AU5503599A - Autologous epithelialisation or endothelialisation of hollow organs or vessels - Google Patents
Autologous epithelialisation or endothelialisation of hollow organs or vessels Download PDFInfo
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- AU5503599A AU5503599A AU55035/99A AU5503599A AU5503599A AU 5503599 A AU5503599 A AU 5503599A AU 55035/99 A AU55035/99 A AU 55035/99A AU 5503599 A AU5503599 A AU 5503599A AU 5503599 A AU5503599 A AU 5503599A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
Abstract
The invention concerns natural or artificial hollow organs and all their parts, in particular vessels and valves, of which the inner or luminal surface is lined with patient-autologous epithelial, in particular endothelial cells, a process for producing these hollow organs and the use of these hollow organs in surgery, in particular cardiac and vascular surgery.
Description
Autologous epithelialisation or endothelialisation of hollow organs or vessels. The invention concerns natural or artificial hollow organs and all their parts, in particular vessels and their valves, of which the inner or luminal surface is lined with patient autologous epithelium, in particular endothelial cells, a process for producing these hollow organs and the use of these hollow organs in surgery, in particular cardiac and vascular surgery. The cryopreservation and banking of organs and human tissue in order to conserve these for utilisation at a later stage is known and in the framework of transplantations to a large degree has become standard procedure, only the techniques used have irrelevant differences. (Brockbank KGM. Basic Principles of Viable Preservation. In: Transplantation Techniques and Use of Cryopreserved Allograft Cardiac Vessels and Vascular Tissue. DR Clarke (ed.), Adams Publishing Group Ltd., Boston.P9-23, American Association of Tissue Banks Standards for Tissue Banking (1995), A.A.T.B., McLean, VA, U.S.A. European Association of Tissue Banks General Standards for Tissue Banking (1995), E.A.T.B., (Vienna, Austria). The utilisation of cryopreserved venous allografts is an established procedure in bypass surgery (Brockbank KGM et al., Cryopreserved vein transplantation. J. Cardiac Surg.7:170 176, 1992; Gelbfish J et al., Cryopreserved homologous saphenous vein: Early and late patency in coronary artery bypass surgical procedures. Ann. Thorac. Surg. 42: 70, 1986 Fujitani RM et al., Cryopreserved saphenous vein allogenic homografts: An alternative conduit in lower extremity arterial reconstruction in infected fields. J. Vasc. Surg. 15: 519 526, 1992) and is utilised for patients who do not have sufficient vessel material of their on available or the vessels are qualitatively not suitable. The utilisation of these types of veins show a poor longevity (Bilfinger TV et al., Cryopreserved Veins in Myocardial Revasculization: Possible Mechanisms for Their Increased Failure. Ann. Thorac. Surg 63: 1063-69, 1997 and commentary Ann. Thorac. Surg: 64: 1524-5, 1997. Marshin RS et al., Cryopreserved Saphenous Vein Allografts for Below Knee Lower Extremity Revascularization. Ann. Surg. 219: 664-72, 1994). The cause for this may be mainly due to an immunologically conditioned degeneration (Carpenter JP, Tomaszewski JE, Immunosuppresion for Human Saphenous Vein Allograft Bypass Surgery: A Prospective Randomised Trial. J Vase. Surg. 26: 32-42, 1997. Carpenter JP, Tomaszewski JE, Human Saphenous Vein Allograft Bypass Grafts: Immune Responses. J Vase. Surg. 27: r 2-9, 1998). In addition premature thrombotic occlusions are often observed. Till now in the
T
framework of cryopreservation these two processes have been traced back to damage of the donor endothelium, which can lead to the total absence of the same or a limited functioning of the preserved endothelium (Brockbank KGM et al, Cryopreserved vein transplantation. J Cardiac Surg. 7:170-176, 1992 Brockbank KGM et al. Functional analysis of cryopreserved veins. J. Vasc. Surg. 11: 94-102, 1990. Laub GW et al, Cryopreserved allograft veins as alternative coronary conduits: early phase results. Ann. Thorac. Surg. 54: 826-31, 1992. Louagie YA et al., Viability of long term cryopreserved human saphenous veins. J. Cardiovasc. Surg. 31: 92-100, 1990). As a result of this known and already patented cryopreserved technologies for allografts and xenografts aim at guaranteeing a possibly higher degree of preservation regarding the vascularity and microvascularity of the donor endothelium after the cleansing process. The longevity of the donor endothelium