Tissue-engineered small-diameter vascular graft and method for making it
SUBSTANCE: invention refers to medicine and tissue engineering, namely to cardiovascular surgery and may be used in coronary artery bypass surgery, as well as in surgical reconstruction of peripheral vessels. What is described is a method for making a porous tubular matrix of a vascular graft of a biodegradable polymer by two-phase electric spinning, with biologically active molecules stimulating the vascular regeneration being incorporated into a matrix wall matrix incorporated biologically active molecules.
EFFECT: creating the tissue-engineered high-patency and durability small-diameter vascular graft for biological re-modelling of the damaged vessels in vivo.
2 cl, 1 ex
The present invention relates to the field of medicine and tissue engineering, namely cardiovascular surgery and can be used in coronary artery bypass surgery, and surgical reconstruction of peripheral vessels.
Now for the surgical treatment of cardiovascular diseases associated with atherosclerotic occlusion of peripheral vessels and coronary arteries, use of autologous arteries and veins or vessels made of Xenomania. At the same time the effective functioning of biological shunts average of 5 years, resulting in the need for revascularization procedures (Bokeria L.A., a High percentage of reoperations in patients with coronary heart disease - modern state of the problem / Bokeria L.A., Berishvili I.I., Solnyshkov etc. // Bulletin of the Bakulev them. Bakulev RAMS. - 2009. No. 10(3). - P.5-27). The use of synthetic materials for the manufacture of vascular prostheses, such as polytetrafluoroethylene (PTFE) or Dacron, allows to solve the problem, however, when the diameter of the grafts less than 6 mm is the rapid formation of blood clots in the lumen of the prosthesis.
Alternative to the use of autologous and xenogenic veins and arteries, as well as synthetic blood vessels for cardiovascular surgery may be deninger the e grafts. The main idea of tissue engineering is the creation of a complete vascular graft for use in cardiovascular surgery, which has led to attempts to create absorbable grafts with cells derived from the patient's body.
Known tissue-engineered blood vessel, consisting of a biocompatible, biodegradable matrix, covered with AutoClean one or a few species, obtained from bone marrow or peripheral blood of the patient (application USA 20090275129 A1, IPC C12N 5/08, C12N 5/06, publ. 05.11.2009). Biocompatible matrix has a porous structure and is made of natural or synthetic biodegradable polymers. Cells obtained from the patient for the settlement of the vascular graft, cultivated in sterile conditions to increase the weight, and then "thrown" on the matrix. For further cell proliferation and formation of extracellular matrix the matrix is placed in a bioreactor.
The disadvantage of this timeintensive blood vessel is the complexity of the fence of sufficient cellular material from the patient, and the duration of the process of cultivation and planting of cells on the matrix to form a complete vessel prior to its implantation.
Closest to the claimed technical solution is tissue-engineered vascular graft of small diameter, is the output for implantation in the blood stream of the patient (application USA 2010/0221304 "Bionanocomposite Materials and Methods For Producing and Using the Same", Saul. 26.02.2010 g , publ. 02.09.2010,, IPC - A61F 2/06, A61L 27/34, A61F 2/82). The graft is made by a method of double electrospinning and consists of two biocompatible bionanocomposite materials, the core of which includes polycaprolactone (PCL), and in the outer layer of the wall matrix incorporate angiogenic growth factors such as transforming growth factor (TGF-b) and fibroblast growth factor (FGF-b).
A disadvantage of the known technical solution is that the core structure of the fiber, in which PCL combined with natural polymers (collagen, chitosan, elastin), or synthetic polymers with short term biodegradation (PLA, PLGA, PGA, PDLLA), will lead to early loss of strength of the graft after implantation in the bloodstream, making the product unsuitable for long operation. In addition, the joint use of TGF-beta and bFGF may trigger the active elements formation of connective tissue, as TGF-beta stimulates the expression of extracellular matrix components such as elastin, collagen, fibronectin, proteoglycans, leading to hyperplasia neointima and obstruction of the graft, especially in small diameter grafts.
The technical result of the invention is the creation of tissue-engineered vascular graft of small diameter for bioremediative damaged blood vessels in vivo with high PR is a need, biogeosociology and durability.
The problem is solved by manufacturing a porous tubular matrix of the vascular graft of the biodegradable polymer by the method of two-phase electrospinning in the wall matrix incorporated biologically active molecules, stimulating the regeneration of the vessel wall in the body.
