaces de formar una biopelícula o biofilm sobre la malla que los protege del sistema inmunitario y de la acción de lo antibióticos. La bacteria se envuelve y se protege, con lo que consigue una adhesión fuerte e irreversible a la superficie del implante sobreviviendo sobre la misma. STATE OF THE PREVIOUS TECHNIQUE The repair of blood processes is one of the most frequent surgical interventions in general surgery behind that of cataracts in the US. When major abdominal wall defects are involved: incisional hernias, (usually secondary to previous laparotomies), tumor removal, etc. The placement of a replacement and / or reinforcement biomaterial is nowadays almost completely agreed by all surgeons. The introduction for the first time of a polypropylene mesh by Uscher in 1962 was considered one of the best advances achieved in this surgery [Uscher, Hernia repair with marlex mesh. Arch Surg., 1962. 84: p. 325-8).]. The positive effects derived from the use of abdominal meshes has stimulated the search for optimal meshes with high biocompatibility and low cell adhesion. There are many meshes made of resorbable, non-absorbable synthetic materials or organic material derived from humans or pigs on the market. This wide variety of systems implies important differences in the interaction of the mesh with the microorganisms after their implantation. One of the most devastating consequences of using a prosthetic material is the appearance of an infection. In the repair of large hernias where the patient undergoes several surgical interventions, the incidence of infection can reach 10%. The microorganisms involved in these infections correspond to bacteria on the patient's skin, specifically Staphylococcus aureus (Sa) and Staphylococcus epidermidis (Se). The infection can alter the integration of the biomaterial in the tissue and therefore the healing process of the patient who may suffer another hernia and therefore another operation. The adhesion of a bacterium to the surface of a biomaterial is the determining step in the pathogenesis of the infection. Some microorganisms are capable of forming a biofilm or biofilm on the mesh that protects them from the immune system and the action of antibiotics. The bacterium is wrapped and protected, thereby achieving strong and irreversible adhesion to the surface of the implant surviving on it.
Una vez que la malla ha sido infectada no existe tratamiento posible y la única solución es extraer la prótesis. En la estrategia de prevención de infección es una buena técnica quirúrgica (menos traumática), minimizar la contaminación durante la cirugía, antibióticos perioperatorios sistémicos. La administración de antibióticos sistémicos profilácticos en monodosis es una medida estándar y ha demostrado ser una medida eficaz en la cirugía de diversos implantes, entre ellos los ortopédicos y las prótesis mamarias (Pittet B, Montandon D, Pittet D. Infection in breast implants. Lancet Infecí Dis. 2005 Feb; 5(2):94-106. Review.) pero no en la hernioplastia con malla primaria lo que podría justificar el uso de la malla como modelo de infección local con recubrimiento liberador de antibiótico además de su simplicidad. La mejor forma de tratar la infección de un implante es prevenir la colonización de los microorganismos en las fases iniciales, evitando la formación de biofilm, que hace que persistan en el biomaterial a pesar de los tratamientos. Es necesario prevenir la adhesión inicial de la bacteria y un método es modificar la superficie del implante, recubriéndolo de polímeros que liberen antibiótico e impidan esa colonización. Hasta la fecha esta aproximación no ha sido desarrollada ni experimental ni comercialmente.
En cuanto a los polímeros formadores de recubrimientos los sistemas acrílicos hidrófilos han sido ampliamente utilizados, concretamente sistemas en base al ácido 2-acrilamido-2-metilpropano sulfónico (AMPS) y/o metacrilato de 2- hidroxietilo (HEMA). El AMPS es un monómero aniónico, portador de un grupo sulfónico (ácido fuerte) ionizado en prácticamente todo el rango de pHs [Tong Z., L.X., Swelling equilibria and volume phase transition in hydrogels with strongly dissociating electrolytes. Macromolecules, 1994. 27]. Once the mesh has been infected there is no possible treatment and the only solution is to remove the prosthesis. In the infection prevention strategy is a good surgical technique (less traumatic), minimize contamination during surgery, systemic perioperative antibiotics. The administration of systemic prophylactic antibiotics in single doses is a standard measure and has proven to be an effective measure in the surgery of various implants, including orthopedic and breast prostheses (Pittet B, Montandon D, Pittet D. Infection in breast implants. Lancet I infected Dis. 2005 Feb; 5 (2): 94-106. Review.) But not in primary mesh hernioplasty which could justify the use of the mesh as a model of local infection with antibiotic-releasing coating in addition to its simplicity. The best way to treat an implant infection is to prevent the colonization of the microorganisms in the initial stages, avoiding the formation of biofilm, which causes them to persist in the biomaterial despite the treatments. It is necessary to prevent the initial adhesion of the bacteria and one method is to modify the surface of the implant, covering it with polymers that release antibiotics and prevent this colonization. To date, this approach has not been developed experimentally or commercially. As for the coating-forming polymers, hydrophilic acrylic systems have been widely used, specifically systems based on 2-acrylamido-2-methylpropane sulfonic acid (AMPS) and / or 2-hydroxyethyl methacrylate (HEMA). AMPS is an anionic monomer, carrier of an ionized sulfonic group (strong acid) in virtually the entire pH range [Tong Z., LX, Swelling equilibria and volume phase transition in hydrogels with strongly dissociating electrolytes. Macromolecules, 1994. 27].
Por otra parte, tanto los polímeros como los copolímeros de HEMA tienen amplias aplicaciones en cirugía y medicina, entre las que cabe destacar: lentes de contacto [Rostoke M.V., L.L., Hema copolymers having high oxygen permeability., N.P.D. Corp, Editor. 1977: EEUU.], cicatrizantes, recubrimientos hemocompatibles, sistemas de liberación de fármacos, prótesis quirúrgicas, membranas de diálisis, córneas artificiales... etc. [López G.P., R.B.D., Rapoza R.J., Horbett T.A., Plasma deposition of ultrathin films of poly(hydroxyethylmethacrylate): Suríace Analysis and protein adsorption measurements. .Macromolecules, 1993. 26(13): p. 3247-3253]. Esto se debe a su capacidad para formar hidrogeles biocompatibles con una excelente tolerancia y buena estabilidad [Montheard J.P., C.M., Chappard D., 2- hydroxyethyl methacrylate (HEMA): chemical properties and applications in the biomedical fields. Macromol Sci Macromol Rev, 1992. 32: p. 1-34]. On the other hand, both HEMA polymers and copolymers have wide applications in surgery and medicine, among which are: contact lenses [Rostoke M.V., L.L., Hema copolymers having high oxygen permeability., N.P.D. Corp, Editor. 1977: USA.], Healing, hemocompatible coatings, drug delivery systems, surgical prostheses, dialysis membranes, artificial corneas ... etc. [López G.P., R.B.D., Rapoza R.J., Horbett T.A., Plasma deposition of ultrathin films of poly (hydroxyethylmethacrylate): Suríace Analysis and protein adsorption measurements. Macromolecules, 1993. 26 (13): p. 3247-3253]. This is due to its ability to form biocompatible hydrogels with excellent tolerance and good stability [Montheard J.P., C.M., Chappard D., 2- hydroxyethyl methacrylate (HEMA): chemical properties and applications in the biomedical fields. Macromol Sci Macromol Rev, 1992. 32: p. 1-34].
DESCRIPCION DE LA INVENCION DESCRIPTION OF THE INVENTION
A la vista del estado de la técnica descrito, un primer objeto o aspecto, de la presente invención es proporcionar una prótesis de malla que comprende una malla médica impregnada con un copolímero acrílico bioactivo, caracterizada porque la cantidad de copolímero acrílico bioactivo está entre el 5 y el 40% p/p (peso/peso) respecto al total y el copolímero acrílico bioactivo comprende: entre un 30 y un 95 % p/p de uno o varios monómeros con grupos hidroxilo; entre un 5 y un 55 % p/p de uno o varios monómeros con grupos sulfónicos; y
entre 0,01 % y un 50% p/p de un agente bioactivo. In view of the state of the art described, a first object or aspect of the present invention is to provide a mesh prosthesis comprising a medical mesh impregnated with a bioactive acrylic copolymer, characterized in that the amount of bioactive acrylic copolymer is between and 40% w / w (weight / weight) with respect to the total and the bioactive acrylic copolymer comprises: between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; Y between 0.01% and 50% w / w of a bioactive agent.
