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Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition)
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Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition)

A special issue of Gels (ISSN 2310-2861). This special issue belongs to the section "Gel Applications".

Deadline for manuscript submissions: closed (30 November 2024) | Viewed by 6336

Special Issue Editors

Dr. Federica Re

E-Mail Website
Guest Editor
Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
Interests: stem cell transplantation; stem cell biology; regenerative medicine; formation of tissues and organs; mesenchymal and hematopoietic stem cells (MSCs and HSCs)
Special Issues, Collections and Topics in MDPI journals
Dr. Elisa Borsani

E-Mail Website
Guest Editor
Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
Interests: morphology and functional imaging of cells; neuroanatomy and neurophysiology; gene therapy; cell therapy; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of scaffolds with optimal characteristics is more readily achievable in polymeric scaffolds. There is currently great research interest in hydrogel-based scaffolds. 

Hydrogel-based scaffolds have recently emerged as the most promising substrates for cell cultures to generate well-defined 3D biofabricated tissue, attracting significant research attention for their potential in medical applications.

These scaffolds act as bioactive substrates and structural supports, providing topographical and chemical stimuli for cell spreading, proliferation and differentiation in vivo. Among the specific scaffold characteristics, high porosity and interconnectivity to facilitate scaffold/cell interactions, nutrient and oxygen infiltration and vascularization aim to obtain specific cellular responses. Scaffolds have sufficient mechanical properties to temporarily substitute the missing tissue and permit essential physiological functions.

This Special Issue is dedicated to the design and development of advanced polymeric scaffolds and their applications for bone/cartilage/skin regeneration in vitro and in vivo.

Dr. Federica Re
Dr. Elisa Borsani
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2100 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hydrogel-based scaffolds
  • resorbable scaffolds
  • synthesis of biomaterials
  • mesenchymal stromal cells
  • bioengineered models
  • bone regeneration
  • cartilage regeneration
  • skin regeneration

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Research

Jump to: Review

18 pages, 8355 KiB  
Article
Ketoprofen Associated with Hyaluronic Acid Hydrogel for Temporomandibular Disorder Treatment: An In Vitro Study
by Diego Garcia Miranda, Lucas de Paula Ramos, Nicole Fernanda dos Santos Lopes, Nicole Van Der Heijde Fernandes Silva, Cristina Pacheco Soares, Flavia Pires Rodrigues, Vinicius de Paula Morais, Thalita Sani-Taiariol, Mauricio Ribeiro Baldan, Luana Marotta Reis de Vasconcellos, Alexandre Luiz Souto Borges, Brigitte Grosgogeat and Kerstin Gritsch
Gels 2024, 10(12), 811; https://doi.org/10.3390/gels10120811 - 10 Dec 2024
Viewed by 398
Abstract
Temporomandibular disorders (TMD) are a public health problem that affects around 12% of the global population. The treatment is based on analgesics, non-steroidal anti-inflammatory, corticosteroids, anticonvulsants, or arthrocentesis associated with hyaluronic acid-based viscosupplementation. However, the use of hyaluronic acid alone in viscosupplementation does [...] Read more.
Temporomandibular disorders (TMD) are a public health problem that affects around 12% of the global population. The treatment is based on analgesics, non-steroidal anti-inflammatory, corticosteroids, anticonvulsants, or arthrocentesis associated with hyaluronic acid-based viscosupplementation. However, the use of hyaluronic acid alone in viscosupplementation does not seem to be enough to regulate the intra-articular inflammatory process. So, we propose to develop and evaluate the physicochemical and biological properties in vitro of hyaluronic acid hydrogels (HA) associated with ketoprofen (KET) as a new therapeutic treatment for TMD. The hydrogels were synthesized with 3% HA and 0.125, 0.250, 0.500, or 1% KET. Physicochemical analyses of Attenuated Total reflectance-Fourier transform infrared spectroscopy (FTIR), Thermogravimetry (TGA), Rheology by Frequency, Amplitude sweeps, temperature ramp, and scanning electron microscopy (SEM) were performed with or without sterilization and cycled. Cytocompatibility and genotoxicity (micronucleus assay) were performed in mouse macrophages (RAW 264-7) for 24 h. Results: FTIR spectrum showed characteristic absorptions of HA and KET. In the TGA, two mass loss peaks were observed, the first representing the water evaporation at 30 and 100 °C, and the second peaks between 200 and 300 °C, indicating the degradation of HA and KET. Rheology tests in the oscillatory regime classified the hydrogels as non-Newtonian fluids, time-dependent, and thixotropic. Mouse macrophages (RAW 264-7) presented viability of 83.6% for HA, 50.7% for KET, and 92.4%, 66.1%, 65.3%, and 87.7% for hydrogels, in addition to the absence of genotoxicity. Conclusions: Hyaluronic acid associated with ketoprofen shows satisfactory physicochemical and biological properties for use as viscosupplementation. As a limiting point of this study, further research is needed to evaluate the pharmacodynamic, toxicological, and pharmacokinetic characteristics of a complete organism Full article
(This article belongs to the Special Issue Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition))
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Figure 1

