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Keywords = 3D peptide hydrogel model

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17 pages, 2163 KiB  
Article
Non-Invasive Nanometer Resolution Assessment of Cell–Soft Hydrogel System Mechanical Properties by Scanning Ion Conductance Microscopy
by Tatiana N. Tikhonova, Anastasia V. Barkovaya, Yuri M. Efremov, Vugara V. Mamed-Nabizade, Vasilii S. Kolmogorov, Peter S. Timashev, Nikolay N. Sysoev, Victor V. Fadeev, Petr V. Gorelkin, Lihi Adler-Abramovich, Alexander S. Erofeev and Evgeny A. Shirshin
Int. J. Mol. Sci. 2024, 25(24), 13479; https://doi.org/10.3390/ijms252413479 - 16 Dec 2024
Viewed by 1046
Abstract
Biomimetic hydrogels have garnered increased interest due to their considerable potential for use in various fields, such as tissue engineering, 3D cell cultivation, and drug delivery. The primary challenge for applying hydrogels in tissue engineering is accurately evaluating their mechanical characteristics. In this [...] Read more.
Biomimetic hydrogels have garnered increased interest due to their considerable potential for use in various fields, such as tissue engineering, 3D cell cultivation, and drug delivery. The primary challenge for applying hydrogels in tissue engineering is accurately evaluating their mechanical characteristics. In this context, we propose a method using scanning ion conductance microscopy (SICM) to determine the rigidity of living human breast cancer cells MCF-7 cells grown on a soft, self-assembled Fmoc-FF peptide hydrogel. Moreover, it is demonstrated that the map of Young’s modulus distribution obtained by the SICM method allows for determining the core location. The Young’s modules for MCF-7 cells decrease with the substrate stiffening, with values of 1050 Pa, 835 Pa, and 600 Pa measured on a Petri dish, Fmoc-FF hydrogel, and Fmoc-FF/chitosan hydrogel, respectively. A comparative analysis of the SICM results and the data obtained by atomic force microscopy was in good agreement, allowing for the use of a composite cell–substrate model (CoCS) to evaluate the ‘soft substrate effect’. Using the CoCS model allowed us to conclude that the MCF-7 softening was due to the cells’ mechanical properties variations due to cytoskeletal changes. This research provides immediate insights into changes in cell mechanical properties resulting from different soft scaffold substrates. Full article
(This article belongs to the Section Molecular Nanoscience)
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17 pages, 4336 KiB  
Article
New Supramolecular Hydrogels Based on Diastereomeric Dehydrotripeptide Mixtures for Potential Drug Delivery Applications
by Carlos B. P. Oliveira, André Carvalho, Renato B. Pereira, David M. Pereira, Loic Hilliou, Peter J. Jervis, José A. Martins and Paula M. T. Ferreira
Gels 2024, 10(10), 629; https://doi.org/10.3390/gels10100629 - 30 Sep 2024
Cited by 2 | Viewed by 1782
Abstract
Self-assembly of peptide building blocks offers unique opportunities for bottom-up preparation of exquisite nanostructures, nanoarchitectures, and nanostructured bulk materials, namely hydrogels. In this work we describe the synthesis, characterization, gelation, and rheological properties of new dehydrotripeptides, Cbz-L-Lys(Cbz)-L,D-Asp-∆Phe-OH [...] Read more.
Self-assembly of peptide building blocks offers unique opportunities for bottom-up preparation of exquisite nanostructures, nanoarchitectures, and nanostructured bulk materials, namely hydrogels. In this work we describe the synthesis, characterization, gelation, and rheological properties of new dehydrotripeptides, Cbz-L-Lys(Cbz)-L,D-Asp-∆Phe-OH and (2-Naph)-L-Lys(2-Naph)-L,D-Asp-∆Phe-OH, containing a N-terminal lysine residue Nα,ε-bis-capped with carboxybenzyl (Cbz) and 2-Naphthylacetyl (2-Naph) aromatic moieties, an aspartic acid residue (Asp), and a C-terminal dehydrophenylalanine (∆Phe) residue. The dehydrotripeptides were obtained as diastereomeric mixtures (L,L,Z and L,D,Z), presumably via aspartimide chemistry. The dehydrotripeptides afforded hydrogels at exceedingly low concentrations (0.1 and 0.04 wt%). The hydrogels revealed exceptional elasticity (G’ = 5.44 × 104 and 3.43 × 106 Pa) and self-healing properties. STEM studies showed that the diastereomers of the Cbz-capped peptide undergo co-assembly, generating a fibrillar 3D network, while the diastereomers of the 2-Naph-capped dehydropeptide seem to undergo self-sorting, originating a fibril network with embedded spheroidal nanostructures. The 2-Naph-capped hydrogel displayed full fast recovery following breakup by a mechanical stimulus. Spheroidal nanostructures are absent in the recovered hydrogel, as seen by STEM, suggesting that the mechanical stimulus triggers rearrangement of the spheroidal nanostructures into fibers. Overall, this study demonstrates that diastereomeric mixtures of peptides can be efficacious gelators. Importantly, these results suggest that the structure (size, aromaticity) of the capping group can have a directing effect on the self-assembly (co-assembly vs. self-sorting) of diastereomers. The cytotoxicity of the newly synthesized gelators was evaluated using human keratinocytes (HaCaT cell line). The results indicated that the two gelators exhibited some cytotoxicity, having a small impact on cell viability. In sustained release experiments, the influence of the charge on model drug compounds was assessed in relation to their release rate from the hydrogel matrix. The hydrogels demonstrated sustained release for methyl orange (anionic), while methylene blue (cationic) was retained within the network. Full article
(This article belongs to the Special Issue Recent Advances in Physical Gels and Their Applications)
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14 pages, 2929 KiB  
Article
Amyloid Beta Peptides Lead to Mast Cell Activation in a Novel 3D Hydrogel Model
by Jingshu Liu, Sihan Liu, Li Zeng and Irene Tsilioni
Int. J. Mol. Sci. 2023, 24(15), 12002; https://doi.org/10.3390/ijms241512002 - 26 Jul 2023
Cited by 4 | Viewed by 2560
Abstract
Alzheimer’s disease (AD) is a prevalent neurodegenerative disease and the world’s primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one [...] Read more.
Alzheimer’s disease (AD) is a prevalent neurodegenerative disease and the world’s primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aβ deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aβ peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aβ1-42, Aβ1-40, and Aβ25-35 caused MCs to secrete inflammatory mediators, with Aβ1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD. Full article
(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)
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15 pages, 3369 KiB  
Article
Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML
by Jenna R. James, Johnathan Curd, Jennifer C. Ashworth, Mays Abuhantash, Martin Grundy, Claire H. Seedhouse, Kenton P. Arkill, Amanda J. Wright, Catherine L. R. Merry and Alexander Thompson
Int. J. Mol. Sci. 2023, 24(4), 4235; https://doi.org/10.3390/ijms24044235 - 20 Feb 2023
Cited by 8 | Viewed by 4104
Abstract
In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires [...] Read more.
In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)
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28 pages, 3223 KiB  
Review
3D Printing Technologies in Personalized Medicine, Nanomedicines, and Biopharmaceuticals
by Dolores R. Serrano, Aytug Kara, Iván Yuste, Francis C. Luciano, Baris Ongoren, Brayan J. Anaya, Gracia Molina, Laura Diez, Bianca I. Ramirez, Irving O. Ramirez, Sergio A. Sánchez-Guirales, Raquel Fernández-García, Liliana Bautista, Helga K. Ruiz and Aikaterini Lalatsa
Pharmaceutics 2023, 15(2), 313; https://doi.org/10.3390/pharmaceutics15020313 - 17 Jan 2023
Cited by 88 | Viewed by 13416
Abstract
3D printing technologies enable medicine customization adapted to patients’ needs. There are several 3D printing techniques available, but majority of dosage forms and medical devices are printed using nozzle-based extrusion, laser-writing systems, and powder binder jetting. 3D printing has been demonstrated for a [...] Read more.