Estas prótesis tienen la ventaja de que los polímeros son reabsorbidos en pocos días evitando así los posibles efectos secundarios, pero a la vez permitiendo la aplicación y la dosificación de forma controlada y localizada de compuestos bioactivos. Por ejemplo en el caso de que el agente bioactivo sea un antibiótico, estos se liberan de una manera adecuada para evitar las infecciones post implante en las críticas primeras 48 h. Además los recubrimientos de las prótesis de malla de la invención demuestran una solubilidad óptima y liberan el principio activo de una manera adecuada. Si estos recubrimientos tuvieran una solubilidad extremada se disolverían en unos pocos minutos/horas, o por el contrario si fueran muy insolubles, no dejarían liberar al principio activo. Adicionalmente, un segundo aspecto de la presente invención es un proceso para la manufacturación de estas prótesis de malla del primer aspecto que comprende al menos las siguientes etapas: i) se disuelve el copolímero acrílico bioactivo en etanol; These prostheses have the advantage that the polymers are reabsorbed in a few days thus avoiding possible side effects, but at the same time allowing the application and dosing in a controlled and localized way of bioactive compounds. For example, in the case that the bioactive agent is an antibiotic, they are released in a suitable way to avoid post-implant infections in the first 48 hours. In addition, the coatings of the mesh prostheses of the invention demonstrate optimum solubility and release the active ingredient in a suitable manner. If these coatings had an extreme solubility they would dissolve in a few minutes / hours, or on the contrary if they were very insoluble, they would not release the active substance. Additionally, a second aspect of the present invention is a process for the manufacture of these mesh prostheses of the first aspect comprising at least the following steps: i) the bioactive acrylic copolymer is dissolved in ethanol;
ii) se deposita la disolución resultante sobre la malla médica; ii) the resulting solution is deposited on the medical mesh;
iii) se evapora el disolvente, preferiblemente a temperatura ambiente. iii) the solvent is evaporated, preferably at room temperature.
Este procedimiento es conocido en el estado de la técnica como "casting" (F. Lecomte J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier , Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug releasepatterns. Journal Control reléase 89, 2003, 457-471 ) y siendo una de sus ventajas principales la sencillez de llevarlo a cabo. Una etapa importante del proceso es que la deposición de la etapa (ii) sea lo más homogénea posible, por lo ésta se puede realizar mediante deposición de la disolución gota a gota hasta el recubrimiento total o por simple inmersión en la solución etanólica. El etanol es importante por su prácticamente
nula toxicidad, y sus características que hacen que durante el secado se disminuyan la formación de grumos en comparación con otros disolventes. This procedure is known in the state of the art as "casting" (F. Lecomte J. Siepmann, M. Walther, RJ MacRae, R. Bodmeier, Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug releasepatterns, Journal Control reread 89, 2003, 457-471) and being one of its main advantages is the simplicity of carrying it out. An important stage of the process is that the deposition of stage (ii) be as homogeneous as possible, so that it can be carried out by deposition of the solution dropwise to the total coating or by simple immersion in the ethanolic solution. Ethanol is important for its practically Zero toxicity, and its characteristics that reduce the formation of lumps during drying compared to other solvents.
Como se puede absorber el copolímero acrílico bioactivo de diferentes maneras conocidas para los expertos en la materia un tercer aspecto es el uso de un copolímero acrílico bioactivo que comprende entre un 30 y un 95 % p/p de uno o varios monómeros con grupos hidroxilo; entre un 5 y un 55 % p/p de uno o varios monómeros con grupos sulfónicos; y entre 0,01 % y un 50% p/p de un agente bioactivo para la impregnación de mallas médicas, preferiblemente malla abdominales. As the bioactive acrylic copolymer can be absorbed in different ways known to those skilled in the art, a third aspect is the use of a bioactive acrylic copolymer comprising between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; and between 0.01% and 50% w / w of a bioactive agent for impregnating medical meshes, preferably abdominal mesh.
DESCRIPCION DETALLADA DE LA INVENCION DETAILED DESCRIPTION OF THE INVENTION
Una realización preferida de la invención son las prótesis de malla caracterizadas porque el monómero con grupos hidroxilo comprende al menos un acrilato de hidroxialquilo o un metacrilato de hidroxialquilo de fórmula general (I): A preferred embodiment of the invention are mesh prostheses characterized in that the monomer with hydroxyl groups comprises at least one hydroxyalkyl acrylate or a hydroxyalkyl methacrylate of the general formula (I):
CH2=C CH 2 = C
COO-(CH2)n-(CH)m-CH2OH COO- (CH 2 ) n- (CH) m-CH 2 OH
OH OH
Fórmula (I) Formula (I)
donde: where:
n es de 0 a 4; n is from 0 to 4;
m es de 0 a 1 ; m is from 0 to 1;
Ri es un hidrógeno o un radical metilo. Ri is a hydrogen or a methyl radical.
Siendo metacrilato de 2-hidroxietilo el monómero con grupos hidroxilos preferido.
Respecto los monómeros con grupos sulfónicos preferidos son los de fórmula general (II): 2-hydroxyethyl methacrylate is the preferred hydroxyl group monomer. With respect to the monomers with preferred sulfonic groups are those of the general formula (II):
Fórmula (II) Formula (II)
donde: where:
Ri es un hidrogeno o radical metilo; Ri is a hydrogen or methyl radical;
R2 y R3 son iguales o diferentes entre sí y representan un hidrógeno o un radical alquilo (C1-C3); R2 and R3 are the same or different from each other and represent a hydrogen or a (C1-C3) alkyl radical;
n es un valor de 1 a 6. n is a value from 1 to 6.
El monómero con grupos sulfónicos más preferido es 2-acrilamido-2- metilpropano sulfónico. En una realización aún más preferida el copolímero acrílico bioactivo comprende monómeros de 2-hidroxietilo y monómeros de 2-acrilamido-2- metilpropano sulfónico. The most preferred sulfonic group monomer is 2-acrylamido-2-methylpropane sulfonic. In an even more preferred embodiment, the bioactive acrylic copolymer comprises 2-hydroxyethyl monomers and 2-acrylamido-2-methylpropane sulfonic monomers.
Los agentes bioactivos pueden ser de diferente naturaleza, pero para aplicaciones biomédicas los más importantes son los antibióticos, los antitrombogénicos, los antiangiogénicos, los proangiogénicos y cualquiera de sus mezclas. Los antibióticos son los más preferidos para evitar las operaciones post implantación. Se conocen diferentes antibióticos que pueden ser útiles para la presente invención como por ejemplo las quinolonas, los glucopéptidos, las tetraciclinas, las oxazolidinonas, los macrolidos, las licosamidas, las estreptograminas, sulfonamidas, polipéptidos, penicilinas, ansamicinas o cualquiera de sus mezclas. Los glucopéptidos son los antibióticos preferidos. Los glucopéptidos
incluyen vancomicina, eritromicin, neomicin estreptomicin, daptomicin, rifamicin, puromicin, lincomicin o cualquiera de sus combinaciones, preferiblemente es vancomicina. En otra realización la cantidad de copolímero acrílico bioactivo está entre el 15 y el 30% p/p. Estos porcentajes permiten la incorporación de una cantidad adecuada de agente bioactivo, recubriendo correctamente el dispositivo, sin zonas descubiertas y sin poros bloqueados. El copolímero acrílico bioactivo muestra buenos perfiles de liberación del agente bioactivo cuando este copolímero comprende entre un 45 y un 75 % p/p de uno o varios monómeros con grupos hidroxilo. Bioactive agents may be of a different nature, but for biomedical applications the most important are antibiotics, antithrombogens, antiangiogenic, proangiogenic and any of their mixtures. Antibiotics are the most preferred to avoid post implantation operations. Different antibiotics are known that can be useful for the present invention such as quinolones, glycopeptides, tetracyclines, oxazolidinones, macrolides, lycosamides, streptogramins, sulfonamides, polypeptides, penicillins, ansamycins or any of their mixtures. Glycopeptides are the preferred antibiotics. Glycopeptides they include vancomycin, erythromycin, neomicin streptomycin, daptomycin, rifamycin, puromycin, lincomycin or any combination thereof, preferably it is vancomycin. In another embodiment the amount of bioactive acrylic copolymer is between 15 and 30% w / w. These percentages allow the incorporation of an adequate amount of bioactive agent, correctly coating the device, without exposed areas and without blocked pores. The bioactive acrylic copolymer shows good release profiles of the bioactive agent when this copolymer comprises between 45 and 75% w / w of one or more monomers with hydroxyl groups.
Con un contenido de monómeros con grupos sulfónicos en el copolímero acrílico bioactivo entre un 10 y un 35 % p/p se obtienen buenos niveles de biocompatibilidad, y ayuda a que la liberación tenga lugar durante las 24 h post operacionales. With a content of monomers with sulphonic groups in the bioactive acrylic copolymer between 10 and 35% w / w, good biocompatibility levels are obtained, and it helps the release take place during the 24 h post operation.
El agente bioactivo puede estar preferentemente entre un 5 y un 30 % p/p en relación con en total de copolímero acrílico bioactivo. The bioactive agent may preferably be between 5 and 30% w / w relative to the total bioactive acrylic copolymer.
Además otros componentes pueden estar en la composición para mejorar la adhesión, liberación de agente bioactivo o para mejorar el proceso de impregnación. Por ejemplo el copolímero acrílico bioactivo puede comprender adicionalmente polietilenglicol, preferiblemente entre un 10 y un 30% p/p el cual es un intervalo adecuado para conseguir un recubrimiento homogéneo sin formación de grumos. In addition other components may be in the composition to improve adhesion, release of bioactive agent or to improve the impregnation process. For example, the bioactive acrylic copolymer may additionally comprise polyethylene glycol, preferably between 10 and 30% w / w, which is a suitable range to achieve a homogeneous coating without lumping.