As a material for the manufacture of a matrix of the vascular graft using a synthetic polymer with a long period of biodegradation - polycaprolacton (poly(e-caprolactone (PCL)), which is well known as strong enough and elastic polymer. In addition, this polymer is biocompatible and bioresistance, and the rate of degradation of PCL fibers obtained by the method of electrospinning in the body ranging from three months to one year. This rate of degradation of PCL promotes long enough to maintain the required mechanical properties of the graft to complete the formation of the native vessel, and the processes of hydrolysis of the polymer and the regeneration vessel coordinated in time and parallel. As a result of biodegradation are formed of non-toxic substances: water and hexanoic acid. Declared vascular graft consists only of PCL, which is a very durable, flexible polymer with a long term degradation, thereby about the capable of withstanding the pressure of the blood stream for a long time, before the formation of the native tissue of the vessel.
Method electrospinning for manufacturing matrix allows to obtain micro - and nantoka fiber and porous structure of the solutions and polymer melts of different composition. The principle of the method consists in the formation of fibers in a strong electric field that occurs between two electrodes of opposite seragnoli, with one electrode placed in the solution or melt polymer material, the second place on the receiving metal collector. Vascular grafts are made at the facility for electrospinning, while the polymer solution is placed in a syringe, the plunger of which slowly pressure pump at a given speed. The syringe attached to the needle with a blunt end, which is supplied with the electrical potential. The polymer at the exit of the syringe solidifies, forming the fiber. Polymer filaments are collected on a rotating collector, connects the second electrode, forming a porous material. The pore size of not more than 20 μm in order to prevent bleeding through the wall of the prosthesis.
For making a vascular graft using the following parameters electrospinning: voltage - 10-50 kV, a flow rate of polymer solution - 1-10 ml/h, the distance between needle and collector - 1-20 cm, the rotation speed of the collector - 10-300 rpm
In the process of electrospinning in the polymer of the second fiber incorporate such biological molecules, as vascular endothelial growth factor (vascular endothelial growth factor (VEGF), fibroblast growth factor (fibroblast growth factor beta (b-FGF)), factor stromal cells (stromal derived factor-1 alpha (SDF-1α)and molecules of heparin. The introduction of VEGF in the structure of the graft, contributes to its faster endothelialization, because this growth factor plays an important role in the regulation of migration and proliferation of endothelial cells. In addition as inducer of proliferation of endothelial cells and fibroblasts used bFGF. In turn, SDF-1α activates the directional migration of autologous stem cells into the injury site, contributing to the regeneration of the vessel wall. The incorporation of molecules of heparin into the wall of the matrix provides a reduced risk of blood clots in the lumen of the conduit.
The incorporation of these growth factors and heparin into the wall of the graft, is carried out by mixing a solution of the biodegradable polymer with a solution of biological molecules in phosphate-buffered saline in a ratio of 20:1, then vupolnyaut electrospinning. Because each type of biomolecules has a wide range of effects on cells, the proposed vascular graft may be composed of or one type of molecules, or combinations thereof.
Declared vascular graft, contains a combination of growth factors: VEGF, bFGF and SDF-1a that JV is contributes to the optimal formation of the wall of the graft and the endothelial layer.
In the process of biodegradation of the polymer incorporated molecules out into the surrounding tissue and carry out their biological functions, stimulating and regulating the formation of a new vessel. Additionally, the molecules are "sealed" in polymer fiber and have no contact with the external environment, which ensures the preservation of their functions sufficiently long period, which allows for the sterilization of these grafts before implantation. Using polycaprolactone for the manufacture of the conduit, prevents immune and allergic reactions on the part of the body after implantation. Due to the low rate of biodegradation of the polymer is ensured continuous delivery of bioactive molecules into the surrounding tissue.
The invention is illustrated by drawings, where figure 1 shows the structure of a vascular graft, a vascular graft in the form of a hollow tube, b - porous structure of the wall of the graft, formed by the fibers of the biopolymer in the process of electrospinning, biomolecules incorporated in the polymer fiber.