3D printing technologies enable medicine customization adapted to patients’ needs. There are several 3D printing techniques available, but majority of dosage forms and medical devices are printed using nozzle-based extrusion, laser-writing systems, and powder binder jetting. 3D printing has been demonstrated for a broad range of applications in development and targeting solid, semi-solid, and locally applied or implanted medicines. 3D-printed solid dosage forms allow the combination of one or more drugs within the same solid dosage form to improve patient compliance, facilitate deglutition, tailor the release profile, or fabricate new medicines for which no dosage form is available. Sustained-release 3D-printed implants, stents, and medical devices have been used mainly for joint replacement therapies, medical prostheses, and cardiovascular applications. Locally applied medicines, such as wound dressing, microneedles, and medicated contact lenses, have also been manufactured using 3D printing techniques. The challenge is to select the 3D printing technique most suitable for each application and the type of pharmaceutical ink that should be developed that possesses the required physicochemical and biological performance. The integration of biopharmaceuticals and nanotechnology-based drugs along with 3D printing (“nanoprinting”) brings printed personalized nanomedicines within the most innovative perspectives for the coming years. Continuous manufacturing through the use of 3D-printed microfluidic chips facilitates their translation into clinical practice. Full article
(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)
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23 pages, 11337 KiB  
Article
GelMA, Click-Chemistry Gelatin and Bioprinted Polyethylene Glycol-Based Hydrogels as 3D Ex Vivo Drug Testing Platforms for Patient-Derived Breast Cancer Organoids
by Nathalie Bock, Farzaneh Forouz, Luke Hipwood, Julien Clegg, Penny Jeffery, Madeline Gough, Tirsa van Wyngaard, Christopher Pyke, Mark N. Adams, Laura J. Bray, Laura Croft, Erik W. Thompson, Thomas Kryza and Christoph Meinert
Pharmaceutics 2023, 15(1), 261; https://doi.org/10.3390/pharmaceutics15010261 - 12 Jan 2023
Cited by 27 | Viewed by 7098
Abstract
3D organoid model technologies have led to the development of innovative tools for cancer precision medicine. Yet, the gold standard culture system (Matrigel®) lacks the ability for extensive biophysical manipulation needed to model various cancer microenvironments and has inherent batch-to-batch variability. [...] Read more.
3D organoid model technologies have led to the development of innovative tools for cancer precision medicine. Yet, the gold standard culture system (Matrigel®) lacks the ability for extensive biophysical manipulation needed to model various cancer microenvironments and has inherent batch-to-batch variability. Tunable hydrogel matrices provide enhanced capability for drug testing in breast cancer (BCa), by better mimicking key physicochemical characteristics of this disease’s extracellular matrix. Here, we encapsulated patient-derived breast cancer cells in bioprinted polyethylene glycol-derived hydrogels (PEG), functionalized with adhesion peptides (RGD, GFOGER and DYIGSR) and gelatin-derived hydrogels (gelatin methacryloyl; GelMA and thiolated-gelatin crosslinked with PEG-4MAL; GelSH). Within ranges of BCa stiffnesses (1–6 kPa), GelMA, GelSH and PEG-based hydrogels successfully supported the growth and organoid formation of HR+,−/HER2+,− primary cancer cells for at least 2–3 weeks, with superior organoid formation within the GelSH biomaterial (up to 268% growth after 15 days). BCa organoids responded to doxorubicin, EP31670 and paclitaxel treatments with increased IC50 concentrations on organoids compared to 2D cultures, and highest IC50 for organoids in GelSH. Cell viability after doxorubicin treatment (1 µM) remained >2-fold higher in the 3D gels compared to 2D and doxorubicin/paclitaxel (both 5 µM) were ~2.75–3-fold less potent in GelSH compared to PEG hydrogels. The data demonstrate the potential of hydrogel matrices as easy-to-use and effective preclinical tools for therapy assessment in patient-derived breast cancer organoids. Full article
(This article belongs to the Special Issue Hydrogels in Pharmaceutical and Biomedical Applications)
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14 pages, 3406 KiB  
Article
Culturing of Cardiac Fibroblasts in Engineered Heart Matrix Reduces Myofibroblast Differentiation but Maintains Their Response to Cyclic Stretch and Transforming Growth Factor β1
by Meike C. Ploeg, Chantal Munts, Tayeba Seddiqi, Tim J. L. ten Brink, Jonathan Breemhaar, Lorenzo Moroni, Frits. W. Prinzen and Frans. A. van Nieuwenhoven
Bioengineering 2022, 9(10), 551; https://doi.org/10.3390/bioengineering9100551 - 14 Oct 2022
Cited by 5 | Viewed by 2728
Abstract
Isolation and culturing of cardiac fibroblasts (CF) induces rapid differentiation toward a myofibroblast phenotype, which is partly mediated by the high substrate stiffness of the culture plates. In the present study, a 3D model of Engineered Heart Matrix (EHM) of physiological stiffness (Youngs [...] Read more.
Isolation and culturing of cardiac fibroblasts (CF) induces rapid differentiation toward a myofibroblast phenotype, which is partly mediated by the high substrate stiffness of the culture plates. In the present study, a 3D model of Engineered Heart Matrix (EHM) of physiological stiffness (Youngs modulus ~15 kPa) was developed using primary adult rat CF and a natural hydrogel collagen type 1 matrix. CF were equally distributed, viable and quiescent for at least 13 days in EHM and the baseline gene expression of myofibroblast-markers alfa-smooth muscle actin (Acta2), and connective tissue growth factor (Ctgf) was significantly lower, compared to CF cultured in 2D monolayers. CF baseline gene expression of transforming growth factor-beta1 (Tgfβ1) and brain natriuretic peptide (Nppb) was higher in EHM-fibers compared to the monolayers. EHM stimulation by 10% cyclic stretch (1 Hz) increased the gene expression of Nppb (3.0-fold), Ctgf (2.1-fold) and Tgfβ1 (2.3-fold) after 24 h. Stimulation of EHM with TGFβ1 (1 ng/mL, 24 h) induced Tgfβ1 (1.6-fold) and Ctgf (1.6-fold). In conclusion, culturing CF in EHM of physiological stiffness reduced myofibroblast marker gene expression, while the CF response to stretch or TGFβ1 was maintained, indicating that our novel EHM structure provides a good physiological model to study CF function and myofibroblast differentiation. Full article
(This article belongs to the Special Issue Cell-ECM Interactions for Tissue Engineering and Tissue Regeneration)
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16 pages, 3400 KiB  
Article
Self-Assembled Peptide Habitats to Model Tumor Metastasis
by Noora Al Balushi, Mitchell Boyd-Moss, Rasika M. Samarasinghe, Aaqil Rifai, Stephanie J. Franks, Kate Firipis, Benjamin M. Long, Ian A. Darby, David R. Nisbet, Dodie Pouniotis and Richard J. Williams
Gels 2022, 8(6), 332; https://doi.org/10.3390/gels8060332 - 25 May 2022
Cited by 2 | Viewed by 3186
Abstract
Metastatic tumours are complex ecosystems; a community of multiple cell types, including cancerous cells, fibroblasts, and immune cells that exist within a supportive and specific microenvironment. The interplay of these cells, together with tissue specific chemical, structural and temporal signals within a three-dimensional [...] Read more.
Metastatic tumours are complex ecosystems; a community of multiple cell types, including cancerous cells, fibroblasts, and immune cells that exist within a supportive and specific microenvironment. The interplay of these cells, together with tissue specific chemical, structural and temporal signals within a three-dimensional (3D) habitat, direct tumour cell behavior, a subtlety that can be easily lost in 2D tissue culture. Here, we investigate a significantly improved tool, consisting of a novel matrix of functionally programmed peptide sequences, self-assembled into a scaffold to enable the growth and the migration of multicellular lung tumour spheroids, as proof-of-concept. This 3D functional model aims to mimic the biological, chemical, and contextual cues of an in vivo tumor more closely than a typically used, unstructured hydrogel, allowing spatial and temporal activity modelling. This approach shows promise as a cancer model, enhancing current understandings of how tumours progress and spread over time within their microenvironment. Full article
(This article belongs to the Collection Hydrogel in Tissue Engineering and Regenerative Medicine)
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14 pages, 3153 KiB  
Article
Bioinspired Sandcastle Worm-Derived Peptide-Based Hybrid Hydrogel for Promoting the Formation of Liver Spheroids
by Yu-Hsu Chen, Yuan-Hao Ku, Kuo-Cheng Wang, Hung-Chi Chiang, Yu-Pao Hsu, Ming-Te Cheng, Ching-Shuen Wang and Yinshen Wee
Gels 2022, 8(3), 149; https://doi.org/10.3390/gels8030149 - 27 Feb 2022
Cited by 5 | Viewed by 3455
Abstract
The generation of hepatic spheroids is beneficial for a variety of potential applications, including drug development, disease modeling, transplantation, and regenerative medicine. Natural hydrogels are obtained from tissues and have been widely used to promote the growth, differentiation, and retention of specific functionalities [...] Read more.
The generation of hepatic spheroids is beneficial for a variety of potential applications, including drug development, disease modeling, transplantation, and regenerative medicine. Natural hydrogels are obtained from tissues and have been widely used to promote the growth, differentiation, and retention of specific functionalities of hepatocytes. However, relying on natural hydrogels for the generation of hepatic spheroids, which have batch to batch variations, may in turn limit the previously mentioned potential applications. For this reason, we researched a way to establish a three-dimensional (3D) culture system that more closely mimics the interaction between hepatocytes and their surrounding microenvironments, thereby potentially offering a more promising and suitable system for drug development, disease modeling, transplantation, and regenerative medicine. Here, we developed self-assembling and bioactive hybrid hydrogels to support the generation and growth of hepatic spheroids. Our hybrid hydrogels (PC4/Cultrex) inspired by the sandcastle worm, an Arg-Gly-Asp (RGD) cell adhesion sequence, and bioactive molecules derived from Cultrex BME (Basement Membrane Extract). By performing optimizations to the design, the PC4/Cultrex hybrid hydrogels can enhance HepG2 cells to form spheroids and express their molecular signatures (e.g., Cyp3A4, Cyp7a1, A1at, Afp, Ck7, Ck1, and E-cad). Our study demonstrated that this hybrid hydrogel system offers potential advantages for hepatocytes in proliferating, differentiating, and self-organizing to form hepatic spheroids in a more controllable and reproducible manner. In addition, it is a versatile and cost-effective method for 3D tissue cultures in mass quantities. Importantly, we demonstrate that it is feasible to adapt a bioinspired approach to design biomaterials for 3D culture systems, which accelerates the design of novel peptide structures and broadens our research choices on peptide-based hydrogels. Full article
(This article belongs to the Special Issue Cancer Cell Biology in Biological Hydrogel)
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23 pages, 5149 KiB  
Article
NGIWY-Amide: A Bioinspired Ultrashort Self-Assembled Peptide Gelator for Local Drug Delivery Applications
by Nikoleta F. Theodoroula, Christina Karavasili, Manos C. Vlasiou, Alexandra Primikyri, Christia Nicolaou, Alexandra V. Chatzikonstantinou, Aikaterini-Theodora Chatzitaki, Christos Petrou, Nikolaos Bouropoulos, Constantinos K. Zacharis, Eleftheria Galatou, Yiannis Sarigiannis, Dimitrios G. Fatouros and Ioannis S. Vizirianakis
Pharmaceutics 2022, 14(1), 133; https://doi.org/10.3390/pharmaceutics14010133 - 6 Jan 2022
Cited by 9 | Viewed by 4570
Abstract
Fibrillar structures derived from plant or animal origin have long been a source of inspiration for the design of new biomaterials. The Asn-Gly-Ile-Trp-Tyr-NH2 (NGIWY-amide) pentapeptide, isolated from the sea cucumber Apostichopus japonicus, which spontaneously self-assembles in water to form hydrogel, pertains [...] Read more.
Fibrillar structures derived from plant or animal origin have long been a source of inspiration for the design of new biomaterials. The Asn-Gly-Ile-Trp-Tyr-NH2 (NGIWY-amide) pentapeptide, isolated from the sea cucumber Apostichopus japonicus, which spontaneously self-assembles in water to form hydrogel, pertains to this category. In this study, we evaluated this ultra-short cosmetic bioinspired peptide as vector for local drug delivery applications. Combining nuclear magnetic resonance, circular dichroism, infrared spectroscopy, X-ray diffraction, and rheological studies, the synthesized pentapeptide formed a stiff hydrogel with a high β-sheet content. Molecular dynamic simulations aligned well with scanning electron and atomic-force microscopy studies, revealing a highly filamentous structure with the fibers adopting a helical-twisted morphology. Model dye localization within the supramolecular hydrogel provided insights on the preferential distribution of hydrophobic and hydrophilic compounds in the hydrogel network. That was further depicted in the diffusion kinetics of drugs differing in their aqueous solubility and molecular weight, namely, doxorubicin hydrochloride, curcumin, and octreotide acetate, highlighting its versatility as a delivery vector of both hydrophobic and hydrophilic compounds of different molecular weight. Along with the observed cytocompatibility of the hydrogel, the NGIWY-amide pentapeptide may offer new approaches for cell growth, drug delivery, and 3D bioprinting tissue-engineering applications. Full article
(This article belongs to the Special Issue Peptide-Based Drug Delivery Systems)
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21 pages, 28998 KiB  
Article
Evaluation of a Model Photo-Caged Dehydropeptide as a Stimuli-Responsive Supramolecular Hydrogel
by Peter J. Jervis, Loic Hilliou, Renato B. Pereira, David M. Pereira, José A. Martins and Paula M. T. Ferreira
Nanomaterials 2021, 11(3), 704; https://doi.org/10.3390/nano11030704 - 11 Mar 2021
Cited by 14 | Viewed by 3598
Abstract
Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels, via self-assembly, in aqueous media. The rheological properties of these readily tunable hydrogels resemble those of the extracellular matrix (ECM) and therefore have potential for various [...] Read more.
Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels, via self-assembly, in aqueous media. The rheological properties of these readily tunable hydrogels resemble those of the extracellular matrix (ECM) and therefore have potential for various biological applications, such as tissue engineering, biosensors, 3D bioprinting, drug delivery systems and wound dressings. We herein report a new photo-responsive supramolecular hydrogel based on a “caged” dehydropeptide (CNB-Phe-ΔPhe-OH 2), containing a photo-cleavable carboxy-2-nitrobenzyl (CNB) group. We have characterized this hydrogel using a range of techniques. Irradiation with UV light cleaves the pendant aromatic capping group, to liberate the corresponding uncaged model dehydropeptide (H-Phe-ΔPhe-OH 3), a process which was investigated by 1H NMR and HPLC studies. Crucially, this cleavage of the capping group is accompanied by dissolution of the hydrogel (studied visually and by fluorescence spectroscopy), as the delicate balance of intramolecular interactions within the hydrogel structure is disrupted. Hydrogels which can be disassembled non-invasively with temporal and spatial control have great potential for specialized on-demand drug release systems, wound dressing materials and various topical treatments. Both 2 and 3 were found to be non-cytotoxic to the human keratinocyte cell line, HaCaT. The UV-responsive hydrogel system reported here is complementary to previously reported related UV-responsive systems, which are generally composed of peptides formed from canonical amino acids, which are susceptible to enzymatic proteolysis in vivo. This system is based on a dehydrodipeptide structure which is known to confer proteolytic resistance. We have investigated the ability of the photo-activated system to accelerate the release of the antibiotic, ciprofloxacin, as well as some other small model drug compounds. We have also conducted some initial studies towards skin-related applications. Moreover, this model system could potentially be adapted for on-demand “self-delivery”, through the uncaging of known biologically active dehydrodipeptides. Full article
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17 pages, 2586 KiB  
Article
RGDS-Modified Superporous Poly(2-Hydroxyethyl Methacrylate)-Based Scaffolds as 3D In Vitro Leukemia Model
by Hana Svozilová, Zdeněk Plichta, Vladimír Proks, Radana Studená, Jiří Baloun, Michael Doubek, Šárka Pospíšilová and Daniel Horák
Int. J. Mol. Sci. 2021, 22(5), 2376; https://doi.org/10.3390/ijms22052376 - 27 Feb 2021
Cited by 11 | Viewed by 3322
Abstract
Superporous poly(2-hydroxyethyl methacrylate-co-2-aminoethyl methacrylate) (P(HEMA-AEMA)) hydrogel scaffolds are designed for in vitro 3D culturing of leukemic B cells. Hydrogel porosity, which influences cell functions and growth, is introduced by adding ammonium oxalate needle-like crystals in the polymerization mixture. To improve cell [...] Read more.