Figure 1
<p>FTIR spectra of HA (line black), KET (line green), and hydrogel 3% HA associated with 1% KET (line blue). The vertically dotted black lines indicate the molecular signatures of HA present in the isolated molecule and in the gel combined with KET. The vertically dotted lines in green indicate the molecular signatures of KET present in the isolated molecule and in the gel combined with HA.</p> Full article ">Figure 2
<p>Analysis of the decomposition of masses in relation to temperature. TGA spectra of HA (line black), KET (line green), and hydrogel 3% HA associated with 1% KET (line blue).</p> Full article ">Figure 3
<p>Frequency sweep of 3% HA + 0.125% KET hydrogel non-autoclaved (<b>A</b>), 3% hyaluronic acid HA + 0.250% KET hydrogel non-autoclaved (<b>B</b>), 3% HA + 0.500% KET hydrogel non-autoclaved (<b>C</b>), 3% HA + 1% KET hydrogel non-autoclaved (<b>D</b>), 3% HA + 0.125% KET hydrogel autoclaved (<b>E</b>), 3% HA + 0.250% KET hydrogel autoclaved (<b>F</b>), 3% HA + 0.500% KET hydrogel autoclaved (<b>G</b>), 3% HA + 1% KET hydrogel autoclaved (<b>H</b>), 3% HA + 0.125% KET hydrogel autoclaved cycled (<b>I</b>), 3% HA + 0.250% KET hydrogel autoclaved cycled (<b>J</b>), 3% HA + 0.500% KET hydrogel autoclaved cycled (<b>K</b>), 3% HA + 1% KET hydrogel autoclaved cycled (<b>L</b>).</p> Full article ">Figure 4
<p>Amplitude sweep of 3% HA + 0.125% KET hydrogel non-autoclaved (<b>A</b>), 3% HA + 0.250% KET hydrogel non-autoclaved (<b>B</b>), 3% HA + 0.500% KET hydrogel non-autoclaved (<b>C</b>), 3% HA + 1% KET hydrogel non-autoclaved (<b>D</b>), 3% HA + 0.125% KET hydrogel autoclaved (<b>E</b>), 3% HA + 0.250% KET hydrogel autoclaved (<b>F</b>), 3% HA + 0.500% KET hydrogel autoclaved (<b>G</b>), 3% HA + 1% KET hydrogel autoclaved (<b>H</b>), 3% HA + 0.125% KET hydrogel autoclaved cycled (<b>I</b>), 3% HA + 0.250% KET hydrogel autoclaved cycled (<b>J</b>), 3% HA + 0.500% KET hydrogel autoclaved cycled (<b>K</b>), 3% HA + 1% KET hydrogel autoclaved cycled (<b>L</b>).</p> Full article ">Figure 5
<p>Temperature ramp of 3% HA + 0.125% KET hydrogel non-autoclaved (<b>A</b>), 3% HA + 0.250% KET hydrogel non-autoclaved (<b>B</b>), 3% HA + 0.500% KET hydrogel non-autoclaved (<b>C</b>), 3% HA + 1% KET hydrogel non-autoclaved (<b>D</b>), 3% HA + 0.125% KET hydrogel autoclaved (<b>E</b>), 3% HA + 0.250% KET hydrogel autoclaved (<b>F</b>), 3% HA + 0.500% KET hydrogel autoclaved (<b>G</b>), 3% HA + 1% KET hydrogel autoclaved (<b>H</b>), 3% HA + 0.125% KET hydrogel autoclaved cycled (<b>I</b>), 3% HA + 0.250% KET hydrogel autoclaved cycled (<b>J</b>), 3% HA + 0.500% KET hydrogel autoclaved cycled (<b>K</b>), 3% HA + 1% KET hydrogel autoclaved cycled (<b>L</b>).</p> Full article ">Figure 6
<p>Micrography of 3% HA hydrogel (<b>A</b>), 3% HA + 0.125% KET hydrogel (<b>B</b>), 3% HA + 0.250% KET hydrogel (<b>C</b>), 3% HA + 0.500% KET hydrogel (<b>D</b>), 3% HA + 1% KET hydrogel (<b>E</b>).</p> Full article ">Figure 7
<p>Cytocompatibility by hydrogels on mouse macrophages (RAW 264.7). <span class="html-italic">p</span> &lt; 0.0021 (**), <span class="html-italic">p</span> &lt; 0.0002 (***), <span class="html-italic">p</span> &lt; 0.0001 (****).</p> Full article ">Figure 8
<p>Genotocixity assay by micronucleus.</p> Full article ">
30 pages, 9043 KiB  
Article
Bone Spheroid Development Under Flow Conditions with Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells in a 3D Porous Hydrogel Supplemented with Hydroxyapatite
by Soukaina El Hajj, Martial Bankoué Ntaté, Cyril Breton, Robin Siadous, Rachida Aid, Magali Dupuy, Didier Letourneur, Joëlle Amédée, Hervé Duval and Bertrand David
Gels 2024, 10(10), 666; https://doi.org/10.3390/gels10100666 - 18 Oct 2024
Viewed by 1480
Abstract
Understanding the niche interactions between blood and bone through the in vitro co-culture of osteo-competent cells and endothelial cells is a key factor in unraveling therapeutic potentials in bone regeneration. This can be additionally supported by employing numerical simulation techniques to assess local [...] Read more.
Understanding the niche interactions between blood and bone through the in vitro co-culture of osteo-competent cells and endothelial cells is a key factor in unraveling therapeutic potentials in bone regeneration. This can be additionally supported by employing numerical simulation techniques to assess local physical factors, such as oxygen concentration, and mechanical stimuli, such as shear stress, that can mediate cellular communication. In this study, we developed a Mesenchymal Stem Cell line (MSC) and a Human Umbilical Vein Endothelial Cell line (HUVEC), which were co-cultured under flow conditions in a three-dimensional, porous, natural pullulan/dextran scaffold that was supplemented with hydroxyapatite crystals that allowed for the spontaneous formation of spheroids. After 2 weeks, their viability was higher under the dynamic conditions (>94%) than the static conditions (<75%), with dead cells central in the spheroids. Mineralization and collagen IV production increased under the dynamic conditions, correlating with osteogenesis and vasculogenesis. The endothelial cells clustered at the spheroidal core by day 7. Proliferation doubled in the dynamic conditions, especially at the scaffold peripheries. Lattice Boltzmann simulations showed negligible wall shear stress in the hydrogel pores but highlighted highly oxygenated zones coinciding with cell proliferation. A strong oxygen gradient likely influenced endothelial migration and cell distribution. Hypoxia was minimal, explaining high viability and spheroid maturation in the dynamic conditions. Full article
(This article belongs to the Special Issue Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition))
►▼ Show Figures

