TY - JOUR A1 - Shkilnyy, Andriy A1 - Gräf, Ralph A1 - Hiebl, Bernhard A1 - Neffe, Axel T. A1 - Friedrich, Alwin A1 - Hartmann, Juergen A1 - Taubert, Andreas T1 - Unprecedented, low cytotoxicity of spongelike calcium phosphate/poly(ethylene imine) hydrogel composites N2 - Covalently crosslinked PEI hydrogels are efficient templates for calcium phosphate mineralization in SBF. In contrast to the PEI hydrogels, non-crosslinked PEI does not lead to calcium phosphate nucleation and growth in SBF. The precipitate is a mixture of brushite and hydroxyapatite. The PEI/calcium phosphate composite material exhibits a sponge like morphology and a chemical composition that is interesting for implants. Cytotoxicity tests using Dictyostelium discoideum amoebae show that both the non-mineralized and mineralized hydrogels have a very low cytotoxicity. This suggests that next generation PEI hydrogels, where also the degradation products are non-toxic, could be interesting for biomedical applications. Y1 - 2009 UR - http://www3.interscience.wiley.com/cgi-bin/jhome/77002860 U6 - https://doi.org/10.1002/mabi.200800266 SN - 1616-5187 ER - TY - JOUR A1 - Folikumah, Makafui Yao A1 - Neffe, Axel T. A1 - Behl, Marc A1 - Lendlein, Andreas T1 - Thiol Michael-Type reactions of optically active mercapto-acids in aqueous medium JF - MRS advances : a journal of the Materials Research Society N2 - Defined chemical reactions in a physiological environment are a prerequisite for the in situ synthesis of implant materials potentially serving as matrix for drug delivery systems, tissue fillers or surgical glues. ‘Click’ reactions like thiol Michael-type reactions have been successfully employed as bioorthogonal reaction. However, due to the individual stereo-electronic and physical properties of specific substrates, an exact understanding their chemical reactivity is required if they are to be used for in-situ biomaterial synthesis. The chiral (S)-2-mercapto-carboxylic acid analogues of L-phenylalanine (SH-Phe) and L-leucine (SH-Leu) which are subunits of certain collagenase sensitive synthetic peptides, were explored for their potential for in-situ biomaterial formation via the thiol Michael-type reaction. In model reactions were investigated the kinetics, the specificity and influence of stereochemistry of this reaction. We could show that only reactions involving SH-Leu yielded the expected thiol-Michael product. The inability of SH-Phe to react was attributed to the steric hindrance of the bulky phenyl group. In aqueous media, successful reaction using SH-Leu is thought to proceed via the sodium salt formed in-situ by the addition of NaOH solution, which was intented to aid the solubility of the mercapto-acid in water. Fast reaction rates and complete acrylate/maleimide conversion were only realized at pH 7.2 or higher suggesting the possible use of SH-Leu under physiological conditions for thiol Michael-type reactions. This method of in-situ formed alkali salts could be used as a fast approach to screen mercapto-acids for thio Michael-type reactions without the synthesis of their corresponding esters. KW - biomaterial KW - biomedical KW - biomimetic (chemical reaction) KW - chemical synthesis Y1 - 2019 U6 - https://doi.org/10.1557/adv.2019.308 SN - 2059-8521 VL - 4 IS - 46-47 SP - 2515 EP - 2525 PB - Springer Nature Switzerland AG CY - Cham ER - TY - JOUR A1 - Neffe, Axel T. A1 - Löwenberg, Candy A1 - Julich-Gruner, Konstanze K. A1 - Behl, Marc A1 - Lendlein, Andreas T1 - Thermally-induced shape-memory behavior of degradable gelatin-based networks JF - International journal of molecular sciences N2 - Shape-memory hydrogels (SMH) are multifunctional, actively-moving polymers of interest in biomedicine. In loosely crosslinked polymer networks, gelatin chains may form triple helices, which can act as temporary net points in SMH, depending on the presence of salts. Here, we show programming and initiation of the shape-memory effect of such networks based on a thermomechanical process compatible with the physiological environment. The SMH were synthesized by reaction of glycidylmethacrylated gelatin with oligo(ethylene glycol) (OEG) alpha,omega-dithiols of varying crosslinker length and amount. Triple helicalization of gelatin chains is shown directly by wide-angle X-ray scattering and indirectly via the mechanical behavior at different temperatures. The ability to form triple helices increased with the molar mass of the crosslinker. Hydrogels had storage moduli of 0.27-23 kPa and Young's moduli of 215-360 kPa at 4 degrees C. The hydrogels were hydrolytically degradable, with full degradation to water-soluble products within one week at 37 degrees C and pH = 7.4. A thermally-induced