Hydrogels for Biomedical Application

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 83032

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Guest Editor
Department of Chemistry, Universita degli Studi di Bari, Bari, Italy
Interests: development and characterization of innovative polymeric biomaterials; surface modification methods; surface analysis techniques; surface composition and properties.
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Special Issue Information

Dear Colleagues,

Since the first appearance of the term hydrogel in 1984, this class of biomaterials has become increasingly more popular, particularly in recent years, as demonstrated by the exponential hike of literature on hydrogels. Over time, scientists have shaped hydrogels’ composition to match the plethora of biomedical applications in which they have been involved. Therefore, from the first hydrogels designed as soft contact lenses, biomaterials science has exploited these water-rich, 3D networks for a wide range of purposes. First, to deliver bioactive molecules, then as cell carriers for tissue regeneration. Recently, bioinks based on hydrogels are rethinking artificial tissue architecture, opening new landscapes in tissue engineering, as well as in biosensors development. Thus, beyond their traditional role of structural support (e.g., wound dressings, soft tissue fillers), hydrogels are becoming smart platforms for tissue regeneration, drug discovery, and delivery.

In this Special Issue, we would like to highlight the wide variety of hydrogel applications in biomedicine, ranging from stimuli-responsive biomaterials for regenerative medicine to smart adjuvants for the ultimate pharmaceutic formulation. This Special Issue, which will serve as an updated reference for biomaterials and pharmaceutical scientists, will collect contributions (original research articles, as well as reviews) dealing with traditional and innovative hydrogel compositions for biomedical applications. Both in vitro and in vivo studies are welcome, with the final goal of shedding light on the new frontiers of hydrogels in biomedicine.

Prof. Elvira De Giglio
Dr. Maria A. Bonifacio
Guest Editors

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Keywords

  • hydrogels
  • tissue engineering
  • multifunctional biomaterials
  • drug delivery
  • bioinks
  • injectable gel
  • composites
  • stimuli-responsive gels
  • shape memory gels
  • self-healing gels

Published Papers (19 papers)

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Research

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15 pages, 5171 KiB  
Article
Controlled Release in Hydrogels Using DNA Nanotechnology
by Chih-Hsiang Hu and Remi Veneziano
Biomedicines 2022, 10(2), 213; https://doi.org/10.3390/biomedicines10020213 - 19 Jan 2022
Cited by 3 | Viewed by 2390
Abstract
Gelatin is a biopolymer widely used to synthesize hydrogels for biomedical applications, such as tissue engineering and bioinks for 3D bioprinting. However, as with other biopolymer-based hydrogels, gelatin-hydrogels do not allow precise temporal control of the biomolecule distribution to mimic biological signals involved [...] Read more.
Gelatin is a biopolymer widely used to synthesize hydrogels for biomedical applications, such as tissue engineering and bioinks for 3D bioprinting. However, as with other biopolymer-based hydrogels, gelatin-hydrogels do not allow precise temporal control of the biomolecule distribution to mimic biological signals involved in biological mechanisms. Leveraging DNA nanotechnology tools to develop a responsive controlled release system via strand displacement has demonstrated the ability to encode logic process, which would enable a more sophisticated design for controlled release. However, this unique and dynamic system has not yet been incorporated within any hydrogels to create a complete release circuit mechanism that closely resembles the sequential distribution of biomolecules observed in the native environment. Here, we designed and synthesized versatile multi-arm DNA motifs that can be easily conjugated within a gelatin hydrogel via click chemistry to incorporate a strand displacement circuit. After validating the incorporation and showing the increased stability of DNA motifs against degradation once embedded in the hydrogel, we demonstrated the ability of our system to release multiple model cargos with temporal specificity by the addition of the trigger strands specific to each cargo. Additionally, we were able to modulate the rate and quantity of cargo release by tuning the sequence of the trigger strands. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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18 pages, 3825 KiB  
Article
Tuning of Hydrogel Architectures by Ionotropic Gelation in Microfluidics: Beyond Batch Processing to Multimodal Diagnostics
by Alessio Smeraldo, Alfonso Maria Ponsiglione, Paolo Antonio Netti and Enza Torino
Biomedicines 2021, 9(11), 1551; https://doi.org/10.3390/biomedicines9111551 - 27 Oct 2021
Cited by 4 | Viewed by 2082
Abstract
Microfluidics is emerging as a promising tool to control physicochemical properties of nanoparticles and to accelerate clinical translation. Indeed, microfluidic-based techniques offer more advantages in nanomedicine over batch processes, allowing fine-tuning of process parameters. In particular, the use of microfluidics to produce nanoparticles [...] Read more.
Microfluidics is emerging as a promising tool to control physicochemical properties of nanoparticles and to accelerate clinical translation. Indeed, microfluidic-based techniques offer more advantages in nanomedicine over batch processes, allowing fine-tuning of process parameters. In particular, the use of microfluidics to produce nanoparticles has paved the way for the development of nano-scaled structures for improved detection and treatment of several diseases. Here, ionotropic gelation is implemented in a custom-designed microfluidic chip to produce different nanoarchitectures based on chitosan-hyaluronic acid polymers. The selected biomaterials provide biocompatibility, biodegradability and non-toxic properties to the formulation, making it promising for nanomedicine applications. Furthermore, results show that morphological structures can be tuned through microfluidics by controlling the flow rates. Aside from the nanostructures, the ability to encapsulate gadolinium contrast agent for magnetic resonance imaging and a dye for optical imaging is demonstrated. In conclusion, the polymer nanoparticles here designed revealed the dual capability of enhancing the relaxometric properties of gadolinium by attaining Hydrodenticity and serving as a promising nanocarrier for multimodal imaging applications. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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13 pages, 2750 KiB  
Article
Affinity-Controlled Double-Network Hydrogel Facilitates Long-Term Release of Anti-Human Papillomavirus Protein
by Chenjia Zhao, Jingyuan Ji, Tianjun Yin, Jing Yang, Yuan Pang and Wei Sun
Biomedicines 2021, 9(10), 1298; https://doi.org/10.3390/biomedicines9101298 - 23 Sep 2021
Cited by 11 | Viewed by 2911
Abstract
Hydrogels have recently received attention as delivery carriers owing to their good biocompatibility and structural similarity to natural extracellular matrices. However, the utilization of traditional single-network (SN) hydrogels is limited by poor mechanical properties and burst drug release. Therefore, we developed a novel [...] Read more.
Hydrogels have recently received attention as delivery carriers owing to their good biocompatibility and structural similarity to natural extracellular matrices. However, the utilization of traditional single-network (SN) hydrogels is limited by poor mechanical properties and burst drug release. Therefore, we developed a novel double-network (DN) hydrogel, which employs an alginate (ALG)/polyethylene glycol diacrylate (PEGDA) network to adjust the mechanical strength and a positively charged monomer AETAC (2-(acryloyloxy)ethyl]trimethyl-ammonium chloride) to regulate the release curve of the electronegative anti-human papillomavirus (HPV) protein (bovine β-lactoglobulin modified with 3-hydroxyphthalic anhydride) based on an affinity-controlled delivery mechanism. The results show that the double-network hydrogel strongly inhibits the burst release, and the burst release amount is about one-third of that of the single-network hydrogel. By changing the concentration of the photoinitiator, the mechanical strength of the DN hydrogels can be adjusted to meet the stiffness requirements for various tissues within the range of 0.71 kPa to 10.30 kPa. Compared with the SN hydrogels, the DN hydrogels exhibit almost twice the mechanical strength and have smaller micropores. Cytotoxicity tests indicated that these SN and DN hydrogels were not cytotoxic with the result of over 100% relative proliferation rate of the HUVECs. Furthermore, DN hydrogels can significantly alleviate the burst release of antiviral proteins and prolong the release time to more than 14 days. Finally, we utilized digital light processing (DLP) technology to verify the printability of the DN hydrogel. Our study indicates that ALG/PEGDA-AETAC DN hydrogels could serve as platforms for delivering proteins and show promise for diverse tissue engineering applications. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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11 pages, 2459 KiB  
Article
3D Printing of Polysaccharide-Based Self-Healing Hydrogel Reinforced with Alginate for Secondary Cross-Linking
by Hyun-Ho Roh, Hyun-Seung Kim, Chunggoo Kim and Kuen-Yong Lee
Biomedicines 2021, 9(9), 1224; https://doi.org/10.3390/biomedicines9091224 - 15 Sep 2021
Cited by 16 | Viewed by 4412
Abstract
Three-dimensional (3D) bioprinting has been attractive for tissue and organ regeneration with the possibility of constructing biologically functional structures useful in many biomedical applications. Autonomous healing of hydrogels composed of oxidized hyaluronate (OHA), glycol chitosan (GC), and adipic acid dihydrazide (ADH) was achieved [...] Read more.
