WO2023057947A1 - A method for the preparation of surfaces, particularly of cardiac prosthesis - Google Patents
A method for the preparation of surfaces, particularly of cardiac prosthesis Download PDFInfo
- Publication number
- WO2023057947A1 WO2023057947A1 PCT/IB2022/059550 IB2022059550W WO2023057947A1 WO 2023057947 A1 WO2023057947 A1 WO 2023057947A1 IB 2022059550 W IB2022059550 W IB 2022059550W WO 2023057947 A1 WO2023057947 A1 WO 2023057947A1
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- WIPO (PCT)
- Prior art keywords
- acid
- biocidal
- phenolic
- prosthesis
- treatment
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
Definitions
- the present invention finds application in the medical field and, in particular, in the preparation of biological surfaces to be in contact with bodily fluids.
- Glutaraldehyde-fixed bioprosthetic heart valves have been reported to be prone to dystrophic calcification after mid- /long- term implantation in humans, with this being the main limiting factor affecting their longevity. Calcification is a complex and multi-factorial process not yet fully understood, which includes atherosclerosis-like tissue remodelling and prolonged exposure to mechanical stress. Among the causes responsible for calcific tissue dystrophy the treatment with glutaraldehyde (GLU) should also be taken into due consideration.
- GLU is often used as the preferred fixative and sterilizing agent for many commercial bioprosthetic products, especially in surgical and transcatheter implantable heart valves (THVs).
- THV implant is considered a minimally invasive procedure that involves the use of a guide catheter for the positioning of the prosthesis, avoiding the opening-heart surgery.
- THVs may be an option for people who are at intermediate or high risk of complications from surgical heart valve replacement.
- the GLU chemical instability is strictly involved in the exposure of potential calcium-binding sites (residual aldehydes, acids, Schiff bases, etc).
- GLU fixation protocols To decrease the influence on the calcification process, several changes in the GLU fixation protocols have been proposed by the BHVs manufacturers, including the addition of novel steps aimed at the chemical stabilization of the reactive aldehyde and carboxylic groups.
- GLU detoxification by urazole, diamine spacer extension, treatment by 2-amino oleic acid or incubation in ethanol are just some of the processes developed in the challenge of stabilizing GLU, with the hope of delaying the calcific tissue dystrophy.
- Anticoagulation therapy (both Novel Oral Anti-coagulants NOACs and warfarin) is effective in reducing the HALT complications, but HALT recurred in 50% of the patients where anticoagulation was discontinued. It is important to note that dual antiplatelet therapy, the standard of care for transcatheter valve implant, resulted not effective in the prevention or treatment of subclinical leaflet thrombosis.
- Infective endocarditis has a significant impact both on the population and patient management. In the USA there are 40,000 to 50,000 new cases/year, with average hospital charges over $120,000/patient. Notwithstanding the improvements in diagnosis and surgical intervention, the 1-year mortality from IE is unchanged in over 2 decades. In the cases that prolonged antibiotic treatment is not sufficient, surgical valve replacement is required.
- BHVs have shown good results also in mid and low-risk patients enormously expanding the number of people subjected to this type of minimally invasive intervention.
- the replacement of a degenerated surgical BHV is frequently performed adopting a valve-in-valve approach.
- a THV is deployed inside the dysfunctional surgical BHV without its preliminary removal. This could potentially lead to bacterial migration from the dysfunctional BHV to the new THV resulting in bacterial growth and tissue colonization.
- pyrogen Greek pyros: fire
- a pyrogenic response induced by a medical device may be due to several causes depending on the presence of so-called “material-mediated pyrogens”.
- One class of well-known and well-characterized exogenous pyrogens is the class of endotoxins. Endotoxins are lipopolysaccharide components present on the cell walls of Gram-negative bacteria.
- exogenous pyrogens are non-endotoxin pyrogens, which include substances such as lipoteichoic acid originating from Gram-positive bacteria, and other compounds originating from fungi, yeast, viruses, bacteria, and parasites.
- the third class of non-endotoxin pyrogens is that of material-mediated pyrogens. Although no formal definition of material-mediated pyrogens exists, it is thought that they may leach from medical device materials or surfaces. Material -mediated pyrogens may also stem from contamination introduced during manufacturing and packaging, such as residues from cutting fluids, mould releases, cleaning agents, and processing aids. Therefore, it is of fundamental importance to develop treatments capable of improving the outcomes of BHVs without introducing chemicals or contaminants responsible to rise pyrogenic reactions.
- the inventors of the present patent application have surprisingly found a method for preventing both the active and the passive early degenerative occurrences in a biological matrix (particularly of medical devices and even more particularly to cardiac prosthesis) achieving an unprecedented GEU stabilization, resistance both to surface platelet adhesion and fibrin release and microorganisms’ surface colonization. Finally, such a method showed an interesting improvement effect on the biomechanical properties of the treated biological matrix.
- Figure 4 Percentage of elongation comparison between polyphenolic-treated and untreated samples
- the present invention discloses a method for the treatment of a surface to be contacted with biological fluids.
- said surface is the surface of a medical device.
- said surface is the surface of a biological prosthesis, which can be a cardiac prosthesis.
- the present invention discloses a surface to be contacted with biological fluids obtained with the method of the invention.
- said surface is the surface of a medical device.
- said surface is the surface of a biological prosthesis, which can be a cardiac prosthesis.
- the medical device, the biological prosthesis and the cardiac prosthesis comprising the surface according to the invention do represent further objects of the invention.
- the present invention discloses a method for the treatment of a disease comprising the use of the medical device, the biological prosthesis or the cardiac prosthesis of the invention.
- said disease is a heart disease.
- said disease is in a human, while per another aspect, said disease is in an animal.
- a solution comprising a phenolic compound or a mixture of phenolic compounds to be used in the method of the present application represents a further object of the invention.
- the present invention discloses a kit for performing the invention method.
- the present invention discloses a method for the treatment of a surface to be contacted with biological fluids.
- a biological fluid within the purposes of the present invention is represented by blood, serum, plasma, vitreous gel, tears, urine, saliva, faeces; including synovial, peritoneal, pericardial, pleural and amniotic fluid.
- a biological surface can be represented by a surface of human or animal origin.
- surfaces of animal origin may have an equine, porcine or bovine origin and preferably have a porcine or bovine origin; such surfaces may be considered as biological matrices.
- said surface is a surface of a medical device.
- Medical devices may be represented by: cardiac valve, tendon, ligament, pericardium, muscular fasciae, dura mater, tympanic membrane, intestinal submucosa, cartilage, adipose and bone tissue, pelvic, abdominal, breast and dermal tissue.
- said surface is the surface of a biological prosthesis.
- a biological prosthesis according to the invention may be represented by: a vessel, a cardiac valve, a tendon, a ligament, pericardium, muscular fasciae, dura mater, tympanic membrane, intestinal submucosa, cartilage, adipose and bone tissue, pelvic, abdominal, breast and dermal tissue.
- the biological prosthesis according to the invention is represented by a cardiovascular prosthesis, such as a cardiac valve, or a pericardial tissue patch.
- a cardiac valve that can be treated according to the present invention is represented by a surgical heart valve.
- the cardiac valve which can be treated according to the present invention is represented by a trans-catheter implantable heart valve; said valve requires to be implanted through a catheter and are folded to be housed within the catheter.
- the disclosed surface is contacted with a solution comprising a phenolic compound or a mixture of phenolic compounds.
- a phenolic compound shall be intended as a phenolic or polyphenolic compound (in some instances they both are referred as “phenolic” or “polyphenolic”, only) used here as synonyms) selected from the group comprising: phenols, phenolic aldehydes, phenolic acids, phenylamines, phenol compounds, flavonoids, phenylpropanoids and tannins.
- a phenolic compound is selected in the group comprising: vanillin, cinnamic acids, phenylalanine, coumarins, xanthones, catechins, flavonons, flavones, chaicones, flavanonols, flavanols, leucoanthocyanidin, anthocyanidin, hydroxycinnamic acids.