Figure 1

Figure 1
<p>Characterization of hydrogels in the dry state: (<b>A1</b>) X-ray microtomography XY slice of a full hydrogel (8.6 mm in diameter, 1.8 mm in thickness), at 500 μm depth, voxel size of (8.4 μm × 8.4 μm × 8.4 μm); (<b>A3</b>) X-ray computed tomography 3D rendering of a scaffold ROI; (<b>A5</b>) Optical Coherence Tomography (OCT) 3D rendering of a scaffold ROI. In the hydrated state: (<b>A2</b>) OCT 2D rendering of a scaffold ROI showing seeded spheroids (dark white circles), scale bar = 1000 µm; (<b>A4</b>) OCT 3D rendering of a scaffold ROI; (<b>A6</b>) 3D rendering following pore labeling and reconstruction of the scaffold center. (<b>A3</b>,<b>A5</b>) ROI (5.6 mm × 0.9 mm × 6.4 mm), voxel size of (0.92 μm × 0.92 μm × 0.92 μm); (<b>A4</b>,<b>A6</b>) ROI (4.9 mm × 4.9 mm × 0.3 mm), voxel size of (8 μm × 8 μm × 1.45 μm).</p> Full article ">Figure 2
<p>White field acquisitions of seeded hydrogel sections, showing the distribution of MSC/HUVEC spheroids in (<b>A1</b>) static culture conditions and (<b>B1</b>) dynamic culture conditions in a perfusion bioreactor, with CSD4 (1,000,000 cells/hydrogel scaffold). Scale bar = 1000 µm. Acquisitions of remaining cell seeding densities are found in the <a href="#app1-gels-10-00666" class="html-app">Supplementary Materials</a>. Segmented OCT acquisitions showing spheroid (in purple) topology and distribution in scaffolds (in blue) with CSD4 (1,000,000 cells/hydrogel scaffold) (<b>A2</b>) At 24 h post implantation, and after (<b>B2</b>) 21 days of dynamic culture conditions. Scale bar = 1000 µm. Evolution of the MSC/HUVEC spheroid diameter (mean + SEM µm) throughout the culture period under (<b>A3</b>) static culture conditions and (<b>B3</b>) dynamic culture conditions. Cell cultures were conducted with CSD1 (400,000 cells/hydrogel scaffold), CSD2 (600,000 cells/hydrogel scaffold), CSD3 (800,000 cells/hydrogel scaffold), and CSD4 (1,000,000 cells/hydrogel scaffold); dynamic culture results are represented with a pattern (░).</p> Full article ">Figure 3
<p>Total number of cells in MSC/HUVEC co-culture over 21 days. (<b>A1</b>) Hydrogels in static culture conditions, and (<b>B1</b>) in dynamic culture conditions. Evolution of MSC/HUVEC viability (mean + SEM %) using a LIVE/DEAD kit. Cells were cultured in (<b>A2</b>) static conditions <span class="html-italic">N</span> = 224, and (<b>B2</b>) dynamic conditions. Cell cultures were conducted with CSD1 (400,000 cells/hydrogel scaffold), CSD2 (600,000 cells/hydrogel scaffold), CSD3 (800,000 cells/hydrogel scaffold), and CSD4 (1,000,000 cells/hydrogel scaffold); dynamic culture results are represented with a pattern (░). * and ** denote <span class="html-italic">p</span> &lt; 0.05 and <span class="html-italic">p</span> &lt; 0.01, respectively. 2D representative projections of confocal z-stack acquisitions showing the distribution of viable cells (calcein-AM, green) and dead cells (ethidium homodimer-1, red) in the co-culture spheroids under (<b>A3</b>) the static culture conditions, and (<b>B3</b>) the dynamic culture conditions. Scale bar = 100 µm.</p> Full article ">Figure 4
<p>2D representative projections of confocal z-stack acquisitions showing the cellular reorganization of the HUVECs stained with PKH-26 (red) and the MSCs stained with PKH-67 (green) in co-culture spheroids (<b>A1</b>) 24-h post-seeding, under (<b>B1</b>) static, and (<b>C1</b>) the dynamic conditions. Scale bar = 100 µm. (<b>A2</b>) the MSCs/the HUVECs spheroid (2D confocal microscopy) after 7 days of dynamic cell culture condition (left). Object-oriented analysis (right). Ripley’s K function describes the spatial distribution of the MSCs (in green) and the HUVECs (in red) with CSD4 (1,000,000 cells/hydrogel scaffold) compared to a random Poisson distribution (in black) (<b>A3</b>) 24-h post-seeding, under (<b>B3</b>) static cell culture conditions; under (<b>C3</b>) dynamic cell culture conditions.</p> Full article ">Figure 5
<p>Digital reconstruction of the hydrogel’s microgeometry (in light blue) and the seeded spheroids (in orange) under perfusion flow (in dark blue) for fluid flow simulations with a cell seeding density of 1,000,000 cells (CSD4) on day 1 (<b>A1</b>) and day 21 (<b>B1</b>). LBM simulations of (<b>A2</b>,<b>B2</b>) the wall shear stress map (Pa) and (<b>A3</b>,<b>B3</b>) the dissolved oxygen concentration map (mol.m<sup>−3</sup>) on day 1 and day 21. Scale bar = 500 µm for all images in this figure.</p> Full article ">Figure 6
