Fibrin glue of fish (Salmo salar) origin: immunological study and development of new pharmaceutical preparation
Date
2012-02-15
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Abstract
Fibriinliimid kuuluvad haavaliimide hulka, mis sisaldavad oma koostises põhitoimeainetena vere koagulatsioonivalke fibrinogeeni ja trombiini. Trombiini toimel tekib fibrinogeenist fibriin - võrgustik, mis peatab verevoolu haavast. Fibriinvõrgustik toimib kui esmane maatriks, kuhu kinnituvad trombotsüüdid ja muud vere vormelemendid, tagades verevoolu peatumise haavast ning luues keskkonna haava migreeruvatele rakkudele ja toetades sellega loomulike haavaparanemismehhanismide käivitamist. Lisaks hemostaasi tagamisele on viimasel kümnendil hakatud fibriinliime uurima kui sobilikke materjale haavade paranemise kiirendamiseks ning substraadina biotehnoloogiliselt kudede valmistamiseks ja hemostaatiliste sidemete ning plaastrite valmistamiseks.
Nagu kõik bioloogilise päritoluga ravimid võivad fibriinliimid kujutada endast ohtu patsiendile. Lisaks kontaminatsiooniohule kaasneb fibriinliimidega ka immunoloogiliste reaktsioonide teke. Võõrvalkude kasutamine põhjustab reeglina antikehade tekke, mis omakorda võivad seostuda vastavate endogeensete valkudega ja ohustada patsiendi koagulatsioonisüsteemi.
Mõned aastad tagasi leiti, et Atlandi lõhe verest eraldatud fibrinogeen ja trombiin võiksid olla sobivad alternatiivid inimese ja veise verest saadavatele proteiinidele.
Käesolevas töös uuriti lõhe vereplasmast eraldatud fibrinogeeni ja trombiini kui uudse fibriinliimi tootmisallika ohutust. Töös hinnatakse lõhe valkude korduva manustamise mõju immuunsüsteemile erinevates loommudelites ja uudse ravimvormi valmistamise võimalust.
Tulemused näitavad, et pärast lõhe valkude kaht järjestikust manustamist tekivad katseloomade vereplasmas ootuspäraselt antikehad lõhe fibrinogeeni ja trombiini vastu. Kuigi üksikute katseloomade plasma antikehad on võimelised nõrgalt seostuma ka vastavate endogeensete valkudega, ei oma need ristreaktsioonid inhibeerivat või neutraliseerivat mõju katseloomade koagulatsioonisüsteemile.
Töö tulemustest võib järeldada, et lõhe vereplasma baasil valmistatud fibriinliim ei oma korduval manustamisel kahjulikku mõju katseloomadele. Lõhe fibrinogeeni ja trombiini sisaldav fibriinliim on väärtuslik materjal uudsete meditsiinis perspektiivsete biomaterjalide väljatöötamiseks koos teiste polümeeridega.
Fibrin glue (fibrin sealant, FG) is produced from polymerization of fibrinogen by thrombin. FG-s has been used for decades for hemorrhage control as adjunct to traditional methods. In treatments of acute injury or surgical wounds, concentrated fibrin preparations mimic the initial matrix that normally prevents bleeding and acts as a scaffold for cells that initiate tissue repair. Apart from FG-s haemostatic and sealing properties there is great interest for using coagulation proteins as wound healing material or in haemostatic dressings. As any biological material, FG must be safe to use in clinical settings. Use of non-autologous proteins usually leads to development of antibodies which can cross-react with endogenous counterparts and pose a serious threat to host coagulation system. To minimize the risk of infection and immunogenicity connected with mammalian blood products, proteins derived from the plasma of farmed Atlantic salmon have been considered as an alternative to these mammalian sources. This study was done to evaluate the safety of salmon derived fibrinogen and thrombin as a new source of FG proteins. We evaluate the impact of salmon proteins to host immune system on animal models and the possibility to produce novel pharmaceutical preparation. Expectedly, our results show that antibodies to salmon fibrinogen and thrombin were detected from experimental animals’ plasma after two following administrations of salmon proteins. In spite of slight antibody crossreactivity to rat endogenous coagulation proteins in small number of animals these reactions had no inhibitory/neutralizing effect on rats’ coagulation profiles. As conclusion these results show that two following administrations of salmon derived FG preparation do not have deleterious effect on experimental animals. Altogether, salmon FG preparation containing salmon fibrinogen and thrombin serves as a valuable basis for the development of novel medicinal products and has a perspective for use in combination with other polymers.
Fibrin glue (fibrin sealant, FG) is produced from polymerization of fibrinogen by thrombin. FG-s has been used for decades for hemorrhage control as adjunct to traditional methods. In treatments of acute injury or surgical wounds, concentrated fibrin preparations mimic the initial matrix that normally prevents bleeding and acts as a scaffold for cells that initiate tissue repair. Apart from FG-s haemostatic and sealing properties there is great interest for using coagulation proteins as wound healing material or in haemostatic dressings. As any biological material, FG must be safe to use in clinical settings. Use of non-autologous proteins usually leads to development of antibodies which can cross-react with endogenous counterparts and pose a serious threat to host coagulation system. To minimize the risk of infection and immunogenicity connected with mammalian blood products, proteins derived from the plasma of farmed Atlantic salmon have been considered as an alternative to these mammalian sources. This study was done to evaluate the safety of salmon derived fibrinogen and thrombin as a new source of FG proteins. We evaluate the impact of salmon proteins to host immune system on animal models and the possibility to produce novel pharmaceutical preparation. Expectedly, our results show that antibodies to salmon fibrinogen and thrombin were detected from experimental animals’ plasma after two following administrations of salmon proteins. In spite of slight antibody crossreactivity to rat endogenous coagulation proteins in small number of animals these reactions had no inhibitory/neutralizing effect on rats’ coagulation profiles. As conclusion these results show that two following administrations of salmon derived FG preparation do not have deleterious effect on experimental animals. Altogether, salmon FG preparation containing salmon fibrinogen and thrombin serves as a valuable basis for the development of novel medicinal products and has a perspective for use in combination with other polymers.
Description
Väitekiri ei ole avaldatav 2012. aasta lõpuni
Keywords
haavaparanemine, ravimpreparaadid, fibriinliim, antikehad, biomaterjalid, wound healing, drug preparations, tissucol, antibodies, biomaterials