- a phenolic compound can be selected in the group comprising: resveratrol, aloin, cyanarin, epigallocatechin, tannic acid, caffeic acid, chlorogenic acid, hydroxy tyro sol, rosmarinic acid, narigenin, gallic acid, hesperitin, quinic acid, eleonolic acid, pinoresinol, luteolin, apigenin, tangeritin, isorhamnetin, kaempferol, myricetin, eriodictyol, hesperetin, naringenin, theaflavin, thearubigins, daidzein, genistein, glycitein, pterostilbene, delphinidin, malvidin, pelargonidin, peonidin, chicoric acid, ferulic acid, salicylic acid.
- derivatives of the above-disclosed phenolic or polyphenolic compound are also encompassed; for instance, salts or esters or isomers may also be used.
- the solution of the invention comprises a mixture of two or more of the above-disclosed phenolic or polyphenolic compounds.
- the solution of the invention may comprise a mixture of two or more of the above-disclosed phenylpropanoids.
- a phenolic or polyphenolic compound is solubilized in an alcoholic solvent.
- the solution comprises a mixture of phenolic compounds and more preferably a mixture of phenylpropanoid compounds.
- a first component is solubilized in an alcoholic solution (Component A), preferably 10% of the final volume of the solution.
- An alcoholic solvent according to the invention may comprise methanol, ethanol, isopropanol, butanol, etc. and preferably comprises or it is represented by ethanol.
- a second component is solubilized in an isotonic buffered solution (Component B), preferably 90% of the final volume of the solution.
- the final solution is a hydroalcoholic solution.
- the solution of a phenolic compound or of a mixture of phenolic compounds preferably has a pH value of between 5 and 7.
- the solution can optionally be filtered with a 0.22 pm filter.
- the surface is contacted with the solution of a phenolic compound or of a mixture of phenolic compounds for a period of time of less than 2 hours.
- the contacting is continued for a period of about one hour.
- the contacting is continued for a period of about 30 minutes.
- the contacting comprises a first step and a second step.
- the first contacting step is performed for 30 minutes and the second contacting step is performed to 30 minutes.
- a rinsing step (also referred to as a washing step) may be performed.
- the method is performed in the dark and more preferably completely in the dark (i.e. avoiding any exposure to light).
- the method is performed while stirring the solution.
- the temperature of the contacting step it is preferably performed at a temperature of about +20°C ⁇ 10°C.
- the treated surface, medical device, biological prosthesis or cardiac prosthesis may be subjected to one or more washing steps.
- each of said washing steps is performed with a suitable buffer; for example, a suitable buffer may be represented by a phosphate buffer.
- each washing step may be performed for a period of about 15-30 minutes.
- each washing step may be performed for a period of about 12-48 hours.
- said biological surface can be previously subjected to a pre-treatment step.
- said pre-treatment step may have one or more of the following effects: stabilizing proteins, stabilizing or removing lipids, stabilizing or removing cell structures, lowering the antigenicity.
- said pre-treatment step may comprise a step of pre-treatment with one or more of glutaraldehyde, formaldehyde, quercetin or genipin as well as a treatment for the removal of phospholipids.
- a capping agent selected from the group comprising: glycerol, heparin, amines (i.e. alkyl amines, amino alcohols, ethanolamine), amino acids (lysine, hydroxylysine, amino sulfonates, taurine, amino sulfates, dextran sulfate, chondroitin sulfate), hydrophilic multifunctional polymers (i.e. polyvinyl alcohol, polyethyleneimine), hydrophobic multifunctional polymers (i.e.
