Browsing by Subject "POLY(2-OXAZOLINE)S"

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  • Hu, Chen; Ahmad, Taufiq; Haider, Malik Salman; Hahn, Lukas; Stahlhut, Philipp; Groll, Juergen; Luxenhofer, Robert (2022)
    Alginates are the most commonly used bioink in biofabrication, but their rheological profiles make it very challenging to perform real 3D printing. In this study, an advanced hybrid hydrogel ink was developed, a mixture of thermogelling diblock copolymer, alginate and clay i.e. Laponite XLG. The reversible thermogelling and shear thinning properties of the diblock copolymer in the ink system improves handling and 3D printability significantly. Various three-dimensional constructs, including suspended filaments, were printed successfully with high shape fidelity and excellent stackability. Subsequent ionic crosslinking of alginate fixates the printed scaffolds, while the diblock copolymer is washed out of the structure, acting as a fugitive material/porogen on the (macro)molecular level. Finally, cell-laden printing and culture over 21 d demonstrated good cytocompatibility and feasibility of the novel hybrid hydrogels for 3D bioprinting. We believe that the developed approach could be interesting for a wide range of bioprinting applications including tissue engineering and drug screening, potentially enabling also other biological bioinks such as collagen, hyaluronic acid, decellularized extracellular matrices or cellulose based bioinks.
  • Hu, Chen; Haider, Malik Salman; Hahn, Lukas; Yang, Mengshi; Luxenhofer, Robert (2021)
    Hydrogels that can be processed with additive manufacturing techniques and concomitantly possess favorable mechanical properties are interesting for many advanced applications. However, the development of novel ink materials with high intrinsic 3D printing performance has been proven to be a major challenge. Herein, a novel 3D printable organic-inorganic hybrid hydrogel is developed from three components, and characterized in detail in terms of rheological property, swelling behavior and composition. The nanocomposite hydrogel combines a thermoresponsive hydrogel with clay LAPONITE (R) XLG and in situ polymerized poly(N,N-dimethylacrylamide). Before in situ polymerization, the thermogelling and shear thinning properties of the thermoresponsive hydrogel provides a system well-suited for extrusion-based 3D printing. After chemical curing of the 3D-printed constructs by free radical polymerization, the resulting interpenetrating polymer network hydrogel shows excellent mechanical strength with a high stretchability to a tensile strain at break exceeding 550%. Integrating with the advanced 3D-printing technique, the introduced material could be interesting for a wide range of applications including tissue engineering, drug delivery, soft robotics and additive manufacturing in general.
  • Drago, Salvatore E.; Craparo, Emanuela F.; Luxenhofer, Robert; Cavallaro, Gennara (2021)
    In this paper, two amphiphilic graft copolymers were synthesized by grafting polylactic acid (PLA) as hydrophobic chain and poly(2-methyl-2-oxazoline) (PMeOx) or poly(2-methyl-2-oxazine) (PMeOzi) as hydrophilic chain, respectively, to a backbone of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA). These original graft copolymers were used to prepare nanoparticles delivering Zileuton in inhalation therapy. Among various tested methods, direct nanoprecipitation proved to be the best technique to prepare nanoparticles with the smallest dimensions, the narrowest dimensional distribution and a spherical shape. To overcome the size limitations for administration by inhalation, the nano-into-micro strategy was applied, encapsulating the nanoparticles in water-soluble mannitol-based microparticles by spray-drying. This process has allowed to produce spherical microparticles with the proper size for optimal lung deposition, and, once in contact with fluids mimicking the lung district, able to dissolve and release non-aggregated nanoparticles, potentially able to spread through the mucus, releasing about 70% of the drug payload in 24hours.
  • Hahn, Lukas; Beudert, Matthias; Gutmann, Marcus; Kessler, Larissa; Stahlhut, Philipp; Fischer, Lena; Karakaya, Emine; Lorson, Thomas; Thievessen, Ingo; Detsch, Rainer; Luehmann, Tessa; Luxenhofer, Robert (2021)
    Hydrogels are key components in bioink formulations to ensure printability and stability in biofabrication. In this study, a well-known Diels-Alder two-step post-polymerization modification approach is introduced into thermogelling diblock copolymers, comprising poly(2-methyl-2-oxazoline) and thermoresponsive poly(2-n-propyl-2-oxazine). The diblock copolymers are partially hydrolyzed and subsequently modified by acid/amine coupling with furan and maleimide moieties. While the thermogelling and shear-thinning properties allow excellent printability, trigger-less cell-friendly Diels-Alder click-chemistry yields long-term shape-fidelity. The introduced platform enables easy incorporation of cell-binding moieties (RGD-peptide) for cellular interaction. The hydrogel is functionalized with RGD-peptides using thiol-maleimide chemistry and cell proliferation as well as morphology of fibroblasts seeded on top of the hydrogels confirm the cell adhesion facilitated by the peptides. Finally, bioink formulations are tested for biocompatibility by incorporating fibroblasts homogenously inside the polymer solution pre-printing. After the printing and crosslinking process good cytocompatibility is confirmed. The established bioink system combines a two-step approach by physical precursor gelation followed by an additional chemical stabilization, offering a broad versatility for further biomechanical adaptation or bioresponsive peptide modification.
  • Hu, Chen; Hahn, Lukas; Yang, Mengshi; Altmann, Alexander; Stahlhut, Philipp; Groll, Jürgen; Luxenhofer, Robert (2021)
    As a promising biofabrication technology, extrusion-based bioprinting has gained significant attention in the last decade and major advances have been made in the development of bioinks. However, suitable synthetic and stimuli-responsive bioinks are underrepresented in this context. In this work, we described a hybrid system of nanoclay Laponite XLG and thermoresponsive block copolymer poly(2-methyl-2-oxazoline)-b-poly(2-n-propyl-2-oxazine) (PMeOx-b-PnPrOzi) as a novel biomaterial ink and discussed its critical properties relevant for extrusion-based bioprinting, including viscoelastic properties and printability. The hybrid hydrogel retains the thermogelling properties but is strengthened by the added clay (over 5 kPa of storage modulus and 240 Pa of yield stress). Importantly, the shear-thinning character is further enhanced, which, in combination with very rapid viscosity recovery (similar to 1 s) and structure recovery (similar to 10 s), is highly beneficial for extrusion-based 3D printing. Accordingly, various 3D patterns could be printed with markedly enhanced resolution and shape fidelity compared to the biomaterial ink without added clay. Graphic abstract
  • Hahn, Lukas; Maier, Matthias; Stahlhut, Philipp; Beudert, Matthias; Flegler, Vanessa; Forster, Stefan; Altmann, Alexander; Toeppke, Fabian; Fischer, Karl; Seiffert, Sebastian; Boettcher, Bettina; Luehmann, Tessa; Luxenhofer, Robert (2020)
    Amphiphilic block copolymers that undergo (reversible) physical gelation in aqueous media are of great interest in ditIerent areas including drug delivery, tissue engineering, regenerative medicine, and biofabrication. We investigated a small library of ABA-type triblock copolymers comprising poly(2-methyl-2-oxazoline) as the hydrophilic shell A and different aromatic poly(2-oxazoline)s and poly(2-oxazine)s cores B in an aqueous solution at different concentrations and temperatures. Interestingly, aqueous solutions of poly(2-methyl-2-oxazoline)-block-poly(2-phenyl-2-oxazine)-block-poly(2-methyl-2-oxazoline) (PMeOx-b-PPheOzi-b-PMeOx) undergo inverse thermogelation below a critical temperature by forming a reversible nanoscale wormlike network. The viscoelastic properties of the resulting gel can be conveniently tailored by the concentration and the polymer composition. Storage moduli of up to 110 kPa could be obtained while the material retains shear-thinning and rapid self-healing properties. We demonstrate three-dimensional (3D) printing of excellently defined and shape-persistent 24-layered scaffolds at different aqueous concentrations to highlight its application potential, e.g., in the research area of biofabrication. A macroporous microstructure, which is stable throughout the printing process, could be confirmed via cryo-scanning electron microscopy (SEM) analysis. The absence of cytotoxicity even at very high concentrations opens a wide range of different applications for this first-in-class material in the field of biomaterials.
  • Pooch, Fabian; Sliepen, Marjolein; Svedström, Kirsi J.; Korpi, Antti; Winnik, Francoise M.; Tenhu, Heikki (2018)
    Miscible block copolymers (BCPs) are rarely studied. When one or both components of such BCPs are semi-crystalline polymers, strong effects on the crystallization behavior can be expected. We present a study of 18 miscible BCPs comprised of poly(lactide) (PLLA, semi-crystalline and PDLLA, amorphous) and poly(2-isopropyl-2-oxazoline) (PiPOx, semi-crystalline) with PiPOx volume fractions of 0.14 <phi(PiPOx) <0.82. All BCPs exhibit a single glass transition and form a homogeneous melt. Mixing has a plasticizing effect on PiPOx and increases its crystallization rates (DSC). In contrast, the crystallization rates of PLLA are dramatically reduced, or in most cases entirely prevented. During isothermal crystallization at 130 degrees C, the crystallization rates of the BCPs were inverted in comparison with those of the parent homopolymers. Crystallization drives the BCPs to phase separate and the formed crystalline structure is that of the parent homopolymers. The fast crystallization of PiPOx confines the observed superstructure. The BCPs were studied on multiple length scales - from the atomic level (WAXS, IR spectroscopy) to the meso level (AFM, SAXS) and the macroscopic superstructure (polarized optical microscopy). A mechanism of the structure evolution is presented.
  • Pooch, Fabian; Sliepen, Marjolein; Knudsen, Kenneth D.; Nyström, Bo; Tenhu, Heikki; Winnik, Francoise M. (2019)
    Poly(2-isopropyl-2-oxazoline)-b-poly(lactide) (PiPOx-b-PLA) diblock copolymers comprise two miscible blocks: the hydrophilic and thermosensitive PiPOx and the hydrophobic PLA, a biocompatible and biodegradable polyester. They self-assemble in water, forming stable dispersions of nanoparticles with hydrodynamic radii (R-h) ranging from similar to 18 to 60 nm, depending on their molar mass, the relative size of the two blocks, and the configuration of the lactide unit. Evidence from H-1 nuclear magnetic resonance spectroscopy, light scattering, small-angle neutron scattering, and cryo-transmission electron microscopy indicates that the nanoparticles do not adopt the typical core-shell morphology. Aqueous nanoparticle dispersions heated from 20 to 80 degrees C were monitored by turbidimetry and microcalorimetry. Nanoparticles of copolymers containing a poly(DL-lactide) block coagulated irreversibly upon heating to 50 degrees C, forming particles' of various shapes (R-h similar to 200-500 nm). Dispersions of PiPOx-b-poly(L-lactide) coagulated to a lesser extent or remained stable upon heating. From the entire experimental evidence, we conclude that PiPOx-b-PLA nanoparticles consist of a core of PLA/PiPOx chains associated via dipole-dipole interactions of the PLA and PiPOx carbonyl groups. The core is surrounded by tethered PiPOx loops and tails responsible for the colloidal stability of the nanoparticles in water. While the core of all nanoparticles studied contains associated PiPOx and PLA blocks, fine details of the nanoparticles morphology vary predictably with the size and composition of the copolymers, yielding particles of distinctive thermosensitivity in aqueous dispersions.
  • Pasztoi, Balazs; Trotschler, Tobias M.; Szabo, Akos; Kerscher, Benjamin; Tenhu, Heikki; Muelhaupt, Rolf; Ivan, Bela (2021)
    Cationic ring-opening polymerization (CROP) of 2-ethyl-2-oxazoline (EtOx) was systematically investigated in benzotrifluoride (BTF), which is considered as an environmentally less harmful solvent than many conventional reaction media. Simultaneously, polymerizations in conventional solvents, such as acetonitrile, N,N-dimethylacetamide and toluene, were also carried out for comparison in the 80-100 degrees C temperature range. Kinetic experiments revealed that the monomer consumption occurs by first order kinetics and the number average molecular weights linearly increase in line with the theoretical molecular weight as a function of monomer conversion. These findings indicate that the polymerization takes place by quasiliving CROP in all the investigated solvents, including BTF as well, resulting in PEtOx with prederminded molecular weights and polydispersities of 1.3-15. The highest polymerization rates were obtained in BTF, resulting in high conversions in short reaction times at 100 degrees C reaction temperature. The Arrhenius parameters of the polymerization of EtOx in BTF indicates relatively high activation energy in comparison with other applied solvents, however, a compensation effect between the activation energies and frequency factor is observed for such polymerization in a variety of solvents. Our findings are expected to enable the convenient synthesis of polyoxazolines and polyoxazoline-based well-defined polymer architectures in BTF, an environmentally advantageous alternative solvent to harmful polymerization media, with high polymerization rates in short reaction times without the need for any special conditions or equipment.