Superporous poly(2-hydroxyethyl methacrylate-co-2-aminoethyl methacrylate) (P(HEMA-AEMA)) hydrogel scaffolds are designed for in vitro 3D culturing of leukemic B cells. Hydrogel porosity, which influences cell functions and growth, is introduced by adding ammonium oxalate needle-like crystals in the polymerization mixture. To improve cell vitality, cell-adhesive Arg-Gly-Asp-Ser (RGDS) peptide is immobilized on the N-(γ-maleimidobutyryloxy)succinimide-activated P(HEMA-AEMA) hydrogels via reaction of SH with maleimide groups. This modification is especially suitable for the survival of primary chronic lymphocytic leukemia cells (B-CLLs) in 3D cell culture. No other tested stimuli (interleukin-4, CD40 ligand, or shaking) can further improve B-CLL survival or metabolic activity. Both unmodified and RGDS-modified P(HEMA-AEMA) scaffolds serve as a long-term (70 days) 3D culture platforms for HS-5 and M2-10B4 bone marrow stromal cell lines and MEC-1 and HG-3 B-CLL cell lines, although the adherent cells retain their physiological morphologies, preferably on RGDS-modified hydrogels. Moreover, the porosity of hydrogels allows direct cell lysis, followed by efficient DNA isolation from the 3D-cultured cells. P(HEMA-AEMA)-RGDS thus serves as a suitable 3D in vitro leukemia model that enables molecular and metabolic assays and allows imaging of cell morphology, interactions, and migration by confocal microscopy. Such applications can prospectively assist in testing of drugs to treat this frequently recurring or refractory cancer. Full article
(This article belongs to the Special Issue Hydrogels in Regenerative Medicine and Other Biomedical Applications)
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14 pages, 2777 KiB  
Article
Anti-Aging Potential of Substance P-Based Hydrogel for Human Skin Longevity
by Da Jung Kim, Song Sun Chang and Jungsun Lee
Int. J. Mol. Sci. 2019, 20(18), 4453; https://doi.org/10.3390/ijms20184453 - 10 Sep 2019
Cited by 20 | Viewed by 6883
Abstract
Skin aging is generally caused by a decline in the components of the extracellular matrix (e.g., collagen and elastin) and due to inflammatory phenomena. Many growth factors and peptides with cell-growth and collagen-synthesis activities have shown promise in their application in anti-aging materials. [...] Read more.
Skin aging is generally caused by a decline in the components of the extracellular matrix (e.g., collagen and elastin) and due to inflammatory phenomena. Many growth factors and peptides with cell-growth and collagen-synthesis activities have shown promise in their application in anti-aging materials. However, the effect of collagen production, without anti-inflammatory effect, and skin penetration may not be enough for their use in anti-aging agents. Previously, we reported a substance P (SP)-based hydrogel (SP gel) that had potential wound-healing activities via induction of skin cell regeneration and collagen synthesis. Here, we analyzed the anti-aging activities and skin absorption effects of SP gel to extend its characterization. Toxicity tests, performed on human dermal fibroblasts (HDFs) and on a reconstructed 3D human skin model, indicated SP gel to be safe for long-term use, without causing irritation, even at high concentrations. In-vitro analysis revealed that SP gel elicited stronger collagen production activities than SP alone, and promoted anti-inflammatory effects with increased skin absorption properties. Moreover, SP gel did not induce melanin synthesis in a keratinocyte-melanocyte co-culture system. Together, the results suggest that SP gel has potential cosmetic effects and applicability as a novel ingredient in anti-aging products. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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25 pages, 7256 KiB  
Article
Three-Dimensional In Vitro Hydro- and Cryogel-Based Cell-Culture Models for the Study of Breast-Cancer Metastasis to Bone
by Laura J. Bray, Constanze Secker, Berline Murekatete, Jana Sievers, Marcus Binner, Petra B. Welzel and Carsten Werner
Cancers 2018, 10(9), 292; https://doi.org/10.3390/cancers10090292 - 27 Aug 2018
Cited by 23 | Viewed by 6371
Abstract
Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models [...] Read more.
Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models provide valuable tools to investigate distinct heterocellular and environmental interactions, sophisticated organ-specific metastasis models are lacking. Previous models used to investigate breast-to-bone metastasis have relied on 2.5D or singular-scaffold methods, constraining the in situ mimicry of in vitro models. Glycosaminoglycan-based gels have demonstrated outstanding potential for tumor-engineering applications. Here, we developed advanced biphasic in vitro microenvironments that mimic breast-tumor tissue (MCF-7 and MDA-MB-231 in a hydrogel) spatially separated with a mineralized bone construct (human primary osteoblasts in a cryogel). These models allow distinct advantages over former models due to the ability to observe and manipulate cellular migration towards a bone construct. The gels allow for the binding of adhesion-mediating peptides and controlled release of signaling molecules. Moreover, mechanical and architectural properties can be tuned to manipulate cell function. These results demonstrate the utility of these biomimetic microenvironment models to investigate heterotypic cell–cell and cell–matrix communications in cancer migration to bone. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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18 pages, 9809 KiB  
Article
Design of Decorated Self-Assembling Peptide Hydrogels as Architecture for Mesenchymal Stem Cells
by Annj Zamuner, Marta Cavo, Silvia Scaglione, Grazia Maria Lucia Messina, Teresa Russo, Antonio Gloria, Giovanni Marletta and Monica Dettin
Materials 2016, 9(9), 727; https://doi.org/10.3390/ma9090727 - 26 Aug 2016
Cited by 35 | Viewed by 6602
Abstract
Hydrogels from self-assembling ionic complementary peptides have been receiving a lot of interest from the scientific community as mimetic of the extracellular matrix that can offer three-dimensional supports for cell growth or can become vehicles for the delivery of stem cells, drugs or [...] Read more.
Hydrogels from self-assembling ionic complementary peptides have been receiving a lot of interest from the scientific community as mimetic of the extracellular matrix that can offer three-dimensional supports for cell growth or can become vehicles for the delivery of stem cells, drugs or bioactive proteins. In order to develop a 3D “architecture” for mesenchymal stem cells, we propose the introduction in the hydrogel of conjugates obtained by chemoselective ligation between a ionic-complementary self-assembling peptide (called EAK) and three different bioactive molecules: an adhesive sequence with 4 Glycine-Arginine-Glycine-Aspartic Acid-Serine-Proline (GRGDSP) motifs per chain, an adhesive peptide mapped on h-Vitronectin and the growth factor Insulin-like Growth Factor-1 (IGF-1). The mesenchymal stem cell adhesion assays showed a significant increase in adhesion and proliferation for the hydrogels decorated with each of the synthesized conjugates; moreover, such functionalized 3D hydrogels support cell spreading and elongation, validating the use of this class of self-assembly peptides-based material as very promising 3D model scaffolds for cell cultures, at variance of the less realistic 2D ones. Furthermore, small amplitude oscillatory shear tests showed that the presence of IGF-1-conjugate did not alter significantly the viscoelastic properties of the hydrogels even though differences were observed in the nanoscale structure of the scaffolds obtained by changing their composition, ranging from long, well-defined fibers for conjugates with adhesion sequences to the compact and dense film for the IGF-1-conjugate. Full article
(This article belongs to the Special Issue Bioinspired and Biomimetic Materials)
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