La malla médica puede tener diferentes naturalezas, pero preferiblemente ésta se selecciona entre los siguientes tipos: Polipropileno monofilamento de bajo peso molecular; Polipropileno monofilamento de alto peso molecular; Polipropileno doble filamento de alto peso molecular; Polipropileno poro grande
multifilamento; Poliéster de alto peso molecular multifilamento; Politetrafuoroetileno (Gore-Tex®). The medical mesh may have different natures, but preferably it is selected from the following types: Low molecular weight polypropylene monofilament; High molecular weight polypropylene monofilament; High molecular weight double filament polypropylene; Polypropylene large pore multifilament; High molecular weight multifilament polyester; Polytetrafuoroethylene (Gore-Tex®).
Respecto al método de síntesis de las prótesis de mallas, preferiblemente en la etapa (i) se disuelve el copolímero acrílico bioactivo en una proporción entre el 1 y el 5% p/v en etanol, obteniéndose viscosidades adecuadas para el recubrimiento de la malla médica. La viscosidad es un parámetro crítico por que si se obtuvieran disoluciones de baja viscosidad el recubrimiento podría ser escaso y, en cambio, viscosidades muy elevadas incentivarían la formación de grumos. Regarding the method of synthesis of the mesh prostheses, preferably in step (i) the bioactive acrylic copolymer is dissolved in a proportion between 1 and 5% w / v in ethanol, obtaining suitable viscosities for the coating of the medical mesh . Viscosity is a critical parameter because if low viscosity solutions were obtained the coating could be low and, on the other hand, very high viscosities would encourage lump formation.
Normalmente se deposita entre 5 y 20 mL de disolución por gramo de malla. Normally between 5 and 20 mL of solution is deposited per gram of mesh.
La evaporación de la etapa (iii) se debe realizar de un modo que el producto obtenido sea homogéneo. Esto se puede conseguir simplemente dejando evaporar el disolvente a temperatura ambiente. The evaporation of step (iii) must be carried out in a way that the product obtained is homogeneous. This can be achieved simply by evaporating the solvent at room temperature.
En una realización aún más preferida el proceso de obtención del copolímero acrílico bioactivo comprende: i') se disuelve el agente bioactivo, preferiblemente junto con polietilenglicol, en agua destilada; In an even more preferred embodiment, the process for obtaining the bioactive acrylic copolymer comprises: i ') the bioactive agent is dissolved, preferably together with polyethylene glycol, in distilled water;
ii') se añade el copolímero acrílico y se agita; ii ') the acrylic copolymer is added and stirred;
iii') se congela la mezcla y se liofiliza. iii ') the mixture is frozen and lyophilized.
En la etapa (i') la concentración preferiblemente de agente bioactivo en la solución de acuosa está entre 5 mg/mL y 40 mg/mL. In step (i ') the concentration of preferably bioactive agent in the aqueous solution is between 5 mg / mL and 40 mg / mL.
En la etapa (i') la concentración preferiblemente de polietilenglicol en la solución de acuosa está entre 5 mg/mL y 40 mg/mL. In step (i ') the concentration of preferably polyethylene glycol in the aqueous solution is between 5 mg / mL and 40 mg / mL.
En una realización todavía más preferida el procedimiento para la obtención del
copolímero acrílico comprende las siguientes etapas: i") disolver los monómeros con un iniciador de polimerización radical en una mezcla de agua:isopropanol; In an even more preferred embodiment, the process for obtaining the Acrylic copolymer comprises the following steps: i ") dissolve the monomers with a radical polymerization initiator in a mixture of water: isopropanol;
ii") desoxigenación del medio de reacción; ii ") deoxygenation of the reaction medium;
iii") someter a tratamiento térmico a una temperatura entre 40 y 75°C; iii ") subject to heat treatment at a temperature between 40 and 75 ° C;
iv") aislar el producto de reacción por evaporación del disolvente, y purificar mediante disolución en agua y lavado mediante membrana de diálisis; iv ") isolate the reaction product by evaporation of the solvent, and purify by dissolving in water and washing by dialysis membrane;
v") liofilizar el copolímero acrílico. v ") lyophilize the acrylic copolymer.
El iniciador de polimerización radical puede ser cualquiera de los conocidos por los expertos en la materia, siendo preferentemente azobis-isobutironitrilo (AIBN), y estando preferiblemente en una proporción entre 0,25 y 2% p/p. La mezcla se desoxigena y esta se puede llevar a cabo con una corriente de nitrógeno. The radical polymerization initiator may be any of those known to those skilled in the art, preferably being azobis-isobutyronitrile (AIBN), and preferably being in a proportion between 0.25 and 2% w / w. The mixture is deoxygenated and this can be carried out with a stream of nitrogen.
En la etapa (iii") el tratamiento térmico se puede efectuar a una temperatura entre 60 y 80°C. In step (iii ") the heat treatment can be carried out at a temperature between 60 and 80 ° C.
A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
Definiciones Definitions
El término malla en el contexto de la presente invención se refiere a una red polimérica tejida o entrelazada de polímeros biocompatibles y bioestables:
poliolefinas, poliesteres, polieteres, poliuretanos o polímeros biodegradables: polihidroxialcanoatos, polilácticos, polibutiratos, poliglicólicos utilizados en diversos procedimientos quirúrgicos por ejemplo abdominales, dentales u ortopédicos con objeto del aislamiento de tejidos u órganos. Preferentemente la malla es abdominal, entre otras cosas por la gran relevancia que tiene las infecciones a los pacientes. The term mesh in the context of the present invention refers to a woven or interwoven polymer network of biocompatible and biostable polymers: polyolefins, polyesters, polyethers, polyurethanes or biodegradable polymers: polyhydroxyalkanoates, polylactic, polybutyrates, polyglycolics used in various surgical procedures such as abdominal, dental or orthopedic for the purpose of insulating tissues or organs. Preferably the mesh is abdominal, among other things because of the great relevance of infections to patients.
BREVE DESCRIPCION DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
Figura 1 .- Espectros normalizados de ATR-FTIR de copolímeros HA80, HA80rec y HA80recV. Se representa transmitancia vs longitud de onda. Figure 1 .- Standardized ATR-FTIR spectra of HA80, HA80rec and HA80recV copolymers. Transmittance vs. wavelength is represented.
Figura 2.- Primera derivada de los termogramas obtenidos por TGA para el sistema HEMA-AMPS. Figure 2.- First derivative of the thermograms obtained by TGA for the HEMA-AMPS system.
Figura 3.- Curva de liberación de vancomicina desde los sistemas HA70recV, HA80recV. Figure 3.- Vancomycin release curve from HA70recV, HA80recV systems.
Figura 4.- Halo de inhibición a las 48 h para el sistema HA80recV. Figure 4.- Halo of inhibition at 48 h for the HA80recV system.
Figura 5.- Curva de muerte para a) S.aureus y b) S.epidermidis. Figure 5.- Death curve for a) S.aureus and b) S.epidermidis.
Figura 6.- Grupos y esquema de localización de lugar de implante. Figure 6.- Groups and location scheme of implant site.
Figura 7.- Fotos macroscópicas de los conejos tratados con los distintos sistemas e infectados con a) S. aureus y b) S. epidermidis. Figure 7.- Macroscopic photos of rabbits treated with the different systems and infected with a) S. aureus and b) S. epidermidis.
Figura 8.- Fotos microscópicas de los conejos tratados con los distintos sistemas e infectados con a) nada, b) S. aureus y c) S. epidermidis. Figure 8.- Microscopic photos of rabbits treated with the different systems and infected with a) nothing, b) S. aureus and c) S. epidermidis.
EJEMPLOS EXAMPLES
Ejemplo 1 : Preparación de sistemas en base de copolímeros de metacrilato de 2-hidroxietilo- ácido 2-acrilamido-2-metilpropanosulfónico y vancomicina.
En primer lugar, se prepararon copolímeros de HEMA/AMPS a partir de composiciones de la alimentación 80/20 y 70/30 %-p (nombrados HA80 y HA70 respectivamente. La reacción se llevó a cabo en disolución, usando agua:isopropanol (50:50) como disolvente, a 50°C y AIBN como iniciador en concentración 1 ,5x10-2 M. Se utilizó isopropanol como disolvente con el fin de obtener copolímeros de peso molecular controlado debido a su baja toxicidad (clasificado por la Food and Drugs Administration (FDA) como clase 3) Guidance for the Industry Q3C Impurities: Residual Solvents. Internacional Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 62 FR67377 (1997) y alta constante de transferencia [Brandrup J., I.E.H., Grulke E.A. , Polymer Handbook, ed. I.E.H. Brandrup J., Grulke E.A. (ed.). 1999, New York: Wiley]. La disolución fue desoxigenada burbujeando nitrógeno durante 30 minutos. La concentración total de monómeros fue 0,50 M. Transcurridas 24 horas de reacción, se eliminó el disolvente de las muestras, se disolvieron en agua, se lavaron mediante membrana de diálisis y se liofilizaron. Example 1: Preparation of systems based on copolymers of 2-hydroxyethyl methacrylate-2-acrylamido-2-methylpropanesulfonic acid and vancomycin. First, HEMA / AMPS copolymers were prepared from 80/20 and 70/30% -p feed compositions (named HA80 and HA70 respectively. The reaction was carried out in solution, using water: isopropanol (50 : 50) as solvent, at 50 ° C and AIBN as initiator in concentration 1.5x10-2 M. Isopropanol was used as solvent in order to obtain copolymers of controlled molecular weight due to its low toxicity (classified by Food and Drugs Administration (FDA) as class 3) Guidance for the Industry Q3C Impurities: Residual Solvents International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 62 FR67377 (1997) and high transfer constant [Brandrup J., IEH, Grulke EA, Polymer Handbook, ed. IEH Brandrup J., Grulke EA (ed.). 1999, New York: Wiley.] The solution was deoxygenated by bubbling nitrogen for 30 minutes.The total concentration of monomers was 0.50 M Pass After 24 hours of reaction, the solvent was removed from the samples, dissolved in water, washed by dialysis membrane and lyophilized.
Posteriormente, se realizó la incorporación del antibiótico al correspondiente copolímero para lo cual se disolvió la vancomicina (20%-p) junto con polietilenglicol (20%-p) en agua destilada y a continuación se añadió el copolímero correspondiente (HA80). Esta mezcla se dejó en agitación magnética durante 24 h y posteriormente se congeló y liofilizó. El sistema se nombró como HA80recV. Se preparó el polímero control en ausencia de vancomicina (HA80rec). Subsequently, the antibiotic was incorporated into the corresponding copolymer for which vancomycin (20% -p) was dissolved together with polyethylene glycol (20% -p) in distilled water and then the corresponding copolymer (HA80) was added. This mixture was left under magnetic stirring for 24 h and subsequently frozen and lyophilized. The system was named as HA80recV. The control polymer was prepared in the absence of vancomycin (HA80rec).
La caracterización estructural de los copolímeros se realizó por espectroscopia infrarroja con transformada de Fourier por Reflectancia Total Atenuada, ATR- FTIR, en un equipo Perkin-Elmer Spectrum One. Para ello se depositó una muestra del correspondiente copolímero sobre la ventana del equipo ejerciendo una presión controlada sobre el mismo para así asegurar un buen contacto ventana-copolímero (figura 1 ).
La estabilidad térmica de los copolímeros se evaluó utilizando una termobalanza (TA Instruments TGAQ500). Para ello se registró la pérdida de peso de la muestra sometida a un ritmo de calentamiento constante de 10°C/min entre 50 y 500°C, en atmósfera de N2. Cada ensayo se realizó por duplicado (figura 2). The structural characterization of the copolymers was carried out by infrared spectroscopy with Fourier transform by Attenuated Total Reflectance, ATR-FTIR, in a Perkin-Elmer Spectrum One device. To this end, a sample of the corresponding copolymer was deposited on the window of the equipment exerting a pressure controlled on it in order to ensure a good window-copolymer contact (figure 1). The thermal stability of the copolymers was evaluated using a thermobalance (TA Instruments TGAQ500). For this, the weight loss of the sample subjected to a constant heating rate of 10 ° C / min between 50 and 500 ° C, in an atmosphere of N 2, was recorded. Each trial was performed in duplicate (figure 2).
El grado de hidratación de estos copolímeros se determinó sumergiendo la muestra en un tampón fosfato (0.1 M PBS) de pH = 7,4 que se preparó de acuerdo con la siguiente composición: NaCI: 0.138M; KCI: 0.0027 M. The degree of hydration of these copolymers was determined by immersing the sample in a phosphate buffer (0.1 M PBS) of pH = 7.4 which was prepared according to the following composition: NaCI: 0.138M; KCI: 0.0027 M.
Se sumergieron tres muestras de cada uno de los distintos copolímeros HEMA AMPS, 80/20PEG sin y con vancomicina, en la disolución tampón y se incubaron a 37°C para simular las condiciones fisiológicas. Se extrajo la muestra a distintos tiempos, se secó su superficie cuidadosamente con papel de filtro y se pesó hasta alcanzar una pesada constante. A ese tiempo se calculó el porcentaje del grado de hidratación (H) mediante la ecuación siguiente.
Three samples of each of the different HEMA AMPS, 80 / 20PEG copolymers without and with vancomycin were immersed in the buffer solution and incubated at 37 ° C to simulate physiological conditions. The sample was extracted at different times, its surface was dried carefully with filter paper and weighed to a constant weight. At that time the percentage of the degree of hydration (H) was calculated by the following equation.
donde PH es el peso de la muestra hinchada una vez alcanzado el equilibrio; Ps es el peso inicial de la muestra seca. where PH is the weight of the swollen sample once equilibrium is reached; Ps is the initial weight of the dry sample.
Los valores de hidratación se muestran en la tabla I Hydration values are shown in table I
t %H %H t% H% H
(min) HA80rec HA80recV (min) HA80rec HA80recV
0 0 0 0 0 0
1 25.65 19.97 1 25.65 19.97
5 41 .01 32.94 5 41 .01 32.94
10 41 .82 36.46 10 41 .82 36.46
20 42.76 38.79 20 42.76 38.79
30 32.92 35.95 30 32.92 35.95
50 31 .38 34.24
80 31 .88 38.78 50 31 .38 34.24 80 31 .88 38.78
Ejemplo 2: Estudio de la liberación in vitro de vancomicina desde prótesis recubiertas con polímero mas antibiótico. Example 2: Study of the in vitro release of vancomycin from prostheses coated with polymer plus antibiotic.
En primer lugar se utilizaron prótesis recubiertas con polímero-antibiótico de 1 cm2 de tamaño (HA70recV; HA80recV) que fueron sumergidas en 10 mi de tampón fosfato (composición detallada en le apartado anterior) e incubadas a 37°C. Durante determinados periodos de tiempo (tabla I) se tomaron muestras del medio de liberación (0.5 mi) que se sustituyeron por medio fresco (0.5 mi). First, prostheses coated with polymer-antibiotic of 1 cm 2 in size (HA70recV; HA80recV) were used, which were immersed in 10 ml of phosphate buffer (composition detailed in the previous section) and incubated at 37 ° C. During certain periods of time (Table I) samples of the release medium (0.5 ml) were taken and replaced by fresh medium (0.5 ml).
Tabla II Table II
Para analizar la cantidad liberada se utilizo como técnica analítica la cromatografía liquida de alta eficacia (HPLC) de Perkin Elmer con bomba peristáltica LC-250 y detector UV-Vis Perkin Elmer LC-95. La columna corresponde a una C-18 μBoundapack (Waters) de 3.9 x 300 mm. La longitud
de onda utilizada fue 215nm. Como fase móvil se utilizo una solución acuosa Metanol/PIC A (60:40) y un flujo de elución de 1 ml/min. Todas las muestras fueron ensayadas por triplicado. El tiempo de retención del antibiótico fue de 2.95±0.05 min. (media ± S.D., n=200). La curva de calibración realizada mostró un coeficiente de correlación de 0.9957. To analyze the amount released, Perkin Elmer's high efficiency liquid chromatography (HPLC) with peristaltic pump LC-250 and Perkin Elmer LC-95 UV-Vis detector was used as an analytical technique. The column corresponds to a C-18 μBoundapack (Waters) of 3.9 x 300 mm. The length Wave used was 215nm. As the mobile phase, an aqueous solution Methanol / PIC A (60:40) and an elution flow of 1 ml / min were used. All samples were tested in triplicate. The antibiotic retention time was 2.95 ± 0.05 min. (mean ± SD, n = 200). The calibration curve performed showed a correlation coefficient of 0.9957.
Ejemplo 3: Actividad bactericida de las prótesis recubiertas en medio líquido. Example 3: Bactericidal activity of the prostheses coated in liquid medium.
La fase experimental in vitro en medio líquido consiste en la realización de una curva de muerte. La curva de muerte, es un método microbiológico para conocer las concentraciones en las que un antibiótico mata a una cepa bacteriana conocida. Es un protocolo descrito por la NCCLS (Nacional Comitee for Clinical Laboratory Standards), de manera que los resultados son reproducibles y comparables. En los estudios de curva de muerte se prueba una concentración conocida de antibiótico y se cuantifican a cada tiempo las unidades formadoras de colonias viables (UFC/ml). En estos estudios se considera que un descenso de 3logioUFC/ml comparado con el grupo control (sin antibiótico) indica una adecuada respuesta bactericida. Se considera bactericida la dosis que consiga ese descenso en UFC. The experimental phase in vitro in liquid medium consists in the realization of a death curve. The death curve is a microbiological method to know the concentrations in which an antibiotic kills a known bacterial strain. It is a protocol described by the NCCLS (National Committee for Clinical Laboratory Standards), so that the results are reproducible and comparable. A known concentration of antibiotic is tested in death curve studies and viable colony forming units (CFU / ml) are quantified at each time. These studies consider that a decrease of 3logioUFC / ml compared to the control group (without antibiotic) indicates an adequate bactericidal response. The dose that achieves this decrease in CFU is considered bactericidal.
