EP2838575A1 - Medical material for reconstruction of blood vessels, the method of its production and use of the medical material for reconstruction of blood vessels - Google Patents

Medical material for reconstruction of blood vessels, the method of its production and use of the medical material for reconstruction of blood vessels

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Publication number
EP2838575A1
EP2838575A1 EP13729821.2A EP13729821A EP2838575A1 EP 2838575 A1 EP2838575 A1 EP 2838575A1 EP 13729821 A EP13729821 A EP 13729821A EP 2838575 A1 EP2838575 A1 EP 2838575A1
Authority
EP
European Patent Office
Prior art keywords
melt
medical material
blood vessels
vascular
reconstruction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP13729821.2A
Other languages
German (de)
French (fr)
Inventor
Izabella Krucinska
Marcin Henryk STRUSZCZYK
Michal Chrzanowski
Olga MAZALEVSKA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Politechnika Lodzka
Original Assignee
Politechnika Lodzka
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Politechnika Lodzka filed Critical Politechnika Lodzka
Publication of EP2838575A1 publication Critical patent/EP2838575A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the subject matter of invention concerns a medical material for blood vessels reconstruction, the method of its production, as well as the use of that medical material reconstruction of blood vessels. More precisely, the invention concerns textile vascular prostheses for the reconstruction of small diameter blood vessels and solvent-free manufacturing method used to obtain the aforementioned small diameter vascular prostheses.
  • the solution presented in this patent application concerns a new method of forming textile nanostructures to be applied in vascular surgery and cardiosurgery, especially in reconstruction of blood vessels below 6 mm in diameter, as well as a substrate for proliferation of vascular endothelium cells.
  • the related patent descriptions present large diameter (> 6mm) knitted vascular prostheses, made of polyester (polyethylene terephthalate - PET) - US3945052 (publ. 1976-03-23), polyester sealed with collagen - US6165489 (publ. 2000-12-26), gelatin, albumin - US6162247 (publ. 2000-12-19) or expanded polytetrafluroethylene (ePTFE) - US4187390 (publ. 1980-02-05).
  • polyester polyethylene terephthalate - PET
  • US3945052 Publ. 1976-03-23
  • polyester sealed with collagen - US6165489 publ. 2000-12-26
  • gelatin gelatin
  • albumin - US6162247 publ. 2000-12-19
  • ePTFE expanded polytetrafluroethylene
  • the prostheses mentioned above are inappropriate, primarily due to their high affinity to platelet activation and the risk of thrombosis (PET) or accumulation of calcium ions in the prostheses structure, promoting the process of implant occlusion, and no integration with natural tissue (ePTFE).
  • PET platelet activation
  • ePTFE thrombosis
  • vascular scaffolds and prostheses produced using the electrospinning from polymer solution technique. This technique makes it possible to obtain fibrous nanostructures, which can provide an alternative appropriate for production of tissue substrates, also in vascular surgery and cardiosurgery.
  • Electrospinning utilizing poly(L-lactide) in dichloromethane solution, or polyurethane in acetone solution for obtaining structures used as scaffolds for cell proliferation is also known from US 6790528 patent description (publ. 2004-09-14).
  • US20110076197 patent description (publ. 2011-03-31) describes a method of spinning flat structures from polyvinylidene fluoride (PVDF), polyurethane (PU), polylactide (PLA), copolymer of lactide and glycolide (PLGA), or polyacrylnitrile (PAN) solutions.
  • PVDF polyvinylidene fluoride
  • PU polyurethane
  • PLA polylactide
  • PLGA copolymer of lactide and glycolide
  • PAN polyacrylnitrile
  • the electrospinning technique utilizing polymer solution has one shortcoming involving the use of a solvent. It results in limitation of potential usefulness of this technique for obtaining medical devices because the solvents used may demonstrate toxic properties (local or systemic toxicity, intradermal reactivity, or allergenic effects).
  • US7824601 (publ. 2010-11-02) describes production of vascular stents (endo vascular prostheses) by the electrospinning at room temperature or at 55°C from poly(L-lactic acid); (PLLA), poly(lactide-co-glycolide); (PLGA) solutions.
  • WO2007/062393 (publ. 2007-05-31) presents the process of electrospinning polyolefins, poly-a-olefins from solution at high temperature.
  • US20100041804 (publ. 2010-02-18), WO/2008/1010151, WO/2010/065350 (publ. 2010-06-10), US20100064647 (publ. 2010-03-18), JP2011162636 (publ. 2011- 08-25), JP201183254, K 20110079249 (publ. 2011-07-07), US20110308386 (publ. 2011-12-22), WO/2008/121338 (publ. 2008-10-09) provide recommendations concerning formation of flat structures by the melt electrospinning for potential applications as filters, scaffolds or substrates for cell cultures.
  • US20110194304 (publ. 2011-08-11) presents a method of obtaining flat nonwovens, which have a smooth surface and a porous structure. Mixtures with solvents and melts with admixtures were prepared. Such polymers as: acrylonitrile, ethylenevinyl alcohol, fluoropolymer, polyamide, polyesters and polyimides, luminescent nanomolecules, catalyzers (Au, Pt, Pd, Pt/Au, Pd/Au etc.) were used.
  • US20100297443 (publ. 2010-25-11) describes the process of obtaining monofilament by the melt spinning and melt electrospinning from ethylvinyl alcohol copolymers, polyesters, polyurethanes, nylon and poly(lactic acid).
  • WO2011/035195 presents the method of obtaining nanofibers to be applied in filtration, components of nanofiber membranes, elements of medical products (dialyzers, blood filters, medical filters).
  • the nonwovens were melt blown from polypropylene, polyethylene terephthalate, polybutyleneterephthalate, or polystyrene.
