I. chirurgická klinika, 1. LF UK, zasedací místnost
Datum odevzdání elektronické podoby:
11.06.2021
Datum proběhlé obhajoby:
17.06.2021
Předmět:
Obhajoba dizertační práce (B90002)
Oponenti:
doc. MUDr. Vilém Rohn, CSc.
doc. MUDr. Ivan Matia, Ph.D.
Seznam odborné literatury
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Předběžná náplň práce
V průběhu projektu byly vyvinuty unikátní kolagenní pěny z kolagenu získaného z kůže sladkovodní ryby (kapr obecný, Cyprinus carpio). Pomocí síťování karbodiimidem byl překonán problém s nestabilitou kolagenní matrix z kolagenu získávaného z chladnokrevných živočichů při tělesné teplotě savců. Následně byly pěny impregnovány antibiotiky (gentamicin a vankomycin) a opětovně lyofilizovány, což je postup, který zajišťuje požadovanou koncentraci antibiotika bez rizika následného vymytí při dalších technologických krocích. Uvedený produkt je, na rozdíl od přípravků z nesíťovaného kolagenu, stabilní i při sterilizaci gamma zářením. Finální sterilizovaný produkt byl testován in vivo napotkaním modelu infikované rány. Byla prokázána efektivita v léčbě potenciálně letální infekce Pseudomonas aeruginosa a kmene Stafylococcus aureus rezistentní k meticilinu (MRSA). Vzhledem k vysoké potřebě profylaxe a terapie infekcí pooperačních a jiných ran právě výše uvedenými polyrezistentními původci se jedná o slibný prostředek k budoucímu klinickému využití. Zkušenosti, které jsme získali v průběhu uvolnování ATB z kolagenních pěn budou v dalším vyvoji použity pro impregnaci zevní kolagenní vrstvy cévní protézy, čímž bychom mohli eliminovat jednu z největších nevýhod a rizik spojených s použitím umělých materiálu a tím je infekce. Dále v průběhu výzkumu jsme vytvořili pilotní technologie k programování porozity a programování degradace těchto kolagenních pěn z rybího kolagenu. Byla provedena celá řada testů včetně analýz sekundárních struktur kolagenových vzorků zdrojového kolagenu a kolagenu získaného z vyrobené cévní náhrady včetně in vivo testů. Míra zachování nativní struktury kolagenu byla sledována pomocí FTIR a elektroforetické analýzy. Dále byl navržen způsob heparinizace kolagenových vzorků a způsob jejich analýzy. Byly zkoumány fyzikální vlastnosti kolagenových lyofilizátů s antibiotiky. Práce byly zaměřeny na návrh složení a přípravy kolagenových lyofilizátů s antibiotiky. Dále byly provedeny analýzy degradačních vlastností připravovaných materiálů a na jejich základě byl postup přípravy doplněn o dodatečné síťování kolagenu. 3 Byly ověřovány různé způsoby síťování a na základě výsledků byl doporučen finální postup přípravy. Na základě výsledků byly ve spolupráci s výrobci kolagenu modifikovány výrobní postupy zaúčelem optimalizace vlastností implantátů. Do hrudní stěny potkanů byly implantovány části nových prototypů za účelem ověření doby vstřebávání prosíťované a sterilizované kolagenní hmoty. Dále probíhalo testování farmakokinetických možností kolagenních pěn, ovlivnění degradace, denaturace, vhojování. Byly formulovány finální postupy pro výrobu kolagenních protéz a pěn.
Předběžná náplň práce v anglickém jazyce
During the project, unique collagen foams were developed from collagen obtained from the skin of freshwater fish (common carp, Cyprinus carpio). The problem of instability of the collagen matrix from collagen obtained from cold-blooded animals at mammalian body temperature was overcome by carbodiimide crosslinking. Subsequently, the foams were impregnated with antibiotics (gentamicin and vancomycin) and re-lyophilized, a process that ensures the required concentration of antibiotic without the risk of subsequent leaching in further technological steps. This product, in contrast to noncrosslinked collagen preparations, is stable even when sterilized by gamma radiation. The final sterilized product was tested in vivo in a rat model of an infected wound. Efficacy in the treatment of potentially lethal Pseudomonas aeruginosa infection has been demonstrated and testing of the dreaded and increasingly common methicillinresistant strain of Staphylococcus aureus (MRSA) is currently underway. Due to the high need for prophylaxis and therapy of postoperative and other wound infections by the above-mentioned polyresistant agents, this is a promising tool for future clinical use. The experience we have gained during the release of ATB from collagen foams will be used in further development to impregnate the outer collagen layer of the vascular prosthesis, which could eliminate one of the biggest disadvantages and risks associated with the use of artificial materials and infection. Furthermore, during the research, we developed pilot technologies to program the porosity and degradation programming of these collagen foams from fish collagen. A number of tests were performed, including analyzes of secondary structures of collagen samples of source collagen and collagen obtained from the produced vascular prosthesis, including in vivo tests. The degree of preservation of the native collagen structure was monitored by FTIR and electrophoretic analysis. Furthermore, a method for heparinization of collagen samples and a method for their analysis was proposed. 5 The physical properties of collagen lyophilisates with antibiotics were investigated. The work was focused on the design of the composition and preparation of collagen lyophilizates with antibiotics. Furthermore, analyzes of the degradation properties of the prepared materials were performed and on the basis of them the preparation process was supplemented by additional crosslinking of collagen. Various cross-linking methods were tested and the final preparation procedure was recommended based on the results. Based on the results, production processes were modified in cooperation with collagen manufacturers in order to optimize the properties of implants. Parts of the new prototypes were implanted in the chest wall of the rats in order to verify the absorption time of the sieved and sterilized collagen mass. Furthermore, testing of pharmacokinetic possibilities of collagen foams, influencing of degradation, denaturation, healing was performed. Final procedures for the production of collagen prostheses and foams were formulated.
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