of cryopreserved tissue is given in the literature as being 50% -80%. (Bambang LS et al., Effects of cryopreservation on the proliferation and anticoagulant activity of human saphenous vein endothelial cells. J Thorac. Surg. 110: 998-1004). However a key position has recently especially been assigned to the vascular and micovascular endothelium in the framework of the acute and chronic organ rejection. Endothelium specific non HLA antigen, which leads to the activation of CD4 T-Cells, enables the donor endothelium to supply - in conjunction with other accessory molecules - the recipient's immune system with foreign antigens. The release of non-HLA antigen by damaged endothelial cells leads to a chronic immune reaction and possibly to graph vasculopathy and chronic rejection. (Rose ML, Role of endothelial cells in allograft rejection. Vasc. Med. 2(2): 105-14, 1997; Reul, RM, Fang JC, Denton MD, et al., CD 40 and CD 40 ligand (CD 154) are coexpressed in microvessels in vivo in human cardiac allograft rejection. Transplantation 64(12): 1765-74, 1997 Salom RN, Maguire JA, Hancock WW, Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology 30 (1): 24-29, 1998). A process for the manufacturing of a non-immunogenic tissue matrix was proposed in the US patents No. 5,843,182 and No. 5,613,982. In this process at first decellularisation to removal native cells with the aid of hydrolytic enzymes (e.g. proteases, lipases, nucleosidases, glycosidases etc.) is carried out, and the matrix obtained is treated with adhesion and growth factors to enable the repopulation of fibroblasts. The main disadvantage of these measures however is that it can not be ruled out that this <\ Nrefptment does not also negatively influence the strength of the other equally decisive )3 components regarding the structural integrity of the hollow organ's walls, for example type I collagen, proteoglycans or glycoproteins. This is even more important, as it is very well known that the most serious complication concerning weakness of the cryopreserved veins' walls, for example tears of the walls of the veins or wall ballooning (aneurysms) lead to repeat operations resulting from complications a long-time after implantation (Lehalle B et al., Early rupture and degeneration of cryopreserved arterial grafts J Vasc. Surg. 25: 751-2, 1997. Couvelard A et al., Human allograft failure. Hum Pathol. 26: 1313-20, 1995). When decellularised tissue serves as a matrix for recellularisation measures, it is necessary to incubate the tissue to be transplanted with high concentrations of special adhesion or growth factors to enable cell repopulation in the wall. (US Pat. No. 5,632,778,and 5,613,928 or U.S. Pat. No. 5,192,312, U.S. Pat. No. 5,843,182, WO 95/2483). These types of preparations are expensive, are mostly not allowed in clinical use and to a large degree, the amount of influence that the high non-physiological concentrations of these substances have on the functional differentiation of tissue is unknown. Pre-treatment of the matrix which leads to the decellularisation poses - just as is the case when treating the decellularised matrix with adhesion or growth factors - immunological risks as well as risks with regard to cell biology, that are not insignificant. Apart from these disadvantages until now he literature concerned has hardly taken into consideration any knowledge from literature regarding the distribution of antithrombogenic or prothrombogenic activities or the active structures in the walls of hollow organs. While vascular endothelium (as the tissue covering the inner or luminal side of all blood vessels and valves in the vessels) is characterised for example by numerous anti-aggregatory, anticoagulatory and profibrinolytical activities (Z Kardiol. 82:Suppl. 5, 13-21, 1993 FASEB J. 2:116-123, 1998) cellular components of the deep vessel walls are mainly characterised by the expression of tissue factor, which initiate an immediate coagulation reaction when coming into contact with plasma factors (Thrombosis Res. 81: 1-41, 1996, J Clin. Invest. 100: 2276 2285, 1997, FASEB J 8: 385-390; 1994, Arterioscler. Thromb. Vase. Biol. 17: 1-9, 1997). Shielding of the walls' prothrombogenic activities is not only of physiological importance regarding blood vessels and their valves but also with all other cryopreserved and non cryopreserved natural or artificial hollow organs or vessels. 