DE4002559A1 - Artificial organs, esp. pancreas - comprising interconnected sensor and reactor for secreting biologically active substances - Google Patents

Artificial organs, esp. pancreas - comprising interconnected sensor and reactor for secreting biologically active substances

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Publication number
DE4002559A1
DE4002559A1 DE19904002559 DE4002559A DE4002559A1 DE 4002559 A1 DE4002559 A1 DE 4002559A1 DE 19904002559 DE19904002559 DE 19904002559 DE 4002559 A DE4002559 A DE 4002559A DE 4002559 A1 DE4002559 A1 DE 4002559A1
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Germany
Prior art keywords
reactor
sensor
implanted
active substances
biologically active
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
DE19904002559
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German (de)
Inventor
Jakob Dr Bodziony
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Individual
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Individual
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Filing date
Publication date
Priority claimed from DE19904001319 external-priority patent/DE4001319A1/en
Application filed by Individual filed Critical Individual
Priority to DE19904002559 priority Critical patent/DE4002559A1/en
Publication of DE4002559A1 publication Critical patent/DE4002559A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/022—Artificial gland structures using bioreactors

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  • Health & Medical Sciences (AREA)
  • Transplantation (AREA)
  • Cardiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

Artificial organs capable of secreting biologically active substances (esp. hormones) comprise a sensor and a reactor, both made of semipermeable material. The sensor is implanted in an artery or vein. The reactor is extracorporeal or implanted. The sensor and reactor are connected together so as to permit the through-flow of biological signals and metabolic substances (sic). Pref. the sensor (A) comprises a hollow-fibre semipermeable membrane coated with endo- or meso-thelial cells and is implanted in a vein. The reactor (B) is an artificial pancreas comprising a hollow-fibre semipermeable membrane contg. isolated allogenic islets of Langerhans and is implanted in the kidney tissue. The sensor and reactor are connected by a closed loop of silicone capillary tubing (C). By means of a pump (D), a perfusion medium is circulated first through the sensor, where it picks up glucose by equilibration with the surrounding plasma, and then through the reactor, where the islets respond to increase in glucose concn. by releasing insulin. The response time is less than 10 mins..

Description

Gattung des AnmeldungsgegenstandesGenre of the object of registration

Die Erfindung betrifft ein extrakorporales oder implantierbares und aus semipermeablem Material gestaltetes bio-artifizielles Organ, das zur Sekre­ tion von biologisch aktiven Substanzen fähig ist. Dieses bio-artifizielle Organ besteht aus einem in die Arterie oder in die Vene implantierten Sensor­ teil (meistens eine Hohlfaser mit der Beschichtung von Endo- und Mesothelial­ zellen) und aus einem extrakorporalen oder einem implantierten Reaktorteil (meistens eine oder mehrere Hohlfasern, mit Zellen, die biologisch aktive Sub­ stanzen sezernieren können), welche so miteinander verbunden sind, daß der Durchfluß von biologischen Signalen und von metabolischen Substanzen möglich ist.The invention relates to an extracorporeal or implantable and semi-permeable material designed bio-artificial organ that is used for secretion tion of biologically active substances. This bio-artificial Organ consists of a sensor implanted in the artery or vein part (mostly a hollow fiber with the coating of endo- and mesothelial cells) and from an extracorporeal or an implanted reactor part (usually one or more hollow fibers, with cells that are biologically active sub can secrete), which are connected so that the Flow of biological signals and of metabolic substances possible is.

Angaben zur GattungInformation on the genus

Das vorgegebene bio-artifizielle Organ soll vor allem die Funktion der beschä­ digten endokrinen Organe (z. B. Langerhansche Inseln des endokrinen Teils des Pankreas, Nebenschilddrüse, Hypophyse usw.) ersetzen. Es kann auch in allen Situationen, wo die Sekretion der biologisch aktiven Substanzen nötig ist, angewandt werden.The specified bio-artificial organ is primarily intended to function as a dam endocrine organs (e.g. Langerhan islands of the endocrine part of the Replace pancreas, parathyroid, pituitary, etc.). It can also be used in all Situations where the secretion of the biologically active substances is necessary be applied.

