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- ItemBiocompatible Micron-Scale Silk Fibers Fabricated by Microfluidic Wet Spinning(Weinheim : Wiley-VCH, 2021) Lüken, Arne; Geiger, Matthias; Steinbeck, Lea; Joel, Anna-Christin; Lampert, Angelika; Linkhorst, John; Wessling, MatthiasFor successful material deployment in tissue engineering, the material itself, its mechanical properties, and the microscopic geometry of the product are of particular interest. While silk is a widely applied protein-based tissue engineering material with strong mechanical properties, the size and shape of artificially spun silk fibers are limited by existing processes. This study adjusts a microfluidic spinneret to manufacture micron-sized wet-spun fibers with three different materials enabling diverse geometries for tissue engineering applications. The spinneret is direct laser written (DLW) inside a microfluidic polydimethylsiloxane (PDMS) chip using two-photon lithography, applying a novel surface treatment that enables a tight print-channel sealing. Alginate, polyacrylonitrile, and silk fibers with diameters down to 1 µm are spun, while the spinneret geometry controls the shape of the silk fiber, and the spinning process tailors the mechanical property. Cell-cultivation experiments affirm bio-compatibility and showcase an interplay between the cell-sized fibers and cells. The presented spinning process pushes the boundaries of fiber fabrication toward smaller diameters and more complex shapes with increased surface-to-volume ratio and will substantially contribute to future tailored tissue engineering materials for healthcare applications. © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
- ItemHow Much Physical Guidance is Needed to Orient Growing Axons in 3D Hydrogels?(Weinheim : Wiley-VCH, 2020) Rose, Jonas C.; Gehlen, David B.; Omidinia-Anarkoli, Abdolrahman; Fölster, Maaike; Haraszti, Tamás; Jaekel, Esther E.; De Laporte, LauraDirecting cells is essential to organize multi-cellular organisms that are built up from subunits executing specific tasks. This guidance requires a precisely controlled symphony of biochemical, mechanical, and structural signals. While many guiding mechanisms focus on 2D structural patterns or 3D biochemical gradients, injectable material platforms that elucidate how cellular processes are triggered by defined 3D physical guiding cues are still lacking but crucial for the repair of soft tissues. Herein, a recently developed anisotropic injectable hybrid hydrogel (Anisogel) contains rod-shaped microgels that orient in situ by a magnetic field and has propelled studying 3D cell guidance. Here, the Anisogel is used to investigate the dependence of axonal guidance on microgel dimensions, aspect ratio, and distance. While large microgels result in high material anisotropy, they significantly reduce neurite outgrowth and thus the guidance efficiency. Narrow and long microgels enable strong axonal guidance with maximal outgrowth including cell sensing over distances of tens of micrometers in 3D. Moreover, nerve cells decide to orient inside the Anisogel within the first three days, followed by strengthening of the alignment, which goes along with oriented fibronectin deposition. These findings demonstrate the potential of the Anisogel to tune structural and mechanical parameters for specific applications. © 2020 The Authors. Published by Wiley-VCH GmbH
- ItemDigitally Fabricated and Naturally Augmented In Vitro Tissues(Weinheim : Wiley-VCH, 2020) Duarte Campos, Daniela F.; De Laporte, LauraHuman in vitro tissues are extracorporeal 3D cultures of human cells embedded in biomaterials, commonly hydrogels, which recapitulate the heterogeneous, multiscale, and architectural environment of the human body. Contemporary strategies used in 3D tissue and organ engineering integrate the use of automated digital manufacturing methods, such as 3D printing, bioprinting, and biofabrication. Human tissues and organs, and their intra- and interphysiological interplay, are particularly intricate. For this reason, attentiveness is rising to intersect materials science, medicine, and biology with arts and informatics. This report presents advances in computational modeling of bioink polymerization and its compatibility with bioprinting, the use of digital design and fabrication in the development of fluidic culture devices, and the employment of generative algorithms for modeling the natural and biological augmentation of in vitro tissues. As a future direction, the use of serially linked in vitro tissues as human body-mimicking systems and their application in drug pharmacokinetics and metabolism, disease modeling, and diagnostics are discussed. © 2020 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
- ItemControlling Structure with Injectable Biomaterials to Better Mimic Tissue Heterogeneity and Anisotropy(Weinheim : Wiley-VCH, 2021) Babu, Susan; Albertino, Filippo; Omidinia-Anarkoli, Abdolrahman; De Laporte, LauraTissue regeneration of sensitive tissues calls for injectable scaffolds, which are minimally invasive and offer minimal damage to the native tissues. However, most of these systems are inherently isotropic and do not mimic the complex hierarchically ordered nature of the native extracellular matrices. This review focuses on the different approaches developed in the past decade to bring in some form of anisotropy to the conventional injectable tissue regenerative matrices. These approaches include introduction of macroporosity, in vivo pattering to present biomolecules in a spatially and temporally controlled manner, availability of aligned domains by means of self-assembly or oriented injectable components, and in vivo bioprinting to obtain structures with features of high resolution that resembles native tissues. Toward the end of the review, different techniques to produce building blocks for the fabrication of heterogeneous injectable scaffolds are discussed. The advantages and shortcomings of each approach are discussed in detail with ideas to improve the functionality and versatility of the building blocks. © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
- ItemNanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma(London : BioMed Central, 2022) Lu, Yi; Gao, Yue; Yang, Huan; Hu, Yong; Li, XinTraditional treatments for advanced hepatocellular carcinoma (HCC), such as surgical resection, transplantation, radiofrequency ablation, and chemotherapy are unsatisfactory, and therefore the exploration of powerful therapeutic strategies is urgently needed. Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects. Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC. Encouragingly, in 2022, icaritin soft capsules were approved by the National Medical Products Administration (NMPA) of China for the immunotherapy of advanced HCC. However, the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency. Recently, functionalized drug delivery systems including stimuli-responsive nanocarriers, cell membrane-coated nanocarriers, and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs, including the low bioavailability and limited delivery efficiency as well as side effects. Taken together, the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC. Herein, we compared the different preparation methods for icaritin, interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC, and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritin-based nanomedicines for advanced HCC immunotherapy. Finally, the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.
