Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
  • A61L24/0089—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing inorganic fillers not covered by groups A61L24/0078 or A61L24/0084
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • 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
  • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

• Tissue adhesive composition a method of producing it, and its application
• the subject of the present invention is a new tissue adhesive composition, a method of manufacturing and its application in daily surgical practice, particularly for the occlusion of insufficient venous vessels or congenital malformations.
• Chronic venous insufficiency is presently a social problem in developed countries. It is estimated that in Great Britain alone the cost of venous ulcers is about 400-600 million pounds, and over a billion in the USA. Studies conducted in Western Europe show that lower limb varicose veins afflict 35-53% of the population, 25-33% of women and 10-20% of men. In Poland, in 2003, a multi-site study on chronic venous insufficiency of all stages of advancement related to almost half of all Poles, women more frequently: 50.99%. Lower limb varicose veins were noted in 34% of subjects, and in 25% of cases in both limbs.
• Chronic venous insufficiency is the disruption of superficial or deep veins. It is caused by the insufficiency of venous valves. It may be a congenital or acquired illness. The insufficiency can concern superficial veins, the side branching's conjoining them, perforators or deep veins. Symptoms which announce venous insufficiency are calf cramps, numbness, tingling, burning sensation, oedema, leg pain, heavy legs, nocturnal leg cramps, and restless legs syndrome. Venous illness is a cause of workplace absenteeism, long term workplace disability, it can contribute to early disability pension and may also lead to thrombosis and pulmonary embolism, which carry a risk of acute death.
• Tissue glues used in medicine are seen as the most advanced method of attachment. Tissue glues can constitute an effective alternative in clinical practice in cases where other methods are not applicable due to contraindications.
• the use of tissue adhesive eases procedure and shortens hospitalization time. Despite the need in various areas of medicine, the choice of tissue adhesives is still small. Moreover, adhesives, despite many promising clinical results, are not without problems. For example, they induce inflammation and degrade in the moist biological environment.
• US7449498 reveals adhesive composition for veins encompassing n-butyl-2-cyanoacrylate and beta-tricalcium phosphate mixed in a 1 :4 or 1 :7 ratios.
• US3667472 discloses the surgical use of monomeric C2-C4 alpha-cyanoacrylate adhesive.
• the problem of this class of adhesive is their unsuitability for use in internal organs, and thereby in anastomoses, due to its well documented toxic and oncogenic properties.
• n-butyl-2-cyanoaciylic tissue adhesive Histoacryl®
• cyan acrylic adhesives There are many controversial findings related to its use, safety and efficacy of treatment.
• the n-butyl-2-cyanoacrylate glue polymerises in contact with living tissue, and polymerizes rapidly with an anionic mechanism. Its polymerization time is dependent on the type of tissue (does not flow in the presence of blood and bodily fluids), and reaches maximum mechanical durability in 60-90 seconds. During polymerization, the temperature is no higher than 45°C (considerable local temperature increases at the sites of adhesion take place).
• the post-curing joint is hard, inelastic and adhesives of this kind quickly initiate haemostasis. They are highly brittle and the adhesive layer is eliminated through hydrolysis. It is used for very small gaps, max. 0.15 mm. The thicker the adhesive layer the less complete is its polymerization.
• the n-butyl-2- cyanoacrylate glue is incapable of filling any gaps and may also be difficult to apply to wounds of a large surface area. During application, n-butyl-2-cyanoacrylate adhesive sticks to gloves and surgical tools which impedes its application and often hardens while it's still being dosed.
• n-butyl-2-cyanoacrylate adhesive is characterized by a sharp, acrid odour which is highly perceptible in dry air. It acts as a respiratory irritant, and the fumes may induce drowsiness and dizziness.
• Literature contains examples of complications due to the use of n-butyl-2-cyanoacrylate, and thrombosis complications, often very serious, have been observed.
• Individual cases of pulmonary, spleen, portal vein embolisms, thromboembolisms in the portal and splenic veins, brain thromboembolisms, as well as in the coronary vessels and spleen were observed.
• One case is known of a thromboembolism in the left kidney artery, inferior vena cava, and in parallel, in the pulmonary artery.