<p>(<b>A1</b>) Representative ALP staining test comparing the osteogenic differentiation capacity of the MSC-IST and the primary MSCs on day 7 of the culture. Scale bar = 500 µm. Standardized ALP expression (nmol/min/µg, mean + SEM) throughout the culture period under (<b>A2</b>) the static conditions and (<b>B2</b>) the dynamic conditions. The cell culture was conducted with CSD1 (400,000 cells/hydrogel scaffold), CSD2 (600,000 cells/hydrogel scaffold), CSD3 (800,000 cells/hydrogel scaffold), and CSD4 (1,000,000 cells/hydrogel scaffold); dynamic culture results are represented with a pattern (░). *, **, and *** denote <span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">p</span> &lt; 0.01, and <span class="html-italic">p</span> &lt; 0.001, respectively. 2D representative projections of confocal z-stack acquisitions showing ALP live stain in co-culture spheroids under (<b>A3</b>) static culture conditions and (<b>B3</b>) dynamic culture conditions on day 7 with CSD4 (1,000,000 cells/hydrogel scaffold). Scale bar = 100 µm. Alizarin red staining of co-culture spheroids on (<b>A4</b>) day 1, and day 21 under (<b>B4</b>) the static conditions and (<b>C4</b>) the dynamic conditions with CSD4. Scale bar = 300 µm. Von Kossa staining of co-culture spheroids on (<b>A5</b>) day 1, (<b>B5</b>) day 21 under the static conditions, and (<b>C5</b>) the dynamic conditions with CSD4. Scale bar = 100 µm. 2D projections of confocal z-stack acquisitions showing the staining of collagen IV (magenta) in co-culture spheroids under (<b>A6</b>) static culture conditions and (<b>B6</b>) dynamic culture conditions on day 21 with CSD4. Scale bar = 100 µm.</p> Full article ">Figure 7
<p>Custom made perfusion bioreactor and bioreactor circuit containing centrally aligned seeded hydrogels. Perfusion flow rate q = 10 mL·min<sup>−1</sup>.</p> Full article ">Figure 8
<p>(<b>A1</b>) Reconstruction of OCT acquisition representing the hydrogel’s microgeometry (in light blue) and the seeded spheroids (in orange) under perfusion flow (in dark blue) for fluid flow simulations. (<b>A2</b>) Selected ROI (6400 μm × 1200 μm × 640 μm) for hydrodynamics simulations. (<b>A3</b>) Selected ROI (2576 μm × 1200 μm × 640 μm) of hydrogel (in blue) with seeded spheroids (in purple) for oxygen transport.</p> Full article ">
13 pages, 3979 KiB  
Article
Synthesis and Photopatterning of Synthetic Thiol-Norbornene Hydrogels
by Umu S. Jalloh, Arielle Gsell, Kirstene A. Gultian, James MacAulay, Abigail Madden, Jillian Smith, Luke Siri and Sebastián L. Vega
Gels 2024, 10(3), 164; https://doi.org/10.3390/gels10030164 - 23 Feb 2024
Viewed by 2202
Abstract
Hydrogels are a class of soft biomaterials and the material of choice for a myriad of biomedical applications due to their biocompatibility and highly tunable mechanical and biochemical properties. Specifically, light-mediated thiol-norbornene click reactions between norbornene-modified macromers and di-thiolated crosslinkers can be used [...] Read more.
Hydrogels are a class of soft biomaterials and the material of choice for a myriad of biomedical applications due to their biocompatibility and highly tunable mechanical and biochemical properties. Specifically, light-mediated thiol-norbornene click reactions between norbornene-modified macromers and di-thiolated crosslinkers can be used to form base hydrogels amenable to spatial biochemical modifications via subsequent light reactions between pendant norbornenes in the hydrogel network and thiolated peptides. Macromers derived from natural sources (e.g., hyaluronic acid, gelatin, alginate) can cause off-target cell signaling, and this has motivated the use of synthetic macromers such as poly(ethylene glycol) (PEG). In this study, commercially available 8-arm norbornene-modified PEG (PEG-Nor) macromers were reacted with di-thiolated crosslinkers (dithiothreitol, DTT) to form synthetic hydrogels. By varying the PEG-Nor weight percent or DTT concentration, hydrogels with a stiffness range of 3.3 kPa–31.3 kPa were formed. Pendant norbornene groups in these hydrogels were used for secondary reactions to either increase hydrogel stiffness (by reacting with DTT) or to tether mono-thiolated peptides to the hydrogel network. Peptide functionalization has no effect on bulk hydrogel mechanics, and this confirms that mechanical and biochemical signals can be independently controlled. Using photomasks, thiolated peptides can also be photopatterned onto base hydrogels, and mesenchymal stem cells (MSCs) attach and spread on RGD-functionalized PEG-Nor hydrogels. MSCs encapsulated in PEG-Nor hydrogels are also highly viable, demonstrating the ability of this platform to form biocompatible hydrogels for 2D and 3D cell culture with user-defined mechanical and biochemical properties. Full article
(This article belongs to the Special Issue Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition))
►▼ Show Figures

Figure 1

Figure 1
<p>Mechanical characterization of PEG-Nor hydrogels. (<b>A</b>) Compressive mechanical testing is performed to measure the elastic modulus, which is calculated as the slope between 10 and 20% strain in a stress–strain curve (blue dashed box). (<b>B</b>) Elastic moduli as a function of DTT concentration for 3, 4, 5 and 6 wt% PEG-Nor hydrogel compositions. (<b>C</b>) Schematic shows an experimental design for secondary reactions of base PEG-Nor hydrogels with mono-thiolated (cRGD, cGFP) and di-thiolated molecules (DTT). (<b>D</b>) Bar graph shows elastic moduli after secondary reactions in 5 wt% PEG-Nor hydrogels with 5 and 7 mM DTT concentration. Bar graphs and scatter plot dots represent the mean and error bars represent standard deviation, * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 2
<p>Photopatterning of mono-thiolated peptides onto PEG-Nor hydrogels. (<b>A</b>) Schematic shows photopatterning process for one peptide (cRhodamine shown) and for two peptides (cRhodamine followed by cGFP). (<b>B</b>) Representative confocal image and plot profile of PEG-Nor hydrogel photopatterned with cRhodamine. (<b>C</b>) Representative confocal image and plot profile of PEG-Nor hydrogel photopatterned with cGFP. (<b>D</b>) Side view and volume view of photopatterned PEG-Nor hydrogel with cGFP. (<b>E</b>) Representative confocal image and intensity plot profiles of sequential photopatterning of PEG-Nor hydrogel with vertical cRhodamine and horizontal cGFP stripes. Scale bars: (<b>B</b>,<b>C</b>,<b>E</b>) = 100 μm.</p> Full article ">Figure 3
<p>MSCs attach and are mechanically active on RGD-functionalized PEG-Nor hydrogels. (<b>A</b>) Schematic of the experimental design for 2D MSC PEG-Nor studies. 2D morphological analysis of cell (<b>B</b>) area, (<b>C</b>) circularity, and (<b>D</b>) aspect ratio of MSCs on RGD-functionalized PEG-Nor hydrogels formed with 5 mM or 7 mM DTT crosslinker concentrations. (<b>E</b>) Quantification of nuclear YAP localization of MSCs on RGD-functionalized PEG-Nor hydrogels formed with 5 mM or 7 mM DTT crosslinker concentrations. Representative images of single MSCs stained for cytoskeletal actin (red), nuclei (blue), and YAP (green) on top of (<b>F</b>) 5 mM DTT and (<b>G</b>) 7 mM DTT RGD-functionalized PEG-Nor hydrogels (dashed white lines denote nuclear outlines). Bars represent the mean and error bars represent standard deviation, *** <span class="html-italic">p</span> &lt; 0.001, while ns indicates not statistically significant. Scale bars: (<b>F</b>,<b>G</b>) = 25 μm.</p> Full article ">Figure 4
<p>MSCs encapsulated in PEG-Nor hydrogels are round and highly viable. (<b>A</b>) Schematic of forming PEG-Nor hydrogels with encapsulated MSCs. 3D morphological analysis of cell (<b>B</b>) volume and (<b>C</b>) sphericity after 1, 3, and 7 days in culture. (<b>D</b>) Percentage of live MSCs after 1, 3, and 7 days in culture, and (<b>E</b>) representative confocal images of viable MSCs encapsulated in PEG-Nor hydrogels after 1, 3, and 7 days in culture. Bars represent the mean, while error bars represent standard deviation, *** <span class="html-italic">p</span> &lt; 0.001, and ns indicates not statistically significant. Scale bar: (<b>E</b>) = 100 μm.</p> Full article ">Figure 5
<p>Synthesis of PEG-Nor hydrogels using thiol-norbornene click chemistry. (<b>A</b>) Solution containing 8-arm PEG-Nor macromer, dithiol crosslinker DTT, and photoinitiator I2959 in the presence of UV light reacts to form PEG-Nor hydrogels. (<b>B</b>) Cylindrically formed 3D PEG-Nor hydrogels with 8 mm diameter and 2 mm height.</p> Full article ">

