@article{SaremAryaHeizmannetal.2018, author = {Sarem, Melika and Arya, Neha and Heizmann, Miriam and Neffe, Axel T. and Barbero, Andrea and Gebauer, Tim P. and Martin, Ivan and Lendlein, Andreas and Shastri, V. Prasad}, title = {Interplay between stiffness and degradation of architectured gelatin hydrogels leads to differential modulation of chondrogenesis in vitro and in vivo}, series = {Acta biomaterialia}, volume = {69}, journal = {Acta biomaterialia}, publisher = {Elsevier}, address = {Oxford}, issn = {1742-7061}, doi = {10.1016/j.actbio.2018.01.025}, pages = {83 -- 94}, year = {2018}, abstract = {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.}, language = {en} } @article{NeffevonRuestenLangeBrauneetal.2014, author = {Neffe, Axel T. and von R{\"u}sten-Lange, Maik and Braune, Steffen and L{\"u}tzow, Karola and Roch, Toralf and Richau, Klaus and Kr{\"u}ger, Anne and Becherer, Tobias and Th{\"u}nemann, Andreas F. and Jung, Friedrich and Haag, Rainer and Lendlein, Andreas}, title = {Multivalent grafting of hyperbranched oligo- and polyglycerols shielding rough membranes to mediate hemocompatibility}, series = {Journal of materials chemistry : B, Materials for biology and medicine}, volume = {2}, journal = {Journal of materials chemistry : B, Materials for biology and medicine}, number = {23}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2050-750X}, doi = {10.1039/c4tb00184b}, pages = {3626 -- 3635}, year = {2014}, abstract = {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.}, language = {en} } @article{BrunacciNeffeWischkeetal.2019, author = {Brunacci, Nadia and Neffe, Axel T. and Wischke, Christian and Naolou, Toufik and N{\"o}chel, Ulrich and Lendlein, Andreas}, title = {Oligodepsipeptide (nano)carriers}, series = {Journal of controlled release}, volume = {301}, journal = {Journal of controlled release}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-3659}, doi = {10.1016/j.jconrel.2019.03.004}, pages = {146 -- 156}, year = {2019}, abstract = {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.}, language = {en} } @article{LuetzowHommesSchattmannNeffeetal.2018, author = {L{\"u}tzow, Karola and Hommes-Schattmann, Paul J. and Neffe, Axel T. and Ahmad, Bilal and Williams, Gareth R. and Lendlein, Andreas}, title = {Perfluorophenyl azide functionalization of electrospun poly(para-dioxanone)}, series = {Polymers for advanced technologies}, volume = {30}, journal = {Polymers for advanced technologies}, number = {5}, publisher = {Wiley}, address = {Hoboken}, issn = {1042-7147}, doi = {10.1002/pat.4331}, pages = {1165 -- 1172}, year = {2018}, abstract = {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.}, language = {en} } @article{NeffevonRuestenLangeBrauneetal.2013, author = {Neffe, Axel T. and von R{\"u}sten-Lange, Maik and Braune, Steffen and L{\"u}tzow, Karola and Roch, Toralf and Richau, Klaus and Jung, Friedrich and Lendlein, Andreas}, title = {Poly(ethylene glycol) grafting to Poly(ether imide) membranes - influence on protein adsorption and Thrombocyte adhesion}, series = {Macromolecular bioscience}, volume = {13}, journal = {Macromolecular bioscience}, number = {12}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1616-5187}, doi = {10.1002/mabi.201300309}, pages = {1720 -- 1729}, year = {2013}, abstract = {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.}, language = {en} } @article{ZhangSaidWischkeetal.2017, author = {Zhang, Nan and Said, Andre and Wischke, Christian and Kral, Vivian and Brodwolf, Robert and Volz, Pierre and Boreham, Alexander and Gerecke, Christian and Li, Wenzhong and Neffe, Axel T. and Kleuser, Burkhard and Alexiev, Ulrike and Lendlein, Andreas and Sch{\"a}fer-Korting, Monika}, title = {Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles - Composition-dependent skin penetration enhancement of a dye probe and biocompatibility}, series = {European Journal of Pharmaceutics and Biopharmaceutics}, volume = {116}, journal = {European Journal of Pharmaceutics and Biopharmaceutics}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0939-6411}, doi = {10.1016/j.ejpb.2016.10.019}, pages = {66 -- 75}, year = {2017}, abstract = {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.}, language = {en} } @article{WangNaolouMaetal.2017, author = {Wang, Weiwei and Naolou, Toufik and Ma, Nan and Deng, Zijun and Xu, Xun and Mansfeld, Ulrich and Wischke, Christian and Gossen, Manfred and Neffe, Axel T. and Lendlein, Andreas}, title = {Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells}, series = {Biomacromolecules : an interdisciplinary journal focused at the interface of polymer science and the biological sciences}, volume = {18}, journal = {Biomacromolecules : an interdisciplinary journal focused at the interface of polymer science and the biological sciences}, publisher = {American Chemical Society}, address = {Washington}, issn = {1525-7797}, doi = {10.1021/acs.biomac.7b01034}, pages = {3819 -- 3833}, year = {2017}, abstract = {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.}, language = {en} } @article{IzraylitHommesSchattmannNeffeetal.2020, author = {Izraylit, Victor and Hommes-Schattmann, Paul J. and Neffe, Axel T. and Gould, Oliver E. C. and Lendlein, Andreas}, title = {Polyester urethane functionalizable through maleimide side-chains and cross-linkable by polylactide stereocomplexes}, series = {European polymer journal}, volume = {137}, journal = {European polymer journal}, publisher = {Elsevier}, address = {Oxford}, issn = {0014-3057}, doi = {10.1016/j.eurpolymj.2020.109916}, pages = {8}, year = {2020}, abstract = {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.}, language = {en} } @article{JulichGrunerLoewenbergNeffeetal.2013, author = {Julich-Gruner, Konstanze K. and L{\"o}wenberg, Candy and Neffe, Axel T. and Behl, Marc and Lendlein, Andreas}, title = {Recent trends in the chemistry of shape-memory polymers}, series = {Macromolecular chemistry and physics}, volume = {214}, journal = {Macromolecular chemistry and physics}, number = {5}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1022-1352}, doi = {10.1002/macp.201200607}, pages = {527 -- 536}, year = {2013}, abstract = {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.}, language = {en} } @article{BlockiLoewenbergJiangetal.2017, author = {Blocki, Anna and L{\"o}wenberg, Candy and Jiang, Yi and Kratz, Karl and Neffe, Axel T. and Jung, Friedrich and Lendlein, Andreas}, title = {Response of encapsulated cells to a gelatin matrix with varied bulk and microenvironmental elastic properties}, series = {Polymers for advanced technologies}, volume = {28}, journal = {Polymers for advanced technologies}, publisher = {Wiley}, address = {Hoboken}, issn = {1042-7147}, doi = {10.1002/pat.3947}, pages = {1245 -- 1251}, year = {2017}, abstract = {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.}, language = {en} }