1<LC> The invention's underlying task is therefore to supply improved vessel material for cardiac and vascular surgery. Another task of this invention in the future is to provide a suitable process for producing the type of material for vessels - in particular blood vessels and their valves - necessary for surgical transplantation purposes. This problem is solved in accordance with the invention, by natural or artificial hollow organs and their components where the inner surface or the luminal surface is lined recipient (patient) autologous epithelium. Preferred in accordance with the invention are hollow organs where the inner surface or the luminal surface is lined with patient autologous endothelial cells. A particularly preferred model of the invention includes vessels and their valves where the inner or luminal surface is lined with recipient autologous endothelial cells Hollow organs in accordance with the invention, in particular vessels, in accordance with the invention where the inner surface is lined with patient autologous endothelial cells, show a better long term patency than hollow organs or vessels that are not lined. Examples of hollow organs, in accordance with the invention, where the inner or luminal surface is lined with patient autologous epithelium are natural blood vessels and their valves; lymph vessels and their valves; ureter and urinary bladder; seminal ducts, bronchi, the heart as a special blood vessel with its valves and any prosthetic replacement of such hollow organs. As particularly preferred vessels in accordance with the invention, cryopreserved or non cryopreserved allogeneic or xenogeneic vessels (arteries, veins, lymph vessels) where the inner surface is lined with autologous endothelial cells come into consideration. Another advantage of the invention is that the anchoring of the epithelial covering (lining ) of the hollow organs, in accordance with the invention is confluent and long-lasting. This is of particular importance as the endothelium of all the larger blood vessels, vascular valves and heart chambers, when in a healthy intact condition, functions simultaneously as an anatomical, physical and metabolic barrier between the blood and the deeper layers of the 5 walls of the vascular structures mentioned and thus allows independent, separated regulation of numerous physiological processes in both these body compartments. In particular the formation of thromboemboli and the triggering off of an immuno reaction on the luminal surface as well as an acute infiltration of the deep layers of the wall by unspecific effective defence cells (granulocytes, monocytes)is prevented through the to be transplanted blood vessels, valves and heart chambers, in accordance with the invention, where the luminal surface is lined with patient autologous endothelium. As the self collected clinical experience has already shown this is the reason why clinically relevant rejection reactions of transplanted autologous endothelised blood vessels do not occur. In addition the invention is concerned with a process for the production of hollow organs in accordance with the invention. The lining process includes the lining, particularly both the long lasting lining of cryopreserved or non-cryopreserved donor hollow organs with patient autologous epithelium and the lining of cryopreserved or non-cryopreserved donor vessels, with patient autologous endothelial cells. A preferred design, in accordance with the invention includes the lining process, in accordance with the invention, as well as the. pre-coating of cryopreserved or non cryopreserved vessels with patient autologous serum. In a particularly preferred design the lining of the vessel (or hollow organ ) with patient autologous endothelial cells is carried out with the help of a special cultivation device, which is characterised by being able to create a pressure gradient between the lumen of the vessel (or hollow organ) and the outer area of the vessel, this prevents the walls of the vessels or the hollow organ from collapsing. The hollow organs that are produced in this way in accordance with the invention have considerable advantages - an endothelial layer can be established on the luminal surface e.g. of a blood vessel This layer is absolutely confluent and is anchored to withstand the shearing force of the blood flowing past in the long term. This does not only act as a complicated antithrombogenic catalyst to prevent the thromboembolisation of he hollow organs, but also as effective protection against a mass scale recruiting of the defence cells from the blood, 6 which is inalienable to the deleterious rejection of the deep wall structures of the hollow organ in the sense of an acute infective reaction The process, in accordance with the invention leads to a long term re-endothelisation with patient autologous endothelium of the recipient. In a preferred design a possible selective de-epithelisation of the cryopreserved or non cryopreserved donor hollow organ (= removal of the donor epithelium) before the lining with patient autologous epithelial cells (= application of the recipient's epithelium) is carried out. Particularly preferred is the production of blood vessels lined with patient autologous endothelium, where the donor epithelium is gently removed beforehand, therefore in this way the other structures in the wall are totally retained. This selective removal of the donor epithelium is carried out mechanically or immunologically (by complement mediated lysis). Enzymatic methods for removing the donor epithelium in particular are to be avoided. The clinical results show that the clinically relevant rejection reaction is not found when the standard cytoimmunological monitoring is carried out, if the pre-treatment in particular with enzymatic means of the matrix which leads to decellularisation is not carried out. In another design, the process, in accordance with the invention,, is included as well as the precoating of the cryopreserved or non- cryopreserved vessels with patient autologous serum. A pre-coating with patient autologous serum, where physiological concentrations are used, promotes not only the adhesion but also the functional differentiation of the seeded endothelium layer. In vitro studies that were carried out with regard to the endothelisation of cryopreserved and non-cryopreserved veins showed that a pre-coating of the veins with serum presents an ideal matrix for the cell repopulation on the veins. This pre-coating was, with what was at the time the standardised coating i.e. fibronectin with and without proteoglycan (e.g. heparin sulphate, see U.S. Pat. No. 5,192,312; U.S. Pat. No. 5, JA,178; U.S. Pat. 5,613,982; U.S. Pat. No. 5,483,182; WO 95/24873, Zilla P. et al., 7 Endothelial seeding of polytetrafluoroethylene grafts in humans. J Vasc. Surg. 6: 535-541, 1987) clearly superior. This presents an advantage worth mentioning, as the clinical use of fibronectin is not permitted in Europe. In a particularly preferred design, the process in accordance with the invention, for coating the vessel (or hollow organ) with patient autologous endothelial cells is carried out with the help of a special cultivation device, which is characterised by being able to create a pressure gradient between the lumen of the vessel (or hollow organ ) and the outer area of the vessel, which prevents the walls of the vessels or the hollow organ from collapsing. In addition it specifically enables unwanted metabolic products of the vessel's wall to be washed out by transmural filtration. The lining process in accordance with the invention, can be used for numerous natural or artificial hollow organs and their components, for example natural blood vessels. The expert can also use the process, in accordance with the invention, for endothelisation of blood vessels and heart valves; lymphatic vessels and their valves; ureters and urinary bladders; seminal ducts, bronchi, the heart as a special blood vessel with its valves and any prosthetic replacement of such hollow organs. It is preferable to use the coating process in accordance with the invention, for cryopreserved donor vessels (veins and arteries) and non-cryopreserved donor vessels (veins and arteries) as well as with allogeneic heart valve replacement. In addition the lining process, in accordance with the invention, can be used for relevant xenografts. In a design that includes the process, in accordance with the invention, for producing hollow organs correspondingly the cryopreservation of hollow organs till the time that they are used; their defrosting; the selective removal of the epithelial or endothelial lining, where an enzymatic treatment is to be avoided; the isolation of patient autologous epithelium, preferably endothelial cells and particularly preferred vascular endothelial cells; the pre coating of the cryopreserved or non-cryopreserved hollow organs, preferably of a donor vessel, particularly a cryopreserved donor vein, with patient autologous serum and the long lasting lining of the hollow organ (or the donor vessel) with patient autologous epithelial or endothelial cells, with the help of the cultivation device in accordance with the invention t ni particularly preferred.