shape-memory effect is demonstrated in bending as well as in compression tests, in which shape recovery with excellent shape-recovery rates R-r close to 100% were observed. In the future, the material presented here could be applied, e.g., as self-anchoring devices mechanically resembling the extracellular matrix. KW - shape-memory hydrogel KW - active polymer KW - biopolymer KW - mechanical KW - properties KW - degradation Y1 - 2021 U6 - https://doi.org/10.3390/ijms22115892 SN - 1422-0067 SN - 1661-6596 VL - 22 IS - 11 PB - Molecular Diversity Preservation International CY - Basel ER - TY - JOUR A1 - Lange, Maik A1 - Braune, Steffen A1 - Luetzow, Karola A1 - Richau, Klaus A1 - Scharnagl, Nico A1 - Weinhart, Marie A1 - Neffe, Axel T. A1 - Jung, Friedrich A1 - Haag, Rainer A1 - Lendlein, Andreas T1 - Surface functionalization of poly(ether imide) membranes with linear, methylated oligoglycerols for reducing thrombogenicity JF - Macromolecular rapid communications N2 - Materials for biomedical applications are often chosen for their bulk properties. Other requirements such as a hemocompatible surface shall be fulfilled by suitable chemical functionalization. Here we show, that linear, side-chain methylated oligoglycerols (OGMe) are more stable to oxidation than oligo(ethylene glycol) (OEG). Poly(ether imide) (PEI) membranes functionalized with OGMes perform at least as good as, and partially better than, OEG functionalized PEI membranes in view of protein resistance as well as thrombocyte adhesion and activation. Therefore, OGMes are highly potent surface functionalizing molecules for improving the hemocompatibility of polymers. KW - hemocompatibility KW - poly(ethylene glycol) KW - polyglycerol KW - polyimides KW - surface chemistry Y1 - 2012 U6 - https://doi.org/10.1002/marc.201200426 SN - 1022-1336 VL - 33 IS - 17 SP - 1487 EP - 1492 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Federico, Stefania A1 - Nöchel, Ulrich A1 - Löwenberg, Candy A1 - Lendlein, Andreas A1 - Neffe, Axel T. T1 - Supramolecular hydrogel networks formed by molecular recognition of collagen and a peptide grafted to hyaluronic acid JF - Acta biomaterialia N2 - The extracellular matrix (ECM) is a nano-structured, highly complex hydrogel, in which the macromolecules are organized primarily by non-covalent interactions. Here, in a biomimetic approach, the decorin-derived collagen-binding peptide LSELRLHNN was grafted to hyaluronic acid (HA) in order to enable the formation of a supramolecular hydrogel network together with collagen. The storage modulus of a mixture of collagen and HA was increased by more than one order of magnitude (G′ = 157 Pa) in the presence of the HA-grafted peptide compared to a mixture of collagen and HA (G′ = 6 Pa). The collagen fibril diameter was decreased, as quantified using electron microscopy, in the presence of the HA-grafted peptide. Here, the peptide mimicked the function of decorin by spatially organizing collagen. The advantage of this approach is that the non-covalent crosslinks between collagen molecules and the HA chains created by the peptide form a reversible and dynamic hydrogel, which could be employed for a diverse range of applications in regenerative medicine. Statement of Significance Biopolymers of the extracellular matrix (ECM) like collagen or hyaluronan are attractive starting materials for biomaterials. While in biomaterial science covalent crosslinking is often employed, in the native ECM, stabilization and macromolecular organization is primarily based on non-covalent interactions, which allows dynamic changes of the materials. Here, we show that collagen-binding peptides, derived from the small proteoglycan decorin, grafted to hyaluronic acid enable supramolecular stabilization of collagen hydrogels. These hydrogels have storage moduli more than one order of magnitude higher than mixtures of collagen and hyaluronic acid. Furthermore, the peptide supported the structural organization of collagen. Such hydrogels could be employed for a diverse range of applications in regenerative medicine. Furthermore, the rational design helps in the understanding ECM structuring. KW - Biopolymers KW - Collagen-binding peptide KW - Hyaluronic acid KW - Hydrogels KW - Mechanical properties Y1 - 2016 U6 - https://doi.org/10.1016/j.actbio.2016.04.018 SN - 1742-7061 SN - 1878-7568 VL - 38 SP - 1 EP - 10 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Löwenberg, Candy A1 - Tripodo, Giuseppe A1 - Julich-Gruner, Konstanze K. A1 - Neffe, Axel T. A1 - Lendlein, Andreas T1 - Supramolecular gelatin networks based on inclusion complexes JF - Macromolecular bioscience N2 - Hydrogel forming physical networks based on gelatin are an attractive approach toward multifunctional biomaterials with the option of reshaping, self-healing, and stimuli-sensitivity. However, it is challenging to design such gelatin-based hydrogels to be stable at body temperature. Here, gelatin functionalized with desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) side chains is crosslinked with cyclodextrin (CD) dimers under formation of inclusions complexes. The supramolecular networks displayed at room temperature decreased water uptake (200-600 wt% for DAT-based systems, 200 wt% for DATT based systems), and increased storage moduli up to 25.6 kPa determined by rheology compared to DAT(T) gelatin. The gel-sol transition temperature increased from 33 up to 42 degrees C. The presented system that is completely based on natural building blocks may form the basis for materials that may potentially respond by dissolution or changes of properties to changes in environmental conditions or to the presence of CD guest molecules. KW - cyclodextrin KW - gelatin KW - inclusion complex KW - supramolecular polymer network Y1 - 2020 U6 - https://doi.org/10.1002/mabi.202000221 SN - 1616-5187 SN - 1616-5195 VL - 20 IS - 10 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Neffe, Axel T. A1 - Izraylit, Victor A1 - Hommes-Schattmann, Paul J. A1 - Lendlein, Andreas T1 - Soft, formstable (Co)polyester blend elastomers JF - Nanomaterials : open access journal N2 - High crystallization rate and thermomechanical stability make polylactide stereocomplexes effective nanosized physical netpoints. Here, we address the need for soft, form-stable degradable elastomers for medical applications by designing such blends from (co)polyesters, whose mechanical properties are ruled by their nanodimensional architecture and which are applied as single components in implants. By careful controlling of the copolymer composition and sequence structure of poly[(L-lactide)-co-(epsilon-caprolactone)], it is possible to prepare hyperelastic polymer blends formed through stereocomplexation by adding poly(D-lactide) (PDLA). Low glass transition temperature T-g <= 0 degrees C of the mixed amorphous phase contributes to the low Young's modulus E. The formation of stereocomplexes is shown in DSC by melting transitions T-m > 190 degrees C and in WAXS by distinct scattering maxima at 2 theta = 12 degrees and 21 degrees. Tensile testing demonstrated that the blends are soft (E = 12-80 MPa) and show an excellent hyperelastic recovery R-rec = 66-85% while having high elongation at break epsilon(b) up to >1000%. These properties of the blends are attained only when the copolymer has 56-62 wt% lactide content, a weight average molar mass >140 kg center dot mol(-1), and number average lactide sequence length >= 4.8, while the blend is formed with a content of 5-10 wt% of PDLA. The devised strategy to identify a suitable copolymer for stereocomplexation and blend formation is transferable to further polymer systems and will support the development of thermoplastic elastomers suitable for medical applications. KW - thermoplastic elastomer KW - biomaterial KW - stereocomplexes KW - mechanical KW - properties KW - form stability KW - crystallinity Y1 - 2021 U6 - https://doi.org/10.3390/nano11061472 SN - 2079-4991 VL - 11 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Piluso, Susanna A1 - Vukicevie, Radovan A1 - Nöchel, Ulrich A1 - Braune, Steffen A1 - Lendlein, Andreas A1 - Neffe, Axel T. T1 - Sequential alkyne-azide cycloadditions for functionalized gelatin hydrogel formation JF - European polymer journal N2 - While click chemistry reactions for biopolymer network formation are attractive as the defined reactions may allow good control of the network formation and enable subsequent functionalization, tailoring of gelatin network properties over a wide range of mechanical properties has yet to be shown. Here, it is demonstrated that copper-catalyzed alkyne-azide cycloaddition of alkyne functionalized gelatin with diazides gave hydrogel networks with properties tailorable by the ratio of diazide to gelatin and diazide rigidity. 4,4′-diazido-2,2′-stilbenedisulfonic acid, which has been used as rigid crosslinker, yielded hydrogels with Young’s moduli E of 50–390 kPa and swelling degrees Q of 150–250 vol.%, while the more flexible 1,8-diazidooctane resulted in hydrogels with E = 125–280 kPa and Q = 225–470 vol.%. Storage moduli could be varied by two orders of magnitude (G′ = 100–20,000 Pa). An indirect cytotoxicity test did not show cytotoxic properties. Even when employing 1:1 ratios of alkyne and azide moieties, the hydrogels were shown to contain both, unreacted alkyne groups on the gelatin backbone as well as dangling chains carrying azide groups as shown by reaction with functionalized fluorescein. The free groups, which can be tailored by the employed ratio of the reactants, are accessible for covalent attachment of drugs, as was demonstrated by functionalization with dexamethasone. The sequential network formation and functionalization with click chemistry allows access to multifunctional materials relevant for medical applications. KW - Click chemistry KW - Hydrogel KW - Polymer functionalization KW - Biopolymer KW - Rheology KW - Multifunctionality Y1 - 2018 U6 - https://doi.org/10.1016/j.eurpolymj.2018.01.017 SN - 0014-3057 SN - 1873-1945 VL - 100 SP - 77 EP - 85 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Hommes-Schattmann, Paul J. A1 - Neffe, Axel T. A1 - Ahmad, Bilal A1 - Williams, Gareth R. A1 - Vanneaux, Valerie A1 - Menasche, Philippe A1 - Kalfa, David A1 - Lendlein, Andreas T1 - RGD constructs with physical anchor groups as polymer co-electrospinnable cell adhesives JF - Polymers for advanced technologies N2 - The tissue integration of synthetic polymers can be promoted by displaying RGD peptides at the biointerface with the objective of enhancing colonization of the material by endogenous cells. A firm but flexible attachment of the peptide to the polymer matrix, still allowing interaction with receptors, is therefore of interest. Here, the covalent coupling of flexible physical anchor groups, allowing for temporary immobilization on polymeric surfaces via hydrophobic or dipole-dipole interactions, to a RGD peptide was investigated. For this purpose, a stearate or an oligo(ethylene glycol) (OEG) was attached to GRGDS in 51-69% yield. The obtained RGD linker constructs were characterized by NMR, IR and MALDI-ToF mass spectrometry, revealing that the commercially available OEG and stearate linkers are in fact mixtures of similar compounds. The RGD linker constructs were co-electrospun with poly(p-dioxanone) (PPDO). After electrospinning, nitrogen could be detected on the surface of the PPDO fibers by X-ray photoelectron spectroscopy. The nitrogen content exceeded the calculated value for the homogeneous material mixture suggesting a pronounced presentation of the peptide on the fiber surface. Increasing amounts of RGD linker constructs in the electrospinning solution did not lead to a detection of an increased amount of peptide on the scaffold surface, suggesting inhomogeneous distribution of the peptide on the PPDO fiber surface. Human adipose-derived stem cells cultured on the patches showed similar viability as when cultured on PPDO containing pristine RGD. The fully characterized RGD linker constructs could serve as valuable tools for the further development of tissue-integrating polymeric scaffolds. Copyright (c) 2016 John Wiley & Sons, Ltd. KW - electrospinning KW - RGD peptides KW - cell adhesion KW - biofunctionalization Y1 - 2017 U6 - https://doi.org/10.1002/pat.3963 SN - 1042-7147 SN - 1099-1581 VL - 28 SP - 1312 EP - 1317 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Blocki, Anna A1 - Löwenberg, Candy A1 - Jiang, Yi A1 - Kratz, Karl A1 - Neffe, Axel T. A1 - Jung, Friedrich A1 - Lendlein, Andreas T1 - Response of encapsulated cells to a gelatin matrix with varied bulk and microenvironmental elastic properties JF - Polymers for advanced technologies N2 - Gelatin-based hydrogels offer various biochemical cues that support encapsulated cells and are therefore suitable as cell delivery vehicles in regenerative medicine. However, besides the biochemical signals, biomechanical cues are crucial to ensure an optimal support of encapsulated cells. Hence, we aimed to correlate the cellular response of encapsulated cells to macroscopic and microscopic elastic properties of glycidylmethacrylate (GMA)-functionalized gelatin-based hydrogels. To ensure that different observations in cellular behavior could be attributed to differences in elastic properties, an identical concentration as well as degree of functionalization of biopolymers was utilized to form covalently crosslinked hydrogels. Elastic properties were merely altered by varying the average gelatin-chain length. Hydrogels exhibited an increased degree of swelling and a decreased bulk elastic modulus G with prolonged autoclaving of the starting solution. This was accompanied by an increase of hydrogel mesh size and thus by a reduction of crosslinking density. Tougher hydrogels retained the largest amount of cells; however, they also interfered with cell viability. Softer gels contained a lower cell density, but supported cell elongation and viability. Observed differences could be partially attributed to differences in bulk properties, as high crosslinking densities interfere with diffusion and cell