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- ItemPoly(2-alkyl-2-oxazoline)-Heparin Hydrogels—Expanding the Physicochemical Parameter Space of Biohybrid Materials(Weinheim : Wiley-VCH, 2021) Hahn, Dominik; Sonntag, Jannick M.; Lück, Steffen; Maitz, Manfred F.; Freudenberg, Uwe; Jordan, Rainer; Werner, CarstenPoly(ethylene glycol) (PEG)-glycosaminoglycan (GAG) hydrogel networks are established as very versatile biomaterials. Herein, the synthetic gel component of the biohybrid materials is systematically varied by combining different poly(2-alkyl-2-oxazolines) (POx) with heparin applying a Michael-type addition crosslinking scheme: POx of gradated hydrophilicity and temperature-responsiveness provides polymer networks of distinctly different stiffness and swelling. Adjusting the mechanical properties and the GAG concentration of the gels to similar values allows for modulating the release of GAG-binding growth factors (VEGF165 and PDGF-BB) by the choice of the POx and its temperature-dependent conformation. Adsorption of fibronectin, growth of fibroblasts, and bacterial adhesion scale with the hydrophobicity of the gel-incorporated POx. In vitro hemocompatibility tests with freshly drawn human whole blood show advantages of POx-based gels compared to the PEG-based reference materials. Biohybrid POx hydrogels can therefore enable biomedical technologies requiring GAG-based materials with customized and switchable physicochemical characteristics. © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.
- ItemKallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma(Basel : MDPI, 2021) Candido, Juliana B; Maiques, Oscar; Boxberg, Melanie; Kast, Verena; Peerani, Eleonora; Tomás-Bort, Elena; Weichert, Wilko; Sananes, Amiram; Papo, Niv; Magdolen, Viktor; Sanz-Moreno, Victoria; Loessner, DanielaAs cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.
- ItemDurable endothelium-mimicking coating for surface bioengineering cardiovascular stents([Bejing] : KeAi Publishing, 2021) Ma, Qing; Shi, Xiuying; Tan, Xing; Wang, Rui; Xiong, Kaiqin; Maitz, Manfred F.; Cui, Yuanyuan; Hu, Zhangmei; Tu, Qiufen; Huang, Nan; Shen, Li; Yang, ZhiluMimicking the nitric oxide (NO)-release and glycocalyx functions of native vascular endothelium on cardiovascular stent surfaces has been demonstrated to reduce in-stent restenosis (ISR) effectively. However, the practical performance of such an endothelium-mimicking surfaces is strictly limited by the durability of both NO release and bioactivity of the glycocalyx component. Herein, we present a mussel-inspired amine-bearing adhesive coating able to firmly tether the NO-generating species (e.g., Cu-DOTA coordination complex) and glycocalyx-like component (e.g., heparin) to create a durable endothelium-mimicking surface. The stent surface was firstly coated with polydopamine (pDA), followed by a surface chemical cross-link with polyamine (pAM) to form a durable pAMDA coating. Using a stepwise grafting strategy, Cu-DOTA and heparin were covalently grafted on the pAMDA-coated stent based on carbodiimide chemistry. Owing to both the high chemical stability of the pAMDA coating and covalent immobilization manner of the molecules, this proposed strategy could provide 62.4% bioactivity retention ratio of heparin, meanwhile persistently generate NO at physiological level from 5.9 ± 0.3 to 4.8 ± 0.4 × 10−10 mol cm−2 min−1 in 1 month. As a result, the functionalized vascular stent showed long-term endothelium-mimicking physiological effects on inhibition of thrombosis, inflammation, and intimal hyperplasia, enhanced re-endothelialization, and hence efficiently reduced ISR.