- ItemGuiding cell adhesion and motility by modulating cross-linking and topographic properties of microgel arrays(San Francisco, California, US : PLOS, 2021) Riegert, Janine; Töpel, Alexander; Schieren, Jana; Coryn, Renee; Dibenedetto, Stella; Braunmiller, Dominik; Zajt, Kamil; Schalla, Carmen; Rütten, Stephan; Zenke, Martin; Pich, Andrij; Sechi, Antonio; Blank, Kerstin G.Biomaterial-driven modulation of cell adhesion and migration is a challenging aspect of tissue engineering. Here, we investigated the impact of surface-bound microgel arrays with variable geometry and adjustable cross-linking properties on cell adhesion and migration. We show that cell migration is inversely correlated with microgel array spacing, whereas directionality increases as array spacing increases. Focal adhesion dynamics is also modulated by microgel topography resulting in less dynamic focal adhesions on surface-bound microgels. Microgels also modulate the motility and adhesion of Sertoli cells used as a model for cell migration and adhesion. Both focal adhesion dynamics and speed are reduced on microgels. Interestingly, Gas2L1, a component of the cytoskeleton that mediates the interaction between microtubules and microfilaments, is dispensable for the regulation of cell adhesion and migration on microgels. Finally, increasing microgel cross-linking causes a clear reduction of focal adhesion turnover in Sertoli cells. These findings not only show that spacing and rigidity of surface-grafted microgels arrays can be effectively used to modulate cell adhesion and motility of diverse cellular systems, but they also form the basis for future developments in the fields of medicine and tissue engineering.
- ItemEfficacy of A Poly(MeOEGMA) Brush on the Prevention of Escherichia coli Biofilm Formation and Susceptibility(Basel : MDPI, 2020) Alves, Patrícia; Gomes, Luciana Calheiros; Rodríguez-Emmenegger, Cesar; Mergulhão, Filipe JoséUrinary tract infections are one of the most common hospital-acquired infections, and they are often associated with biofilm formation in indwelling medical devices such as catheters and stents. This study aims to investigate the antibiofilm performance of a polymer brush—poly[oligo(ethylene glycol) methyl ether methacrylate], poly(MeOEGMA)—and evaluate its effect on the antimicrobial susceptibility of Escherichia coli biofilms formed on that surface. Biofilms were formed in a parallel plate flow chamber (PPFC) for 24 h under the hydrodynamic conditions prevailing in urinary catheters and stents and challenged with ampicillin. Results obtained with the brush were compared to those obtained with two control surfaces, polydimethylsiloxane (PDMS) and glass. The polymer brush reduced by 57% the surface area covered by E. coli after 24 h, as well as the number of total adhered cells. The antibiotic treatment potentiated cell death and removal, and the total cell number was reduced by 88%. Biofilms adapted their architecture, and cell morphology changed to a more elongated form during that period. This work suggests that the poly(MeOEGMA) brush has potential to prevent bacterial adhesion in urinary tract devices like ureteral stents and catheters, as well as in eradicating biofilms developed in these biomedical devices. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemEndOxy: Dynamic Long-Term Evaluation of Endothelialized Gas Exchange Membranes for a Biohybrid Lung(Weinheim : Wiley-VCH, 2020) Klein, Sarah; Hesselmann, Felix; Djeljadini, Suzana; Berger, Tanja; Thiebes, Anja Lena; Schmitz-Rode, Thomas; Jockenhoevel, Stefan; Cornelissen, Christian G.In the concept of a biohybrid lung, endothelial cells seeded on gas exchange membranes form a non-thrombogenic an anti-inflammatory surface to overcome the lacking hemocompatibility of today’s oxygenators during extracorporeal membrane oxygenation. To evaluate this concept, the long-term stability and gas exchange performance of endothelialized RGD-conjugated polydimethylsiloxane (RGD-PDMS) membranes was evaluated. Human umbilical vein endothelial cells (ECs) were cultured on RGD-PDMS in a model system under physiological wall shear stress (WSS) of 0.5 Pa for up to 33 days. Gas exchange performance was tested with three biological replicates under elevated WSS of 2.5 Pa using porcine blood adjusted to venous values following ISO 7199 and blood gas analysis. EC morphology was assessed by immunocytochemistry (n = 3). RGD-PDMS promoted endothelialization and stability of endothelialized membranes was shown for at least 33 days and for a maximal WSS of 2.5 Pa. Short-term exposure to porcine blood did not affect EC integrity. The gas transfer tests provided evidence for the oxygenation and decarboxylation of the blood across endothelialized membranes with a decrease of transfer rates over time that needs to be addressed in further studies with larger sample sizes. Our results demonstrate the general suitability of RGD-PDMS for biohybrid lung applications, which might enable long-term support of patients with chronic lung failure in the future. © 2019, The Author(s).