spreading and thus can impede cell viability. Interestingly, a microscopic elastic modulus in the range of native soft tissue supported cell viability and elongation best while ensuring a good cell entrapment. In conclusion, gelatin-based hydrogels providing a soft tissue-like microenvironment represent adequate cell delivery vehicles for tissue engineering approaches. Copyright (c) 2016 John Wiley & Sons, Ltd. KW - mechanotransduction KW - hydrogel KW - gelatin KW - cell encapsulation KW - matrix elasticity Y1 - 2017 U6 - https://doi.org/10.1002/pat.3947 SN - 1042-7147 SN - 1099-1581 VL - 28 SP - 1245 EP - 1251 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Julich-Gruner, Konstanze K. A1 - Löwenberg, Candy A1 - Neffe, Axel T. A1 - Behl, Marc A1 - Lendlein, Andreas T1 - Recent trends in the chemistry of shape-memory polymers JF - Macromolecular chemistry and physics N2 - Shape-memory polymers (SMPs) are stimuli-sensitive materials capable of performing complex movements on demand, which makes them interesting candidates for various applications, for example, in biomedicine or aerospace. This trend article highlights current approaches in the chemistry of SMPs, such as tailored segment chemistry to integrate additional functions and novel synthetic routes toward permanent and temporary netpoints. Multiphase polymer networks and multimaterial systems illustrate that SMPs can be constructed as a modular system of different building blocks and netpoints. Future developments are aiming at multifunctional and multistimuli-sensitive SMPs. KW - multifunctional polymers KW - networks KW - shape-memory polymers KW - stimuli-sensitive polymers KW - triple-shape effect Y1 - 2013 U6 - https://doi.org/10.1002/macp.201200607 SN - 1022-1352 VL - 214 IS - 5 SP - 527 EP - 536 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Izraylit, Victor A1 - Hommes-Schattmann, Paul J. A1 - Neffe, Axel T. A1 - Gould, Oliver E. C. A1 - Lendlein, Andreas T1 - Polyester urethane functionalizable through maleimide side-chains and cross-linkable by polylactide stereocomplexes JF - European polymer journal N2 - Sustainable multifunctional alternatives to fossil-derived materials, which can be functionalized and are degradable, can be envisioned by combining naturally derived starting materials with an established polymer design concept. Modularity and chemical flexibility of polyester urethanes (PEU) enable the combination of segments bearing functionalizable moieties and the tailoring of the mechanical and thermal properties. In this work, a PEU multiblock structure was synthesized from naturally derived L-lysine diisocyanate ethyl ester (LDI), poly(L-lactide) diol (PLLA) and N-(2,3-dihydroxypropyl)-maleimide (MID) in a one-step reaction. A maleimide side-chain (MID) provided a reactive site for the catalyst-free coupling of thiols shown for L-cysteine with a yield of 94%. Physical cross-links were generated by blending the PEU with poly(D-lactide) (PDLA), upon which the PLLA segments of the PEU and the PDLA formed stereocomplexes. Stereocomplexation occurred spontaneously during solution casting and was investigated with WAXS and DSC. Stereocomplex crystallites were observed in the blends, while isotactic PLA crystallization was not observed. The presented material platform with tailorable mechanical properties by blending is of specific interest for engineering biointerfaces of implants or carrier systems for bioactive molecules. KW - Functionalization KW - Polylactide stereocomplex KW - Biomolecules coupling Y1 - 2020 U6 - https://doi.org/10.1016/j.eurpolymj.2020.109916 SN - 0014-3057 SN - 1873-1945 VL - 137 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Wang, Weiwei A1 - Naolou, Toufik A1 - Ma, Nan A1 - Deng, Zijun A1 - Xu, Xun A1 - Mansfeld, Ulrich A1 - Wischke, Christian A1 - Gossen, Manfred A1 - Neffe, Axel T. A1 - Lendlein, Andreas T1 - Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells JF - Biomacromolecules : an interdisciplinary journal focused at the interface of polymer science and the biological sciences N2 - The rational design of a polyplex gene carrier aims to balance maximal effectiveness of nucleic acid transfection into cells with minimal adverse effects. Depsipeptide blocks with an M (n) similar to 5 kDa exhibiting strong physical interactions were conjugated with PEI moieties (2.5 or 10 kDa) to di- and triblock copolymers. Upon nanoparticle formation and complexation with DNA, the resulting polyplexes (sizes typically 60-150 nm) showed remarkable stability compared to PEI-only or lipoplex and facilitated efficient gene delivery. Intracellular trafficking was visualized by observing fluorescence-labeled pDNA and highlighted the effective