The study of the functioning of the vascular PCL grafts carried out on the basis of The Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Vascular grafts (internal diameter 2 mm, thickness 100 μm) of the biodegradable polymer polycaprolactone (poly(caprolactone), PCL,) (M=80.000), were manufacturing the mould is prepared since the method electrospinning and implanted five male Wistar rats (400-450 g). PCL-graft implanted in the abdominal aorta between the renal artery and the bifurcation of the aorta. After removing the clamps the blood flow through the graft was evaluated using Doppler. After 6 weeks, the animals were taken from experiment, and conducted an evaluation of the anastomosis and graft on histological preparations with staining hematoxylin-eosin, Mallory and van Gison.
Histological examination in the lumen of the graft and anastomosis was identified by a continuous layer neointima. The inner surface of the graft was covered with endothelial cells, most of which had increased hyperchromic nuclei and reduced nuclear-cytoplasmic index compared to endothelial cells of the native aorta. The graft was infiltrated cells with morphological features of myofibroblasts and macrophages. The accumulation zones of the collagen rich glycosaminoglycans, laminin and fibronectin, were vyyavleny throughout the thickness and length of the graft. When macroscopic evaluation of an implanted conduit in perivascular tissue was not detected signs of bleeding.
Thus, the study showed the formation of structures on the PCL-graft characteristic of a blood vessel that makes the data of polymer grafts promising for use in cardiovascular surgery as tone the engineering of the vascular conduit.
1. Tissue-engineered vascular graft of small diameter, made of biodegradable polymer, polycaprolactone (PCL), by the method of two-phase electrospinning, while the porous structure of the walls of the matrix contains the incorporated fibroblast growth factor (FGF-b), characterized in that the wall thickness of the matrix incorporate vascular endothelial growth factor (VEGF) and factor stromal cells (SDF-1α), and molecules of heparin.
2. A method of manufacturing a tissue-engineered vascular graft according to claim 1, characterized in that the incorporation of biological molecules in the wall of the matrix is carried out by mixing a solution of polycaprolactone (PCL) with a solution of biological molecules in phosphate-buffered saline in a ratio of 20:1.
SUBSTANCE: invention refers to medicine, namely to textile treatment for cardiovascular surgery. A method involves textile treatment with a composition containing gelatin and intermolecular cross-linking of gelatin by an aqueous solution of glutaric dialdehyde, an antibiotic and 0.9% sodium chloride in certain proportions.
EFFECT: method enables make textiles hermetic and antimicrobial, reduced postoperative chemotherapeutic load on the patient.
5 cl, 11 tbl, 11 ex
SUBSTANCE: invention refers to the field of polymer chemistry and medicine, namely to method for obtaining thromboresistant polymer materials which have widespread application in medical industry for manufacturing workpieces on blood contact, for example blood-vessels prostheses, parts of bioartificial organs implanted into living body, bloodlines for artificial blood-circulation apparatus, storages for storage and blood transfusion etc. Method for obtaining thromboresistant polymer materials implies mixture polymer with extender, and is inert to blood coagulation water-soluble compounds in amounts of 0.3-3.5 wt % used as extender.
EFFECT: invention enables to produce thromboresistant polymer materials with lowered tendency to adhesion of platelets and lowered ability to formation of fibrinous thrombs on the surface of material in the absence of influence of whole blood coagulation system, as evidenced by increase of buildup time of fibrinous clod from 60-80 seconds to 110-240 seconds.
3 tbl, 36 ex
SUBSTANCE: invention relates to method of manufacturing medication-releasing medical device, selected from group consisting of vascular devices, prostheses, probes, catheters, tooth implants or similar, applied in treatment an/or prevention of vessel restenosis, which leads to acute circulatory collapse , conditioned by reduction of circulating blood weight. Claimed method includes application on device by means of submerging into suitable solution or by means of dispersion, of at least one medication layer, when necessary introduced into polymer able to release said medication; polymer which has active functional groups, selected from group consisting of amino groups and sulphhydryl groups capable of chemical binding of biological molecules in one step by means of cold plasma methods; and biological molecules on said polymer surface. Also described is medication-releasing medical device, obtained by said method and application of polymers with reactive functional groups for covering medical devices, preferably vessel stents, by means of cold plasma application.
EFFECT: due to application of definite class of polymers using cold plasma, claimed method is more technological, namely facilitates application of polymer without destroying its functional groups properties and better polymer binding with biomolecules resulting in slower, controlled release of medication from medical device.