  • US20090162276 (publ. 2009-06-25) presents the method of obtaining melt- blown materials from polyglycolide (PGA), polyhydroxyalkanoates (PHAs) for implantation purposes.
  • PGA polyglycolide
  • PHAs polyhydroxyalkanoates
  • WO2010/036697 presents the method of obtaining nonwoven which is a carrier of a medicinal product.
  • the matrix constituting the textile substrate can be produced by the electrospinning.
  • the fibers were formed from polyamide (PA), polyurethane (PU), fluoropolymers, polyolefins, polyimide, polyglycolide (PGA), poly(lactic acid) (PLA), poly(L-lactide-co-glycolide) (PLGA), polyethylene glycol (PEG), polycaprolactone (PCL). Growth factors such as: VEGF, FGF, PFGF, HIFla were used.
  • the medicinal products were applied onto the obtained tubular structure (4 mm in diameter).
  • US2010010022 (publ. 2010-01-14) describes a three-dimensional, porous medical product obtained from a biocompatible polymer using the melt blow technique. To reinforce the structure, horseshoe-shaped plastic fittings made of PUR, PET or PP were added. The above-mentioned products can be used for post-traumatic reconstruction of external tissues or organs (e.g. the ear) or for the promotion of cell growth.
  • US20110171335 (publ. 2011-07-14) presents also obtaining flat nonwovens by melt electroblowing with polyethylene oxide (PEO) used.
  • PEO polyethylene oxide
  • the goal of this invention is to obtain textile prosthetic structures for the reconstruction of small diameter blood vessels and the method of their production.
  • none of the available documents addresses obtaining tubular textile nanostructures to be used in prosthetics of small diameter ( ⁇ 6 mm) blood vessels made of non-degradable (polypropylene) and/or biodegradable (polylactide) polymers, melt blown, or produced by melt electrospinning or melt electroblowing.
  • a solution including a new method of formation of the textile nanostructures applicable in vascular and cardiac surgery, especially in reconstructions of blood vessels below 6 mm in diameter, or as substrates for cell proliferation, has been obtained.
  • the technique used according to the invention makes it possible to obtain fibrous nanostructures, which can provide an alternative for the production of tissue substrates, as well as for applications in vascular surgery and cardiosurgery.
  • the surface topography of nonwoven structures obtained by melt electrospinning, melt blowing and melt electroblowing, as well as the mechanical properties of the obtained structures are favorable for the application of nonwoven techniques in the vascular reconstructions.
  • the above factors have contributed to the utilization of solvent-free nonwoven techniques for obtaining a nonwoven structure optimal for the use in reconstruction surgery.
  • the subject of the invention is a medical material for the vascular reconstructions, characterized by the content of at least one compound selected from polypropylene and/or polylactide, with the melt flow index (MFI) of polypropylene falling within the 3 to 500 g/10 cm range, whereas the melt flow index (MFI) of polylactide falls within the 20 to 80 g/10 cm range, and the obtained material has a tubular structure and the surface mass of the medical material falls within the 10 - 170 g/m range, the structure porosity within the 60 - 95% range, and the fiber diameter between 0.07 and 20 ⁇ .
  • MFI melt flow index
  • MFI melt flow index
  • the material is obtained using one of the methods selected from among the following ones: melt blown, melt electrospinning or melt electroblowing.
  • the material is melt blown, its surface mass ranges from 20 to 170 g/m 2 , structure porosity from 60 to 90%, and fiber diameter from 0.08 to 5 ⁇ .
  • the material is obtained by melt electrospinning, its surface mass ranges from 10 to 60 g/m 2 , structure porosity from 70 to 90%, and fiber diameter from 0.17 to 20 ⁇ .
  • the material is obtained by the melt electroblowing, its surface mass ranges from 10 to 30 g/m , structure porosity from 60 to 95%, and fiber diameter from 0.07 to 10 ⁇ .
  • its form is tubular with the internal diameter ranging from 1 to 300 mm, preferably to 6 mm.
  • the product has a truncated cone form, with the smaller internal diameter ranging from 1 mm to 20 mm, preferably from 1 mm to 5 mm and the larger diameter ranging from 2 mm to 30 mm, preferably from 2 mm to 6 mm.
  • the product is designed for the reconstruction of small diameter blood vessels, preferably below 6 mm.
  • the polylactide used is selected from among amorphous, or semicrystalline polymers.
  • Another subject of the invention is the method of the production of the medical material for vascular reconstructions described above, characterized by the use of solvent-free techniques, formation of textile structures by melt-based technique selected from among melt blown, melt electrospining and/or melt electroblowing techniques, with the use of an extruder having up to seven heating zones.
  • the temperature in the subsequent heating sections amounts to 180 - 290°C, and extruder spinning head temperature to 320°C for polypropylene, whereas for polylactide it amounts to 100 - 210°C in heating sections, and in the extruder nozzle to 220°C, the rotary speed of the extruder screws fall within the 0 to 10 rpm, and the polymer stream is expanded with hot compressed air and/or high voltage; for polypropylene compressed air of 200 - 320°C temperature with air flow rate of 0 - 40 Nm 3 h is applied, with the respective parameters for polylactide 100 - 220°C and 0 - 40 Nm 3 /h.
  • the voltages used to expand the polymer stream range from 0 to 50 kV.
  • hot compressed air is used in combination with high voltage.
  • Another subject of the invention is the use of the medical material described above for the reconstruction of the blood vessels, and in particular for production of vascular prostheses, vascular implants, tubular scaffolds for proliferation of vascular endothelial cells.
  • Figure 1 presents the view of a three-dimensional fibrous structures of 5 mm and 1 mm internal diameters
  • Figure 2 presents the view of wall structure of the variants described in example 1 , with Figs. 2a - 2d presenting melt-blown textile structures of 0.92 ( ⁇ 0.37) ⁇ to 0.53 ( ⁇ 0.46) ⁇ average fiber diameter for polypropylene, whereas Figs. 2e - 2h presenting melt-blown textile structures of 1.26 ( ⁇ 0.63) ⁇ to 0.41 ( ⁇ 0.21) ⁇ average fiber diameter for polylactide;
  • Figure 3 presents the view of the wall of the variants described in example 2, with Figs. 3a - 3d presenting tubular textile structures obtained by melt electrospinning, of average fiber diameter in the case of the utilization of polypropylene as the raw material, ranging from 3.48 ( ⁇ 1.81) ⁇ to 2.56 ( ⁇ 0.98) ⁇ , and in Figs. 3e and f those obtained for polylactide, ranging from 3.34 ( ⁇ 1.03) ⁇ to 0.8 ( ⁇ 1.44) ⁇ ;
  • Figure 4 presents the view of the wall of the variants described in example 3, obtained by melt electroblowing, with Figs. 4a and b presenting the average diameters for the structures obtained as a result of utilization of polypropylene: from 0.64 ( ⁇ 0.87) ⁇ to 0.38 ( ⁇ 0.28) ⁇ , whereas for polylactide they ranged from 0.83 ( ⁇ 0.64) ⁇ to 0.70 ( ⁇ 0.61) um (Fig.s 4. c, d).
  • Tubular structures were formed using a co-rotating double-screw extruder with seven heating zones and a collector making it possible to obtain textile structures with melt- based techniques, including in particular melt electrospinning, melt blown and melt electroblowing.
  • the temperature in the consecutive heating sections for the non-degradable polymer - polypropylene - was 180 - 290°C, and the extruder spinning head temperature up to 320°C.
  • the temperature in the heating sections was 100 - 210°C, and in the extruder spinning head up to 220°C.
  • the rotary speed of the extruder screws ranged from 0 to 10 rpm. Hot compressed air and/or high voltage was used to for extension of the polymer stream.
  • air of 200 to 320°C temperature was used and air flow rate ranged from 0 to 40 m 3 /h, whereas for polylactide the air temperature ranged from 100 to 220°C and the air flow rate from 0 to 40 m 3 /h.
  • the voltage within the 0 to 50 kV was used for all the processed polymers.
  • the collecting device allowing to obtain tubular structures of 1 mm or more in diameter was used.
  • the collector spindle speed ranged from 0 to 30 rpm, and the spindle oscillation speed from 0 to 11 mm/s.
  • the collector makes it possible to produce structures of up to 30 cm length.
  • the distance between the collector and the extruder ranged from 0.5 to 40 cm.
  • Fig. 1. presents the view of a three-dimensional fibrous structures of 5mm and 1mm internal diameters.
  • melt flow index (MFI) of the polymers was measured with a melt flow indexer (Bexhill on Sea TN39 3LG) according to the PN-EN ISO 1133:2011 standard. The nominal load of 2.16 kg was applied. The measurements were carried out at 230°C temperature.
  • polylactide 4060D • polylactide 4060D, amorphous, melt flow index (MFI) 40 g/10 cm or polylactide 620 ID, semicrystalline, melt flow index (MFI) 50 g/10 cm.
  • MFI melt flow index
  • the polymer granulate was processed using a co-rotating double-screw extruder, having seven heating zones.
  • Detailed characteristics of production parameters for the obtained tubular structures has been presented in Table 1.
  • the temperature in the consecutive heating sections ranged from 140 to 320°C; it was favorable when the temperature increased on the subsequent heating sections, with the temperature of the extruder spinning head no lower than the temperature of the last heating section.
  • the solution variant includes the extruder spinning head temperature within the 150 to 320°C range, and the rotary speed of the extruder screws from 0 to 30 rpm.
  • the distance between the extruder and the collector ranged from 5 to 30 cm.
  • the collector spindle speed ranged from 15 to 30 rpm, spindle oscillation speed from 1 to 11 mm/s.
  • Fig. 2 presents a view of wall structure of the described product variants.
  • polymer granulate used for production as well as the used processing parameters of the extruder and the collector are presented in example 1.
  • Expanding the formed polymer streams was possible owing to high voltage of 1 to 50 kV supply.
  • the distance between the extruder spinneret and the collector ranged from 4 to 30 cm.
  • a favorable variant of the solution involves positioning of the collector in relation to the extruder spinneret at 0 to 45° angle.
  • Fig. 3 presents a view of wall structure of the described product variants.
  • polymer granulate used for the production as well as the used processing parameters of the extruder and the collector are presented in example 1.
  • Melt blown textile structures are characterized by average fiber diameter for polypropylene of 0.92 ( ⁇ 0.37) ⁇ to 0.53 ( ⁇ 0.46) ⁇ (Fig. 2 a, c), and for polylactide of 1.26 ( ⁇ 0.63) ⁇ to 0.41 ( ⁇ 0.21) ⁇ (Fig. 2. f, h). Higher temperature set on the extruder head as well as air temperature, and increased air flow rate results in decreased fiber diameter.
  • tubular textile structures of the mean fiber diameter from 3.48 ( ⁇ 1.81) ⁇ to 2.56 ( ⁇ 0.98) ⁇ for propylene used as the raw material (Fig. 3. a, b), and from 3.34 ( ⁇ 1.03) ⁇ to 0,8 ( ⁇ 1.44) ⁇ for polylactide (Fig. 3 e, f) were obtained.
  • increase of the head temperature and decrease of the distance from the collector to the extruder spinneret is important for the parameters of the resultant structures.
  • the average diameter obtained for polypropylene-based structures ranged from 0.64 ( ⁇ 0.87) ⁇ to 0,38 ( ⁇ 0.28) ⁇ (Fig. 4. a, b), and in the case of polylactide from 0.83 ( ⁇ 0,64) ⁇ to 0.70 ( ⁇ 0.61) ⁇ (Fig. 4. c, d).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Nonwoven Fabrics (AREA)
  • Spinning Methods And Devices For Manufacturing Artificial Fibers (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Materials For Medical Uses (AREA)

Abstract

The invention claimed concerns a medical material for reconstruction of blood vessels, the method of its production, as well as the application of that medical material reconstruction of blood vessels. More precisely, the invention concerns textile vascular prostheses for the reconstruction of small diameter blood vessels and solvent-free manufacturing method used to obtain the aforementioned small diameter vascular prostheses. The solution presented in this patent application concerns a new method of forming textile nanostructures to be applied in vascular surgery and cardiosurgery, especially in prosthetics of blood vessels below 6 mm in diameter, as well as a substrate for proliferation of vascular endothelium cells.

Description

Medical material for reconstruction of blood vessels, the method of its production and use of the medical material for reconstruction of blood vessels
The subject matter of invention concerns a medical material for blood vessels reconstruction, the method of its production, as well as the use of that medical material reconstruction of blood vessels. More precisely, the invention concerns textile vascular prostheses for the reconstruction of small diameter blood vessels and solvent-free manufacturing method used to obtain the aforementioned small diameter vascular prostheses. The solution presented in this patent application concerns a new method of forming textile nanostructures to be applied in vascular surgery and cardiosurgery, especially in reconstruction of blood vessels below 6 mm in diameter, as well as a substrate for proliferation of vascular endothelium cells.
The related patent descriptions present large diameter (> 6mm) knitted vascular prostheses, made of polyester (polyethylene terephthalate - PET) - US3945052 (publ. 1976-03-23), polyester sealed with collagen - US6165489 (publ. 2000-12-26), gelatin, albumin - US6162247 (publ. 2000-12-19) or expanded polytetrafluroethylene (ePTFE) - US4187390 (publ. 1980-02-05).
In the case of reconstruction of the peripheral blood vessels with small diameter (< 6 mm), such as coronary, tibial, popliteal arteries, as well as microvascular reconstructions), the prostheses mentioned above are inappropriate, primarily due to their high affinity to platelet activation and the risk of thrombosis (PET) or accumulation of calcium ions in the prostheses structure, promoting the process of implant occlusion, and no integration with natural tissue (ePTFE).
The solutions known on the basis of patent descriptions include vascular scaffolds and prostheses produced using the electrospinning from polymer solution technique. This technique makes it possible to obtain fibrous nanostructures, which can provide an alternative appropriate for production of tissue substrates, also in vascular surgery and cardiosurgery.
US 4689196 patent descriptions (publ. 1987-08-25), US5024789 (publ. 1991-06- 18), US4323525 (publ. 1982-04-06) popularized the application of electrospinning from solution to produce porous structures of relatively small fiber diameters and low surface mass.
US7112293 patent descriptions (publ. 2006-09-26)present the constructions of vascular prostheses obtained by electrospinning from polytetrafluorethylene (PTFE), polyamide (PA), polyacrylnitrile (PAN) solutions.
Electrospinning utilizing poly(L-lactide) in dichloromethane solution, or polyurethane in acetone solution for obtaining structures used as scaffolds for cell proliferation is also known from US 6790528 patent description (publ. 2004-09-14).
US20110076197 patent description (publ. 2011-03-31) describes a method of spinning flat structures from polyvinylidene fluoride (PVDF), polyurethane (PU), polylactide (PLA), copolymer of lactide and glycolide (PLGA), or polyacrylnitrile (PAN) solutions.
Despite numerous advantages, the electrospinning technique utilizing polymer solution has one shortcoming involving the use of a solvent. It results in limitation of potential usefulness of this technique for obtaining medical devices because the solvents used may demonstrate toxic properties (local or systemic toxicity, intradermal reactivity, or allergenic effects).
The application of direct writing in combination with melt electrospinning for design of vascular scaffolds is known from the literature. Toby D. Brown et al. [1] developed vascular scaffolds of 6 and 10 mm internal diameter using polycaprolactone (PCL) fibers ca. 60 μπι in diameter.
Methods of production of tubular structures potentially applicable in medicine as scaffolds for tissue engineering, making use of combination of melt spinning with electrospinning from a solution are also known from the literature [2-3].
Sung Jing Kim et al. [2] described production of scaffolds for tissue regeneration of poly(lactide-co-glycolide); (PLGA), nano/microfibers.
Sangwon Chung et al. [3] described the production process of laminar vascular scaffolds from poly(L-lactide-co-caprolactone);(PLCL) by the application of layers obtained by melt spinning method and their sealing with a layer obtained by solution electrospinning process.
US20090232874 (publ. 2009-09-17) presents a production process of biodegradable polyamide ester- based flat and tubular structures by the solution electrospinning for application as scaffolds for tissue engineering as well as drug carriers. The description also claims melt electrospinning.
US7824601 (publ. 2010-11-02), US8083983 (publ. 2011-12-27), US20120015331 (publ. 2012-01-19), WO2005/065079 (publ. 2007-01-25) patent descriptions present obtaining flat structures by electrospinning from solution at high temperature.
US7824601 (publ. 2010-11-02) describes production of vascular stents (endo vascular prostheses) by the electrospinning at room temperature or at 55°C from poly(L-lactic acid); (PLLA), poly(lactide-co-glycolide); (PLGA) solutions.
US8083983 (publ. 2010-03-04) concerning solution electrospinning of flat structures from polymers of the polyolefins group at high temperature - 25°C-100°C is known. Application of the obtained structures as filtering or medical products was proposed.
Also in US20120015331 (publ. 2012-01-19) a flat structure electrospinning process from polyglycolide (PGA), poly(L-lactic acid) (PLLA), poly(lactide-co- glycolide); (PLGA), polycaprolactone; (PCL), or their copolymers solutions at high temperature - 260°C-274°C - is presented.
WO2007/062393 (publ. 2007-05-31) presents the process of electrospinning polyolefins, poly-a-olefins from solution at high temperature.
From US7592277 (publ. 2006-11-23) also a combination of electrospinning from solution and melt of polycaprolactone (PCL) is known. Use of the obtained structures as filters or medical products was proposed.
Devices enabling electrospinning from high temperature solution or from polymer melt are also known, e.g. US8088324 (publ. 2011-02-10) and US201101408005. Also US8052407 (publ. 2008-03-13) presents a device for solution electrospinning which can also be applied for melt electrospinning.
US20100041804 (publ. 2010-02-18), WO/2008/1010151, WO/2010/065350 (publ. 2010-06-10), US20100064647 (publ. 2010-03-18), JP2011162636 (publ. 2011- 08-25), JP201183254, K 20110079249 (publ. 2011-07-07), US20110308386 (publ. 2011-12-22), WO/2008/121338 (publ. 2008-10-09) provide recommendations concerning formation of flat structures by the melt electrospinning for potential applications as filters, scaffolds or substrates for cell cultures.
US20110194304 (publ. 2011-08-11) presents a method of obtaining flat nonwovens, which have a smooth surface and a porous structure. Mixtures with solvents and melts with admixtures were prepared. Such polymers as: acrylonitrile, ethylenevinyl alcohol, fluoropolymer, polyamide, polyesters and polyimides, luminescent nanomolecules, catalyzers (Au, Pt, Pd, Pt/Au, Pd/Au etc.) were used.
US20100297443 (publ. 2010-25-11) describes the process of obtaining monofilament by the melt spinning and melt electrospinning from ethylvinyl alcohol copolymers, polyesters, polyurethanes, nylon and poly(lactic acid).
From US7501085 (publ. 2006-04-20), WO2008/134305 (publ. 2008-11-06), US5582907 (1996-12-10), US6695804 (publ. 2002-10-24), US20080081323 (publ. 2008-04-03), US20110151738 (publ. 2011-06-23), US20110196327 (publ. 2011-08-11) melt blown structures potentially applicable in medicine, among others as substrates for proliferation of cells or as filtering materials, are known.
WO2011/035195 (publ. 2011-03-24) presents the method of obtaining nanofibers to be applied in filtration, components of nanofiber membranes, elements of medical products (dialyzers, blood filters, medical filters). The nonwovens were melt blown from polypropylene, polyethylene terephthalate, polybutyleneterephthalate, or polystyrene.
US20090162276 (publ. 2009-06-25) presents the method of obtaining melt- blown materials from polyglycolide (PGA), polyhydroxyalkanoates (PHAs) for implantation purposes.
From US20100305687 (publ. 2010-12-02) the method of obtaining melt-blown nonwovens from polyethylene terephthalate (PET), polycarbonate (PC), polytrimethylene terephthalate (PTT) and poly(lactic acid) (PLLA) is known. Flat structures were produced, as well as tubular ones obtained by welding the flat nonwoven on a cylindrical mandrel of 6 mm diameter for 30 min at 90°C, as well as for 30 min under pressure.
WO2010/036697 (publ. 2010-04-01) presents the method of obtaining nonwoven which is a carrier of a medicinal product. The matrix constituting the textile substrate can be produced by the electrospinning. The fibers were formed from polyamide (PA), polyurethane (PU), fluoropolymers, polyolefins, polyimide, polyglycolide (PGA), poly(lactic acid) (PLA), poly(L-lactide-co-glycolide) (PLGA), polyethylene glycol (PEG), polycaprolactone (PCL). Growth factors such as: VEGF, FGF, PFGF, HIFla were used. The medicinal products were applied onto the obtained tubular structure (4 mm in diameter). The claims included also the possibility of obtaining such structures using the melt blown technique
The literature reports successful attempts to form vascular scaffolds from polyurethane (PU) of fiber diameter ranging from 10 to 50 μιη (Gulbins, [4]), polyethylene terephthalate (PET) of the smallest fiber diameter from 1 to 5 μιη (Moreno, [5]) using the melt blown technique.
US2010010022 (publ. 2010-01-14) describes a three-dimensional, porous medical product obtained from a biocompatible polymer using the melt blow technique. To reinforce the structure, horseshoe-shaped plastic fittings made of PUR, PET or PP were added. The above-mentioned products can be used for post-traumatic reconstruction of external tissues or organs (e.g. the ear) or for the promotion of cell growth.
Production of tubular structures to be used as filters is presented in US5141699 (publ. 1992-08-25), US55409642, US6342283 (publ. 2002-01-29), US6662842 (publ. 2002-02-28).
US20110171335 (publ. 2011-07-14) presents also obtaining flat nonwovens by melt electroblowing with polyethylene oxide (PEO) used.
Despite the solutions existing to date, there is still a need to obtain textile vascular prostheses for reconstruction of small diameter blood vessels, especially in the case of the reconstruction of peripheral blood vessels with small diameter (< 6 mm), such as coronary, tibial, popliteal arteries, as well as microvascular reconstructions. The existing state-of-art solutions are inappropriate, primarily due to their high affinity to platelet activation and the risk of thrombosis. The problem concerning the electrospinning technique is also important, since this technique has, despite numerous advantages, a significant shortcoming associated with the use of a solvent. It results in limitation of the potential usefulness of this technique for obtaining advanced medical devices because the solvents used may demonstrate toxic properties (local or systemic toxicity, intradermal reactivity, or allergenic, genotoxic and in extreme cases carcinogenic effects).