• the patient also exhibited a septicaemia complication in the form of pneumonia due to pulmonary infarction and recurrent severe kidney ulcers. Septicaemia and complications were observed in patients with pulmonary embolisms. Very difficult, terminal cases occur sporadically.
• the goal of the present invention is to design an adhesive formulation that would minimize the deleterious effects of currently used adhesive substances.
• the goal of the present invention is to deliver a composition of medical adhesive in which the components are selected quantitatively and qualitatively such that the adhesive joint facilitates the elastic and permanent adhesion to the vein walls.
• the technical problem solved by the present invention is to deliver a composition of medical adhesive for the occlusion and sealing of insufficient vessels of the venous system or congenital vascular anomalies.
• the composition will allow for the anchoring of the adhesive substance in the pores and irregularities of the joined surfaces, and for its cohesion, such that a strong joint is formed characterised by impermeability, good physio-chemical properties (durability, hardness, elasticity) and resistance to enzymes.
• the subject of the present invention is a tissue adhesive composition for occluding or sealing insufficient vessels of the venous system or congenital vascular anomalies comprising:
• the viscosity of poly(methyl-vinyl-siloxane) is 18 000 mPa-s - 23 000 mPa-s at a temperature of 25°C.
• the BET surface area for the silicon dioxide is 175-225 m 2 /g.
• the cross linker is a platinum catalyst.
• the medical adhesive composition contains 85%> by weight poly(methyl-vinyl- siloxane), 6.5%> by weight silicon dioxide, 8.5%> by weight platinum catalyst.
• the subject the present invention is also a method of producing a composition of tissue adhesive for occluding or sealing insufficient vessels of the venous system or congenital vascular anomalies as above, comprising:
• the silicon dioxide is dried for 48h at a temperature of 50°C in a laboratory drier.
• the cross linker is a platinum catalyst.
• the subject the present invention is also a tissue adhesive composition defined above for use in treatment of insufficient vessels of the venous system or congenital vascular anomalies.
• An adhesive a composition according to the present invention is denoted as R 88 herein.
• the base of the adhesive is a poly(methyl-vinyl-siloxane) binder, encompassing in its general structure functional groups directly bound to the siloxane: methylene groups, hydroxyethyl groups (viscosity of 18 000 mPa - 23 000 mPa at a temperature of 25°C), moreover the new composition contains silicon dioxide (the BET surface area 175-225 m 2 /g) and a cross linker - a platinum catalyst.
• a glue according to the present invention is a synthetic adhesive, and therefore excludes the risk entailed by the presence of human or animal components (bacteria, viruses, allergies).
• the resulting adhesive cures by reacting with moisture (first, a "crust" is formed on the surface, and then the curing process progresses into the interior of the joint, and the reaction is additionally accelerated by the increased temperature of 37°C, whereas the time-to-cure is slightly elongated by a lower moisture content.
• the adhesive composition is capable of linking at a temperature of 37°C, and has excellent thermal stability when hardened.
• a glue according to the present invention is highly elastic and has compensatory properties, which means that the site of adhesion is not damaged even during compression loads and returns to its position when the load is removed.
• adhesive R 88 When applied gradually, adhesive R 88 is capable of entirely filling the vein lumen, adapting to the shape, and penetrates porosity due to its capillary nature. When introduced into the vein, it initiates a complex reaction between blood components and the adhesive' s surface, undergoing polymerization in the moist environment. It is retained in the vein and is not ejected out of it by the blood, at the same time staunching haemorrhaging from the vein. The cured adhesive joint effectively forms a seal, while maintaining its elasticity.
• the present solution delivers an adhesive joint encompassing material factors (structure and adhesive properties), technological (a method of preparing and applying the adhesive mass), curing conditions for the adhesive joint, structural (loading, joint shape), working conditions for the adhesive (aggressiveness, temperature range, magnitude and character of stresses). Additionally, the formulated and produced glue for binding surfaces exhibits elasticity such that the glued structures can deform in accordance with their natural behaviour in the human or animal body.
• the medical glue according to the present invention fulfils the criteria required from materials for implantation, and at the same time is characterised by the durability of the adhesive- surface interface, and exhibits good adherence while maintaining appropriate elasticity and durability in a biological environment.