- alpha-dicarbonyls methylglyoxal, 3-deoxyglucosone, glyoxal
- hydrazides i.e. adipic hydrazide
- N,N- disuccinimidyl carbonate carbodiimide
- EDC N-cyclohexyl-N'-(2-morpholino ethyl)carbodiimide — CMC, 1,3-di-cyclohexyl carbodiimide — DCC, 2- chloro- 1-methyl pyridinium iodide - CMPI, 2-chloro-l-methyl pyridinium iodide - CMPI), antibiotics, cell recruiting agents, hemocompatibility agents, anti-inflammatory agents, antiproliferative agents, reducing agents (i.e. sodium cyanoborohydride, sodium borohydride, sodium bisulfite + acetylacetone, formic acid — formaldehyde, mono-, di- or polyepoxy alkanes).
- reducing agents i.e. sodium cyanoborohydride, sodium borohydride, sodium bisulfite + acetylacetone, formic acid — formaldehyde, mono-, di- or polyepoxy alkanes.
- the method for the treatment of a surface to be contacted with a biological fluid according to the invention is a stabilization method.
- said stabilization method inactivates the available reacting groups on the pre-treated surface.
- said stabilization method inactivates the available aldehydic and carboxylic groups on the pre-treated surface.
- the disclosed method is an anti-calcific method.
- a surface obtained with the method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and particularly a cardiac prosthesis comprising the surface obtained according to the method of the present application represent further objects of the present invention.
- a surface obtained with the pre-treatment and the treatment method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and particularly a cardiac prosthesis comprising the surface obtained according to the pre-treatment and the treatment method of the present application represent further objects of the present invention.
- the method for the treatment of a surface to be contacted with a biological fluid according to the invention is a protective method.
- said protective method prevents subclinical thrombosis occurrences.
- the method of the invention is an anti-platelet adhesiveness method.
- the method of the invention prevents the synthesis of fibrin.
- fibrin The synthesis of fibrin is releated to the activation of soluble fibrinogen to insoluble fibrin polymers. Such polymers aggregate laterally to make fibers, which then branch to yield a three-dimensional network and, interacting with circulating platelet, lead to the formation of the fibrin clot essential for haemostasis and wound coagulation. If the clot enters the bloodstream it is called thrombus and it can obstruct small/medium-sized vessels causing ischemia, stroke and heart attack.
- the protective method of the invention has proved to prevent and avoid the anchoring of circulating platelets on the biological surfaces treated and/ or pre-treated according to the invention.
- a surface obtained with the method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and particularly a cardiac prosthesis comprising the surface obtained according to the method of the present application represent further objects of the present invention.
- a surface obtained with the pre-treatment and the treatment method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and a cardiac prosthesis comprising the surface obtained according to the pre-treatment and the treatment method of the present application represent further objects of the present inventiom
- the method for the treatment of a surface to be contacted with a biological fluid according to the invention is a method to preserve and maintain the proper structural biomechanical properties.
- the method of the invention has proved to increase the elongation properties of the biological treated tissues.
- said method preserves the collagen structure of the BHVs leaflets.
- the method for the treatment of a surface to be contacted with a biological fluid according to the invention is a protective method for maintaining the proper physiological haemo- and fluid-dynamics properties of the treated BHVs.
- a surface obtained with the method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and a cardiac prosthesis comprising the surface obtained according to the method of the present application represent further objects of the present invention.
- a surface obtained with the pre-treatment and the treatment method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and a cardiac prosthesis comprising the surface obtained according to the pre-treatment and the treatment method of the present application represent further objects of the present invention.
- the method for the treatment of a surface to be contacted with a biological fluidaccording to the invention is an anti-microbial and an anti-viral method, in that it is a disinfecting method of the treated surface.
- the anti-microbial method of the invention has a biocidal action.
- the antimicrobial method of the invention is active against microorganisms that are responsible for the onset of endocarditis.
- said microorganisms are Gram + bacteria, Gram- bacteria, yeasts and moulds.
- said microorganisms are mycobacteria, such as Mycobacterium chelonae.
- the method for the treatment of a surface to be contacted with a biological fluid according to the invention is an anti Gram + method, an anti-Gram- method, an anti-yeast method, an antimould method, an anti-mycobacteria method.
- the anti-viral method of the invention has a virucidal action against viruses.
- said virucidal action is according to the standard EN 14476.