The goal of this invention is to obtain textile prosthetic structures for the reconstruction of small diameter blood vessels and the method of their production. Despite the existence of some solutions, none of the available documents addresses obtaining tubular textile nanostructures to be used in prosthetics of small diameter (< 6 mm) blood vessels made of non-degradable (polypropylene) and/or biodegradable (polylactide) polymers, melt blown, or produced by melt electrospinning or melt electroblowing.
Unexpectedly, a solution including a new method of formation of the textile nanostructures applicable in vascular and cardiac surgery, especially in reconstructions of blood vessels below 6 mm in diameter, or as substrates for cell proliferation, has been obtained. The technique used according to the invention makes it possible to obtain fibrous nanostructures, which can provide an alternative for the production of tissue substrates, as well as for applications in vascular surgery and cardiosurgery. The surface topography of nonwoven structures obtained by melt electrospinning, melt blowing and melt electroblowing, as well as the mechanical properties of the obtained structures are favorable for the application of nonwoven techniques in the vascular reconstructions. The above factors have contributed to the utilization of solvent-free nonwoven techniques for obtaining a nonwoven structure optimal for the use in reconstruction surgery.
The subject of the invention is a medical material for the vascular reconstructions, characterized by the content of at least one compound selected from polypropylene and/or polylactide, with the melt flow index (MFI) of polypropylene falling within the 3 to 500 g/10 cm range, whereas the melt flow index (MFI) of polylactide falls within the 20 to 80 g/10 cm range, and the obtained material has a tubular structure and the surface mass of the medical material falls within the 10 - 170 g/m range, the structure porosity within the 60 - 95% range, and the fiber diameter between 0.07 and 20 μιη.
Preferably, the material is obtained using one of the methods selected from among the following ones: melt blown, melt electrospinning or melt electroblowing.
Preferably, the material is melt blown, its surface mass ranges from 20 to 170 g/m2, structure porosity from 60 to 90%, and fiber diameter from 0.08 to 5 μπι.
Preferably, the material is obtained by melt electrospinning, its surface mass ranges from 10 to 60 g/m2, structure porosity from 70 to 90%, and fiber diameter from 0.17 to 20 μπι. Preferably, the material is obtained by the melt electroblowing, its surface mass ranges from 10 to 30 g/m , structure porosity from 60 to 95%, and fiber diameter from 0.07 to 10 μιη.
Preferably, its form is tubular with the internal diameter ranging from 1 to 300 mm, preferably to 6 mm.
Preferably, the product has a truncated cone form, with the smaller internal diameter ranging from 1 mm to 20 mm, preferably from 1 mm to 5 mm and the larger diameter ranging from 2 mm to 30 mm, preferably from 2 mm to 6 mm.
Preferably, the product is designed for the reconstruction of small diameter blood vessels, preferably below 6 mm.
Preferably, the polylactide used is selected from among amorphous, or semicrystalline polymers.
Another subject of the invention is the method of the production of the medical material for vascular reconstructions described above, characterized by the use of solvent-free techniques, formation of textile structures by melt-based technique selected from among melt blown, melt electrospining and/or melt electroblowing techniques, with the use of an extruder having up to seven heating zones.
Preferably, the temperature in the subsequent heating sections amounts to 180 - 290°C, and extruder spinning head temperature to 320°C for polypropylene, whereas for polylactide it amounts to 100 - 210°C in heating sections, and in the extruder nozzle to 220°C, the rotary speed of the extruder screws fall within the 0 to 10 rpm, and the polymer stream is expanded with hot compressed air and/or high voltage; for polypropylene compressed air of 200 - 320°C temperature with air flow rate of 0 - 40 Nm3 h is applied, with the respective parameters for polylactide 100 - 220°C and 0 - 40 Nm3/h.
Preferably, the voltages used to expand the polymer stream range from 0 to 50 kV. Preferably, hot compressed air is used in combination with high voltage.
Another subject of the invention is the use of the medical material described above for the reconstruction of the blood vessels, and in particular for production of vascular prostheses, vascular implants, tubular scaffolds for proliferation of vascular endothelial cells.
For better illustration of the invention, the subject of the invention has been presented in figures, where: Figure 1 presents the view of a three-dimensional fibrous structures of 5 mm and 1 mm internal diameters;
Figure 2 presents the view of wall structure of the variants described in example 1 , with Figs. 2a - 2d presenting melt-blown textile structures of 0.92 (±0.37) μπι to 0.53 (±0.46) μηι average fiber diameter for polypropylene, whereas Figs. 2e - 2h presenting melt-blown textile structures of 1.26 (±0.63) μηι to 0.41 (±0.21) μιη average fiber diameter for polylactide;
Figure 3 presents the view of the wall of the variants described in example 2, with Figs. 3a - 3d presenting tubular textile structures obtained by melt electrospinning, of average fiber diameter in the case of the utilization of polypropylene as the raw material, ranging from 3.48 (±1.81) μιη to 2.56 (±0.98) μιη, and in Figs. 3e and f those obtained for polylactide, ranging from 3.34 (±1.03) μιη to 0.8 (±1.44) μηι;
Figure 4 presents the view of the wall of the variants described in example 3, obtained by melt electroblowing, with Figs. 4a and b presenting the average diameters for the structures obtained as a result of utilization of polypropylene: from 0.64 (±0.87) μπι to 0.38 (±0.28) μιη, whereas for polylactide they ranged from 0.83 (±0.64) μιη to 0.70 (±0.61) um (Fig.s 4. c, d).
For better understanding of the invention, examples of invention with references to the figures have been presented below.
Examples
Tubular structures were formed using a co-rotating double-screw extruder with seven heating zones and a collector making it possible to obtain textile structures with melt- based techniques, including in particular melt electrospinning, melt blown and melt electroblowing.
Obtaining tubular structures with solvent-free methods mentioned above, at appropriate technological parameters of the extruder.
The temperature in the consecutive heating sections for the non-degradable polymer - polypropylene - was 180 - 290°C, and the extruder spinning head temperature up to 320°C. For the biodegradable polymer - polylactide, the temperature in the heating sections was 100 - 210°C, and in the extruder spinning head up to 220°C. The rotary speed of the extruder screws ranged from 0 to 10 rpm. Hot compressed air and/or high voltage was used to for extension of the polymer stream. For polypropylene, air of 200 to 320°C temperature was used and air flow rate ranged from 0 to 40 m3/h, whereas for polylactide the air temperature ranged from 100 to 220°C and the air flow rate from 0 to 40 m3/h.
The use of high voltage is also favorable.
The voltage within the 0 to 50 kV was used for all the processed polymers.
It is favorable when hot compressed air is used in combination with high voltage.
The applied technological parameters as well as the metrological characteristics of the obtained textile structures have been specified below in the respective tables.
The collecting device allowing to obtain tubular structures of 1 mm or more in diameter was used. The collector spindle speed ranged from 0 to 30 rpm, and the spindle oscillation speed from 0 to 11 mm/s. The collector makes it possible to produce structures of up to 30 cm length. The distance between the collector and the extruder ranged from 0.5 to 40 cm. Fig. 1. presents the view of a three-dimensional fibrous structures of 5mm and 1mm internal diameters.
The melt flow index (MFI) of the polymers was measured with a melt flow indexer (Bexhill on Sea TN39 3LG) according to the PN-EN ISO 1133:2011 standard. The nominal load of 2.16 kg was applied. The measurements were carried out at 230°C temperature.
Example 1
Method of production of tubular structures for the reconstruction of blood vessels, especially small diameter ones, using melt blown technique.
Polymers used:
• polypropylene Moplen HP 462R, melt flow index (MFI) 25 g/10 cm or polypropylene Moplen HP 500N, melt flow index (MFI) 17 g/10 cm;
• polylactide 4060D, amorphous, melt flow index (MFI) 40 g/10 cm or polylactide 620 ID, semicrystalline, melt flow index (MFI) 50 g/10 cm.
The polymer granulate was processed using a co-rotating double-screw extruder, having seven heating zones. Detailed characteristics of production parameters for the obtained tubular structures has been presented in Table 1. The temperature in the consecutive heating sections ranged from 140 to 320°C; it was favorable when the temperature increased on the subsequent heating sections, with the temperature of the extruder spinning head no lower than the temperature of the last heating section. The solution variant includes the extruder spinning head temperature within the 150 to 320°C range, and the rotary speed of the extruder screws from 0 to 30 rpm.
Compressed air of 150 to 300°C temperature supplied to the extruder head with air flow rate within the 5 to 30 Nm /h range made it possible to stretch out formed polymer streams. The distance between the extruder and the collector ranged from 5 to 30 cm. The collector spindle speed ranged from 15 to 30 rpm, spindle oscillation speed from 1 to 11 mm/s. A tubular structure with parameters presented in the table below (Tab. 2) was obtained.
The selected variants of tubular structures have been characterized in Table 2. Fig. 2 presents a view of wall structure of the described product variants.
Table 1. Characterization of parameters applied in production of tubular structures
Table 2. Characteristics of selected variants of tubular structures formed
Example 2
Method of production of tubular structures for the reconstruction of blood vessels, especially small diameter ones, using melt electrospinning technique.
The polymer granulate used for production, as well as the used processing parameters of the extruder and the collector are presented in example 1.
Expanding the formed polymer streams was possible owing to high voltage of 1 to 50 kV supply. The distance between the extruder spinneret and the collector ranged from 4 to 30 cm. A favorable variant of the solution involves positioning of the collector in relation to the extruder spinneret at 0 to 45° angle.
The production parameters of the obtained tubular structures have been characterized in Table 3, whereas Table 4 characterizes the selected variants of tubular structures. Fig. 3 presents a view of wall structure of the described product variants.
Characterization of parameters applied in production of tubular structures
Table 4. Characteristics of selected variants of tubular structures formed
Example 3
Method of production of tubular structures for the reconstruction of blood vessels, especially small diameter ones, using melt electroblowing technique.
The polymer granulate used for the production, as well as the used processing parameters of the extruder and the collector are presented in example 1.
Expanding the formed polymer streams was possible owing to supply of high voltage of the values presented in example 2 and of compressed air, the air flow rate of which is described in example 1. The distance between the extruder spinneret and the collector ranged from 4 to 30 cm. The production parameters of the obtained tubular structures have been characterized in Table 5, whereas Table 6 characterizes the selected variants of tubular structures. Fig. 4 presents a view of wall structure of the described product variants.
Table 5. Characterization of parameters applied in production of tubular structures
Table 6. Characteristics of selected variants of tubular structures formed
As it follows from the studies, solvent-free techniques allow to obtain tubular nanostructures which can be applied for the reconstruction of blood vessels, especially small diameter ones (< 6mm).
Melt blown textile structures are characterized by average fiber diameter for polypropylene of 0.92 (±0.37) μπι to 0.53 (±0.46) μπι (Fig. 2 a, c), and for polylactide of 1.26 (±0.63) μπι to 0.41 (±0.21) μιη (Fig. 2. f, h). Higher temperature set on the extruder head as well as air temperature, and increased air flow rate results in decreased fiber diameter.
In the case of melt electrospinning, tubular textile structures of the mean fiber diameter from 3.48 (±1.81) μιη to 2.56 (±0.98) μιη for propylene used as the raw material (Fig. 3. a, b), and from 3.34 (±1.03) μηι to 0,8 (±1.44) μπι for polylactide (Fig. 3 e, f) were obtained. Just like in the case of melt blown technique, increase of the head temperature and decrease of the distance from the collector to the extruder spinneret is important for the parameters of the resultant structures.
