The drug delivery field is a branch in continuous development and research by the scientific community, due to the utility in the practical life for disease treatments, tissue regeneration, tailored therapeutics releasing. Cells “in loco” delivery is also a deeply investigated field, especially for anti-tumour treatments and wound healing. These objectives can be achieved using combinations of different solutions or exploiting composite materials, made of two or more different constituents with distinct chemical or physical properties of other two or more systems. This allows to exploit the best characteristics from a great quantities of technologies. In this work we investigated the uses of 3D- printed devices, that thanks to superficial tension, can be tightly coated with drug or cells loaded hydrogels. The aim is to have both the on-target delivery of different types of cells and diffusion- based release of both hydrophilic and hydrophobic drugs loaded in a hydrophilic hydrogel matrix. In the Macromolecular Engineering Laboratory of ETH ZÜRICH, the biocompatible support made of polycaprolactone has been 3D printed and coated with two different hydrogels, methacrylated gelatin (GelMa) and sodium alginate. Regarding the metallic support, this has been printed in DL60 resin by the +LAB of Politecnico di Milano and metallized by the SEE Lab of Politecnico di Milano, using the layer by layer teqnique. Considering the cells delivery part, NIH/3T3 (ATCC® CRL-1658™) fibroblasts have been encapsulated in GelMa. For the drug delivery part of the project we loaded two types of model drugs: • Rhodamine B Isothiocyanate, hydrophilic, loaded thanks to steric phenomena • Oil Red O, hydrophobic, loaded into GelMa and sodium alginate using polymeric nanoparticles of polyethylene glycol linked to polylactic acid (PEG-PLA Nanoparticles). The crosslinking kinetic has been evaluated through rheologic analysis for both the systems. The entire experimental work has been carried out at ETH ZÜRICH. For further experimentation, at the end of the project, we started to synthesized, in liquid phase, the RGD peptide sequence (arginylglycylaspartic acid), with the future outlook of chemically linked it to the sodium alginate molecules using amidic bonds, in order to analyse which of the two systems between GelMa and sodium alginate would be better for cells delivery application. Sodium alginate does not naturally contain the RGD sequenced that enable the cells to attached to the hydrogel matrix.
Il settore del “drug delivery” è una branca in costante sviluppo e ricerca da parte della comunità scientifica, grazie all'utilità nella vita pratica per i trattamenti delle malattie, la rigenerazione dei tessuti, il rilascio di terapie su misura. Anche la consegna “in loco” delle cellule è un campo profondamente studiato, in particolare per i trattamenti anti-tumorali e la guarigione delle ferite. Questi obiettivi possono essere raggiunti utilizzando combinazioni di soluzioni diverse o sfruttando materiali compositi, costituiti da due o più componenti diversi con proprietà chimiche o fisiche distinte di altri due o più sistemi. Ciò consente di sfruttare le migliori caratteristiche da una più grande quantità di tecnologie. In questo lavoro abbiamo studiato gli usi dei dispositivi stampati in 3D che, grazie alla tensione superficiale, possono essere saldamente rivestiti con idrogels contenenti farmaci o cellule. L'obiettivo è quello di avere sia la consegna in uno specifico punto di diversi tipi di cellule sia il rilascio basato sulla diffusione di farmaci idrofili e idrofobici caricati in una matrice idrofila o idrofoba. Nel laboratorio di ingegneria macromolecolare dell’ ETH ZÜRICH, il supporto biocompatibile in policaprolattone è stato stampato in 3D e rivestito con due diversi idrogels, la gelatina metacrilata (GelMa) e l’alginato di sodio. Per quanto riguarda il supporto metallico, questo è stato stampato in resina DL60 dal + LAB del Politecnico di Milano e metallizzato dal SEE Lab del Politecnico di Milano, utilizzando la tecnica del layer by layer. Per la parte del progetto riguardante il trasporto in loco di cellule, sono stati incapsulati fibroblasti NIH / 3T3 (ATCC® CRL-1658 ™) direttamente nell’hydrogel di GelMa. Per la parte relativa alla consegna dei farmaci invece, abbiamo caricato due tipi di molecole “modello”: • Rodamina B, idrofila, caricata grazie a proprietà steriche • Oil Red O, idrofobo, caricato sia nel GelMa che nell’alginato di sodio usando nanoparticelle polimeriche di polietilenglicole legate all'acido polilattico (nanoparticelle PEG-PLA). La cinetica di crosslinking è stata valutata mediante analisi reologiche per entrambi i sistemi. L'intero lavoro sperimentale è stato svolto presso l'ETH ZÜRICH. Per ulteriori sperimentazioni, alla fine del progetto, abbiamo iniziato a sintetizzare, in fase liquida, la sequenza peptidica RGD (acido arginilglicilaspartico), in prospettiva futura di legarlo chimicamente alle molecole di alginato di sodio usando legami amidici, al fine di analizzare poi quale dei due sistemi tra GelMa e alginato di sodio sarebbe più indicato per il trasporto ed il supporto cellulare.
Surface tension assisted devices for drugs and cells delivery using hydrogels
CHIOZZI, VIOLA
2019/2020
Abstract
The drug delivery field is a branch in continuous development and research by the scientific community, due to the utility in the practical life for disease treatments, tissue regeneration, tailored therapeutics releasing. Cells “in loco” delivery is also a deeply investigated field, especially for anti-tumour treatments and wound healing. These objectives can be achieved using combinations of different solutions or exploiting composite materials, made of two or more different constituents with distinct chemical or physical properties of other two or more systems. This allows to exploit the best characteristics from a great quantities of technologies. In this work we investigated the uses of 3D- printed devices, that thanks to superficial tension, can be tightly coated with drug or cells loaded hydrogels. The aim is to have both the on-target delivery of different types of cells and diffusion- based release of both hydrophilic and hydrophobic drugs loaded in a hydrophilic hydrogel matrix. In the Macromolecular Engineering Laboratory of ETH ZÜRICH, the biocompatible support made of polycaprolactone has been 3D printed and coated with two different hydrogels, methacrylated gelatin (GelMa) and sodium alginate. Regarding the metallic support, this has been printed in DL60 resin by the +LAB of Politecnico di Milano and metallized by the SEE Lab of Politecnico di Milano, using the layer by layer teqnique. Considering the cells delivery part, NIH/3T3 (ATCC® CRL-1658™) fibroblasts have been encapsulated in GelMa. For the drug delivery part of the project we loaded two types of model drugs: • Rhodamine B Isothiocyanate, hydrophilic, loaded thanks to steric phenomena • Oil Red O, hydrophobic, loaded into GelMa and sodium alginate using polymeric nanoparticles of polyethylene glycol linked to polylactic acid (PEG-PLA Nanoparticles). The crosslinking kinetic has been evaluated through rheologic analysis for both the systems. The entire experimental work has been carried out at ETH ZÜRICH. For further experimentation, at the end of the project, we started to synthesized, in liquid phase, the RGD peptide sequence (arginylglycylaspartic acid), with the future outlook of chemically linked it to the sodium alginate molecules using amidic bonds, in order to analyse which of the two systems between GelMa and sodium alginate would be better for cells delivery application. Sodium alginate does not naturally contain the RGD sequenced that enable the cells to attached to the hydrogel matrix.| File | Dimensione | Formato | |
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https://hdl.handle.net/10589/151198