- ItemIntelligent H2S release coating for regulating vascular remodeling(Bejing : KeAi Publishing, 2021) Lu, Bingyang; Han, Xiao; Zhao, Ansha; Luo, Dan; Maitz, Manfred F.; Wang, Haohao; Yang, Ping; Huang, NanCoronary atherosclerotic lesions exhibit a low-pH chronic inflammatory response. Due to insufficient drug release control, drug-eluting stent intervention can lead to delayed endothelialization, advanced thrombosis, and unprecise treatment. In this study, hyaluronic acid and chitosan were used to prepare pH-responsive self-assembling films. The hydrogen sulfide (H2S) releasing aspirin derivative ACS14 was used as drug in the film. The film regulates the release of the drug adjusted to the microenvironment of the lesion, and the drug balances the vascular function by releasing the regulating gas H2S, which comparably to NO promotes the self-healing capacity of blood vessels. Drug releasing profiles of the films at different pH, and other biological effects on blood vessels were evaluated through blood compatibility, cellular, and implantation experiments. This novel method of self-assembled films which H2S in an amount, which is adjusted to the condition of the lesion provides a new concept for the treatment of cardiovascular diseases.
- ItemPhoto-functionalized TiO2 nanotubes decorated with multifunctional Ag nanoparticles for enhanced vascular biocompatibility(Bejing : KeAi Publishing, 2021) Chen, Jiang; Dai, Sheng; Liu, Luying; Maitz, Manfred F.; Liao, Yuzhen; Cui, Jiawei; Zhao, Ansha; Yang, Ping; Huang, Nan; Wang, YunbingTitanium dioxide (TiO2) has a long history of application in blood contact materials, but it often suffers from insufficient anticoagulant properties. Recently, we have revealed the photocatalytic effect of TiO2 also induces anticoagulant properties. However, for long-term vascular implant devices such as vascular stents, besides anticoagulation, also anti-inflammatory, anti-hyperplastic properties, and the ability to support endothelial repair, are desired. To meet these requirements, here, we immobilized silver nanoparticles (AgNPs) on the surface of TiO2 nanotubes (TiO2-NTs) to obtain a composite material with enhanced photo-induced anticoagulant property and improvement of the other requested properties. The photo-functionalized TiO2-NTs showed protein-fouling resistance, causing the anticoagulant property and the ability to suppress cell adhesion. The immobilized AgNPs increased the photocatalytic activity of TiO2-NTs to enhances its photo-induced anticoagulant property. The AgNP density was optimized to endow the TiO2-NTs with anti-inflammatory property, a strong inhibitory effect on smooth muscle cells (SMCs), and low toxicity to endothelial cells (ECs). The in vivo test indicated that the photofunctionalized composite material achieved outstanding biocompatibility in vasculature via the synergy of photo-functionalized TiO2-NTs and the multifunctional AgNPs, and therefore has enormous potential in the field of cardiovascular implant devices. Our research could be a useful reference for further designing of multifunctional TiO2 materials with high vascular biocompatibility.
- ItemA Complementary and Revised View on the N-Acylation of Chitosan with Hexanoyl Chloride(Basel : MDPI, 2021) Reis, Berthold; Gerlach, Niklas; Steinbach, Christine; Haro Carrasco, Karina; Oelmann, Marina; Schwarz, Simona; Müller, Martin; Schwarz, DanaThe modification of the biobased polymer chitosan is a broad and widely studied field. Herein, an insight into the hydrophobization of low-molecular-weight chitosan by substitution of amino functionalities with hexanoyl chloride is reported. Thereby, the influence of the pH of the reaction media was investigated. Further, methods for the determination of the degree of substitution based on 1H-NMR, FTIR, and potentiometric titration were compared and discussed regarding their accuracy and precision. 1H-NMR was the most accurate method, while FTIR and the potentiometric titration, though precise and reproducible, underlie the influence of complete protonation and solubility issues. Additionally, the impact of the pH variation during the synthesis on the properties of the samples was investigated by Cd2+ sorption experiments. The adjusted pH values during the synthesis and, therefore, the obtained degrees of substitution possessed a strong impact on the adsorption properties of the final material.
- ItemTargeted RNAi of BIRC5/Survivin Using Antibody-Conjugated Poly(Propylene Imine)-Based Polyplexes Inhibits Growth of PSCA-Positive Tumors(Basel : MDPI, 2021) Jugel, Willi; Aigner, Achim; Michen, Susanne; Hagstotz, Alexander; Ewe, Alexander; Appelhans, Dietmar; Schackert, Gabriele; Temme, Achim; Tietze, StefanieDelivery of siRNAs for the treatment of tumors critically depends on the development of efficient nucleic acid carrier systems. The complexation of dendritic polymers (dendrimers) results in nanoparticles, called dendriplexes, that protect siRNA from degradation and mediate non-specific cellular uptake of siRNA. However, large siRNA doses are required for in vivo use due to accumulation of the nanoparticles in sinks such as the lung, liver, and spleen. This suggests the exploration of targeted nanoparticles for enhancing tumor cell specificity and achieving higher siRNA levels in tumors. In this work, we report on the targeted delivery of a therapeutic siRNA specific for BIRC5/Survivin in vitro and in vivo to tumor cells expressing the surface marker prostate stem cell antigen (PSCA). For this, polyplexes consisting of single-chain antibody fragments specific for PSCA conjugated to siRNA/maltose-modified poly(propylene imine) dendriplexes were used. These polyplexes were endocytosed by PSCA-positive 293TPSCA/ffLuc and PC3PSCA cells and caused knockdown of reporter gene firefly luciferase and Survivin expression, respectively. In a therapeutic study in PC3PSCA xenograft-bearing mice, significant anti-tumor effects were observed upon systemic administration of the targeted polyplexes. This indicates superior anti-tumor efficacy when employing targeted delivery of Survivin-specific siRNA, based on the additive effects of siRNA-mediated Survivin knockdown in combination with scFv-mediated PSCA inhibition.
- ItemMatrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis(New York, NY [u.a.] : Elsevier, 2021) Geervliet, Eline; Moreno, Silvia; Baiamonte, Luca; Booijink, Richell; Boye, Susanne; Wang, Peng; Voit, Brigitte; Lederer, Albena; Appelhans, Dietmar; Bansal, RuchiLiver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
- ItemUltrathin 2D Titanium Carbide MXene (Ti3C2Tx) Nanoflakes Activate WNT/HIF-1α-Mediated Metabolism Reprogramming for Periodontal Regeneration(Weinheim : Wiley-VCH, 2021) Cui, Di; Kong, Na; Ding, Liang; Guo, Yachong; Yang, Wenrong; Yan, FuhuaPeriodontal defect regeneration in severe periodontitis relies on the differentiation and proliferation of periodontal ligament cells (PDLCs). Recently, an emerging 2D nanomaterial, MXene (Ti3C2Tx), has gained more and more attention due to the extensive antibacterial and anticancer activity, while its potential biomedical application on tissue regeneration remains unclear. Through a combination of experimental and multiscale simulation schemes, Ti3C2Tx has exhibited satisfactory biocompatibility and induced distinguish osteogenic differentiation of human PDLCs (hPDLCs), with upregulated osteogenesis-related genes. Ti3C2Tx manages to activate the Wnt/β-catenin signaling pathway by enhancing the Wnt-Frizzled complex binding, thus stabilizing HIF-1α and altering metabolic reprogramming into glycolysis. In vivo, hPDLCs pretreated by Ti3C2Tx display excellent performance in new bone formation and osteoclast inhibition with enhanced RUNX2, HIF-1α, and β-catenin in an experimental rat model of periodontal fenestration defects, indicating that this material has high efficiency of periodontal regeneration promotion. It is demonstrated in this work that Ti3C2Tx has highly efficient therapeutic effects in osteogenic differentiation and periodontal defect repairment. © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
- ItemSelective vulnerability of inhibitory networks in multiple sclerosis(Berlin ; Heidelberg : Springer, 2021) Zoupi, Lida; Booker, Sam A.; Eigel, Dimitri; Werner, Carsten; Kind, Peter C.; Spires-Jones, Tara L.; Newland, Ben; Williams, Anna C.In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments. © 2021, The Author(s).