Combination of two techniques had a beneficial effect on fiber diameter reduction. The average diameter obtained for polypropylene-based structures ranged from 0.64 (±0.87) μπι to 0,38 (±0.28) μηι (Fig. 4. a, b), and in the case of polylactide from 0.83 (±0,64) μπι to 0.70 (±0.61) μπι (Fig. 4. c, d).
Increasing the distance between the collector and the extruder spinneret results in reduction of the fiber diameter (the polymer stream is stretched out directly by compressed air, and also due to high voltage supplied).
References
[1] Brown, T.D. Slotosch, A. Thibaudeau, L. Taubenberger, A. Loessner, D. Vaquette, C. Dalton, P.D. Hutmacher D. W.: Design and Fabrication of Tubular Scaffolds via Direct Writing in a Melt Electrospinning Mode, Biointerphases, 2012, 7:13, 1-13.
[2] Kim, J.S. Jang, D.H. Park. W. H. Min B.M.: Fabrication and Characterization of 3 Dimensional PLGA Nanofibre/Microfibre composite scaffolds, Polymer, 2010, 51, 1320-27.
[3] Chung S, Ingle NP, Montero GA, Kim SH, King MW. Bioresorbable elastomeric vascular tissue engineering scaffolds via melt spinning and electrospinning. Acta Biomater. 2010 Jun;6(6): 1958-67. Epub 2009 Dec 1 1.
[4] Gulbins, H. Dauner, M. Petzold, R. Goldemund, A. Anderson, I. Doser, M. Meiser, B. Reichart B.: Development of an artificial vessel lined with human vascular cells, Cardiopulmonary support and physiology, 2004, 128, 372-377.
[5] Moreno, MJ. Ajji, A. Mohebbi-Kalhori, D. Rukhlova, M. Hadjizadeh, A. Bureau, MN.: Development of a compliant and cytocompatible micro-fibrous polyethylene terephthalate vascular scaffold. J Biomed Mater Res B Appl Biomater, 2011, 97(2), 201-14.

Claims

Patent claims
1. Medical material for vascular reconstructions, characterized in that it is fabricated from at least one compound selected from among polypropylene and/or polylactide, with the melt flow index (MFI) for polypropylene ranging from 3 to 500 g/10 cm, whereas the melt flow index (MFI) for polylactide ranges from 20 to 80 g/10 cm, the obtained material demonstrates a tubular structure, the surface mass of the medical material falls within the 10 - 170 g/m range, structure porosity amounts to 60 - 95%, and fiber diameter ranges from 0.07 to 20 μιη.
2. Medical material according to claim 1, characterized in that it is obtained using one of the methods selected from among melt blown, melt electrospinning or melt electroblowing techniques.
3. Medical material according to claim 2, characterized in that when the material is melt blown, the surface mass falls within the 20 - 170 g/m2 range, structure porosity amounts to 60 - 90%, and fiber diameter ranges from 0.08 to 5 μπι.
4. Medical material according to claim 2, characterized in that when the material is obtained by melt electrospinning, the surface mass falls within the 10 - 60 g/m2 range, structure porosity amounts to 70 - 90%, and fiber diameter ranges from 0.17 to 20 μπι.
5. Medical material according to claim 2, characterized in that when the material is obtained by melt electroblowing, the surface mass falls within the 10 -30 g/m2 range, structure porosity amounts to 60 - 95%, and fiber diameter ranges from 0.07 to 10 μιη.
6. Medical material according to claims froml to 5, characterized by tubular structure of 1 to 300 mm diameter, preferably up to 6 mm.
7. Medical material according to claims from 1 to 5, characterized by the form of a truncated cone with the smaller internal diameter ranging from 1 mm to 20 mm, preferably from 1 mm to 5 mm and the larger diameter from 2 mm to 30 mm, preferably from 2 mm to 6 mm.
8. Medical material according to claim 1, characterized in that it is designed for small diameter blood vessels, preferably below 6 mm.
9. Medical material according to claim 1 , characterized in that the selected polylactide is either an amorphous or a semicrystalline polymer.
10. Method of production of the medical material for vascular reconstructions defined in claims 1 to 9, characterized by the use of solvent-free methods, fabrication of textile structures with melt-based techniques selected from among pneumothermic (melt blown), melt electrospinning or/and melt electroblowing, techniques and the use of an extruder having up to seven heating zones.
11. Method according to claim 10, characterized by temperature in the consecutive heating sections for polypropylene within the 180 - 290°C, and in the extruder spinning head up to 320°C, for polylactide in the heating sections within the 100 - 210°C range, and in the extruder spinning head up to 220°C, rotary speed of the extruder screws of 0 to 10 rpm, as well as by the use of hot compressed air and/or high voltage for polymer stream extension; for polypropylene, air temperature of 200 to 320°C and air flow rate ranging from 0 to 40 Nm3/h is used, and for polylactide air temperature of 100 to 220°C and air flow rate ranging from 0 to 40 Nm3/h.
12. Method according to claim 1 1, characterized by the use of high voltages ranging fromO to 50 kV for extension of the polymer stream.
13. Method according to claim 1 1, characterized by simultaneous application of hot compressed air and high voltage.
14. Use of the medical material defined in claims 1 to 9 for the reconstruction of blood vessels, and in particular for production of vascular prostheses, vascular implants, tubular scaffolds for proliferation of vascular endothelial cells.
EP13729821.2A 2012-04-17 2013-04-17 Medical material for reconstruction of blood vessels, the method of its production and use of the medical material for reconstruction of blood vessels Ceased EP2838575A1 (en)

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