Se hicieron tres grupos: malla de polipropileno desnuda (PP), que era el grupo control, malla de polipropileno recubierta de polímero sin antibiótico (POL) y malla recubierta de polímero con vancomicina (VC). Cada grupo contaba con tres mallas. Se utilizó también un control de esterilidad. Todas las mallas fueron esterilizadas mediante oxido de etileno. La malla que se utilizó en los diferentes ejemplos de la presente memoria fue la polipropileno monofilamento de bajo peso molecular (Parietene®, K991400 Sofradim, Trevoux (Francia)) Three groups were made: bare polypropylene mesh (PP), which was the control group, polymer coated polypropylene mesh without antibiotic (POL) and polymer coated mesh with vancomycin (VC). Each group had three meshes. A sterility control was also used. All meshes were sterilized by ethylene oxide. The mesh that was used in the different examples herein was the low molecular weight monofilament polypropylene (Parietene®, K991400 Sofradim, Trevoux (France))
La curva de muerte se realizó con dos microorganismos, por separado, Staphylococcus epidermidis, de una muestra de un catéter vascular de un paciente, y Staphylococcus aureus (ATCC 25923), con sensibilidad demostrada a la vancomicina (CMI= 1 mg/L). A tiempo cero se consigue una concentración
bacteriana de aproximadamente 1 ,5 x 106 UFC/ mi en tubos con 10 mi de medio Mueller Hinton líquido. Para ello se preparó previamente una suspensión bacteriana equivalente a un estándar de 0,5 McFarland (1 ,5 x 108 UFC/ml) por nefelometría. Para cada tubo de 10 ce se inocularon 100 microlitros de la suspensión bacteriana 0,5 McFarland. Los tubos se incubaron a una temperatura de 37 0 C y se obtuvieron muestras a las 0, 3, 6, y 24 horas para S. aureus y 0, 2, 4, 6, y 24 horas para S. epidermidis. Para cada tiempo el contaje microbiológico, vorteando previamente, con el método de las diluciones seriadas en Agar Mueller Hinton, con una muestra de 100 microlitros, siendo el limite de detección de 10 UFC/ mi. The death curve was performed with two microorganisms, separately, Staphylococcus epidermidis, from a sample of a patient's vascular catheter, and Staphylococcus aureus (ATCC 25923), with demonstrated sensitivity to vancomycin (MIC = 1 mg / L). At zero time a concentration is achieved Bacterial of approximately 1.5 x 106 CFU / ml in tubes with 10 ml of liquid Mueller Hinton medium. A bacterial suspension equivalent to a standard of 0.5 McFarland (1.5 x 108 CFU / ml) was previously prepared by nephelometry. For each 10-ce tube, 100 microliters of the 0.5 McFarland bacterial suspension was inoculated. The tubes were incubated at 37 0 C and samples were collected at 0, 3, 6, and 24 hours for S. aureus and 0, 2, 4, 6, and 24 hours for S. epidermidis. For each time the microbiological count, previously vortexing, with the serial dilution method in Mueller Hinton Agar, with a sample of 100 microliters, the detection limit being 10 CFU / mi.
La medición de los niveles de vancomicina, se realizó con una técnica automatizada de inmunoensayo de polarización fluorescente (Tdx/Flx®, de laboratorios Abbott), cuyo umbral mínimo de detección 2 μg/ml. Vancomycin levels were measured using an automated fluorescent polarization immunoassay technique (Tdx / Flx®, from Abbott laboratories), with a minimum detection threshold of 2 μg / ml.
Se aprecia una diferencia significativa mayor de 3logioUFC/ml entre el grupo control de polipropileno desnudo (PP) y vancomicina y el grupo de malla con polímero y vancomicina (VC), lo que indica una adecuada respuesta bactericida en la muestra de las 24 horas, tanto para S. aureus como S. epidermidis (figura 3). No parece haber diferencia entre el grupo PP control y el grupo de malla recubierta de polímero (POL) por lo que la actividad bactericida se debe a la vancomicina. A significant difference greater than 3log CFU / ml is seen between the control group of bare polypropylene (PP) and vancomycin and the mesh group with polymer and vancomycin (VC), which indicates an adequate bactericidal response in the 24-hour sample, for both S. aureus and S. epidermidis (figure 3). There seems to be no difference between the control PP group and the polymer coated mesh (POL) group, so the bactericidal activity is due to vancomycin.
Ejemplo 4: Actividad bactericida de las prótesis recubiertas. Test de Agar. Example 4: Bactericidal activity of coated prostheses. Agar test
La actividad bactericida de las prótesis recubiertas se determina mediante el método de difusión sobre agar en placa Se utilizaron placas de Agar sangre comerciales y se cultivaron a 37 0 C durante veinticuatro horas y catorce días. Como cultivos modelo se usan las cepas Staphylococcus aureus (ATCC 25923) y Staphylococcus epidermides de una muestra de un catéter vascular de un paciente. Ambos cultivos se preservan almacenándolos a -80°C en mezclas de glicerina/agua (20% v/v).
Se trabajó con tres grupos de placas, para cada tiempo. Uno sin siembra bacteriana, otro con Staphylococcus aureus y otro con Staphylococcus epidermididis. El inoculo hizo por siembra de una colonia, de veinticuatro horas de edad, por cada cuadrante. Cada placa se dividió en 4 cuadrantes, de los cuales uno quedó libre y en cada uno de los otros 3 se colocó un fragmento de 1 cm2 de cada una de las mallas a estudiar: Prótesis reticular monofilamento de Polipropileno (PP), polipropileno con recubrimiento polimérico (Pol) y Polipropileno con polímero y vancomicina (Vaneo). En cada grupo se emplearon 5 placas para cada uno de los tiempos de estudio, los cuales fueron establecidos a las 24 horas, y 14 días. El área del halo se mide mediante el programa morfométrico ImageJ, en fotos de las placas de agar sangre, y se procesan estadísticamente con el test estadístico U-Mann Whitney para la media de datos apareados independientes del halo de las placas con Staphylococcus aureus y Staphylococcus epidermididis. The bactericidal activity of the coated prosthesis is determined by the diffusion method on agar plate commercial blood agar plates were used and cultured at 37 0 C for twenty four hours and fourteen days. The Staphylococcus aureus (ATCC 25923) and Staphylococcus epidermides strains of a sample from a patient's vascular catheter are used as model cultures. Both cultures are preserved by storing them at -80 ° C in glycerin / water mixtures (20% v / v). We worked with three groups of plates, for each time. One without bacterial seeding, another with Staphylococcus aureus and another with Staphylococcus epidermididis. The inoculum was done by planting a colony, twenty-four hours old, for each quadrant. Each plate was divided into 4 quadrants, of which one was free and in each of the other 3 a 1 cm 2 fragment of each mesh was studied: Polypropylene monofilament reticular prosthesis (PP), polypropylene with polymeric coating (Pol) and Polypropylene with polymer and vancomycin (Vaneo). In each group, 5 plates were used for each of the study times, which were established at 24 hours and 14 days. The halo area is measured by the ImageJ morphometric program, in photos of the blood agar plates, and statistically processed with the U-Mann Whitney statistical test for the average of paired data independent of the halo of the plates with Staphylococcus aureus and Staphylococcus epidermididis
En este ensayo se mide la actividad bactericida del polímero evaluando la inhibición o el retardo del desarrollo de colonias justo en las zonas de contacto directo con la superficie de la prótesis. En todas las placas con inoculo bacteriano, y hasta el día 14, se aprecia halo de inhibición en la malla de polipropileno recubierta de polímero con vancomicina, frente a la malla desnuda o con polímero sin vancomicina, en la que su cuadrante en la placa está cubierta de gérmenes. La media de halo para Staphylococcus aureus fue de 1 ,75 centímetros cuadrados (0,59 de desviación estándar) y para Staphylococcus epidermidis fue de 1 ,84 centímetros cuadrados (0,12 de desviación estándar). No hubo diferencias estadísticamente significativas en el tamaño del halo para el epidermidis o el aureus. (Figura 4).
Ejemplo 5: Modelo experimental in vivo: Defectos en pared abdominal de conejo. In this test the bactericidal activity of the polymer is measured by evaluating the inhibition or retardation of the development of colonies just in the areas of direct contact with the surface of the prosthesis. In all plaques with bacterial inoculum, and until day 14, halo of inhibition can be seen in the polypropylene mesh covered with polymer with vancomycin, compared to the bare mesh or with polymer without vancomycin, in which its quadrant in the plate is Germ cover. The mean halo for Staphylococcus aureus was 1.75 square centimeters (0.59 standard deviation) and for Staphylococcus epidermidis it was 1.84 square centimeters (0.12 standard deviation). There were no statistically significant differences in halo size for epidermidis or aureus. (Figure 4). Example 5: In vivo experimental model: Rabbit abdominal wall defects.
Como animal de experimentación se utilizó el conejo blanco Nueva Zelanda macho. El peso de los animales se encontraba comprendido entre los 3,200 y 3,500 Kg al comienzo del estudio. As an experimental animal, the white New Zealand male rabbit was used. The weight of the animals was between 3,200 and 3,500 kg at the beginning of the study.
El manejo de los animales se hizo conforme a la Normativa Internacional vigente sobre animales de experimentación (609/86/CEE y ETS 123). The management of the animals was done in accordance with the current International Regulations on experimental animals (609/86 / EEC and ETS 123).
Los animales fueron divididos en 3 grupos de estudio, en total se utilizaron 84 conejos, 12 de grupo control, 36 conejos a 14 días y 36 conejos a 30 días. Los grupos de estudio son los siguientes: - Grupo Control, sin inoculo bacteriano: Se utilizó el mismo conejo para los subgrupos control de PP y POL, implantando cada malla a un lado de la línea alba. The animals were divided into 3 study groups, in total 84 rabbits were used, 12 from the control group, 36 rabbits at 14 days and 36 rabbits at 30 days. The study groups are the following: - Control Group, without bacterial inoculum: The same rabbit was used for the control subgroups of PP and POL, implanting each mesh on one side of the alba line.
Subgrupos: PP (n=6), Pol (n=6), Vaneo (n=6) Subgroups: PP (n = 6), Pol (n = 6), Vaneo (n = 6)
- Infectados con S. aureus (1 implante por animal): - Infected with S. aureus (1 implant per animal):
Subgrupos: PP (n=6), Pol (n=6), Vaneo (n=6) Subgroups: PP (n = 6), Pol (n = 6), Vaneo (n = 6)
- Infectados con S. epidermidis (1 implante por animal): - Infected with S. epidermidis (1 implant per animal):
Subgrupos: PP (n=6), Pol (n=6), Vaneo (n=6) Subgroups: PP (n = 6), Pol (n = 6), Vaneo (n = 6)
Previamente a la cirugía, los animales fueron anestesiados con una mezcla de clorhidrato de ketamina, 70 mg/kg, diazepam, 1 .5 mg/kg y clorpromazina, administrada por vía intramuscular. En algunos de los animales fue necesario administrar una dosis adicional por vía intraperitoneal durante la intervención. Prior to surgery, the animals were anesthetized with a mixture of ketamine hydrochloride, 70 mg / kg, diazepam, 1.5 mg / kg and chlorpromazine, administered intramuscularly. In some of the animals it was necessary to administer an additional dose intraperitoneally during the intervention.
Tras el rasurado y desinfección con povidona yodada de toda la pared anterior del abdomen, se seccionó de la piel y el tejido celular subcutáneo.
Se crearon defectos en la pared muscular anterior del abdomen (flanco lateral derecho e izquierdo en el grupo control y flanco derecho en los grupo infectados), que comprendían el oblicuo externo e interno, conservando el músculo transverso, la fascia transversalis y el peritoneo parietal para evitar el contacto de los microorganismos con el peritoneo visceral. La superficie final del defecto fue de 15 cm2, correspondiente a un defecto rectangular de 5 cm de eje longitudinal y 3 cm de eje transversal. Dicho defecto fue reparado por una de las mallas objeto de estudio (PP, Pol, o Vaneo). El biomaterial fue fijado a los bordes del defecto (interfaz prótesis - tejido de anclaje) mediante una sutura continua de polipropileno de 4/0 interrumpida únicamente en las esquinas. La incisión cutánea fue cerrada con una seda de 3/0. La técnica se puede observar en las fotos de técnica quirúrgica. After shaving and disinfection with povidone iodine of the entire anterior abdominal wall, the skin and subcutaneous cellular tissue were sectioned. Defects were created in the anterior muscular wall of the abdomen (right and left lateral flank in the control group and right flank in the infected groups), which included the external and internal oblique, retaining the transverse muscle, the transversalis fascia and the parietal peritoneum to avoid contact of microorganisms with the visceral peritoneum. The final surface of the defect was 15 cm 2 , corresponding to a rectangular defect of 5 cm of longitudinal axis and 3 cm of transverse axis. This defect was repaired by one of the meshes under study (PP, Pol, or Vaneo). The biomaterial was fixed to the edges of the defect (prosthetic interface - anchor fabric) by means of a continuous 4/0 polypropylene suture interrupted only at the corners. The skin incision was closed with a 3/0 silk. The technique can be seen in the surgical technique photos.
En los grupos en los que se contaminó el lecho del defecto, se inoculó con 0,5 mi de suspensión de 108 CFU/ml de Staphylococcus aureus (Sa) o Staphylococcus epidermidis (Se), antes de colocar el biomaterial. La concentración de microorganismos se obtuvo por nefelometría (0,5 McFarland). Los animales fueron sacrificados a los 14 y 30 días y las piezas de pared abdominal se dividieron en tres y se procesaron para estudio histológico a microscopía óptica y electrónica de barrido, y para estudio inmunohistoquímico. In the groups in which the defect bed was contaminated, it was inoculated with 0.5 ml of 108 CFU / ml suspension of Staphylococcus aureus (Sa) or Staphylococcus epidermidis (Se), before placing the biomaterial. The concentration of microorganisms was obtained by nephelometry (0.5 McFarland). The animals were sacrificed at 14 and 30 days and the abdominal wall pieces were divided into three and processed for histological study with scanning and scanning electron microscopy, and for immunohistochemical study.
Para el estudio morfológico se tomaron muestras de la interfaz prótesis/tejido receptor para su estudio histológico a microscopía óptica. For the morphological study, samples of the prosthesis / recipient tissue interface were taken for histological study under optical microscopy.
Las piezas fueron fijadas en solución F13, incluidas en parafina, cortadas en secciones de 5 μηι y teñidas con hematoxilina-eosina o tricrómico de Masson (variedad Goldner-Gabe). Por último, fueron observadas en un microscopio Zeiss Axiophot (Cari Zeiss, Oberkochen, Germany). The pieces were fixed in solution F13, included in paraffin, cut into sections of 5 μηι and stained with hematoxylin-eosin or Masson's trichrome (Goldner-Gabe variety). Finally, they were observed under a Zeiss Axiophot microscope (Cari Zeiss, Oberkochen, Germany).
El estudio inmunohistoquímico fue efectuado empleando un anticuerpo monoclonal especifico para Staphylococcus aureus (Abcam, ab8067, Cambridge, UK) y Staphylococcus epidermidis (Abcam, ab20942, Cambridge, UK). Tras la rehidratación de las muestras en solución de buffer fosfato salino
(PBS) pH 7.4 y el bloqueo específico con albúmina de suero bovino (BSA) al 3%, las muestras se incubaran con el anticuerpo primario durante 12 h a 4o C. A continuación las preparaciones fueron lavadas con PBS-BSA, e incubadas con un anticuerpo anti-ratón biotinado (IgG, Sigma, St. Louis, USA) durante 1 h, lavadas con PBS-BSA, incubadas con Estreptoavidina-Fostatasa alcalina (Sigma, St. Louis, USA). El mareaje fue detectado empleando un sustrato cromogénico, Fast red. Los núcleos fueron contrastados con hematoxilina. The immunohistochemical study was carried out using a monoclonal antibody specific for Staphylococcus aureus (Abcam, ab8067, Cambridge, UK) and Staphylococcus epidermidis (Abcam, ab20942, Cambridge, UK). After rehydration of the samples in saline phosphate buffer solution (PBS) pH 7.4 and specific blocking with 3% bovine serum albumin (BSA), the samples were incubated with the primary antibody for 12 h at 4 o C. Then the preparations were washed with PBS-BSA, and incubated with a biotinylated anti-mouse antibody (IgG, Sigma, St. Louis, USA) for 1 h, washed with PBS-BSA, incubated with Streptoavidin-Alkaline Phostatase (Sigma, St. Louis, USA). The marking was detected using a chromogenic substrate, Fast red. The nuclei were contrasted with hematoxylin.
El análisis estadístico de los datos se realizó mediante el empleo del programa Graph Pad Prism 4. Los resultados fueron expresados como los valores medios ± la desviación estándar. Se utilizó el test de la U de Mann Withney para comparar los datos de los diferentes grupos de estudio. El nivel de significación estadística se consideró con p<0.05. No hubo signos de infección ni otras alteraciones en los animales del grupo control. Los animales del grupo PP y del grupo POL infectados con S. aureus en los primeros días tras la intervención presentaron clínica de infección con pérdida de apetito y pérdida de peso y una tasa de mortalidad que fue de un 16,67% en el grupo PP, y del 8,33% en grupo Pol. En el grupo VC no hubo esa repercusión clínica de perdida de peso y la mortalidad fue de un 0%. The statistical analysis of the data was performed using the Graph Pad Prism 4 program. The results were expressed as mean values ± the standard deviation. The Mann Withney U test was used to compare data from different study groups. The level of statistical significance was considered with p <0.05. There were no signs of infection or other alterations in the animals of the control group. The animals of the PP group and the POL group infected with S. aureus in the first days after the intervention presented clinical signs of infection with loss of appetite and weight loss and a mortality rate of 16.67% in the PP group. , and 8.33% in the Pol group. In the VC group there was no clinical impact of weight loss and mortality was 0%.
El análisis macroscópico de la zona del defecto permitió observar la presencia de importantes abscesos, y casos de dehiscencia y necrosis cutánea en los implantes de PP y Pol infectados con S. aureus tanto a los 14 como a los 30 días post-implante. Sin embargo, las prótesis portadoras de vancomicina, mostraron un aspecto similar al observado en el grupo control sin inoculación bacteriana. The macroscopic analysis of the defect area allowed to observe the presence of important abscesses, and cases of dehiscence and cutaneous necrosis in the implants of PP and Pol infected with S. aureus both at 14 and 30 days post-implant. However, vancomycin-bearing prostheses showed an appearance similar to that observed in the control group without bacterial inoculation.