Three-dimensional (3D) bioprinting has been attractive for tissue and organ regeneration with the possibility of constructing biologically functional structures useful in many biomedical applications. Autonomous healing of hydrogels composed of oxidized hyaluronate (OHA), glycol chitosan (GC), and adipic acid dihydrazide (ADH) was achieved after damage. Interestingly, the addition of alginate (ALG) to the OHA/GC/ADH self-healing hydrogels was useful for the dual cross-linking system, which enhanced the structural stability of the gels without the loss of their self-healing capability. Various characteristics of OHA/GC/ADH/ALG hydrogels, including viscoelastic properties, cytotoxicity, and 3D printability, were investigated. Additionally, potential applications of 3D bioprinting of OHA/GC/ADH/ALG hydrogels for cartilage regeneration were investigated in vitro. This hydrogel system may have potential for bioprinting of a custom-made scaffold in various tissue engineering applications. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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18 pages, 11455 KiB  
Article
3D Collagen Hydrogel Promotes In Vitro Langerhans Islets Vascularization through ad-MVFs Angiogenic Activity
by Monica Salamone, Salvatrice Rigogliuso, Aldo Nicosia, Simona Campora, Carmelo Marco Bruno and Giulio Ghersi
Biomedicines 2021, 9(7), 739; https://doi.org/10.3390/biomedicines9070739 - 27 Jun 2021
Cited by 13 | Viewed by 3464
Abstract
Adipose derived microvascular fragments (ad-MVFs) consist of effective vascularization units able to reassemble into efficient microvascular networks. Because of their content in stem cells and related angiogenic activity, ad-MVFs represent an interesting tool for applications in regenerative medicine. Here we show that gentle [...] Read more.
Adipose derived microvascular fragments (ad-MVFs) consist of effective vascularization units able to reassemble into efficient microvascular networks. Because of their content in stem cells and related angiogenic activity, ad-MVFs represent an interesting tool for applications in regenerative medicine. Here we show that gentle dissociation of rat adipose tissue provides a mixture of ad-MVFs with a length distribution ranging from 33–955 μm that are able to maintain their original morphology. The isolated units of ad-MVFs that resulted were able to activate transcriptional switching toward angiogenesis, forming tubes, branches, and entire capillary networks when cultured in 3D collagen type-I hydrogel. The proper involvement of metalloproteases (MMP2/MMP9) and serine proteases in basal lamina and extracellular matrix ECM degradation during the angiogenesis were concurrently assessed by the evaluation of alpha-smooth muscle actin (αSMA) expression. These results suggest that collagen type-I hydrogel provides an adequate 3D environment supporting the activation of the vascularization process. As a proof of concept, we exploited 3D collagen hydrogel for the setting of ad-MVF–islet of Langerhans coculture to improve the islets vascularization. Our results suggest potential employment of the proposed in vitro system for regenerative medicine applications, such as the improving of the islet of Langerhans engraftment before transplantation. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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13 pages, 2991 KiB  
Article
Digital Light Processing Bioprinted Human Chondrocyte-Laden Poly (γ-Glutamic Acid)/Hyaluronic Acid Bio-Ink towards Cartilage Tissue Engineering
by Alvin Kai-Xing Lee, Yen-Hong Lin, Chun-Hao Tsai, Wan-Ting Chang, Tsung-Li Lin and Ming-You Shie
Biomedicines 2021, 9(7), 714; https://doi.org/10.3390/biomedicines9070714 - 23 Jun 2021
Cited by 15 | Viewed by 2883
Abstract
Cartilage injury is the main cause of disability in the United States, and it has been projected that cartilage injury caused by osteoarthritis will affect 30% of the entire United States population by the year 2030. In this study, we modified hyaluronic acid [...] Read more.
Cartilage injury is the main cause of disability in the United States, and it has been projected that cartilage injury caused by osteoarthritis will affect 30% of the entire United States population by the year 2030. In this study, we modified hyaluronic acid (HA) with γ-poly(glutamic) acid (γ-PGA), both of which are common biomaterials used in cartilage engineering, in an attempt to evaluate them for their potential in promoting cartilage regeneration. As seen from the results, γ-PGA-GMA and HA, with glycidyl methacrylate (GMA) as the photo-crosslinker, could be successfully fabricated while retaining the structural characteristics of γ-PGA and HA. In addition, the storage moduli and loss moduli of the hydrogels were consistent throughout the curing durations. However, it was noted that the modification enhanced the mechanical properties, the swelling equilibrium rate, and cellular proliferation, and significantly improved secretion of cartilage regeneration-related proteins such as glycosaminoglycan (GAG) and type II collagen (Col II). The cartilage tissue proof with Alcian blue further demonstrated that the modification of γ-PGA with HA exhibited suitability for cartilage tissue regeneration and displayed potential for future cartilage tissue engineering applications. This study built on the previous works involving HA and further showed that there are unlimited ways to modify various biomaterials in order to further bring cartilage tissue engineering to the next level. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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18 pages, 35786 KiB  
Article
Porcine Decellularized Diaphragm Hydrogel: A New Option for Skeletal Muscle Malformations
by Daniele Boso, Eugenia Carraro, Edoardo Maghin, Silvia Todros, Arben Dedja, Monica Giomo, Nicola Elvassore, Paolo De Coppi, Piero Giovanni Pavan and Martina Piccoli
Biomedicines 2021, 9(7), 709; https://doi.org/10.3390/biomedicines9070709 - 22 Jun 2021
Cited by 19 | Viewed by 3465
Abstract
Hydrogels are biomaterials that, thanks to their unique hydrophilic and biomimetic characteristics, are used to support cell growth and attachment and promote tissue regeneration. The use of decellularized extracellular matrix (dECM) from different tissues or organs significantly demonstrated to be far superior to [...] Read more.