• the formulated adhesive can be used for occluding and sealing insufficient vessels of the venous system. Description of figures
• Fig. 1 Sealing veins.
• the procedure of inserting the adhesive into a vessel is performed gradually using a calibrated gun-like dosing applicator.
• the glue is applied into the lumen of the varicosity using a special catheter set. This facilitates the controlled occlusion of the insufficient venous vessel, (http://www.centerforvein.com/blog/new-treatment-methods-in- phlebology, nasmed.com.pl).
• Fig. 2 Plot of the changes in pH of adhesive R 88 in Ringer's solution over 33 months of incubation.
• Fig. 4 Comparison of the relative viability of cells in contact with adhesive R 88 and the binder for a dilution series of conditioned medium (100%, 50%, 25%, 12.5%).
• Fig. 5 Relative viability index for cells in a dilution series of conditioned medium (0.2%, 0.15%, 0.1%, 0.05%).
• Fig. 8 Microscopic image of a rabbit ear surface, the vein completely filled with adhesive R 88 after 90 days post-implantation.
• Fig. 9a Macroscopic image following the operation after 14 days post-gluing the marginal vein of the rabbit ear with adhesive R 88.
• Fig. 9b Control group after 14 following the operation - cyan acrylic tissue adhesive (Histoacryl®), Macroscopic image after 14 days following the operation of gluing the gluing the marginal vein in a rabbit ear.
• Fig. 10a Macroscopic image after 90 days following gluing the marginal vein in a rabbit ear with adhesive R 88.
• Control group Macroscopic image after 90 days following the operation of gluing the marginal vein in a rabbit ear with Histoacryl® tissue adhesive.
• Fig. 11a Results after 2 weeks for adhesive R 88, Histoacryl® control adhesive) Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• Fig. 1 lb Histology results following 2 weeks, image demonstrating the behaviours or the vein beside the site glued with adhesive R 88, Histoacryl® (control adhesive), Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• Fig. 12a Histology results after 30 days for a vein with adhesive R 88 and Histoacryl® (control adhesive) Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• Fig. 12b Comparison of the vein adjoining the site of gluing with adhesive R 88 and Histoacryl® (control adhesive) after 30 days. Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• Fig. 13a Histology results after 90 days for a vein occluded with adhesive R 88 and Histoacryl® (control adhesive), Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• Fig. 13b Comparison of the vein adjoining the site of gluing with adhesive R 88 and Histoacryl® (control adhesive) after 90 days. Microscopic image of healthy skin with surrounding tissues, cartilage and vasculature. Erythrocytes are visible in the vascular lumen. HE staining, mag. lOOx.
• the adhesive binder (viscosity of 18 000 mPa'S - 23 000 mPa-s at a temperature of 25°C) was mixed with silicon dioxide (BET surface area 175 - 225 m 2 /g), the entirety is homogenized over 60 min at 300 RPM with a mechanical laboratory mixer, and then set aside for 12h, where after the platinic cross linker is added. The entirety is homogenized after adding all of the mentioned components in the given amounts and sequence for a further 5 minutes at about
• This adhesive contains no softeners, plasticizers, nor the like, nor stabilizers.
• the silicon dioxide Before being added to the binder, the silicon dioxide is dried in for 48h at a temperature of
• the method consists of the visual evaluation of the adhesive solution (like for evaluating the solubility of the adhesive), samples of the adhesive were enclosed in sealed glass containers and stored at room temperature. After 24 hours, we evaluated the state of the adhesive mass - whether it did not stratify. The stability of the adhesive mass is shown in Table 2.
• Hardness was measured after 3 s from the application of the hardness meter to the sample. The hardness result is an arithmetic mean of all of the measurements. The difference between the individual measurements cannot exceed more than ⁇ 2 Shore units. Shore type A hardness is shown in Table 3.
• the method consists of the visual evaluation of the adhesive solution (like for evaluating the solubility of the adhesive), samples of the adhesive were enclosed in sealed glass containers and stored at room temperature. After 24 hours, we evaluated the state of the adhesive mass - whether it did not stratify (Table 4).
• Stability changes of the formulated adhesive samples were monitored by measuring pH in the Ringer's solution and distilled water. The measurements were made using an Elamtron CP- 315 pH-meter, which was calibrated before every measurement. The results show that adhesive samples in the Ringer's solution simulating a living organism at a temperature of 37°C do not alter the pH throughout the entire time of the degradation study. These results are in accordance to the ISO 10993-12 norm. The evaluated material is stable and behaves very stably in a physiological fluid environment. The samples taken therefrom were clear, colourless and odour-free.
• extracts we used material at a rate of 3 cm 2 surface/lml medium with serum. The extracts were incubated for 24h at a temperature of 37°C. We prepared the following extract dilution series: 100%, 50%, 25%, and 12.5%.
• Tissue glues that come into contact with blood must be characterized by biocompatibility, though to some degree they always interact with platelets and act on thrombosis and fibrinolytic factors. The negative effect of this activity is clotting, which may lead to the occlusion of the vein lumen or constitute a source of thromboembolic complications.
• the viability of cells in the conditioned medium makes it possible to analyse the interaction of the evaluated adhesive with the culture medium simulating the bodily fluids, and makes it possible to predict the behaviour of the evaluated adhesive during prolonged contact with bodily fluids and to evaluate its effect on the biological response.
• the medium was supplemented with FBS (Lonza)- 10%, and L-glutamine with streptomycin (lOmg/ml) and penicillin (10,000 U/ml) (Sigma)-1%, in accordance with recommendations.
• V (P b /P k )-100% [%]
• the MTT assay facilitates the quantitative evaluation of the cytotoxicity of the evaluated compounds.
• the test is based on the conversion of yellow tetrazolium salt (MTT) in the mitochondria of living cells to a purple derivative - formazan. Toxicity degrees for the test using the extracts (as per PN-EN ISO 10993-5:2009) are shown in Table 5.
• cell viability at 70% or less and changes in the cell culture in excess of stage 2 indicate the cytotoxicity of the biomaterial.
• binder which is the chief component of the tissue adhesive and is conditional to its desired adhesiveness and the mechanical durability of the joint, after its curing, we observed the inhibition of cell growth to 66.70%, and did not observe cell lysis beyond stage 2.
• Adhesive R 88 exhibited a cell viability of 96.92%.
• composition of the adhesive according to the present invention is its non-toxic character, which enables the composition to be used as an internal adhesive, without fear of safety, because literature data shows that GRF adhesive compositions have achieved limited success due to the use of hot gelatine solutions and in many cases tissues are irritated through the use of aldehydes. Intravenous fibrin glues can lead to thromboembolisms and systemic intravascular clotting.
• cytotoxic activity of the adhesive binder is shown in Table 6.
• the cytotoxic activity of the adhesive R 88 is shown in Table 7.
• the properties of the formulated adhesive were tested on animals (permit obtained from the Local Ethics Committee in Wroclaw, decision No. 60/2012 dated October 17, 2012 for experiments on 20 albino rabbits).
• the tissue glue was preclinical tested in animals - albino rabbits of both sexes, weighing ca. 3200-3500 g.
• the animals were housed and fed in identical conditions (separate room in standard laboratory cages under controlled humidity (45-55%) and air temperature (18-25°C). They were given free-choice access to pelleted chow for rabbits and water.
• the tissue glue Histoacryl - blue constituted the comparative model for the formulated adhesive R 88. Histoacryl - blue is used in the ablation of varicosities; both haemorrhaging and non- haemorrhaging ones.
• the rabbits were injected in the marginal vein of the ear with adhesive at a rate of 0.5 ml (0.7 ⁇ 30 micro point needle).
• a Leica 2125RT microtome was used to cut thick sections of about 4 ⁇ .
• the preparations were stained with Haematoxylin (Van Gieson (VG) method).
• VG Haematoxylin

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Citations (5)

• 2016
  • 2016-01-12 PL PL415767A patent/PL229593B1/pl unknown
• 2017
  • 2017-01-10 WO PCT/PL2017/050002 patent/WO2017123109A1/en active Application Filing

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