Microfluidic production and characterization of liposomes towards localized payload release
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Tartu Ülikooli Kirjastus
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Arstid ja teadlased on juba üle sajandi otsinud nn hõbekuuli – täpset lahendust, mis võimaldaks ravimeid toimetada täpselt sinna, kus neid vaja on. Aastate jooksul on välja pakutud mitmesuguseid ravimikandjaid, näiteks vesiikuleid ehk liposoome.
Vesiikulid on kerajad mahutid, mis koosnevad fosfolipiidsest membraanist. Samasugustest fosfolipiididest on ehitatud ka meie kõigi rakumembraanid. Sünteetilisi vesiikuleid nimetataksegi liposoomideks. Need on osutunud väga kasulikuks nii ravimite kohaletoimetamisel kui ka teadusuuringutes.
Liposoomide valmistamiseks on tohutult palju viise, alates kaootilisematest meetoditest kuni täpsemalt suunatud variantideni. Viimastel aastatel on populaarsust kogunud mikrovoolutus. Selle puhul pumbatakse vedelikke läbi mikrovoolutuse kiibi, milles on rida imeväikesi kanaleid ja ühenduskohti. Selliste tehnikate eeliseks on võimalus loodavate liposoomide omadusi täpselt ohjata, kuid alustamine võib olla üsna kallis.
Selle lõputöö üks peamisi eesmärke on muuta liposoomide tootmine kättesaadavamaks, et soodustada edasisi uuringuid ravimite täppis manustamise vallas. Selleks hinnati kahte rõhupõhist süsteemi vedelike juhtimiseks ning kahte mikrovoolutusel põhinevat meetodit. Üks süsteem kasutas tavalist vaakumpumpa, kus katse läbiviija pidi käsitsi reguleerima vedelikumahutite kõrgust. Teine süsteem oli arvutijuhitav ja soodsa hinnaga piesoelektriline rõhuregulaator PEPC, mis töötati välja just selle töö raames, ning mida juhitakse spetsiaalselt selleks välja töötatud tarkvaraga PCS. Lisaks tutvustati töös liposoomide loendamise tarkvara LC ja pildianalüüsi programmi EasyFlow koos kolme standardiseeritud andmetöötlusahelaga. Need täiendavad teadlaste tööriistakasti liposoomide ja tilkade analüüsimisel.
Kokkuvõtteks võib öelda, et töö tulemusena paranes mikrovoolutusel põhineva liposoomide tootmise kättesaadavus.
Doctors and scientists have been looking for a silver bullet that could be used to deliver drugs only to the precise spot needed, for over a century. Over the years, many kinds of drug delivery carriers have been proposed, one of which are vesicles/liposomes. Vesicles are spherical containers that consist of a phospholipid membrane, which is what all our cellular membranes are made of. The special name for synthetic vesicles is liposome. They have been found to be quite useful for drug delivery and research applications. There is a myriad of ways to create liposomes, ranging from chaotic methods, like thin film hydration, to more controlled options. Some of the more popular liposome production methods in recent years have been based on microfluidics, where liquids are pumped through a microfluidic chip containing a series of small (micrometer scale) diameter flow channels and junctions, creating liposomes. These techniques have the upside of being able to control the properties of the liposomes created, but can also be rather expensive to get started. One of the main goals of this thesis is to lower the barrier of entry into liposome production to enable more research into liposome based drug delivery. For this, two pressure based microfluidic liquid driver systems were evaluated by making liposomes along with two microfluidic liposome production methods. One of these systems used an "off the shelf" vacuum pump and relied on the experimenters manually adjusting the heights of the reservoirs containing the input liquids for the experiment, and the other was a computer controlled custom pressure regulator system with a low cost, named the piezoelectric pressure controller (PEPC), using specialized piezoelectric linear pressure regulation valves that was newly developed for this thesis. This is combined with the newly developed pressure controller software (PCS). In both cases, the stability of the liposomes was assessed. In addition, a Liposome counter (LC) software and a post-image analysis software called EasyFlow along with three standardized post-image pipelines, were introduced to enhance the toolbox available to researchers who are interested in the analysis of liposome and droplet images.
Doctors and scientists have been looking for a silver bullet that could be used to deliver drugs only to the precise spot needed, for over a century. Over the years, many kinds of drug delivery carriers have been proposed, one of which are vesicles/liposomes. Vesicles are spherical containers that consist of a phospholipid membrane, which is what all our cellular membranes are made of. The special name for synthetic vesicles is liposome. They have been found to be quite useful for drug delivery and research applications. There is a myriad of ways to create liposomes, ranging from chaotic methods, like thin film hydration, to more controlled options. Some of the more popular liposome production methods in recent years have been based on microfluidics, where liquids are pumped through a microfluidic chip containing a series of small (micrometer scale) diameter flow channels and junctions, creating liposomes. These techniques have the upside of being able to control the properties of the liposomes created, but can also be rather expensive to get started. One of the main goals of this thesis is to lower the barrier of entry into liposome production to enable more research into liposome based drug delivery. For this, two pressure based microfluidic liquid driver systems were evaluated by making liposomes along with two microfluidic liposome production methods. One of these systems used an "off the shelf" vacuum pump and relied on the experimenters manually adjusting the heights of the reservoirs containing the input liquids for the experiment, and the other was a computer controlled custom pressure regulator system with a low cost, named the piezoelectric pressure controller (PEPC), using specialized piezoelectric linear pressure regulation valves that was newly developed for this thesis. This is combined with the newly developed pressure controller software (PCS). In both cases, the stability of the liposomes was assessed. In addition, a Liposome counter (LC) software and a post-image analysis software called EasyFlow along with three standardized post-image pipelines, were introduced to enhance the toolbox available to researchers who are interested in the analysis of liposome and droplet images.
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