36 cl, 1 tbl, 5 ex, 2 dwg
FIELD: medicine, in particular coating composition for implanted medical device.
SUBSTANCE: claimed composition contains at least one polymer and at least one biologically active substance, such as naphthazarin and/or naphthazarin derivative, in particular shikonin. Coated devices are useful as substituents of skin, bone, or cartilage and as prosthesis for vascular surgery.
EFFECT: new coating composition for implanted medical devices.
22 cl, 1 dwg, 2 tbl, 1 ex
SUBSTANCE: invention refers to medicine. What is described is an implanted multilayer chondral reparation flap showing biological compatibility and physiological resorption, and what is also described is a method providing surgical management in situ for intra-articular regeneration of cartilaginous tissue in joint damages and/or defects. The chondral reparation flap comprises a first external cell-impermeable layer and a second external cell-permeable layer adapted for placement in an immediate proximity from a subchondral bone on a wound portion, and also a cartilage-forming matrix located between the first and second layers. The cartilage-forming matrix represents an accepting medium for diffusion of autologous stem cells and contains chemical components promoting formation of a hyaline-like cartilage in the presence of said autologous stem cells. The method prevents a fibrous cartilaginous replacement tissue from forming within the injury region.
EFFECT: method provides autologous compositions which when used in a combination with the reparation flap form the medical system for formation of the replacement hyaline-like intra-articular cartilage.
17 cl, 7 dwg, 1 ex
SUBSTANCE: porous matrix based on biocompatible polymer or polymer mix for tissue engineering is obtained by compression of polymer and sodium chloride particle mix with defined particle size, and further removal of sodium chloride by dissolution. Porosity grade of matrix lies within 93 to 98%, its pores fall into different sizes, with definite pore distribution by size within certain limits.
EFFECT: obtained matrices are free-shaped yet pertain stability and hardness characteristics required to withstand surgical implantation methods and counteract mechanical forces applied at the implantation point.
40 cl, 2 tbl, 8 ex
SUBSTANCE: present group of inventions concerns medicine, more specifically coated implants and devices. There is offered ceramic composition-precursor for making high-strength bio-elements used as an absorbable or partially absorbable biomaterial where the composition contains at least one silicate with Ca as a base cation with the absorption rate less or equal to the bone growth rate, and this at least one silicate acts as a base binding phase in a biomaterial, and this at least one silicate Ca is present in amount 50 wt % or more, and all other components if any are presented by additives, such as an inert phase, and/or additives which make a biomaterial to be radiopaque. There is offered hardened ceramic material which is based on the ceramic composition-precursor and is in the hydrated form. There is offered a medical implant, application of the medical implant, and also a device or a substrate coated with the uncured ceramic composition-precursor and/or hardened ceramic material.
EFFECT: invention provides a biomaterial having initial and constant durability which is dissolved in due time and reacts with an organism to generate a new tissue.
29 cl, 1 ex, 3 tbl
SUBSTANCE: invention relates to field of medicine. Claimed is composition with hyaluronic acid (HA), which includes gel particles of bound water-insoluble hydrated HA. HA includes bindings, represented with the following structural formula: HK'-U-R2-U-TK'. Where each group HA' represents the same or other molecule of bound HA'; each U independently represents optionally substituted 0-acylisourea or N-acylurea; and R2 represents optionally substituted alkyl, alkenyl, alkinyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkinyl, aryl, heteroaryl, heterocyclic radical, cycloaliphatic alkyl, aralkyl, heteroaralkyl or heterocyclolalkyl. Also claimed is method of developing tissues in individual, including introduction of needle into individual in place where development of tissues is necessary, needle is connected to syringe filled with composition with HA, and applying force to syringe in order to supply composition with HA to individual. Method of obtaining composition with HA includes formation of water-insoluble dehydrated particles of bound HA, separating insoluble in water particles by their average diameter, selection of subset of particles by average diameter and hydration of subset of dehydrated particles by means of physiologically compatible water solution. Other method of obtaining composition with bound HA includes binding precursor of bound HA by means of bis-carbodiimide in presence of pH buffer and dehydration of bound HA. Also included is method of developing tissues in individual that needs tissue development. Method of stabilisation of bound HA includes hydration of water-insoluble dehydrated bound HA by means of physiologically compatible water solution which includes local anesthetic, so that value of elasticity module G' for stabilised composition constitutes not less than approximately 110% from value G' for non-stabilised composition.