Hydrogels are biomaterials that, thanks to their unique hydrophilic and biomimetic characteristics, are used to support cell growth and attachment and promote tissue regeneration. The use of decellularized extracellular matrix (dECM) from different tissues or organs significantly demonstrated to be far superior to other types of hydrogel since it recapitulates the native tissue’s ECM composition and bioactivity. Different muscle injuries and malformations require the application of patches or fillers to replenish the defect and boost tissue regeneration. Herein, we develop, produce, and characterize a porcine diaphragmatic dECM-derived hydrogel for diaphragmatic applications. We obtain a tissue-specific biomaterial able to mimic the complex structure of skeletal muscle ECM; we characterize hydrogel properties in terms of biomechanical properties, biocompatibility, and adaptability for in vivo applications. Lastly, we demonstrate that dECM-derived hydrogel obtained from porcine diaphragms can represent a useful biological product for diaphragmatic muscle defect repair when used as relevant acellular stand-alone patch. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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14 pages, 2753 KiB  
Article
Self-Supporting Hydrogels Based on Fmoc-Derivatized Cationic Hexapeptides for Potential Biomedical Applications
by Carlo Diaferia, Elisabetta Rosa, Enrico Gallo, Giovanni Smaldone, Mariano Stornaiuolo, Giancarlo Morelli and Antonella Accardo
Biomedicines 2021, 9(6), 678; https://doi.org/10.3390/biomedicines9060678 - 15 Jun 2021
Cited by 23 | Viewed by 3356
Abstract
Peptide-based hydrogels (PHGs) are biocompatible materials suitable for biological, biomedical, and biotechnological applications, such as drug delivery and diagnostic tools for imaging. Recently, a novel class of synthetic hydrogel-forming amphiphilic cationic peptides (referred to as series K), containing an aliphatic region and a [...] Read more.
Peptide-based hydrogels (PHGs) are biocompatible materials suitable for biological, biomedical, and biotechnological applications, such as drug delivery and diagnostic tools for imaging. Recently, a novel class of synthetic hydrogel-forming amphiphilic cationic peptides (referred to as series K), containing an aliphatic region and a Lys residue, was proposed as a scaffold for bioprinting applications. Here, we report the synthesis of six analogues of the series K, in which the acetyl group at the N-terminus is replaced by aromatic portions, such as the Fmoc protecting group or the Fmoc-FF hydrogelator. The tendency of all peptides to self-assemble and to gel in aqueous solution was investigated using a set of biophysical techniques. The structural characterization pointed out that only the Fmoc-derivatives of series K keep their capability to gel. Among them, Fmoc-K3 hydrogel, which is the more rigid one (G’ = 2526 Pa), acts as potential material for tissue engineering, fully supporting cell adhesion, survival, and duplication. These results describe a gelification process, allowed only by the correct balancing among aggregation forces within the peptide sequences (e.g., van der Waals, hydrogen bonding, and π–π stacking). Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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20 pages, 4726 KiB  
Article
Deciphering the Molecular Mechanism of Water Interaction with Gelatin Methacryloyl Hydrogels: Role of Ionic Strength, pH, Drug Loading and Hydrogel Network Characteristics
by Margaux Vigata, Christoph Meinert, Nathalie Bock, Bronwin L. Dargaville and Dietmar W. Hutmacher
Biomedicines 2021, 9(5), 574; https://doi.org/10.3390/biomedicines9050574 - 19 May 2021
Cited by 30 | Viewed by 5056
Abstract
Water plays a primary role in the functionality of biomedical polymers such as hydrogels. The state of water, defined as bound, intermediate, or free, and its molecular organization within hydrogels is an important factor governing biocompatibility and hemocompatibility. Here, we present a systematic [...] Read more.
Water plays a primary role in the functionality of biomedical polymers such as hydrogels. The state of water, defined as bound, intermediate, or free, and its molecular organization within hydrogels is an important factor governing biocompatibility and hemocompatibility. Here, we present a systematic study of water states in gelatin methacryloyl (GelMA) hydrogels designed for drug delivery and tissue engineering applications. We demonstrate that increasing ionic strength of the swelling media correlated with the proportion of non-freezable bound water. We attribute this to the capability of ions to create ion–dipole bonds with both the polymer and water, thereby reinforcing the first layer of polymer hydration. Both pH and ionic strength impacted the mesh size, having potential implications for drug delivery applications. The mechanical properties of GelMA hydrogels were largely unaffected by variations in ionic strength or pH. Loading of cefazolin, a small polar antibiotic molecule, led to a dose-dependent increase of non-freezable bound water, attributed to the drug’s capacity to form hydrogen bonds with water, which helped recruit water molecules in the hydrogels’ first hydration layer. This work enables a deeper understanding of water states and molecular arrangement at the hydrogel–polymer interface and how environmental cues influence them. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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22 pages, 4040 KiB  
Article
Extrusion-Printing of Multi-Channeled Two-Component Hydrogel Constructs from Gelatinous Peptides and Anhydride-Containing Oligomers
by Jan Krieghoff, Johannes Rost, Caroline Kohn-Polster, Benno M. Müller, Andreas Koenig, Tobias Flath, Michaela Schulz-Siegmund, Fritz-Peter Schulze and Michael C. Hacker
Biomedicines 2021, 9(4), 370; https://doi.org/10.3390/biomedicines9040370 - 1 Apr 2021
Cited by 6 | Viewed by 3156
Abstract
The performance of artificial nerve guidance conduits (NGC) in peripheral nerve regeneration can be improved by providing structures with multiple small channels instead of a single wide lumen. 3D-printing is a strategy to access such multi-channeled structures in a defined and reproducible way. [...] Read more.
The performance of artificial nerve guidance conduits (NGC) in peripheral nerve regeneration can be improved by providing structures with multiple small channels instead of a single wide lumen. 3D-printing is a strategy to access such multi-channeled structures in a defined and reproducible way. This study explores extrusion-based 3D-printing of two-component hydrogels from a single cartridge printhead into multi-channeled structures under aseptic conditions. The gels are based on a platform of synthetic, anhydride-containing oligomers for cross-linking of gelatinous peptides. Stable constructs with continuous small channels and a variety of footprints and sizes were successfully generated from formulations containing either an organic or inorganic gelation base. The adjustability of the system was investigated by varying the cross-linking oligomer and substituting the gelation bases controlling the cross-linking kinetics. Formulations with organic N‑methyl-piperidin-3-ol and inorganic K2HPO4 yielded hydrogels with comparable properties after manual processing and extrusion-based 3D-printing. The slower reaction kinetics of formulations with K2HPO4 can be beneficial for extending the time frame for printing. The two-component hydrogels displayed both slow hydrolytic and activity-dependent enzymatic degradability. Together with satisfying in vitro cell proliferation data, these results indicate the suitability of our cross-linked hydrogels as multi-channeled NGC for enhanced peripheral nerve regeneration. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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17 pages, 4761 KiB  
Article
Neuronal Differentiation from Induced Pluripotent Stem Cell-Derived Neurospheres by the Application of Oxidized Alginate-Gelatin-Laminin Hydrogels
by Thomas Distler, Ines Lauria, Rainer Detsch, Clemens M. Sauter, Farina Bendt, Julia Kapr, Stephan Rütten, Aldo R. Boccaccini and Ellen Fritsche
Biomedicines 2021, 9(3), 261; https://doi.org/10.3390/biomedicines9030261 - 5 Mar 2021
Cited by 23 | Viewed by 5221
Abstract
Biodegradable hydrogels that promote stem cell differentiation into neurons in three dimensions (3D) are highly desired in biomedical research to study drug neurotoxicity or to yield cell-containing biomaterials for neuronal tissue repair. Here, we demonstrate that oxidized alginate-gelatin-laminin (ADA-GEL-LAM) hydrogels facilitate neuronal differentiation [...] Read more.