Stand der TechnikState of the art

Bisherige Versuche der Bildung der bio-artifizielen Organe, welche biologisch aktive Substanzen sezernieren, waren vor allem zur Konstruktion von semiperme­ ablen Diffusionskammern begrenzt. Diese Kammern enthielten Zellen, die biolo­ gisch aktive Substanzen produzierten (Jolley und Mitarb., 1977; Gates und Lazarus, 1977; Theodoru und Howell 1979; Bodziony und Mitarb., 1985; Bodziony und Stanosek, 1985; Kojima und Mitarb., 1987). Previous attempts at the formation of bio-artificial organs, which are biological Secreting active substances were primarily for the construction of semiperme limited diffusion chambers limited. These chambers contained cells that were biolo genetically active substances (Jolley et al., 1977; Gates and Lazarus, 1977; Theodoru and Howell 1979; Bodziony and co-workers, 1985; Bodziony and Stanosek, 1985; Kojima et al., 1987).  

Kritik des Standes der TechnikCritique of the state of the art

Bio-artifizielle Organe, mit Zellen, die biologisch aktive Substanzen sezer­ nieren und mit der Umgebung nur auf dem Weg der Diffusion kommunizieren, was im Fall der semipermeablen Kammern stattfindet, können leider nicht die auf sie gesetzten Erwartungen erfüllen. Unzureichender Zufluß der Nähr­ stoffe (Garvey und Mitarb., 1979), die Fremdkörperreaktion (Theodoru und Mitarb., 1980; Bodziony und Stanosek, 1985) und die verlangsamte Übertragung des biologischen Signals (Theodoru und Howell, 1979) sind Hauptursachen für die Einstellung der Hormonsekretion und das Absterben der Zellen.Bio-artificial organs, with cells that secrete biologically active substances kidneys and communicate with the environment only by diffusion, Unfortunately, what happens in the case of semi-permeable chambers cannot meet the expectations placed on them. Inadequate nutrient inflow substances (Garvey and co-workers, 1979), the foreign body reaction (Theodoru and Coworker, 1980; Bodziony and Stanosek, 1985) and the slowed down transmission of the biological signal (Theodoru and Howell, 1979) are the main causes of the cessation of hormone secretion and cell death.

Aufgabetask

Die Konstruktion eines extrakorporalen oder implantierbaren bio-artifiziellen Organs, das zur Sekretion von biologisch aktiven Substanzen fähig ist. Dieses Organ soll aus einem in die Arterie oder in die Vene implantierten Sensorteil, das schnellen Austausch von biologischen Signalen und von metabolischen Sub­ stanzen durch die Ultrafiltration ermöglicht und aus einem extrakorporealen oder einem implantierten Reaktorteil mit Zellen, die biologisch aktive Sub­ stanzen produzieren, bestehen. Beide Teile sollen so verbunden werden, daß die Übertragung von biologischen Signalen und von Nährstoffen weniger als 15 min dauert.The construction of an extracorporeal or implantable bio-artificial Organ capable of secreting biologically active substances. This Organ should consist of a sensor part implanted in the artery or vein, the rapid exchange of biological signals and of metabolic sub punching made possible by ultrafiltration and from an extracorporeal or an implanted reactor part with cells that are biologically active sub produce, pass. Both parts should be connected so that the transmission of biological signals and nutrients less than Takes 15 min.

Lösungsolution

Diese Aufgabe wird erfindungsmäßig dadurch gelöst, daß das entsprechend der vorherigen Patentanmeldung (Bodziony, 1989) angefertigte Sensorteil mit dem Reaktorteil, wie auf dem Bild 1 und 2 gezeigt, durch die Silikonkapillaren verbunden ist. Der Durchfluß des Perfusionsmedium ist durch die entsprechende Pumpe in dieser Weise erzwungen, daß es zuerst im Sensorteil auf dem Weg der Ultrafiltration und Diffusion zum Austausch von Nährstoffen und von biologi­ schen Signalen (z. B. Glukose, Ca++) kommt und danach das mit dem Plasma bio­ chemisch ausgeglichene Medium zum Reaktorteil überpumpt wird. Im Reaktorteil (meistens eine oder mehrere Hohlfasern) sind die allo- oder xenogenen Zellen, die biologisch aktive Substanzen produzieren, in dieser Weise von außen oder von innen angebracht, daß ihre mehrjährige Funktion möglich ist. Die entspre­ chenden biologisch aktiven Substanzen beeinflussen meistens das Niveau des biologischen Signals (z. B. senkt das Insulin die Konzentration von Glukose, Parathormon erhöht die Konzentration von Ga++, usw.) und schließen nach der Ultrafiltration und Diffusion aus dem Reaktorteil die Rückkopplungsschleife. This object is achieved in terms that the previous according to the patent application (Bodziony, 1989)-built sensor part with the part of the reactor, as shown on the figure 1 and 2, is connected by the Silikonkapillaren. The flow of the perfusion medium is forced by the corresponding pump in such a way that it first comes to the exchange of nutrients and biological signals (e.g. glucose, Ca ++ ) in the sensor part on the way of ultrafiltration and diffusion and then that with the plasma bio-chemically balanced medium is pumped over to the reactor part. In the reactor part (usually one or more hollow fibers), the allo- or xenogenic cells that produce biologically active substances are attached from the outside or from the inside in such a way that their multi-year function is possible. The corresponding biologically active substances mostly influence the level of the biological signal (e.g. insulin lowers the concentration of glucose, parathyroid hormone increases the concentration of Ga ++ , etc.) and closes the feedback loop after ultrafiltration and diffusion from the reactor part .

Erzielbare VorteileAchievable advantages

Das oben beschriebene bio-artifizielle Organ ermöglicht die mit dem positiven und negativen Feedback regulierte Sekretion der biologisch aktiven Substanzen. Das angewandte semipermeable Material ist als sog. biomechanische Barriere benutzt (Bodziony und Mitarb., 1985), was die Verwendung von allo- und xeno­ genen Zellen möglich macht. Der Gegenstand der Erfindung ist durch die Her­ stellung des bio-artifiziellen Organs mit allo- oder xenogenen Zellen, die biologisch aktive Substanzen produzieren, gewerblich anwendbar. Dieses bioartifizielle Organ kann die Funktion der beschädigten endokrinen Organe (z. B. Langerhanssche Inseln, Nebenschilddrüse, Hypophyse) ersetzen.The bio-artificial organ described above enables those with the positive and negative feedback regulated secretion of the biologically active substances. The semi-permeable material used is a so-called biomechanical barrier used (Bodziony and Mitarb., 1985), what the use of allo- and xeno gene cells possible. The object of the invention is through the Her Position of the bio-artificial organ with allo- or xenogenic cells that Produce biologically active substances, industrially applicable. This bioartificial organ can damage the function of damaged endocrine organs (e.g. Langerhans Islands, parathyroid gland, pituitary).

Beschreibung des AusführungsbeispielsDescription of the embodiment

Abb. 1 und 2 zeigen in einer experimentellen (Abb. 1) und in einer klinischen Situation das implantierbare bio-artifizielle Organ. Ein in die Vene implan­ tiertes Sensorteil (A - Hohlfaser mit der Beschichtung von Zellen, die mehr­ jährige Implantation in Arterien und Venen ermöglichen) ist durch Silikon­ kapillaren (C) mit einem in das Nierengewebe implantierten Reaktorteil (B) verbunden. Dieses Reaktorteil enthält allogene Langerhanssche Inseln, die Insulin, Glukagon und Somatostatin, wichtigste Hormone des Kohlenhydratstoff­ wechsels sezernieren. Das Perfusionsmedium wird durch die Pumpe (D) in Bewegung gesetzt und zuerst wird das Sensorteil perfundiert, wo die biochemische Aus­ gleichung mit dem Plasma stattfindet. Danach werden die isolierten Langerhan­ sschen Inseln im Reaktorteil (B) perfundiert. Diese Inseln antworten auf die Erhöhung der Konzentration der Glukose im Perfusionsmedium mit der entspre­ chenden Insulinfreisetzung, die so lange dauert, bis die Glukosekonzentration wieder gesunken ist. Die Antwort auf eine intravenöse Glukosebelastung dauert weniger als 10 min, was die präzise Regulierung der Glukose- und Insulinkon­ zentration ermöglicht. Fig. 1 and 2 show the implantable bio-artificial organ in an experimental ( Fig. 1) and in a clinical situation. A sensor part implanted in the vein (A - hollow fiber with the coating of cells that allow years of implantation in arteries and veins) is connected by silicone capillaries (C) to a reactor part (B) implanted in the kidney tissue. This part of the reactor contains allogeneic Langerhans islands, which secrete insulin, glucagon and somatostatin, the most important hormones of the carbohydrate metabolism. The perfusion medium is set in motion by the pump (D) and first the sensor part is perfused, where the biochemical equation with the plasma takes place. The isolated Langerhan islands in the reactor part (B) are then perfused. These islands respond to the increase in the concentration of glucose in the perfusion medium with the corresponding insulin release, which lasts until the glucose concentration has decreased again. The response to an intravenous glucose load takes less than 10 minutes, which enables precise regulation of the glucose and insulin concentration.

FundstellenSites

  • 1. Bodziony J., Gasior U., Stanosek J.: Funktionsbeurteilung isolierter Langerhansscher Inseln in semipermeablen Kammern. Z. exp. Chir. Transplant. künstl. Organe, 1985, 18/4, 204-214.1. Bodziony J., Gasior U., Stanosek J .: Functional evaluation of isolated Langerhans Islands in semi-permeable chambers. Z. exp. Chir. Transplant. artificial Organs, 1985, 18/4, 204-214.
  • 2. Bodziony J., Stanosek J.: Die Behandlung des Diabetes durch Implantationen von isolierten Langerhansschen Inseln in semipermeablen Kammern. Z. exp. Chir. Transplant. künstl. Organe, 1985, 18/4, 215-223.2. Bodziony J., Stanosek J .: Treatment of diabetes by implantation of isolated Langerhans islands in semi-permeable chambers. Z. exp. Chir. Transplant. artificial Organs, 1985, 18/4, 215-223.
  • 3. Bodziony J.: Hohlfaser mit der Beschichtung von Zellen, die mehrjährige Implantation in Arterien und Venen ermöglichen. Deutsches Patentamt, Patent­ anmeldung Nr. P 39 41 873.1.3. Bodziony J .: hollow fiber with the coating of cells, the perennial Allow implantation in arteries and veins. German Patent Office, patent application no.P 39 41 873.1.
  • 4. Gates R.J., Lazarus N.R.: Reversal of streptozotocin-induced diabetes in rats by intraperitoneal implantation of encapsulated neonatal rabbit pan­ creatic tissue. Lancet, 1977, 17, 1257-1259.4. Gates R.J., Lazarus N.R .: Reversal of streptozotocin-induced diabetes in rats by intraperitoneal implantation of encapsulated neonatal rabbit pan creative tissue. Lancet, 1977, 17, 1257-1259.
  • 5. Garvey J.F.W., Morris P.J., Finch D.R.A., Millard P.R., Poole M.: Experi­ mental pancreas transplantation. Lancet, 1979, 971-972.5. Garvey J.F.W., Morris P.J., Finch D.R.A., Millard P.R., Poole M .: Experi mental pancreas transplantation. Lancet, 1979, 971-972.
  • 6. Jolley W.B., Hinshaw D.B., Call T.W., Alrord L.S.: Xenogeneic pancreatic islet transplantation in proteolytic enzyme-bounded diffusion chambers in diabetic rats. Transplantation Proceedings, 1979, 9/1, 363-365.6. Jolley W.B., Hinshaw D.B., Call T.W., Alrord L.S .: Xenogeneic pancreatic islet transplantation in proteolytic enzyme-bounded diffusion chambers in diabetic rats. Transplantation Proceedings, 1979, 9/1, 363-365.
  • 7. Kojima Y., Fukushima W., Note M., Kinoshita H., Nahagawara G.: Xenogeneic pancreatic islet transplantation using a millipore diffusion chamber. Trans­ plantation Proceedings, 1987, 19/1, 981-983.7. Kojima Y., Fukushima W., Note M., Kinoshita H., Nahagawara G .: Xenogeneic pancreatic islet transplantation using a millipore diffusion chamber. Trans plantation proceedings, 1987, 19/1, 981-983.
  • 8. Theodoru N.A., Howell S.L.: An assesment of diffusion chambers for use in pancreatic islet cell transplantation. Transplantation, 1979, 27/5, 350- 352.8. Theodoru N.A., Howell S.L .: An assesment of diffusion chambers for use in pancreatic islet cell transplantation. Transplantation, 1979, 27/5, 350- 352.
  • 9. Theodoru N.A., Vrbova H., Tyhurst M., Howell S.L.: Problems in the use of polycarbonate diffusion chambers for syngeneic pancreatic islet transplan­ tations in rats. Diabetologia, 1980, 18, 313-317.9. Theodoru N.A., Vrbova H., Tyhurst M., Howell S.L .: Problems in the use of polycarbonate diffusion chambers for syngeneic pancreatic islet transplan tations in rats. Diabetologia, 1980, 18, 313-317.

Claims (1)

Ein extrakorporales oder implantierbares und aus semipermeablem Material gestaltetes bio-artifizielles Organ, fähig zur Sekretion von biologisch aktiven Substanzen (vor allem Hormone), gekennzeichnet durch ein in die Arterie oder in die Vene implantiertes Sensorteil (meistens eine Hohlfaser mit der Beschichtung von Endo- oder Mesothelial Zellen) und durch ein extra­ korporales oder ein implantiertes Reaktorteil (meistens eine oder mehrere Hohlfasern, mit Zellen, die biologisch aktive Substanzen sezernieren können) , so miteinander verbunden, daß der Durchfluß von biologischen Signalen und von metabolischen Substanzen möglich ist.An extracorporeal or implantable and made of semi-permeable material designed bio-artificial organ, capable of the secretion of biological active substances (especially hormones), characterized by an in the Artery or sensor part implanted in the vein (usually a hollow fiber with the coating of endo- or mesothelial cells) and with an extra corporal or an implanted reactor part (usually one or more Hollow fibers, with cells that can secrete biologically active substances), connected so that the flow of biological signals and of metabolic substances is possible.
DE19904002559 1990-01-18 1990-01-30 Artificial organs, esp. pancreas - comprising interconnected sensor and reactor for secreting biologically active substances Ceased DE4002559A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19904002559 DE4002559A1 (en) 1990-01-18 1990-01-30 Artificial organs, esp. pancreas - comprising interconnected sensor and reactor for secreting biologically active substances

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19904001319 DE4001319A1 (en) 1990-01-18 1990-01-18 Implantable substitute endocrine gland with sensor and reactor - sections formed of cell-bearing fibres transferring signals and secreted prod.
DE19904002559 DE4002559A1 (en) 1990-01-18 1990-01-30 Artificial organs, esp. pancreas - comprising interconnected sensor and reactor for secreting biologically active substances

Publications (1)

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DE4002559A1 true DE4002559A1 (en) 1991-10-02

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4123629A1 (en) * 1990-08-06 1992-02-20 Jakob Dr Bodziony Implantable semi-permeable bio-artificial organ - allowing biological signal and metabolic substance flow by pressure gradient
EP1689321A2 (en) * 2003-11-07 2006-08-16 The University of Connecticut Artificial tissue systems and uses thereof
FR2955179A1 (en) * 2010-01-13 2011-07-15 Univ Bordeaux 1 SENSOR FOR MEASURING INSULIN NEEDS OF A PATIENT AND METHOD FOR MANUFACTURING THE SAME

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3422639C2 (en) * 1984-06-19 1986-07-10 Gebrüder Sulzer AG, Winterthur Glandular prosthesis
GB2185408A (en) * 1986-01-16 1987-07-22 Rhode Island Hospital Neovascularization
EP0259536A2 (en) * 1986-09-11 1988-03-16 BAXTER INTERNATIONAL INC. (a Delaware corporation) Biological implant with textured surface
EP0286284A1 (en) * 1987-03-30 1988-10-12 Brown University Research Foundation Semipermeable nerve guidance channels
WO1989007425A2 (en) * 1988-02-17 1989-08-24 Genethics Limited Clinical developments using amniotic cells

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3422639C2 (en) * 1984-06-19 1986-07-10 Gebrüder Sulzer AG, Winterthur Glandular prosthesis
GB2185408A (en) * 1986-01-16 1987-07-22 Rhode Island Hospital Neovascularization
DE3701148C2 (en) * 1986-01-16 1989-08-31 Rhode Island Hospital, Providence, R.I., Us
EP0259536A2 (en) * 1986-09-11 1988-03-16 BAXTER INTERNATIONAL INC. (a Delaware corporation) Biological implant with textured surface
EP0286284A1 (en) * 1987-03-30 1988-10-12 Brown University Research Foundation Semipermeable nerve guidance channels
WO1989007425A2 (en) * 1988-02-17 1989-08-24 Genethics Limited Clinical developments using amniotic cells
EP0333328A2 (en) * 1988-02-17 1989-09-20 Genethics Limited Clinical developments using amniotic cells

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4123629A1 (en) * 1990-08-06 1992-02-20 Jakob Dr Bodziony Implantable semi-permeable bio-artificial organ - allowing biological signal and metabolic substance flow by pressure gradient
EP1689321A2 (en) * 2003-11-07 2006-08-16 The University of Connecticut Artificial tissue systems and uses thereof
EP1689321B1 (en) * 2003-11-07 2017-01-04 The University of Connecticut Artificial tissue systems and uses thereof
FR2955179A1 (en) * 2010-01-13 2011-07-15 Univ Bordeaux 1 SENSOR FOR MEASURING INSULIN NEEDS OF A PATIENT AND METHOD FOR MANUFACTURING THE SAME
WO2011086105A1 (en) * 2010-01-13 2011-07-21 Universite De Bordeaux 1 Sensor for measuring the activity of beta-pancreatic cells or of islets of langerhans, manufacture and use of such a sensor
AU2011206641B2 (en) * 2010-01-13 2016-06-09 Centre National De La Recherche Scientifique Sensor for measuring the activity of beta-pancreatic cells or of islets of Langerhans, manufacture and use of such a sensor
AU2011206641A8 (en) * 2010-01-13 2016-07-07 Centre National De La Recherche Scientifique Sensor for measuring the activity of beta-pancreatic cells or of islets of Langerhans, manufacture and use of such a sensor
US9962113B2 (en) 2010-01-13 2018-05-08 Universite De Bordeaux 1 Sensor for measuring the activity of beta-pancreatic cells or of islets of langerhans, manufacture and use of such a sensor

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