- said viruses belong to the families of Picornaviridae, Adenoviridae and Caliciviridae.
- said microorganisms are Poliovirus Type 1 LSc-2ab (RVB-1260), Adenovirus Type 5 (ATCC VR-5) and Murine norovirus strain S-99 (RVB-651).
- a surface obtained with the method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and a cardiac prosthesis comprising the surface obtained according to the method of the present application represent further objects of the present invention.
- a surface obtained with the pre-treatment and the treatment method of the invention represents another object of the present application.
- a biological prosthesis, a medical device and a cardiac prosthesis comprising the surface obtained according to the pre-treatment and optionally the treatment method of the present application represent further objects of the present invention. More, in particular, said biological prosthesis may be represented by a cardiovascular prosthesis obtained with the pre-treatment and optionally the treatment method of the invention.
- a method for the treatment of a disease comprising the use of the medical device, the biological prosthesis or the cardiac prosthesis above disclosed.
- said disease is a heart disease.
- said disease is in a human, while per another aspect, said disease is in an animal.
- the method for the treatment of the disease according to the invention comprises a valve-in-valve approach, wherein a valve is deployed inside a dysfunctional valve without its preliminary removal.
- the preparation of said solution comprises a first step, wherein the phenolic compound is solubilized in an alcoholic solvent.
- a further phenolic compound can be solubilized in an isotonic buffered solution.
- the solution of compound A represents 10% (volume) of the final solution and the solution of compound B represents 90% (volume) of the final solution.
- the preparation of the solution is carried out in the dark and preferably in the complete darkness, i.e. avoiding any exposure to light.
- the following experimental session shows the results of assays carried out on surfaces treated according to the present invention.
- the surfaces have been treated with the Solution 5 according to the above disclosure.
- Caffeic acid as Component A has been weighted according to the indicated concentrations and solubilized in ethanol to a 10% final volume of the polyphenol mixture.
- Tannic acid as the Component B column has been weighted according to the indicated concentrations and solubilized in modified phosphate buffer to 90% final volume of the polyphenol mixture. Both steps are performed in the dark.
- solubilization is complete, the two solutions are admixed. pH is adjusted to 5-7. The solution is filtered with a 0.22 pm filter. This solution is referred to as Solution 5 or the Polyphenolic Solution.
- pericardial tissue was incubated in a buffered GTU solution for three steps of 24 hs each in a dark room.
- a GTU solution is a 0.6% ⁇ 0.5% v/v for the first and second steps followed by a 0.2% ⁇ 0.15% v/v for the third ones.
- GTU treated pericardial patches were subjected to two washing steps in phosphate buffer for 15 minutes each.
- the pericardial patches were included in OCT (Optimal Cutting Temperature) and frozen by immersion in isopentane pre-cooled in liquid nitrogen. Cryosections with a thickness of 7 pm were then produced using MirrIR slides suitable for infrared reflectance studies as support and analyzed by FT-IR microscopy in reflectance and mosaic mode with 64 scans for each selected area.
- the detector used is FPA with 4 cm resolution.
- the treated tissues showed a lower concentration of carboxyl groups at wave number 1233 cm 4 (corresponding to the C-O bonds stretching of carboxyl groups) compared to samples fixed only in GLU. Considering the total of free carboxylic groups quantified in the GLU fixed samples as 100% of the available groups, treated samples reported a decrease equal to 76% of the total.
- Tissue samples should be prepared to have a wet weight of approximately 20 mg each. Each sample is incubated at 100°C in 2 ml of Solution C for 20 minutes in the dark, cooled in water and diluted with 15 ml of 50% Isopropanol. The developed colour is read at 570 nm within 30 minutes. The nmoles of aldehyde groups are determined with respect to a glycine standard.
- pericardial tissue was incubated in a buffered GLU solution for three steps of 24 hs each in a dark room.
- a GLU solution is a 0.6% ⁇ 0.5% v/v for the first and second steps followed by a 0.2% ⁇ 0.15% v/v for the third ones.
- GLU treated pericardial patches were subjected to two washing steps in phosphate buffer for 15 minutes each.
- the treated patches were subjected to five washes in phosphate buffer for 15 to 30 minutes each. Samples are referred to as TREATED.
- Heparinized bovine blood was collected from 3 different animals and radioisotope was added for thrombus quantification.
- Pericardial tissue strips were deployed in a 25.4 mm conduit and blood flow at 2.5 L/min was enabled with a peristaltic pump for 1 hour. The strips were rinsed with saline and placed in a gamma counter for quantification of radiation (reflective of relative thrombosis). The mean radiation values are 73.133 counts per minute (cpm) for Glu and 35.165 cpm for treated samples.
- results are expressed as a percentage of platelets propensity reduction in polyphenolic-treated tissues taking into account GLU samples as 100%.
- Each stripe was dimensionally characterized in terms of length (useful length 50 mm), width and thickness (average value of the measurements) and the cross-sectional area was calculated (with x thickness). The following parameters were obtained from each tensile curve:
- the average value was calculated from the samples, obtaining one value for each patch.
- the average value was calculated again from the patches, obtaining one value for each test group.
- Figure 3 shows the ultimate Tensile Strength comparison between treated and untreated samples (GEU).
- the Ultimate Tensile Strength (UTS) often shortened to tensile strength (TS), is the maximum stress that a material can withstand while being stretched or pulled before breaking.
- the polyphenolic treatment does not report a statistically significant difference from the control sample (GLU).
- Figure 4 shows the percentage of elongation comparison between treated and untreated samples (GLU).
- FIG. 5 shows Young’s Modulus correlation between treated and untreated samples (GLU).
- the percentage of elongation is strictly related to Young’s Modulus.
- the Young’s Modulus or Modulus of Elasticity is a feature, characteristic of a material, which expresses the relationship between tension and deformation in the case of uniaxial load conditions and the case of elastic (reversible) behaviour of the material. It is defined as the ratio between the applied stress and the resulting deformation.
- the Young’s Modulus increases, also the stiffness of the material increases.
- the increase in the elasticity level of the treated tissue leads to a consequent decrease in its Young’s Modulus compared to the untreated pericardium (GLU).
- the gain in elasticity allows a better distribution of the mechanical load, especially to the advantage of the BHVs areas subjected to greater pressure. This avoids the formation of tears and preserves the collagen structure of the valve leaflets.
- the Bactericidal Activity (BA) of the polyphenolic solutions of the invention was evaluated regarding the following different micro-organism: Staphyloccoccus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 9027, Cnterococcus faecalis ATCC 29212, Listeria monocytogenes ATCC 19111, Salmonella enterica typhimurium ATCC 14028, Streptococcus viridans ATCC 6249, a nontuberculous mycobacterium Mycobacterium chelonae ATCC 35752, a yeast Candida albicans ATCC 10231 and a fungus Aspergillus brasiliensis ATCC 16404.
- BA assay consists of a suspension method with a single incubation for 24 hours of the bacteria with a known concentration of the Solution 5 of the invention (inoculum). At the end of the incubation time, the content of each test tube is seeded into 90 mm sterile Petri dishes in a specific agar medium, with pour plate or spread plate technique depending on the micro-organisms tested, after dilution in Tryptone Salt Broth (MRD Broth). Then the plates obtained are incubated at specific conditions and temperatures according to the growth requirements of each micro-organism.
- MRD Broth Tryptone Salt Broth
- a microbial suspension in MRD Broth was quantified through the spectrophotometer at 620 nm wavelength in disposable 10 mm path length cuvette.
- the absorbance of an aliquot part of the suspension is measured: the range between 0.150 and 0.460 corresponds to a concentration of cells between lxlO A 8 CFU/ml and 3xlO A 8 CFU/ml (with Candida albicans between lxlO A 7 CFU/ml and 3xlO A 7 CFU/ml).
- Streptococcus oralis as there was no correlation between the absorbance measure and the bacteria concentration, the quantification was performed by cell count at the microscope.
- the table here below reports the percentage of bactericidal activity compared to standard antibodies and ethanol solution.
- the virucidal activity of the polyphenolic Solution 5 was assessed according to the guidelines: Test method and requirements European Standard EN 14476:2013+A2:2019/UNI EN 14476:2019 — Chemical disinfectants and antiseptics. Quantitative suspension test for the evaluation of virucidal activity in the medical area. Test method and requirements (Phase 2/Step 1). The virucidal assay was performed regarding the following viruses strain: Poliovirus Type 1 ESc-2ab (RVB-1260), Adenovirus Type 5 (ATCC VR-5) and Murine norovirus S99 (RVB-651). The table here below reports the percentage of virucidal activity of the polyphenolic Solution 5 diluted to 80% (corresponding to the highest possible concentration assessable according to the method).
- the anti-adhesive activity on the treated surfaces was assessed with reference to the following different micro-organism: Staphyloccoccus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 9027, Pinterococcus faecalis ATCC 29212, Listeria monocytogenes ATCC 19111, Salmonella enterica typhimurium ATCC 14028, Streptococcus viridans ATCC 6249, a nontuberculous mycobacterium Mycobacterium chelonae ATCC 35752, a yeast Candida albicans ATCC 10231 and a fungus Aspergillus brasiliensis ATCC 16404.
- antibiotics 300 gg/mL
- Different types of antibiotics specific to each type of microorganism strain were used (neomycin, penicillin, cephalosporin, polymyxin, rifamycin, lipiarmycin, quinolone, sulfonamide, macrolide, lincosamide, tetracycline, aminoglycoside, doxycycline, minocycline, ampicillin, amoxicillin/clavulanic acid, azithromycin, carbapenems, piperacillin/tazobactam, quinolones, chloramphenicol, ticarcillin, trimethoprim/sulfamethoxazole).
- tissue patches were washed extensively in PBS to remove any trace of unbound antibiotic. Subsequently, the treated and untreated samples were exposed singularly to the different strains of micro-organism strain (micro-organism load 1 x 10 7 CFU/mL) for 90 minutes at room temperature under moderate but constant agitation. At the end of the incubation, the tissue samples were subjected to three moderate vortexing passages to facilitate the detachment of the loosely bound bacteria. Finally, the samples were homogenized by Stomacher® 400 and serial dilutions of the obtained homogenates, plated in Petri dishes containing the appropriate selective growth media. After 24 hours of incubation at 37°C, the colony-formed units were counted for each type of sample.
- Results were expressed as the percentage decrease of the attached micro-organisms assessed in the treated pericardial patches by comparison with untreated GLU fixed pericardial patches (n— 5 for each microorganism strain) .
- the monocyte activation test has been qualified and validated for the detection of pyrogens by the European Center for the Validation of Alternative Methods (ECVAM) in 2005 and by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in 2008. It has been among the compendial methods for pyrogen detection in the European Pharmacopeia since 2010 (Chapter 2.6.30) and mentioned by the FDA "Guidance For Industry — Pyrogen and Endotoxins testing: Questions and Answers".
- the monocyte activation test (MAT) is the human in-vitro alternative to the rabbit pyrogen test (RPT) and allows the detection of the full range of pyrogens, including endotoxins and non-endotoxin pyrogens (NEPs).
- Tissue processing Eight-teen samples of bovine pericardia of approximately 2 cm 2 each have been processed with the GLU solution as above disclosed (“Tissue processing”). GLU treated pericardial samples were subjected to two washing steps in phosphate buffer for 15 minutes each. Nine patches were incubated with the Solution 5 under moderate but constant stirring in the dark, for two-step of 25 ⁇ 10 minutes each, at room temperature. At the end of the incubation, the treated patches were subjected to five washes in phosphate buffer for 15 to 30 minutes each. Samples are referred to as TREATED.
- the method of the invention has proved not to alter the other properties of the surfaces treated and optionally pre-treated according to the above disclosure, and of the medical devices, biological prosthesis and particularly cardiac prosthesis comprising said surfaces.
- the disclosed method has shown to inactivate the available aldehydic and carboxylic reacting groups on the treated or pre-treated surface.
- the method of the invention prevent the impairment of the functionality of the BHVs. It has been found that the protective action of the method of the invention is responsible for a better distribution of the mechanical load, which avoids the formation of tears, abrasion and holes.
- the method of the invention prevents the adhesion of microorganisms and the formation of bio films on the treated and optionally pre-treated surfaces.
- the disclosed method avoid the bacterial and viral contamination of a surface treated and optionally pre-treated according to the present invention.
- the disclosed method maintains the non-pyrogenic characteristic of the treated and optionally pre-treated surfaces.
Abstract
Description
Claims
Priority Applications (2)
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AU2022360405A AU2022360405A1 (en) | 2021-10-06 | 2022-10-06 | A method for the preparation of surfaces, particularly of cardiac prosthesis |
CA3230427A CA3230427A1 (en) | 2021-10-06 | 2022-10-06 | A method for the preparation of surfaces, particularly of cardiac prosthesis |
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IT102021000025796 | 2021-10-08 | ||
IT102021000025796A IT202100025796A1 (en) | 2021-10-08 | 2021-10-08 | METHOD FOR THE PREPARATION OF SURFACES, IN PARTICULAR OF HEART PROSTHESES |
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Citations (7)
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US6350251B1 (en) * | 2000-01-18 | 2002-02-26 | Biolink Corporation | Biocidal locks |
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US20090164005A1 (en) * | 2007-12-21 | 2009-06-25 | Edwards Lifesciences Corporation | Capping Bioprosthetic Tissue to Reduce Calcification |
US20120088671A1 (en) * | 2010-10-06 | 2012-04-12 | Board Of Trustees University Of Arkansas | Anti-biofilm compositions and methods for using |
WO2020201055A1 (en) * | 2019-03-29 | 2020-10-08 | Evonik Operations Gmbh | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by pneumoviridae |
WO2020208644A1 (en) * | 2019-04-10 | 2020-10-15 | Meril Life Sciences Pvt. Ltd. | A process for prevention of degradation and degeneration of tissue used in bioprosthesis |
US20200368178A1 (en) * | 2019-05-22 | 2020-11-26 | Biocompatibility Innovation S.r.l. | Method for preventing the formation of calcified deposits and for inactivating xenoantigens in biological matrices |
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2022
- 2022-10-06 AU AU2022360405A patent/AU2022360405A1/en active Pending
- 2022-10-06 WO PCT/IB2022/059550 patent/WO2023057947A1/en active Application Filing
- 2022-10-06 CA CA3230427A patent/CA3230427A1/en active Pending
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US6350251B1 (en) * | 2000-01-18 | 2002-02-26 | Biolink Corporation | Biocidal locks |
WO2007133479A2 (en) * | 2006-05-10 | 2007-11-22 | Cook Incorporated | Delivery of elastin-stabilizing compound within a body lumen |
US20090164005A1 (en) * | 2007-12-21 | 2009-06-25 | Edwards Lifesciences Corporation | Capping Bioprosthetic Tissue to Reduce Calcification |
US20120088671A1 (en) * | 2010-10-06 | 2012-04-12 | Board Of Trustees University Of Arkansas | Anti-biofilm compositions and methods for using |
WO2020201055A1 (en) * | 2019-03-29 | 2020-10-08 | Evonik Operations Gmbh | Preparations containing berry extracts for use in the prophylaxis and/or treatment of viral infections caused by pneumoviridae |
WO2020208644A1 (en) * | 2019-04-10 | 2020-10-15 | Meril Life Sciences Pvt. Ltd. | A process for prevention of degradation and degeneration of tissue used in bioprosthesis |
US20200368178A1 (en) * | 2019-05-22 | 2020-11-26 | Biocompatibility Innovation S.r.l. | Method for preventing the formation of calcified deposits and for inactivating xenoantigens in biological matrices |
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