Biodegradable hydrogels that promote stem cell differentiation into neurons in three dimensions (3D) are highly desired in biomedical research to study drug neurotoxicity or to yield cell-containing biomaterials for neuronal tissue repair. Here, we demonstrate that oxidized alginate-gelatin-laminin (ADA-GEL-LAM) hydrogels facilitate neuronal differentiation and growth of embedded human induced pluripotent stem cell (hiPSC) derived neurospheres. ADA-GEL and ADA-GEL-LAM hydrogels exhibiting a stiffness close to ~5 kPa at initial cell culture conditions of 37 °C were prepared. Laminin supplemented ADA-GEL promoted an increase in neuronal differentiation in comparison to pristine ADA-GEL, with enhanced neuron migration from the neurospheres to the bulk 3D hydrogel matrix. The presence of laminin in ADA-GEL led to a more than two-fold increase in the number of neurospheres with migrated neurons. Our findings suggest that laminin addition to oxidized alginate—gelatin hydrogel matrices plays a crucial role to tailor oxidized alginate-gelatin hydrogels suitable for 3D neuronal cell culture applications. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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16 pages, 4603 KiB  
Article
Platelet-Derived Growth Factor Stimulated Migration of Bone Marrow Mesenchymal Stem Cells into an Injectable Gelatin-Hydroxyphenyl Propionic Acid Matrix
by Wanting Niu, Teck Chuan Lim, Abdulmonem Alshihri, Ravikumar Rajappa, Lishan Wang, Motoichi Kurisawa and Myron Spector
Biomedicines 2021, 9(2), 203; https://doi.org/10.3390/biomedicines9020203 - 17 Feb 2021
Cited by 8 | Viewed by 2772
Abstract
Bone marrow mesenchymal stem cells (bMSCs) are responsible in the repair of injured tissue through differentiation into multiple cell types and secretion of paracrine factors, and thus have a broad application profile in tissue engineering/regenerative medicine, especially for the musculoskeletal system. The lesion [...] Read more.
Bone marrow mesenchymal stem cells (bMSCs) are responsible in the repair of injured tissue through differentiation into multiple cell types and secretion of paracrine factors, and thus have a broad application profile in tissue engineering/regenerative medicine, especially for the musculoskeletal system. The lesion due to injury or disease may be a closed irregular-shaped cavity deep within tissue necessitating an injectable biomaterial permissive of host (endogenous) cell migration, proliferation and differentiation. Gelatin-hydroxyphenyl propionic acid (Gtn-HPA) is a natural biopolymer hydrogel which is covalently cross-linked by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) in situ and can be delivered to the lesion by needle injection. Growth factors and cytokines can be directly incorporated into the gel or into nano- and micro-particles, which can be employed for sustained release of biomolecules while maintaining their bioactivity. In this study, we selected polyelectrolyte complex nanoparticles (PCNs) prepared with dextran sulfate and chitosan as the carrier for platelet-derived growth factor (PDGF)-BB and stromal cell-derived factor (SDF)-1α, which have been tested effectively in recruiting stem cells. Our in vitro results showed a high degree of viability of bMSCs through the process of Gtn-HPA covalent cross-linking gelation. The Gtn-HPA matrix was highly permissive of bMSC migration, proliferation, and differentiation. PDGF-BB (20 ng/mL) directly incorporated into the gel and, alternatively, released from PCNs stimulated bMSC migration and proliferation. There were only small differences in the results for the direct incorporation of PDGF into the gel compared with its release from PCNs, and for increased doses of the growth factor (200 ng/mL and 2 µg/mL). In contrast, SDF-1α elicited an increase in migration and proliferation only when released from PCNs; its effect on migration was notably less than PDGF-BB. The in vitro results demonstrate that PDGF-BB substantially increases migration of bMSCs into Gtn-HPA and their proliferation in the gel, and that these benefits can be derived from incorporation of a relatively low dose of the growth factor directly into the gel. These findings commend the use of Gtn-HPA/PDGF-BB as an injectable therapeutic agent to treat defects in musculoskeletal tissues. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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19 pages, 5874 KiB  
Article
Light Cross-Linkable Marine Collagen for Coaxial Printing of a 3D Model of Neuromuscular Junction Formation
by Borja Sanz, Ane Albillos Sanchez, Bonnie Tangey, Kerry Gilmore, Zhilian Yue, Xiao Liu and Gordon Wallace
Biomedicines 2021, 9(1), 16; https://doi.org/10.3390/biomedicines9010016 - 26 Dec 2020
Cited by 24 | Viewed by 5095
Abstract
Collagen is a major component of the extracellular matrix (ECM) that modulates cell adhesion, growth, and migration, and has been utilised in tissue engineering applications. However, the common terrestrial sources of collagen carry the risk of zoonotic disease transmission and there are religious [...] Read more.
Collagen is a major component of the extracellular matrix (ECM) that modulates cell adhesion, growth, and migration, and has been utilised in tissue engineering applications. However, the common terrestrial sources of collagen carry the risk of zoonotic disease transmission and there are religious barriers to the use of bovine and porcine products in many cultures. Marine based collagens offer an attractive alternative and have so far been under-utilized for use as biomaterials for tissue engineering. Marine collagen can be extracted from fish waste products, therefore industry by-products offer an economical and environmentally sustainable source of collagen. In a handful of studies, marine collagen has successfully been methacrylated to form collagen methacrylate (ColMA). Our work included the extraction, characterization and methacrylation of Red Snapper collagen, optimisation of conditions for neural cell seeding and encapsulation using the unmodified collagen, thermally cross-linked, and the methacrylated collagen with UV-induced cross-linking. Finally, the 3D co-axial printing of neural and skeletal muscle cell cultures as a model for neuromuscular junction (NMJ) formation was investigated. Overall, the results of this study show great potential for a novel NMJ in vitro 3D bioprinted model that, with further development, could provide a low-cost, customizable, scalable and quick-to-print platform for drug screening and to study neuromuscular junction physiology and pathogenesis. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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Review

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19 pages, 681 KiB  
Review
Hydrogels: 3D Drug Delivery Systems for Nanoparticles and Extracellular Vesicles
by Yashna Chabria, Garry P. Duffy, Aoife J Lowery and Róisín M. Dwyer
Biomedicines 2021, 9(11), 1694; https://doi.org/10.3390/biomedicines9111694 - 15 Nov 2021
Cited by 20 | Viewed by 4496
Abstract
Synthetic and naturally occurring nano-sized particles present versatile vehicles for the delivery of therapy in a range of clinical settings. Their small size and modifiable physicochemical properties support refinement of targeting capabilities, immune response, and therapeutic cargo, but rapid clearance from the body [...] Read more.
Synthetic and naturally occurring nano-sized particles present versatile vehicles for the delivery of therapy in a range of clinical settings. Their small size and modifiable physicochemical properties support refinement of targeting capabilities, immune response, and therapeutic cargo, but rapid clearance from the body and limited efficacy remain a major challenge. This highlights the need for a local sustained delivery system for nanoparticles (NPs) and extracellular vesicles (EVs) at the target site that will ensure prolonged exposure, maximum efficacy and dose, and minimal toxicity. Biocompatible hydrogels loaded with therapeutic NPs/EVs hold immense promise as cell-free sustained and targeted delivery systems in a range of disease settings. These bioscaffolds ensure retention of the nano-sized particles at the target site and can also act as controlled release systems for therapeutics over a prolonged period of time. The encapsulation of stimuli sensitive components into hydrogels supports the release of the content on-demand. In this review, we highlight the prospect of the sustained and prolonged delivery of these nano-sized therapeutic entities from hydrogels for broad applications spanning tissue regeneration and cancer treatment. Further understanding of the parameters controlling the release rate of these particles and efficient transfer of cargo to target cells will be fundamental to success. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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22 pages, 938 KiB  
Review
Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives
by Kenny T. Lin, Athena Wang, Alexandra B. Nguyen, Janaki Iyer and Simon D. Tran
Biomedicines 2021, 9(9), 1203; https://doi.org/10.3390/biomedicines9091203 - 12 Sep 2021
Cited by 17 | Viewed by 3803
Abstract
With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions [...] Read more.
With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions induced by cataract surgery, such as suturing and stromal hydration, are less than ideal due to the potential for surgically induced astigmatism or wound leakage. Vitrectomy performed on patients with diabetic retinopathy requires an artificial vitreous substitute, with current offerings having many shortcomings such as retinal toxicity. The use of stem cells has also been investigated in retinal degenerative diseases; however, an optimal delivery system is required for successful transplantation. The incorporation of hydrogels into ocular therapy has been a critical focus in overcoming the limitations of current treatments. Previous reviews have extensively documented the use of hydrogels in drug delivery; thus, the goal of this review is to discuss recent advances in hydrogel technology in surgical applications, including dendrimer and gelatin-based hydrogels for ocular adhesives and a variety of different polymers for vitreous substitutes, as well as recent advances in hydrogel-based retinal pigment epithelium (RPE) and retinal progenitor cell (RPC) delivery to the retina. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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20 pages, 2501 KiB  
Review
Hyaluronic Acid Hydrogels Crosslinked in Physiological Conditions: Synthesis and Biomedical Applications
by Luis Andrés Pérez, Rebeca Hernández, José María Alonso, Raúl Pérez-González and Virginia Sáez-Martínez
Biomedicines 2021, 9(9), 1113; https://doi.org/10.3390/biomedicines9091113 - 30 Aug 2021
Cited by 65 | Viewed by 9060
Abstract
Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. [...] Read more.
Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. This review compiles the currently used approaches for the development of hyaluronic acid hydrogels under physiological/mild conditions. These methods include dynamic covalent processes such as boronic ester and Schiff-base formation and click chemistry mediated reactions such as thiol chemistry processes, azide-alkyne, or Diels Alder cycloaddition. Thermoreversible gelation of HA hydrogels at physiological temperature is also discussed. Finally, the most outstanding biomedical applications are indicated for each of the HA hydrogel generation approaches. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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22 pages, 8307 KiB  
Review
Smart Hydrogels Meet Carbon Nanomaterials for New Frontiers in Medicine
by Simone Adorinni, Petr Rozhin and Silvia Marchesan
Biomedicines 2021, 9(5), 570; https://doi.org/10.3390/biomedicines9050570 - 18 May 2021
Cited by 39 | Viewed by 5638
Abstract
Carbon nanomaterials include diverse structures and morphologies, such as fullerenes, nano-onions, nanodots, nanodiamonds, nanohorns, nanotubes, and graphene-based materials. They have attracted great interest in medicine for their high innovative potential, owing to their unique electronic and mechanical properties. In this review, we describe [...] Read more.
Carbon nanomaterials include diverse structures and morphologies, such as fullerenes, nano-onions, nanodots, nanodiamonds, nanohorns, nanotubes, and graphene-based materials. They have attracted great interest in medicine for their high innovative potential, owing to their unique electronic and mechanical properties. In this review, we describe the most recent advancements in their inclusion in hydrogels to yield smart systems that can respond to a variety of stimuli. In particular, we focus on graphene and carbon nanotubes, for applications that span from sensing and wearable electronics to drug delivery and tissue engineering. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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15 pages, 1851 KiB  
Review
Angiogenic Potential in Biological Hydrogels
by Maria Vittoria Giraudo, Dalila Di Francesco, Marta Calvo Catoira, Diego Cotella, Luca Fusaro and Francesca Boccafoschi
Biomedicines 2020, 8(10), 436; https://doi.org/10.3390/biomedicines8100436 - 20 Oct 2020
Cited by 12 | Viewed by 3238
Abstract
Hydrogels are three-dimensional (3D) materials able to absorb and retain water in large amounts while maintaining their structural stability. Due to their considerable biocompatibility and similarity with the body’s tissues, hydrogels are one of the most promising groups of biomaterials. The main application [...] Read more.
Hydrogels are three-dimensional (3D) materials able to absorb and retain water in large amounts while maintaining their structural stability. Due to their considerable biocompatibility and similarity with the body’s tissues, hydrogels are one of the most promising groups of biomaterials. The main application of these hydrogels is in regenerative medicine, in which they allow the formation of an environment suitable for cell differentiation and growth. Deriving from these hydrogels, it is, therefore, possible to obtain bioactive materials that can regenerate tissues. Because vessels guarantee the right amount of oxygen and nutrients but also assure the elimination of waste products, angiogenesis is one of the processes at the base of the regeneration of a tissue. On the other hand, it is a very complex mechanism and the parameters to consider are several. Indeed, the factors and the cells involved in this process are numerous and, for this reason, it has been a challenge to recreate a biomaterial able to adequately sustain the angiogenic process. However, in this review the focal point is the application of natural hydrogels in angiogenesis enhancing and their potential to guide this process. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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30 pages, 5648 KiB  
Systematic Review
Collagen Bioinks for Bioprinting: A Systematic Review of Hydrogel Properties, Bioprinting Parameters, Protocols, and Bioprinted Structure Characteristics
by Jana Stepanovska, Monika Supova, Karel Hanzalek, Antonin Broz and Roman Matejka
Biomedicines 2021, 9(9), 1137; https://doi.org/10.3390/biomedicines9091137 - 1 Sep 2021
Cited by 35 | Viewed by 7279
Abstract
Bioprinting is a modern tool suitable for creating cell scaffolds and tissue or organ carriers from polymers that mimic tissue properties and create a natural environment for cell development. A wide range of polymers, both natural and synthetic, are used, including extracellular matrix [...] Read more.
Bioprinting is a modern tool suitable for creating cell scaffolds and tissue or organ carriers from polymers that mimic tissue properties and create a natural environment for cell development. A wide range of polymers, both natural and synthetic, are used, including extracellular matrix and collagen-based polymers. Bioprinting technologies, based on syringe deposition or laser technologies, are optimal tools for creating precise constructs precisely from the combination of collagen hydrogel and cells. This review describes the different stages of bioprinting, from the extraction of collagen hydrogels and bioink preparation, over the parameters of the printing itself, to the final testing of the constructs. This study mainly focuses on the use of physically crosslinked high-concentrated collagen hydrogels, which represents the optimal way to create a biocompatible 3D construct with sufficient stiffness. The cell viability in these gels is mainly influenced by the composition of the bioink and the parameters of the bioprinting process itself (temperature, pressure, cell density, etc.). In addition, a detailed table is included that lists the bioprinting parameters and composition of custom bioinks from current studies focusing on printing collagen gels without the addition of other polymers. Last but not least, our work also tries to refute the often-mentioned fact that highly concentrated collagen hydrogel is not suitable for 3D bioprinting and cell growth and development. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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