EFFECT: claimed composition of hyaluronic acid and method of preparation and application of HA composition are efficient for development of tissue and/or drug delivery.
27 cl, 22 ex, 2 tbl, 7 dwg
SUBSTANCE: effect is achieved by using compositions based on different stereoregular amorphous biodegradable polymers - polylactides and copolymers of lactides with glycolides (18-72 mass ratio) as the second component of biocompatible mineral filler - hydroxyapatite with particle size of the main fraction of 1-12 mcm (8-41 mass ratio), as well as an organic solvent with boiling temperature equal to or higher than softening temperature by 3-20°C (20-41 mass ratio). After preparation of a homogenous mixture, the composition is undergoes thermal treatment at 80-130°C in a vacuum in a shaping vessel with the required shape. A porous product is obtained due to removal of solvent. Density of the obtained porous product is about 0.4-0.8 g/cm3.
EFFECT: design of a method of obtaining porous biodegradable composite polymer products based on polylactides or copolymers of lactides and gylcolides.
3 cl, 3 ex
SUBSTANCE: described are implants based on biodegradable thixotropic compound with pseudo-plastic properties and implant injected under skin or into skin in fibrous tissue. Containing microparticles of at least one biocompatible ceramic compound in suspension, in at least one liquid carrier containing at least one compound based hyaluronic acid and at least one biodegradable thixotropic compound with pseudo-plastic properties. Also disclosed is kit for preparation such implants directly before application, as well as implant production and using for filling of crinkles, and/or skin cavity, and/or cicatrices.
EFFECT: implants of simplified injection.
14 cl, 4 ex
SUBSTANCE: invention refers to medical equipment and may be used in cardiac surgery for replacement of an injured aortic root with an aortic valve. A valve-containing aortic root prosthesis comprises a vascular prosthesis 1 with a cuff 3 attached from a proximal side, and a valve 4 inserted in the cuff 3. The prosthesis is provided with a ring plate 5 attached to the cuff 3 along the internal perimetre. The plate 5 is pulled to the vascular prosthesis to approach the cuff 3, and intraoperatively anchored over the cuff 3 to seal a junction of the cuff and coronary tendons.
EFFECT: higher reliability and reduced risk of postoperative complications associated with a leaking junction of the prosthesis and the coronary tendons of the valve prosthesis.
4 cl, 2 dwg
SUBSTANCE: invention relates to medicine and pharmaceutical industry, in particular to method of manufacturing elongated hollow body (1). Body, containing crystalline cellulose, has multiple projections (3, 4), which project into lumen of hollow body (1), on internal wall. Method of manufacturing elongated hollow body (1), includes stages: manufacturing hollow form (12), cultivation of cellulose-forming organisms in internal space, formed by hollow form (12), aimed at providing growth of hollow body (1) in internal space; operation of removal of hollow body from form (12). At the stage of removal from form (12), at least, part of hollow form (12) is irreversibly deformed.
EFFECT: increased efficiency of manufacturing method.
16 cl, 8 dwg
SUBSTANCE: invention refers to medical equipment and can be used in cardiosurgery. A valve-containing aortic root prosthesis comprises a vascular prosthesis with a cuff 2 attached from a proximal side, and a valve inserted in the cuff 2. On the cuff 2, there are three marks inclined at 120 degrees, dividing the cuff on three zones 4 related to right coronary, left coronary and non-coronary sinuses. The vascular prosthesis has two holes above the zones related to the right and left coronary sinuses. The vascular prostheses are anchored to each hole to couple with the adjoining coronary artery.
EFFECT: invention provides simplifying a procedure of prosthesis implantation and a lower risk of postoperative complications.
SUBSTANCE: valve-containing graft comprises an internal blocking element in the form of three flexible petals 1, external elements adjoining thereto in the form of convex envelopes 2 and segments of vascular grafts 2 sutured together with an elastic filament 4 passing through holes 5 formed by a needle body. The flexible petals 1, the convex envelopes 2, the segments of vascular grafts 3 and the elastic filament 4 are made of porous polytetrafluoroethylene with a filament diameter 4 is greater or equal to a diameter of the holes 5 formed by the needle when bringing the elastic filament through walls of said elements.