cytoplasmic uptake of polyplexes and release of DNA to the perinuclear space. Specifically, a triblock copolymer with a middle depsipeptide block and two 10 kDa PEI swallowtail structures mediated the highest levels of transgenic VEGF secretion in mesenchymal stem cells with low cytotoxicity. These nanocarriers form the basis for a delivery platform technology, especially for gene transfer to primary human cells. Y1 - 2017 U6 - https://doi.org/10.1021/acs.biomac.7b01034 SN - 1525-7797 SN - 1526-4602 VL - 18 SP - 3819 EP - 3833 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Zhang, Nan A1 - Said, Andre A1 - Wischke, Christian A1 - Kral, Vivian A1 - Brodwolf, Robert A1 - Volz, Pierre A1 - Boreham, Alexander A1 - Gerecke, Christian A1 - Li, Wenzhong A1 - Neffe, Axel T. A1 - Kleuser, Burkhard A1 - Alexiev, Ulrike A1 - Lendlein, Andreas A1 - Schäfer-Korting, Monika T1 - Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles - Composition-dependent skin penetration enhancement of a dye probe and biocompatibility JF - European Journal of Pharmaceutics and Biopharmaceutics N2 - Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1% and particle size ranged from 35 to 244 nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis. Hence, systematic variations of nanoparticle properties allows gaining insights into critical criteria for biocompatibility and functionality of novel nanocarriers for topical drug delivery and risks associated with environmental exposure. KW - Biocompatibility testing KW - Drug delivery systems KW - Nanoparticle KW - Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] KW - Polymers KW - Skin absorption Y1 - 2017 U6 - https://doi.org/10.1016/j.ejpb.2016.10.019 SN - 0939-6411 SN - 1873-3441 VL - 116 SP - 66 EP - 75 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Neffe, Axel T. A1 - von Rüsten-Lange, Maik A1 - Braune, Steffen A1 - Lützow, Karola A1 - Roch, Toralf A1 - Richau, Klaus A1 - Jung, Friedrich A1 - Lendlein, Andreas T1 - Poly(ethylene glycol) grafting to Poly(ether imide) membranes - influence on protein adsorption and Thrombocyte adhesion JF - Macromolecular bioscience N2 - The chain length and end groups of linear PEG grafted on smooth surfaces is known to influence protein adsorption and thrombocyte adhesion. Here, it is explored whether established structure function relationships can be transferred to application relevant, rough surfaces. Functionalization of poly(ether imide) (PEI) membranes by grafting with monoamino PEG of different chain lengths (M-n=1kDa or 10kDa) and end groups (methoxy or hydroxyl) is proven by spectroscopy, changes of surface hydrophilicity, and surface shielding effects. The surface functionalization does lead to reduction of adsorption of BSA, but not of fibrinogen. The thrombocyte adhesion is increased compared to untreated PEI surfaces. Conclusively, rough instead of smooth polymer or gold surfaces should be investigated as relevant models. KW - biomaterials KW - poly(ethylene glycol) KW - protein adsorption KW - surface functionalization KW - thrombocyte adhesion Y1 - 2013 U6 - https://doi.org/10.1002/mabi.201300309 SN - 1616-5187 SN - 1616-5195 VL - 13 IS - 12 SP - 1720 EP - 1729 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Lützow, Karola A1 - Hommes-Schattmann, Paul J. A1 - Neffe, Axel T. A1 - Ahmad, Bilal A1 - Williams, Gareth R. A1 - Lendlein, Andreas T1 - Perfluorophenyl azide functionalization of electrospun poly(para-dioxanone) JF - Polymers for advanced technologies N2 - Strategies to surface-functionalize scaffolds by covalent binding of biologically active compounds are of fundamental interest to control the interactions between scaffolds and biomolecules or cells. Poly(para-dioxanone) (PPDO) is a clinically established polymer that has shown potential as temporary implant, eg, for the reconstruction of the inferior vena cava, as a nonwoven fiber mesh. However, PPDO lacks suitable chemical groups for covalent functionalization. Furthermore, PPDO is highly sensitive to hydrolysis, reflected by short in vivo half-life times and degradation during storage. Establishing a method for covalent functionalization without degradation of this hydrolyzable polymer is therefore important to enable the surface tailoring for tissue engineering applications. It was hypothesized that treatment of PPDO with an N-hydroxysuccinimide ester group bearing perfluorophenyl azide (PFPA) under UV irradiation would allow efficient surface functionalization of the scaffold. X-ray photoelectron spectroscopy and attenuated total reflectance Fourier-transformed infrared spectroscopy investigation revealed the successful binding, while a gel permeation chromatography study showed that degradation did not occur under these conditions. Coupling of a rhodamine dye to the N-hydroxysuccinimide esters on the surface of a PFPA-functionalized scaffold via its amine linker showed a homogenous staining of the PPDO in laser confocal microscopy. The PFPA method is therefore applicable even to the surface functionalization of hydrolytically labile polymers, and it was demonstrated that PFPA chemistry may serve as a versatile tool for the (bio-)functionalization of PPDO scaffolds. KW - biological applications of polymers KW - fibers KW - functionalization of polymers KW - microstructure Y1 - 2018 U6 - https://doi.org/10.1002/pat.4331 SN - 1042-7147 SN - 1099-1581 VL - 30 IS - 5 SP - 1165 EP - 1172 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Brunacci, Nadia A1 - Neffe, Axel T. A1 - Wischke, Christian A1 - Naolou, Toufik A1 - Nöchel, Ulrich A1 - Lendlein, Andreas T1 - Oligodepsipeptide (nano)carriers BT - computational design and analysis of enhanced drug loading JF - Journal of controlled release N2 - High drug loads of nanoparticles are essential to efficiently provide a desired dosage in the required timeframe, however, these conditions may not be reached with so far established degradable matrices. Our conceptual approach for increasing the drug load is based on strengthening the affinity between drug and matrix in combination with stabilizing drug-matrix-hybrids through strong intermolecular matrix interactions. Here, a method for designing such complex drug-matrix hybrids is introduced employing computational methods (molecular dynamics and docking) as well as experimental studies (affinity, drug loading and distribution, drug release from films and nanoparticles). As model system, dexamethasone (DXM), relevant for the treatment of inflammatory diseases, in combination with poly[(rac-lactide)-co-glycolide] (PLGA) as standard degradable matrix or oligo[(3-(S)-sec-butyl) morpholine-2,5-dione] diol (OBMD) as matrix with hypothesized stronger interaction with DXM were investigated. Docking studies predicted higher affinity of DXM to OBMD than PLGA and displayed amide bond participation in hydrogen bonding with OBMD. Experimental investigations on films and nanoparticles, i.e. matrices of different shapes and sizes, confirmed this phenomenon as shown e.g. by a similar to 10 times higher solid state solubility of DXM in OBMD than in PLGA. DXM-loaded particles of similar to 150 nm prepared by nanoprecipitation in aqueous environment had a drug loading (DL) up to 16 times higher when employing OBMD as matrix compared to PLGA carriers due to enhanced drug retention in the OBMD phase. Importantly, drug relase periods were not altered as the release from films and particles was mainly ruled by the diffusion length as well as matrix degradation rather than the matrix type, which can be assigned to water diffusing into the matrix and breaking up of drug-matrix hydrogen bonds. Overall, the presented design and fabrication scheme showed predictive power and might universally enable the screening of drug/matrix interactions particularly to expand the oligodepsipeptide platform technology, e.g. by varying the depsipeptide side chains, for drug carrier and release systems. KW - Oligodepsipeptide KW - Drug loading KW - Nanoparticles KW - Docking study KW - Molecular interaction design Y1 - 2019 U6 - https://doi.org/10.1016/j.jconrel.2019.03.004 SN - 0168-3659 SN - 1873-4995 VL - 301 SP - 146 EP - 156 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Neffe, Axel T. A1 - von Rüsten-Lange, Maik A1 - Braune, Steffen A1 - Lützow, Karola A1 - Roch, Toralf A1 - Richau, Klaus A1 - Krüger, Anne A1 - Becherer, Tobias A1 - Thünemann, Andreas F. A1 - Jung, Friedrich A1 - Haag, Rainer A1 - Lendlein, Andreas T1 - Multivalent grafting of hyperbranched oligo- and polyglycerols shielding rough membranes to mediate hemocompatibility JF - Journal of materials chemistry : B, Materials for biology and medicine N2 - Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo-and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials. Y1 - 2014 U6 - https://doi.org/10.1039/c4tb00184b SN - 2050-750X SN - 2050-7518 VL - 2 IS - 23 SP - 3626 EP - 3635 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Sarem, Melika A1 - Arya, Neha A1 - Heizmann, Miriam A1 - Neffe, Axel T. A1 - Barbero, Andrea A1 - Gebauer, Tim P. A1 - Martin, Ivan A1 - Lendlein, Andreas A1 - Shastri, V. Prasad T1 - Interplay between stiffness and degradation of architectured gelatin hydrogels leads to differential modulation of chondrogenesis in vitro and in vivo JF - Acta biomaterialia N2 - The limited capacity of cartilage to heal large lesions through endogenous mechanisms has led to extensive effort