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6 A particularly preferred cultivation device is shown in figure . This cultivation device includes a culture vessel that is filled with a medium, in which the vessel (e.g. vein) is placed. The lumen of both vein ends are connected to both the vents of the cultivation vessel by means of two hoses. There are two sterifilters have been placed (7, 13) in between these and outside the vessel there are two three-way taps (6, 14). The one hose is connected to a Boyle Marriott vessel filled with a medium, the other ends in a drainage vessel. The pressure gradient Ap (dependant on cannula (2) and the hose clamp (15) are set so as to prevent the vein collapsing and provide the endothelial cells with a constant flow of culture medium as a source of nutrition. By opening the hose clamp (15) a complete exchange of the medium within the vein can be carried out as often as required. The medium exchange can also be automated by means of an electronically controlled pump. The vessels, in accordance with the invention, can be used in cardiac or vascular surgery, especially in aortacoronary bypass in the case of cardiac disease and as the graft in the case of every type of vessel reconstruction. This, for example includes peripheral arterial occlusion, aneurysmal changes to vessels which result in the replacement of vessels as well as numerous repeat cardiac or vascular surgery. The vessels are an ideal conduit for usage in infected areas. Another indication for using this type of vessel is the numerous inborn malformations (for example any form of shunt operations can be mentioned). In addition these types of vessels are suitable for pure scientific research, for example arteriosclerosis research or permeation testing of pharmaceutical drugs. Another design of the invention concerns vessels, whose inner surface have been lined with patient endothelial cells which were obtained from a different source (e.g. peripheral blood, bone marrow, fatty tissue, genetically modified or manufactured endothelium, xenogenous and when necessary genetically modified xenogenous endothelium. In another design the patient autologous epithelium is manufactured using gene technology , so that the epithelium imitates the surface's characteristics of the patient autologous epithelium and its immunological properties. An additional design involves the utilisation of matrixes of xenogenous origin for the construction of new vessels and their endothelisation (e.g. destroying the tissue of bovine 9 chest wall arteries by means of e.g. forced cryopreservation of these vessels to the basic structure of the vessel's connective tissue and the seeding of endothelium on these vessels). In another design the outer surface of the hollow organ, in accordance with the invention, is enclosed by a supplementary coat made of synthetic (man-made) material. The definition of synthetic material as used here, means any organic and/or inorganic product that is suitable for such purposes. In an a design that is especially preferred the hollow organ, in accordance with the invention, is enclosed in a supplementary coat made of reabsorbable synthetic material. In a design that is especially preferred the coat is made of synthetic polyglycon acids. The hollow organ, in accordance with the invention is enclosed by a supplementary coat for example of polyglycon acids, has the advantage of being stabilised for many months. Another design involves the seeding of epithelium on reabsorbable material (e.g. polydioxanon) for the purpose of tissue engineering of a vessel. The figure serves as an illustration of the invention. Figure 1 shows the culture device used for the process, in accordance with the invention, for cryopreserved and non-cryopreserved vessels. The following examples explain the invention and are must not limit the conception. Example 1: Patient autologous endothelisation of cryopreserved veins. During the pre-operative phase approx. 500ml of whole blood without coagulation inhibitors is taken from the patient, stored at 4*C for 24 hours and then the solid components are removed centrifugally. The serum is frozen until required. Simultaneously a donor vein, if not already available, is cryopreserved according to a specific scheme (Brockbank KGM et al., SCryopreserved Vein Transplantation. J. Cardiac Surg. 7: 170-176, 1992; Gelbish J, et al., U-. 0' 10 Cryopreserved homologous saphenous vein: Early and late patency in coronary artery bypass surgical procedures. Ann Thorac. Surg. 42:70, 1986; Brockbank KGM et al. Functional analysis of cryopreserved veins. J Vasc. Surg. 11: 94-102, 1990). During a pre-operation a piece of vein, about 5 cm in length is removed under local anaesthetic from the patient who is to receive the treated/coated prosthesis. The cell isolation and the multiplication of isolated endothelial cells results from the current cell culture techniques (Jaffe EA, Nachman RL, Becker CG, et al. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunological criteria. J Clin. Invest. 52: 2745-56, 1973). Medium 199 (Seromed) supplemented with 20% autologous serum and 2ng/ml of recombined bFGF (basic fibroblast growth factor) for example can be used as a culture medium. After the required number of cells for the lining have been obtained, the vein that had been cryopreserved is defrosted in a bath of water at 37*C. Preferably the donor vein is freed of all residual donor epithelium by pulling a blown up balloon catheter (e.g. Fogarty's catheter, Fa. Baxter) through the vein in the direction of the blood flow (note venous valves!). In other approaches the endothelium can also be specifically removed by antibody induced complementary lysis. The vein is filled with patient autologous serum and in this state is incubated for 12 - 24 hours. Here the two ends of the vein are sealed by a universal adapter stopper (which is tied in), which in turn is closed off with a removable stopper. Finally the serum is drained by removing the stopper, the pre coated vein is then filled with autologous patient endothelium having a defined number of cells (80.000-120.000 cells/cm 3 graft surface) and is closed again by reintroducing the stopper. Now the vein is placed in a rotating device, based on the one which has been described numerous times in the literature [Kadletz M, Moser R, Preiss, P et al., In vitro lining of fibronectin coated PTFE grafts with cryopreserved saphenous vein endothelial cells. Thorac. Surg. 35 Spec No. 2 143-147, 11/1987] and rotated in an incubator (Functionline, Heraeus Instruments) at 37*C. This results in regular adhesion of the cells to the graft's surface. After this the vein is taken out of the rotation devise and placed into the special cultivation device (see Fig. 1). Figure 1 shows the special cultivation device that was especially developed for the cultivation of endothelised vessels, that mainly is made of biologically inert autoclavible parts. With this device a constant pressure gradient (0 - 20cm H20) can be built up between the vein's walls
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11 to prevent the vein to be cultivated from collapsing. In addition a continual exchange of the medium under sterile conditions can be carried out. The Boyle Marriott vessel (1) comprises of a 500ml glass bottle which is equipped with a universal stopper (3) that admits a cannula (2). This cannula which serves to adjust the pressure gradient is equipped with a sterifilter (Millipore) (4) to the atmosphere. In the lower third of the bottle there is an opening (5) which by means of a three way tap (6) and another sterifilter (7) is linked to the actual culture vessel (8). A sealable glass culture dish serves as the culture vessel, which mid-way up the sides is equipped with two supports one leading to (9) and the other away (10) from the cultivation vessel, thus the wall of the vein has penetrating supports. In order to cultivate veins of varying lengths a viton hose (11) is attached to both sides of the supports which can later be connected to a vein adapter (12) so that a continual flow of the medium from the Boyle Marriott vessel to the drainage vessel. A vitron hose (Labokron)with the appropriate adapters (identical to those that will be used for the vein) is placed exactly where the vein will go. The outlet is connected to a drainage vessel (16) via a sterifilter (13) and an adjustable three-way tap (14) and a regulatable hose clamp (15).In a sealed state the necessary gaseous exchange (5% C02, saturated water vapour) for the cultivation of cells occurs via a sterifilter (17) mounted on the cover of the bowl. When preparing the system the Boyle-Marriott bottle and the culture vessel are 2/3 filled with a culture medium and the hose system is bled by opening the three-way tap. The preparations for the cultivation of the vein are complete. The culture vessel it is opened in order to place the vein (18) that is to be coated in it. The adapter of the vein is connected to the culture vessel after the removal of the sealed stopper and the viton hose which had served the purpose of keeping the vein's place. During this procedure attention must be paid to prevent the entry of air bubbles (disconnection and reconnection are done under the level of the level of the medium). The daily exchange of the medium is carried out by opening the hose clamp and the draining off approx. 20ml of medium. In addition it is necessary to monitor the level of the medium in the Boyle-Marriott bottle and the culture vessel, in order to detect any possible leakage from the vein. After 4 - 9, preferably 6 - 9 days of cultivation in the incubator the implantation of the graph is carried out according to the standard surgical procedure. (Kirklin JW, Barratt-Boyes BG: Cardiac surgery: p. 299-311. New York, Edinburgh, London, Madrid, Melbourne, Tokyo. 1993).