EFFECT: higher graft durability and thrombus resistance, higher safety of the use ensured by lower risk of haemorrhage through the sutures connecting graft elements.
SUBSTANCE: invention refers to medicine, specifically to cardiovascular surgery and may be used for modification of synthetic implanted medical devices. What is described is a method for processing synthetic textile implanted medical devices involving coating the devices with hydrogel of natural biodegradable polymers wherein the natural biodegradable polymer is presented by polysaccharide chitosan or its derivatives (carboxymethykated sulphated chitosan) in a combination with polyester-poly-3-hydroxybutyrate. The coating is dried and transferred in the water-soluble state by thermal processing at 100°C.
EFFECT: method for processing synthetic textile implanted blood contact medical devices enables providing the devices with a complex of the required properties: higher thromboresistance and antimicrobial action, zero surgical porosity and prolonged drug release.
3 cl, 1 tbl, 5 ex
SUBSTANCE: invention relates to medical equipment, namely, to surgical instruments and can be applied in implanted devices for providing and supporting lumen of vessel or hollow organ. Implant device for human and animal vessels is made from material with shape memory in form of multi-coil body of rotation, connected with delivering device. Multi-coil body of rotation is made from flat pipe which has multiple perforation. Butt end of pipe are rigidly connected with formation of closed figure from doubled coils, terminal ones of which are connected between each other by rings. Coils are placed one to another without gap. Size of body of rotation in working condition corresponds to size of damaged region of vessel, and has form of cylinder or double-cone figure with the largest diameter in the middle. Terminal doubled coils of multi-coil body of rotation are bent by longitudinal axis with formation of loops. Delivering device for said implant is made in from of flexible catheter with tip, which is equipped with cut for connection with loop of coil of multi-coil body of rotation and face for safe removal of catheter.
EFFECT: reduction of vessel trauma during introduction and placement of claimed implant and safe provision with medicinal substance.
5 cl, 13 dwg
SUBSTANCE: invention relates to system and method of stent-graft positioning in vivo in arc of thoracic aorta. System contains first and second positioners for detachable connection to tubular stent-graft closer to its first than to second end by means of flexible connection. System also contains first and second connectors for connection of positioners with control means. Connectors can pass from positioners through internal canal of stent-graft and go out from it closer to second than to first end of stent-graft. One of positioners can go beyond first end of stent-graft to provide turning point, which makes it possible to extract stent-graft in one direction. Other positioner is intended for extraction of stent-graft in another direction. Such system implementation makes it possible to ensure a pair of powers for creation of torsion torque.
EFFECT: application of claimed invention will make it possible to position stent-graft in arc of thoracic aorta more precisely due to possibility of setting angle of stent-graft proximal end c positioning with respect to vessel wall and to reduce risk of disturbing stent-graft fixation, especially on internal arc radius.
14 cl, 5 dwg
SUBSTANCE: invention relates to medical equipment, namely, to stent-graft and, in particular, to spiral stent-graft for placing in thoracic artery. Stent-graft contains material of graft in form of tube and material, which gives rigidity to graft material. Stent-graft has, at least, two separate sections, each of which contains continuous and integral piece of material and is made in form of spiral with longitudinal axis, in fact, parallel to longitudinal axis of tube. One section rests against another section or is placed as close as possible to it to eliminate discontinuity in ensuring graft material rigidity.
EFFECT: invention insures lesser weakening of construction in case of wire break, possibility of selection of wires which are optimised for different zones of implant, elimination of tendency to successive falling of reinforcing spiral coils.
8 cl, 1 dwg
SUBSTANCE: present invention refers to medicine, more specifically to a biodegradable stents consisting of an internal biodegradable metal frame and an external polymer coating. The biodegradable coating consists of biodegradable polymers and can additionally contain at least one pharmacologically active substance, such as an anti-inflammatory, cytostatic, cytotoxic, antiproliferative agent, an anti-microtubule agent, an antiangiogenic, anti-restenosis (for restenosis), antifungicidal, anti-cancer, anti-migration, hypocoagulation and/or anti-thrombosis agent. The stent has a function of vessel lumen maintenance only during a period of time before repaired tissue is able to perform this function again.
EFFECT: making the biodegradable stent.
12 cl, 24 ex