Review

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25 pages, 4010 KiB  
Review
Nanoclay-Composite Hydrogels for Bone Tissue Engineering
by Hee Sook Hwang and Chung-Sung Lee
Gels 2024, 10(8), 513; https://doi.org/10.3390/gels10080513 - 3 Aug 2024
Cited by 2 | Viewed by 1625
Abstract
Nanoclay-composite hydrogels represent a promising avenue for advancing bone tissue engineering. Traditional hydrogels face challenges in providing mechanical strength, biocompatibility, and bioactivity necessary for successful bone regeneration. The incorporation of nanoclay into hydrogel matrices offers a potential unique solution to these challenges. This [...] Read more.
Nanoclay-composite hydrogels represent a promising avenue for advancing bone tissue engineering. Traditional hydrogels face challenges in providing mechanical strength, biocompatibility, and bioactivity necessary for successful bone regeneration. The incorporation of nanoclay into hydrogel matrices offers a potential unique solution to these challenges. This review provides a comprehensive overview of the fabrication, physico-chemical/biological performance, and applications of nanoclay-composite hydrogels in bone tissue engineering. Various fabrication techniques, including in situ polymerization, physical blending, and 3D printing, are discussed. In vitro and in vivo studies evaluating biocompatibility and bioactivity have demonstrated the potential of these hydrogels for promoting cell adhesion, proliferation, and differentiation. Their applications in bone defect repair, osteochondral tissue engineering and drug delivery are also explored. Despite their potential in bone tissue engineering, nanoclay-composite hydrogels face challenges such as optimal dispersion, scalability, biocompatibility, long-term stability, regulatory approval, and integration with emerging technologies to achieve clinical application. Future research directions need to focus on refining fabrication techniques, enhancing understanding of biological interactions, and advancing towards clinical translation and commercialization. Overall, nanoclay-composite hydrogels offer exciting opportunities for improving bone regeneration strategies. Full article
(This article belongs to the Special Issue Hydrogel-Based Scaffolds with a Focus on Medical Use (2nd Edition))
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Figure 1