  • Kirila, Tatyana; Smirnova, Anna; Aseyev, Vladimir; Tenkovtsev, Andrey; Tenhu, Heikki; Filippov, Alexander (2021)
    The behavior of star-shaped six-arm poly-2-alkyl-2-oxazines and poly-2-alkyl-2-oxazolines in aqueous solutions on heating was studied by light scattering, turbidimetry and microcalorimetry. The core of stars was hexaaza [2(6)] orthoparacyclophane and the arms were poly-2-ethyl-2-oxazine, poly-2-isopropyl-2-oxazine, poly-2-ethyl-2-oxazoline, and poly-2-isopropyl-2-oxazoline. The arm structure affects the properties of polymers already at low temperatures. Molecules and aggregates were present in solutions of poly-2-alkyl-2-oxazines, while aggregates of two types were observed in the case of poly-2-alkyl-2-oxazolines. On heating below the phase separation temperature, the characteristics of the investigated solutions did not depend practically on temperature. An increase in the dehydration degree of poly-2-alkyl-2-oxazines and poly-2-alkyl-2-oxazolines led to the formation of intermolecular hydrogen bonds, and aggregation was the dominant process near the phase separation temperature. It was shown that the characteristics of the phase transition in solutions of the studied polymer stars are determined primarily by the arm structure, while the influence of the molar mass is not so significant. In comparison with literature data, the role of the hydrophobic core structure in the formation of the properties of star-shaped polymers was analyzed.
  • Haider, Malik Salman; Luebtow, Michael M.; Endres, Sebastian; Forster, Stefan; Flegler, Vanessa J.; Boettcher, Bettina; Aseyev, Vladimir; Pöppler, Ann-Christin; Luxenhofer, Robert (2020)
    Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles.
  • Haider, Malik Salman; Ahmad, Taufiq; Yang, Mengshi; Hu, Chen; Hahn, Lukas; Stahlhut, Philipp; Groll, Jurgen; Luxenhofer, Robert (2021)
    As one kind of "smart" material, thermogelling polymers find applications in biofabrication, drug delivery and regenerative medicine. In this work, we report a thermosensitive poly(2-oxazoline)/poly(2-oxazine) based diblock copolymer comprising thermosensitive/moderately hydrophobic poly(2-N-propyl-2-oxazine) (pPrOzi) and thermosensitive/moderately hydrophilic poly(2-ethyl-2-oxazoline) (pEtOx). Hydrogels were only formed when block length exceeded certain length (approximate to 100 repeat units). The tube inversion and rheological tests showed that the material has then a reversible sol-gel transition above 25 wt.% concentration. Rheological tests further revealed a gel strength around 3 kPa, high shear thinning property and rapid shear recovery after stress, which are highly desirable properties for extrusion based three-dimensional (3D) (bio) printing. Attributed to the rheology profile, well resolved printability and high stackability (with added laponite) was also possible. (Cryo) scanning electron microscopy exhibited a highly porous, interconnected, 3D network. The sol-state at lower temperatures (in ice bath) facilitated the homogeneous distribution of (fluorescently labelled) human adipose derived stem cells (hADSCs) in the hydrogel matrix. Post-printing live/dead assays revealed that the hADSCs encapsulated within the hydrogel remained viable (approximate to 97%). This thermoreversible and (bio) printable hydrogel demonstrated promising properties for use in tissue engineering applications.