12 The utilisation of the described cultivation device (Fig. 1) in the lining process, in accordance with the invention, is particularly preferred, as it provides the following advantages: A constant pressure gradient across the vein's walls is maintained. Through this the collapsing of the vein is prevented. In addition the medium is transported across the vein's wall, which serves the purpose of nourishing the seeded endothelial cells and the Vein's walls. The pressure gradient is kept constant even when the level of the medium sinks as a result of the Boyle-Marriott bottle's principle. The complete exchange of the medium which is necessary for the nutrition of the endothelial cells which are establishing themselves (newly acquired intima of the vessel) can be done easily and under sterile conditions by means of the regulatable hose clamp. This procedure can also be automated by means of a computer controlled pump. This device is a simple, easy to operate, cheap and safe aid for the epithelisation of every type of vessel. Perfusion trials carried out with endothelised cryopreserved or non-cryopreserved donor vessels show no difference in the morphology of the endothelium and the stability against the shearing power when compared to totally intact newly gained veins or arteries. With regard to judging the long-term patency of the treated vessels on statistic significant levels, a sufficiently large clinical study has not yet been carried out. The first clinical usage of this type of bypass, carried out in January 1993 was unusually successful. Example 2: Patient autologous endothelisation of non- cryopreserved veins The endothelisation of a non-cryopreserved vein was carried out according to the process in example 1. Example 3: Patient autologous endothelisation of another vessel e.g. an artery. The endothelisation of an artery was carried out in exactly the same way as the described endothelisation of the vein in example 1. < LLIij; IL 13 Example 4 Epithelisation of another hollow organ, i.e. a ureter. The epithelisation of a ureter carried out according to the epithelisation of a cryopreserved vein described in example 1, the only difference being that urothelium was used. Example 5: Lining process where the endothelial cells are gained from a different source (see above). Lining process as in example 1. The isolation of the corresponding endothelial cells were obtained from peripheral blood, bone marrow and abdominal fat. This isolation of endothelial cells is of importance to the patient, as this provides a process for those patients who do not have sufficient vascular substrate for the extraction of autologous'endothelium. In addition this process is less invasive for the patient.
Claims (21)
1. Natural or artificial hollow organ and its complete components which have a lining of patient autologous epithelium on the inner surface or the luminal surface.
2. Hollow organ according to claim 1 characterized in that the patient autologous epithelium is patient autologous endothelial cells.
3. Hollow organ according to claim 1 or 2, characterized in that the hollow organ is a vessel.
4. Hollow organ according to claim 3, characterized in that the vessel is a cryopreserved or non-cryopreserved allogenous or xenogenous vessel.
5. Hollow organ according to any one of claims 2 - 4, characterized in that the patient autologous endothelial cells originate from peripheral blood, bone marrow or fat tissue or consist of genetically modified or manufactured endothelium or genetically modified xenogenous endothelium.
6. Hollow organ according to any one of claims 2 - 4, characterized in that the used endothelium or epithelium in an immuno-compatible form used was manufactured using gene technology.
7. Hollow organ according to any one of claims I - 6, characterized in that the hollow organ is enclosed additionally by a coat made of synthetic material.
8. Hollow organ according to claim 7, characterized in that the hollow organ is enclosed by a coat made of reabsorbable material.
9. Hollow organ according to claim 8, characterized in that the coat of synthetic material is made of polyglycon acid.
10. Process for the manufacturing of hollow organs according to any one of claims I - 6, comprising the lining of a cryopreserved or non cryopreserved donor hollow organ with patient autologous epithelium. 15
11. Process for the manufacturing of the vessels according to claims 3 or 4 comprising the lining of a cryopreserved or non cryopreserved donor vessel with patient autologous endothelial cells.
12. Process according to claim 11, characterized in that a selective removal of donor endothelium is carried out before lining with patient autologous endothelial cells.
13. Process according to claim 12, characterized in that the selective removal of donor endothelium is carried out mechanically, immunologically (through complement mediated lysis).
14. Process according to any one of claims 11 - 13, characterized in that prior to the lining a precoating of the cryopreserved or non-cryopreserved vessels with patient autologous serum is carried out.
15. Process according to any one of claims 10 to 14, characterized in that the lining is carried out by using a cultivation device with which a pressure gradient can be built up between the lumen of the hollow organ and its external environment, which prevents the walls of the hollow organ from collapsing.
16. Process according to any one of claims 10 - 14, characterized in that the lining is carried out using the cultivation device, comprising Boyle-Marriott vessel (1), a cannula (2) with universal stoppers (3), an opening (5), and a culture vessel (8), which is equipped with supports on both sides one leading to (9) and the other away (10) from it.
17. Use of the hollow organ according to any one of claims 1 to 9 in cardiac and vascular surgery, visceral surgery and urology.
18. Use of the hollow organ according to any one of claims I to 9 in aortacoronary bypass for coronary cardiac disease and as vessel transplant.
19. Use of the hollow organ according to any one of claims I to 9, in peripheral occlusive arterial disease, aneurysmal changes to vessels and inborn malformations of vessels.
20. Cultivation vessel comprising a Boyle-Marriott vessel (1), a cannula (2) with universal stoppers (3), an opening (5), and a culture vessel (8), which is equipped with supports on both sides one leading to (9) and the other away (10) from it.
21. Transplant, comprising a hollow organ according to any one of claims I to 9. t7
Applications Claiming Priority (5)
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DE19828428 | 1998-06-25 | ||
DE19828428 | 1998-06-25 | ||
DE19841264A DE19841264A1 (en) | 1998-06-25 | 1998-09-09 | Hollow organ, especially blood vessel, for implantation into recipient |
DE19841264 | 1998-09-09 | ||
PCT/DE1999/001871 WO1999066965A1 (en) | 1998-06-25 | 1999-06-24 | Autologous epithelialisation or endothelialisation of hollow organs or vessels |
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AU55035/99A Ceased AU750772B2 (en) | 1998-06-25 | 1999-06-24 | Autologous epithelialisation or endothelialisation of hollow organs or vessels |
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JP (1) | JP2003526386A (en) |
AT (1) | ATE206936T1 (en) |
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CA (1) | CA2335980A1 (en) |
DK (1) | DK1085919T3 (en) |
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US6866686B2 (en) * | 2000-01-28 | 2005-03-15 | Cryolife, Inc. | Tissue graft |
WO2003002243A2 (en) | 2001-06-27 | 2003-01-09 | Remon Medical Technologies Ltd. | Method and device for electrochemical formation of therapeutic species in vivo |
DE602005002745T2 (en) * | 2004-05-20 | 2008-07-17 | Boston Scientific Ltd., Barbados | MEDICAL DEVICES AND METHOD FOR THEIR MANUFACTURE |
US8840660B2 (en) | 2006-01-05 | 2014-09-23 | Boston Scientific Scimed, Inc. | Bioerodible endoprostheses and methods of making the same |
ES2356274T3 (en) | 2006-12-28 | 2011-04-06 | Boston Scientific Limited | BIODEGRADABLE ENDOPROTESIS AND MANUFACTURING PROCEDURES OF THE SAME. |
EP2268326B1 (en) | 2008-04-30 | 2016-11-23 | Ethicon, Inc | Tissue engineered blood vessel |
US8236046B2 (en) | 2008-06-10 | 2012-08-07 | Boston Scientific Scimed, Inc. | Bioerodible endoprosthesis |
US8668732B2 (en) | 2010-03-23 | 2014-03-11 | Boston Scientific Scimed, Inc. | Surface treated bioerodible metal endoprostheses |
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US5246451A (en) * | 1991-04-30 | 1993-09-21 | Medtronic, Inc. | Vascular prosthesis and method |
GB9116036D0 (en) * | 1991-07-25 | 1991-09-11 | Univ Leicester | Preparing grafts for implantation |
AU2517395A (en) * | 1994-05-20 | 1995-12-18 | Vec Tec, Inc. | Methods rendering grafts nonthrombogenic and substantially nonimmunogenic |
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EP1085919B1 (en) | 2001-10-17 |
ATE206936T1 (en) | 2001-11-15 |
AU750772B2 (en) | 2002-07-25 |
ES2166220T3 (en) | 2002-04-01 |
WO1999066965A1 (en) | 1999-12-29 |
EP1085919A1 (en) | 2001-03-28 |
DK1085919T3 (en) | 2002-01-28 |
JP2003526386A (en) | 2003-09-09 |
PT1085919E (en) | 2002-04-29 |
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