En el grupo infectado con S. epidermidis todos lo animales sobrevivieron hasta el final del estudio. El grupo PP y Pol mostraron tres casos de infección de la herida quirúrgica superficial. Un conejo del grupo PP presento necrosis cutánea. Un conejo del grupo POL desarrollo un importante seroma. El grupo
VC demostró mejor curación de la herida cutánea, sin infección y sin abscesificación. In the group infected with S. epidermidis all animals survived until the end of the study. The PP and Pol group showed three cases of superficial surgical wound infection. A rabbit from the PP group presented cutaneous necrosis. A rabbit from the POL group developed an important seroma. The group VC demonstrated better healing of the skin wound, without infection and without abscessing.
A microscopía óptica, en el grupo control, el tejido neoformado se disponía de forma concéntrica alrededor de los filamentos protésicos. Estaba constituido por fibras de colágeno y células inflamatorias. En los biomateriales con polímero (Pol y Vaneo) dicho recubrimiento aparecía también rodeado por células macrofágicas y células gigantes de cuerpo extraño, siendo evidente en algunas de las muestras estudiadas, signos de degradación (figura 8) Under optical microscopy, in the control group, the neoformed tissue was arranged concentrically around the prosthetic filaments. It was made up of collagen fibers and inflammatory cells. In the biomaterials with polymer (Pol and Vaneo) this coating also appeared surrounded by macrophage cells and giant foreign body cells, being evident in some of the samples studied, signs of degradation (Figure 8)
En el grupo infectado con S. aureus los filamentos protésicos de PP y Pol aparecían en la mayor parte de las muestras estudiadas infiltradas por tejido de granulación compuesto por matriz extracelular, células blancas y microorganismos S. aureus positivos, tal como evidenció el mareaje inmunohistoquímico (mareaje rojo). En ocasiones el mareaje podía apreciarse en el interior de las células macrofágicas. A los 30 días, los abscesos eran rodeados por tejido fibroso compacto. En el grupo de Vancomicina fue evidente la ausencia de esos grandes abscesos purulentos frente a los otros grupos, observándose únicamente en una de las muestras restos de infección de forma aislada. El resto de las muestras observadas de este grupo presentó un aspecto similar al del grupo control (figura 8). In the group infected with S. aureus, the prosthetic filaments of PP and Pol appeared in most of the studied samples infiltrated by granulation tissue composed of extracellular matrix, white cells and S. aureus positive microorganisms, as evidenced by immunohistochemical marking ( red tide). Sometimes the marking could be seen inside macrophage cells. At 30 days, the abscesses were surrounded by compact fibrous tissue. In the Vancomycin group, the absence of these large purulent abscesses was evident compared to the other groups, with only one of the specimens remaining in infection. The rest of the samples observed in this group presented an aspect similar to that of the control group (Figure 8).
En general, el grupo infectado con S. epidermidis no mostró grandes diferencias respecto al grupo control. El mareaje inmunohistoquímico para S. epidermidis fue leve, apreciándose solo en algunas muestras de forma aislada y en la mayoría de las ocasiones, en el citoplasma de los macrófagos (mareaje rojo, figura 8).
In general, the group infected with S. epidermidis did not show large differences from the control group. Immunohistochemical treatement for S. epidermidis was mild, being seen only in some samples in isolation and in most cases, in the macrophage cytoplasm (red tide, figure 8).
Claims
1 . - Una prótesis de malla que comprende una malla médica impregnada con un copolímero acrílico bioactivo, caracterizada porque la cantidad de copolímero acrílico bioactivo está entre el 5 y el 40% p/p respecto al total y el copolímero acrílico bioactivo comprende: entre un 30 y un 95 % p/p de uno o varios monómeros con grupos hidroxilo; entre un 5 y un 55 % p/p de uno o varios monómeros con grupos sulfónicos; y entre 0,01 % y un 50% p/p de un agente bioactivo. one . - A mesh prosthesis comprising a medical mesh impregnated with a bioactive acrylic copolymer, characterized in that the amount of bioactive acrylic copolymer is between 5 and 40% w / w relative to the total and the bioactive acrylic copolymer comprises: between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; and between 0.01% and 50% w / w of a bioactive agent.
2. - La prótesis de malla según la reivindicación anterior, caracterizada porque el monómero con grupos hidroxilo comprende al menos un acrilato de hidroxialquilo o un metacrilato de hidroxialquilo de fórmula general (I): 2. - The mesh prosthesis according to the preceding claim, characterized in that the monomer with hydroxyl groups comprises at least one hydroxyalkyl acrylate or a hydroxyalkyl methacrylate of the general formula (I):
CH2=C CH 2 = C
COO-(CH2)n-(CH)m-CH2OH COO- (CH 2 ) n- (CH) m-CH 2 OH
OH OH
Fórmula (I) Formula (I)
donde: where:
n es de 0 a 4; n is from 0 to 4;
m es de 0 a 1 ; m is from 0 to 1;
Ri es un hidrógeno o un radical metilo. Ri is a hydrogen or a methyl radical.
3. - La prótesis de malla según la reivindicación anterior, caracterizada porque el monómero con grupos hidroxilo comprende metacrilato de 2-hidroxietilo. 3. - The mesh prosthesis according to the preceding claim, characterized in that the monomer with hydroxyl groups comprises 2-hydroxyethyl methacrylate.
4. - La prótesis de malla según cualquiera de las tres reivindicaciones anteriores, caracterizada porque el monómero con grupos sulfónicos comprende monómeros con la fórmula general (I I): 4. - The mesh prosthesis according to any of the three preceding claims, characterized in that the monomer with sulfonic groups comprises monomers with the general formula (II):
Fórmula (II) Formula (II)
donde: where:
R1 es un hidrogeno o radical metilo; R1 is a hydrogen or methyl radical;
R2 y R3 son iguales o diferentes entre sí y representan un hidrógeno o un radical alquilo (C1-C3); R 2 and R 3 are the same or different from each other and represent a hydrogen or a (C 1 -C 3) alkyl radical;
n es un valor de 1 a 6. n is a value from 1 to 6.
5.- La prótesis de malla según la reivindicación anterior, caracterizada porque el monómero con grupos sulfónicos comprende 2-acrilamido-2-metilpropano sulfónico. 5. The mesh prosthesis according to the preceding claim, characterized in that the monomer with sulfonic groups comprises 2-acrylamido-2-methylpropane sulfonic.
6. - La prótesis de malla según la reivindicación anterior, caracterizada porque comprende monómeros de metacrilato de 2-hidroxietilo y monómeros de 2- acrilamido-2-metilpropano sulfónico. 6. - The mesh prosthesis according to the preceding claim, characterized in that it comprises 2-hydroxyethyl methacrylate monomers and 2-acrylamido-2-methylpropane sulfonic monomers.
7. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque el agente bioactivo se selecciona entre un antibiótico, un antitrombogénico, un antiangiogénico, un proangiogénico y cualquiera de sus mezclas. 7. - The mesh prosthesis according to any of the preceding claims, characterized in that the bioactive agent is selected from an antibiotic, an antithrombogenic, an antiangiogenic, a proangiogenic and any of its mixtures.
8. - La prótesis de malla según la reivindicación anterior, caracterizada porque el bioactivo es un antibiótico. 8. - The mesh prosthesis according to the preceding claim, characterized in that the bioactive is an antibiotic.
9.- La prótesis de malla según la reivindicación anterior, caracterizada porque el antibiótico es una quinolona, un glucopéptido, una tetraciclina, una oxazolidinona, un macrólido, una liposamida, un estreptogramin sulfonamidas, polipeptidos, penicilinas, ansamicinas o cualquiera de sus mezclas. 9. The mesh prosthesis according to the preceding claim, characterized in that the antibiotic is a quinolone, a glycopeptide, a tetracycline, an oxazolidinone, a macrolide, a liposamide, a streptogramin sulfonamides, polypeptides, penicillins, ansamycins or any of their mixtures.
10. - La prótesis de malla según la reivindicación anterior, caracterizada porque el bioactivo es un glucopéptido. 10. - The mesh prosthesis according to the preceding claim, characterized in that the bioactive is a glycopeptide.
11 . - La prótesis de malla según la reivindicación anterior, caracterizada porque el glucopéptido es vancomicina, eritromicin, neomicin, estreptomicin, daptomicin, rifamicin, puromicin, lincomicin o cualquiera de sus combinaciones. eleven . - The mesh prosthesis according to the preceding claim, characterized in that the glycopeptide is vancomycin, erythromycin, neomycin, streptomycin, daptomycin, rifamycin, puromycin, lincomycin or any combination thereof.
12. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque la cantidad de copolímero acrílico bioactivo está entre el 15 y el 30% p/p. 12. - The mesh prosthesis according to any of the preceding claims, characterized in that the amount of bioactive acrylic copolymer is between 15 and 30% w / w.
13. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque el copolímero acrílico bioactivo comprende entre un 45 y un 75 % p/p de uno o varios monómeros con grupos hidroxilo. 13. - The mesh prosthesis according to any of the preceding claims, characterized in that the bioactive acrylic copolymer comprises between 45 and 75% w / w of one or more monomers with hydroxyl groups.
14. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque el copolímero acrílico bioactivo comprende entre un 10 y un 35 % p/p de uno o varios monómeros con grupos sulfónicos. 14. - The mesh prosthesis according to any of the preceding claims, characterized in that the bioactive acrylic copolymer comprises between 10 and 35% w / w of one or more monomers with sulfonic groups.
15.- La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque el copolímero acrílico bioactivo comprende entre un 5 y un 30 % p/p de agente bioactivo. 15. The mesh prosthesis according to any of the preceding claims, characterized in that the bioactive acrylic copolymer comprises between 5 and 30% w / w bioactive agent.
16. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque el copolímero acrílico bioactivo comprende polietilenglicol, preferiblemente entre un 10 y un 30% p/p. 16. - The mesh prosthesis according to any of the preceding claims, characterized in that the bioactive acrylic copolymer comprises polyethylene glycol, preferably between 10 and 30% w / w.
17. - La prótesis de malla según cualquiera de las reivindicaciones anteriores, caracterizada porque la malla médica está compuesta por polipropileno monofilamento de bajo peso molecular, polipropileno monofilamento de alto peso molecular, polipropileno doble filamento de alto peso molecular, polipropileno poro grande multifilamento, poliéster de alto peso molecular multifilamento, politetrafuoroetileno o cualquiera de sus combinaciones. 17. - The mesh prosthesis according to any of the preceding claims, characterized in that the medical mesh is composed of low molecular weight monofilament polypropylene, high molecular weight monofilament polypropylene, high molecular weight double filament polypropylene, multifilament large pore polypropylene, polyester high molecular weight multifilament, polytetrafuoroethylene or any combination thereof.
18. - Procedimiento para la obtención de la prótesis de malla como se definen en cualquiera de las reivindicaciones 1 a 17, caracterizado porque: iv) se disuelve el copolímero acrílico bioactivo en etanol; 18. - Procedure for obtaining the mesh prosthesis as defined in any of claims 1 to 17, characterized in that: iv) the bioactive acrylic copolymer is dissolved in ethanol;
v) se deposita la disolución resultante sobre la malla médica, preferiblemente gota a gota hasta el recubrimiento total o por inversión; v) the resulting solution is deposited on the medical mesh, preferably dropwise to the total coating or by inversion;
vi) se evapora el disolvente, preferiblemente a temperatura ambiente. vi) the solvent is evaporated, preferably at room temperature.
19. - El procedimiento según la reivindicación anterior, caracterizado porque en la etapa (i) se disuelve el copolímero acrílico bioactivo en una proporción entre el 1 y el 5% p/v en etanol. 19. - The process according to the preceding claim, characterized in that in step (i) the bioactive acrylic copolymer is dissolved in a proportion between 1 and 5% w / v in ethanol.
20. - El procedimiento según cualquiera de las dos reivindicaciones anteriores, caracterizado porque en la etapa (ii) se deposita entre 5 y 20 ml_ de disolución por gramo de malla. 20. - The method according to any of the two preceding claims, characterized in that in step (ii) between 5 and 20 ml of solution per gram of mesh is deposited.
21 . - El procedimiento según cualquiera de las tres reivindicaciones anteriores, caracterizado porque en la etapa (iii) se evapora el disolvente a temperatura ambiente. twenty-one . - The process according to any of the three preceding claims, characterized in that in step (iii) the solvent is evaporated at room temperature.
22. - El procedimiento según cualquiera de las reivindicaciones 18 a 20, caracterizado porque el proceso de obtención del copolímero acrílico bioactivo comprende: i') se disuelve el agente bioactivo, preferiblemente junto con polietilenglicol, en agua destilada; 22. - The process according to any of claims 18 to 20, characterized in that the process of obtaining the bioactive acrylic copolymer comprises: i ') the bioactive agent is dissolved, preferably together with polyethylene glycol, in distilled water;
ii') se añade el copolímero acrílico y se agita; ii ') the acrylic copolymer is added and stirred;
iii') se congela la mezcla y se liofiliza. iii ') the mixture is frozen and lyophilized.
23.- El procedimiento según cualquiera de las dos reivindicaciones anteriores, caracterizado porque en la etapa (i') la concentración de agente bioactivo en la solución de acuosa está entre 5 mg/mL y 40 mg/mL. 23. The process according to any of the two preceding claims, characterized in that in step (i ') the concentration of bioactive agent in the aqueous solution is between 5 mg / mL and 40 mg / mL.
24.- El procedimiento según cualquiera de las dos reivindicaciones anteriores, caracterizado porque en la etapa (i') la concentración de polietilenglicol en la solución de acuosa está entre 5 mg/mL y 40 mg/mL. 24. The process according to any of the two preceding claims, characterized in that in step (i ') the concentration of polyethylene glycol in the aqueous solution is between 5 mg / mL and 40 mg / mL.
25. - El procedimiento según cualquiera de las reivindicaciones 18 a 24, caracterizado porque el procedimiento para la obtención del copolímero acrílico comprende las siguientes etapas: i") disolver los monómeros con un iniciador de polimerización radical en una mezcla de agua:isopropanol; 25. - The process according to any of claims 18 to 24, characterized in that the process for obtaining the acrylic copolymer comprises the following steps: i ") dissolve the monomers with a radical polymerization initiator in a mixture of water: isopropanol;
ii") desoxigenación del medio de reacción; ii ") deoxygenation of the reaction medium;
iii") someter a tratamiento térmico a una temperatura entre 40 y 75°C; iii ") subject to heat treatment at a temperature between 40 and 75 ° C;
iv") aislar el producto de reacción por evaporación del disolvente, y purificar mediante disolución en agua y lavado mediante membrana de diálisis; iv ") isolate the reaction product by evaporation of the solvent, and purify by dissolving in water and washing by dialysis membrane;
v") liofilizar el copolímero acrílico. v ") lyophilize the acrylic copolymer.
26. - El procedimiento según la reivindicación anterior, caracterizado porque el iniciador de polimerización radical es el azobis-isobutironitrilo (AIBN), y está en una proporción entre 0,25 y 2% p/p. 26. - The process according to the preceding claim, characterized in that the radical polymerization initiator is azobis-isobutyronitrile (AIBN), and is in a proportion between 0.25 and 2% w / w.
27.- El procedimiento según cualquiera de las dos reivindicaciones anteriores, caracterizado porque en (ii") la mezcla de reacción se desoxigena con una corriente de nitrógeno. 27. The process according to any of the two preceding claims, characterized in that in (ii ") the reaction mixture is deoxygenated with a stream of nitrogen.
28.- El procedimiento según cualquiera de las tres reivindicaciones anteriores, caracterizado porque en la etapa (iii") el tratamiento térmico se efectúa a una temperatura de entre 60 y 80°C. 28.- The method according to any of the three preceding claims, characterized in that in step (iii ") the heat treatment is carried out at a temperature between 60 and 80 ° C.
29.- El uso de un copolímero acrílico bioactivo que comprende entre un 30 y un 95 % p/p de uno o varios monómeros con grupos hidroxilo; entre un 5 y un 55 % p/p de uno o varios monómeros con grupos sulfónicos; y entre 0,01 % y un 50% p/p de un agente bioactivo para la impregnación de mallas médicas. 29.- The use of a bioactive acrylic copolymer comprising between 30 and 95% w / w of one or more monomers with hydroxyl groups; between 5 and 55% w / w of one or more monomers with sulfonic groups; and between 0.01% and 50% w / w of a bioactive agent for impregnating medical meshes.
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ESP200930975 | 2009-11-10 | ||
ES200930975A ES2359321B1 (en) | 2009-11-10 | 2009-11-10 | POLY? HYDROPHILE MEROS AS BIOACTIVE COMPOUND RELEASE SYSTEMS IN SURGICAL APPLICATION BADS. |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0596615A1 (en) * | 1992-10-30 | 1994-05-11 | Medtronic, Inc. | Articles having bioactive surfaces |
WO2002013871A2 (en) * | 2000-08-15 | 2002-02-21 | Surmodics, Inc. | Medicament incorporation matrix |
WO2008024510A2 (en) * | 2006-08-25 | 2008-02-28 | Boston Scientific Scimed, Inc. | Medical devices having improved mechanical performance |
WO2008109098A2 (en) * | 2007-03-05 | 2008-09-12 | Boston Scientific Scimed, Inc. | Medical devices having improved performance |
-
2009
- 2009-11-10 ES ES200930975A patent/ES2359321B1/en active Active
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2010
- 2010-11-10 WO PCT/ES2010/070725 patent/WO2011058208A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0596615A1 (en) * | 1992-10-30 | 1994-05-11 | Medtronic, Inc. | Articles having bioactive surfaces |
WO2002013871A2 (en) * | 2000-08-15 | 2002-02-21 | Surmodics, Inc. | Medicament incorporation matrix |
WO2008024510A2 (en) * | 2006-08-25 | 2008-02-28 | Boston Scientific Scimed, Inc. | Medical devices having improved mechanical performance |
WO2008109098A2 (en) * | 2007-03-05 | 2008-09-12 | Boston Scientific Scimed, Inc. | Medical devices having improved performance |
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