to develop materials to facilitate chondrogenesis. Although physical-chemical properties of biomaterials have been shown to impact in vitro chondrogenesis, whether these findings are translatable in vivo is subject of debate. Herein, architectured 3D hydrogel scaffolds (ArcGel) (produced by crosslinking gelatin with ethyl lysine diisocyanate (LDI)) were used as a model system to investigate the interplay between scaffold mechanical properties and degradation on matrix deposition by human articular chondrocytes (HAC) from healthy donors in vitro and in vivo. Using ArcGel scaffolds of different tensile and shear modulus, and degradation behavior; in this study, we compared the fate of ex vivo engineeredArcGels-chondrocytes constructs, i.e. the traditional tissue engineering approach, with the de novo formation of cartilaginous tissue in HAC laden ArcGels in an ectopic nude mouse model. While the softer and fast degrading ArcGel (LNCO3) was more efficient at promoting chondrogenic differentiation in vitro, upon ectopic implantation, the stiffer and slow degrading ArcGel (LNCO8) was superior in maintaining chondrogenic phenotype in HAC and retention of cartilaginous matrix. Furthermore, surprisingly the de novo formation of cartilage tissue was promoted only in LNCO8. Since HAC cultured for only three days in the LNCO8 environment showed upregulation of hypoxia-associated genes, this suggests a potential role for hypoxia in the observed in vivo outcomes. In summary, this study sheds light on how immediate environment (in vivo versus in vitro) can significantly impact the outcomes of cell-laden biomaterials. Statement of Significance In this study, 3D architectured hydrogels (ArcGels) with different mechanical and biodegradation properties were investigated for their potential to promote formation of cartilaginous matrix by human articular chondrocytes in vitro and in vivo. Two paradigms were explored (i) ex vivo engineering followed by in vivo implantation in ectopic site of nude mice and (ii) short in vitro culture (3 days) followed by implantation to induce de novo cartilage formation. Softer and fast degrading ArcGel were better at promoting chondrogenesis in vitro, while stiffer and slow degrading ArcGel were strikingly superior in both maintaining chondrogenesis in vivo and inducing de novo formation of cartilage. Our findings highlight the importance of the interplay between scaffold mechanics and degradation in chondrogenesis. KW - Cartilage repair KW - Scaffold stiffness KW - Scaffold contraction KW - Scaffold degradation KW - Matrix metalloproteinase KW - Hypoxia Y1 - 2018 U6 - https://doi.org/10.1016/j.actbio.2018.01.025 SN - 1742-7061 SN - 1878-7568 VL - 69 SP - 83 EP - 94 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Zaupa, Alessandro A1 - Neffe, Axel T. A1 - Pierce, Benjamin F. A1 - Nöchel, Ulrich A1 - Lendlein, Andreas T1 - Influence of tyrosine-derived moieties and drying conditions on the formation of helices in gelatin JF - Biomacromolecules : an interdisciplinary journal focused at the interface of polymer science and the biological sciences N2 - The single and triple helical organization of protein chains strongly influences the mechanical properties of gelatin-based materials. A chemical method for obtaining different degrees of helical organization in gelatin is covalent functionalization, while a physical method for achieving the same goal is the variation of the drying conditions of gelatin solutions. Here we explored how the introduction of desaminotyrosine (DAT) and desaminotyrosyl tyrosine (DATT) linked to lysine residues of gelatin influenced the kinetics and thermodynamic equilibrium of the helicalization process of single and triple helices following different drying conditions. Drying at a temperature above. the helix-to-coil transition temperature of gelatin (T > T-c, called nu(short)) generally resulted in gelatins with relatively lower triple helical content (X-c,X-t = 1-2%) than lower temperature drying (T < T-c, called nu(long)) (X-c,X-t = 8-10%), where the DAT(T) functional groups generally disrupted helix formation. While different helical contents affected the thermal transition temperatures only slightly, the mechanical properties were strongly affected for swollen hydrogels (E = 4-13 kPa for samples treated by nu(long) and E = 120-700 kPa for samples treated by nu(short)). This study shows that side group functionalization and different drying conditions are viable options to control the helicalization and macroscopic properties of gelatin-based materials. Y1 - 2011 U6 - https://doi.org/10.1021/bm101029k SN - 1525-7797 VL - 12 IS - 1 SP - 75 EP - 81 PB - American Chemical Society CY - Washington ER -