Figure 1
<p>Properties of hydrogels for bone tissue engineering.</p> Full article ">Figure 2
<p>Considerations and benefits of nanoclay reinforcement in hydrogels for bone tissue engineering.</p> Full article ">Figure 3
<p>Nanoclay-composite hydrogel for 3D printing biomaterial ink. (<b>A</b>) Synthesis process and representative images of a nanoclay sol-like mixture, a nanoclay-methacrylated hyaluronic acid mixture, and a nanoclay-methacrylated hyaluronic acid-alginate gel-like mixture. (<b>B</b>) Representative images of a straight filament and straight filament rotating around the collecting rod. (<b>C</b>) Optical images of straight filaments with diameters of 100, 200, and 300 µm, respectively. (<b>D</b>) Filaments can be formed into spiral shapes to endure extensive stretching, subsequently used to create a handmade clover. (<b>E</b>) 3D printing of complex architectures based on hydrogels. (<b>F</b>) Macroscopic and fluorescence images of the non-porous scaffold and 3D printed porous scaffold based on hydrogels. (<b>G</b>) In vivo micro-CT reconstructed images of calvarial defects at 4 weeks and 8 weeks after implantation. Reproduced with permission from Guo et al. [<a href="#B97-gels-10-00513" class="html-bibr">97</a>].</p> Full article ">Figure 4
<p>Dual nanoengineered DNA hydrogel (DAC) hydrogel for vascularized bone regeneration. (<b>A</b>) Schematic illustration of preparation of DAC hydrogel. (<b>B</b>) Schematics of the extrusion 3D printing process, scale bar: 5 mm. (<b>C</b>) Stability of 3D-printed DAC hydrogels at different pH values. (<b>D</b>) Reaction scheme of QK peptide-conjugated amyloid fibrils (AF-QK). (<b>E</b>) Stimulation effects of various hydrogels on HUVEC migration (<b>Left</b>). Quantitative migration ratio after HUVECs being cultured for 24 h (<b>Right</b>). (<b>F</b>) qRT–PCR analysis of angiogenesis-related gene (VEGF, PDGF-B, CD31, and VWF) expression in HUVECs cultured for 3 days. (<b>G</b>) Mineralized matrix determined by Alizarin red staining for 7 and 14 days. (<b>H</b>) Representative micro-CT images with cross-section and longitudinal section of skull defects implanted with hydrogels. (<b>I</b>) Quantitative analysis of OCN, CD31, and VEGF expression at 4, 8, and 12 weeks. *, <span class="html-italic">p</span> &lt; 0.05; **, <span class="html-italic">p</span> &lt; 0.01; ***, <span class="html-italic">p</span> &lt; 0.001. AF = amyloid fibrils, DA = DNA/AF hydrogel, DAC1.0 = DNA/AF/nanoclay hydrogel. Reproduced with permission from Yang et al. [<a href="#B98-gels-10-00513" class="html-bibr">98</a>].</p> Full article ">Figure 5
<p>Gelatin–Sumecton composite hydrogels. (<b>A</b>) Macroscopical images of lyophilized hydrogels. Scale bar = 5 mm. (<b>B</b>) Swelling ratio after 24 h of hydration. Statistical significance: *** <span class="html-italic">p</span> &lt; 0.001. (<b>C</b>) Scanning electron microscopy (SEM) representative images. Scale bar = 200 μm. (<b>D</b>) Compressive stress–strain curves of hydrogels. (<b>E</b>) Histomorphometric analysis showing the percentage of repair among all experimental groups. Same letters displayed in different histograms denote significant differences (<span class="html-italic">p</span> &lt; 0.001) among these groups. (<b>F</b>) Cross-sectional representative images stained with VOF trichrome dye of the defect site. SUM0: gelatin hydrogel without Sumecton, SUM0.5: gelatin–Sumecton composite hydrogel with Sumecton 0.5%, SUM1: gelatin–Sumecton composite hydrogel with Sumecton 1%, SUM2: gelatin–Sumecton composite hydrogel with Sumecton 2%, CT: Connective tissue, DS: Defect site, NB: Newly formed bone. Scale bar is 500 μm in (<b>F</b>). Reproduced with permission from Lukin et al. [<a href="#B114-gels-10-00513" class="html-bibr">114</a>].</p> Full article ">Figure 6
<p>Halloysite nanotube-composite chitosan hydrogels. In vitro biocompatibility of scaffolds: (<b>A</b>) OD values; and (<b>B</b>) live/dead staining of free (control) and encapsulated hASCs in different hydrogels on days 1, 3, and 5 of culture. In vitro osteogenic differentiation of free (control) and encapsulated hASCs in normal medium (NM) and osteogenic medium (OM): (<b>C</b>) ALP activity on days 7 and 14 of culture; and (<b>D</b>) Alizarin red staining on day 21 of culture; scaffolds: (a) CS/GP = chitosan/β-glycerophosphate hydrogel, (b) mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs, and (c) IC@mHNT2CS/GP = chitosan/β-glycerophosphate hydrogel with chitosan-modified HNTs and Icariin. * <span class="html-italic">p</span> &lt; 0.03, ** <span class="html-italic">p</span> &lt; 0.002, *** <span class="html-italic">p</span> &lt; 0.001. Reproduced with permission from Aghdam et al. [<a href="#B119-gels-10-00513" class="html-bibr">119</a>].</p> Full article ">
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