- ItemEndOxy: Mid-term stability and shear stress resistance of endothelial cells on PDMS gas exchange membranes(Oxford [u.a.] : Wiley-Blackwell, 2020) Hellmann, Ariane; Klein, Sarah; Hesselmann, Felix; Djeljadini, Suzana; Schmitz-Rode, Thomas; Jockenhoevel, Stefan; Cornelissen, Christian G.; Thiebes, Anja LenaEndothelialized oxygenator devices (EndOxy) with a physiological, nonthrombogenic, and anti-inflammatory surface offer the potential to overcome current shortcomings of conventional extracorporeal membrane oxygenation such as complications like thromboembolism and bleeding that deteriorate adequate long-term hemocompatibility. The approach of endothelialization of gas exchange membranes, and thus the formation of a nonthrombogenic and anti-inflammatory surface, is promising. In this study, we investigated the mid-term shear stress resistance as well as gas transfer rates and cell densities of endothelial cells seeded on RGD-conjugated polydimethylsiloxane (RGD-PDMS) gas exchange membranes under dynamic conditions. Human umbilical vein endothelial cells were seeded on RGD-PDMS and exposed to defined shear stresses in a microfluidic bioreactor. Endothelial cell morphology was assessed by bright field microscopy and immunocytochemistry. Furthermore, gas transfer measurement of blank, RGD-conjugated, and endothelialized PDMS oxygenator membranes was performed. RGD-PDMS gas exchange membranes proved suitable for the dynamic culture of endothelial cells for up to 21 days at a wall shear stress of 2.9 dyn/cm2. Furthermore, the cells resisted increased wall shear stresses up to 8.6 dyn/cm2 after a previous dynamic preculture of each one hour at 2.9 dyn/cm2 and 5.7 dyn/cm2. Also, after a longer dynamic preculture of three days at 2.9 dyn/cm2 and one hour at 5.7 dyn/cm2, increased wall shear stresses of 8.6 dyn/cm2 were tolerated by the cells and cell integrity could be remained. Gas transfer (GT) tests revealed that neither RGD conjugation nor endothelialization of RGD-PDMS significantly decrease the gas transfer rates of the membranes during short-term trials. Gas transfer rates are stable for at least 72 hours of dynamic cultivation of endothelial cells. Immunocytochemistry showed that the cell layer stained positive for typical endothelial cell markers CD31 and von Willebrand factor (VWF) after all trials. Cell density of EC on RGD-PDMS increased between 3 and 21 days of dynamic culture. In this study, we show the suitability of RGD-PDMS membranes for flow resistant endothelialization of gas-permeable membranes, demonstrating the feasibility of this approach for a biohybrid lung. © 2020 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC
- ItemAnisometric Microstructures to Determine Minimal Critical Physical Cues Required for Neurite Alignment(Weinheim : Wiley-VCH, 2021) Vedaraman, Sitara; Perez-Tirado, Amaury; Haraszti, Tamas; Gerardo-Nava, Jose; Nishiguchi, Akihiro; De Laporte, LauraIn nerve regeneration, scaffolds play an important role in providing an artificial extracellular matrix with architectural, mechanical, and biochemical cues to bridge the site of injury. Directed nerve growth is a crucial aspect of nerve repair, often introduced by engineered scaffolds imparting linear tracks. The influence of physical cues, determined by well-defined architectures, has been mainly studied for implantable scaffolds and is usually limited to continuous guiding features. In this report, the potential of short anisometric microelements in inducing aligned neurite extension, their dimensions, and the role of vertical and horizontal distances between them, is investigated. This provides crucial information to create efficient injectable 3D materials with discontinuous, in situ magnetically oriented microstructures, like the Anisogel. By designing and fabricating periodic, anisometric, discreet guidance cues in a high-throughput 2D in vitro platform using two-photon lithography techniques, the authors are able to decipher the minimal guidance cues required for directed nerve growth along the major axis of the microelements. These features determine whether axons grow unidirectionally or cross paths via the open spaces between the elements, which is vital for the design of injectable Anisogels for enhanced nerve repair. © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH