Hydrogels with Advanced Functionalities for Application in Regenerative Medicine and Tissue Engineering

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 20614

Special Issue Editors

3B’s Research Group, I3B’s – Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark - Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
Interests: tissue engineering; regenerative medicine; stem cells; hydrogels; bioprinting; skin; wound healing
Special Issues, Collections and Topics in MDPI journals
3B’s Research Group, I3B’s Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark—Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
Interests: tissue engineering; regenerative medicine; stem cells; skin; wound healing
1. 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
2. ICVS/3B’s–PT Government Associate Laboratory, Braga, 4805-017 Guimarães, Portugal
Interests: tissue engineering; regenerative medicine; biomaterials; biomimetics; biodegradable materials; 3D in vitro models; cancer modelling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to bioengineers developing new hydrogels with advanced functionalities for application in the regenerative medicine and tissue engineering fields.

Hydrogels are biomaterials of reference in the field of tissue engineering and regenerative medicine; they are a tridimensional network of crosslinked polymer chains which, due to the hydrophilic nature of the polymers, retain high water amounts. The water content allows the natural diffusion of molecules within the hydrogels, providing them with a soft mechanical appearance. These features, closely resembling the characteristics of the extracellular matrix of tissues, have attracted bioengineers to use hydrogels for biomedical purposes, e.g., as sustained-release drug depots or for cell encapsulation. Since then, first-generation hydrogels with varied physical–chemical, mechanical and biological properties have appeared through the tailoring of polymer(s) type(s) and amount, or by varying the processing method. The swiftly evolving field of biotechnology triggered the development of more advanced hydrogels, enabling the occurrence of a boost in tissue engineering upon the biofunctionalization of hydrogels with cell-adhesive sites (e.g., RGD sequence) for improved adhesion, by tethering growth factors to stimulate a specific response (e.g., FGF-2 to enhance proliferation) or by adding metalloproteinase-sensitive degradation sites for cell-mediated remodeling. The control of hydrogels’ rheological and mechanical properties came to be of particular interest since the revolution of 3D bioprinting, with the demand for adequate rheological properties for printing and a sol–gel transition postprinting. Smart, stimuli-responsive hydrogels capable of responding to a stimulus (e.g., temperature, pH, magnetic or electric fields) with a specific behavior (e.g., softening, swelling or molecule release) also present a great potential as biosensors. All these frontline strategies enrich the current state-of-the-art of hydrogels and bring new opportunities to the regenerative medicine and tissue engineering fields. We welcome submissions in this exciting field and look forward to learning the knowledge these new works will provide.

Dr. Lucília P. da Silva
Dr. Alexandra P. Marques
Prof. Dr. Rui L. Reis
Guest Editors

Manuscript Submission Information

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Keywords

  • biomaterial
  • hydrogel
  • biofunctionalization
  • tissue engineering
  • regenerative medicine

Published Papers (9 papers)

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Research

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23 pages, 4616 KiB  
Article
New Photocrosslinked 3D Foamed Scaffolds Based on GelMA Copolymers: Potential Application in Bone Tissue Engineering
Gels 2023, 9(5), 403; https://doi.org/10.3390/gels9050403 - 11 May 2023
Cited by 4 | Viewed by 1550
Abstract
The production of customized polymeric hydrogels in the form of 3D scaffolds with application in bone tissue engineering is currently a topic of great interest. Based on gelatin methacryloyl (GelMa) as one of the most popular used biomaterials, GelMa with two different methacryloylation [...] Read more.
The production of customized polymeric hydrogels in the form of 3D scaffolds with application in bone tissue engineering is currently a topic of great interest. Based on gelatin methacryloyl (GelMa) as one of the most popular used biomaterials, GelMa with two different methacryloylation degrees (DM) was obtained, to achieve crosslinked polymer networks by photoinitiated radical polymerization. In this work, we present the obtention of new 3D foamed scaffolds based on ternary copolymers of GelMa with vinylpyrrolidone (VP) and 2-hydroxyethylmethacrylate (HEMA). All biopolymers obtained in this work were characterized by infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA), whose results confirm the presence of all copolymers in the crosslinked biomaterial. In addition, scanning electron microscopy (SEM) pictures were obtained verifying the presence of the porosity created by freeze-drying process. In addition, the variation in its swelling degree and its enzymatic degradation in vitro was analyzed as a function of the different copolymers obtained. This has allowed us to observe good control of the variation in these properties described above in a simple way by varying the composition of the different comonomers used. Finally, with these concepts in mind, biopolymers obtained were tested through assessment of several biological parameters such as cell viability and differentiation with MC3T3-E1 pre-osteoblastic cell line. Results obtained show that these biopolymers maintain good results in terms of cell viability and differentiation, along with tunable properties in terms of hydrophilic character, mechanical properties and enzymatic degradation. Full article
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17 pages, 1877 KiB  
Article
Growth Factor Binding Peptides in Poly (Ethylene Glycol) Diacrylate (PEGDA)-Based Hydrogels for an Improved Healing Response of Human Dermal Fibroblasts
Gels 2023, 9(1), 28; https://doi.org/10.3390/gels9010028 - 29 Dec 2022
Cited by 3 | Viewed by 1418
Abstract
Growth factors (GF) are critical cytokines in wound healing. However, the direct delivery of these biochemical cues into a wound site significantly increases the cost of wound dressings and can lead to a strong immunological response due to the introduction of a foreign [...] Read more.
Growth factors (GF) are critical cytokines in wound healing. However, the direct delivery of these biochemical cues into a wound site significantly increases the cost of wound dressings and can lead to a strong immunological response due to the introduction of a foreign source of GFs. To overcome this challenge, we designed a poly(ethylene glycol) diacrylate (PEGDA) hydrogel with the potential capacity to sequester autologous GFs directly from the wound site. We demonstrated that synthetic peptide sequences covalently tethered to PEGDA hydrogels physically retained human transforming growth factor beta 1 (hTGFβ1) and human vascular endothelial growth factor (hVEGF) at 3.2 and 0.6 ng/mm2, respectively. In addition, we demonstrated that retained hTGFβ1 and hVEGF enhanced human dermal fibroblasts (HDFa) average cell surface area and proliferation, respectively, and that exposure to both GFs resulted in up to 1.9-fold higher fraction of area covered relative to the control. After five days in culture, relative to the control surface, non-covalently bound hTGFβ1 significantly increased the expression of collagen type I and hTGFβ1 and downregulated vimentin and matrix metalloproteinase 1 expression. Cumulatively, the response of HDFa to hTGFβ1 aligns well with the expected response of fibroblasts during the early stages of wound healing. Full article
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16 pages, 4418 KiB  
Article
From Macro to Micro: Comparison of Imaging Techniques to Detect Vascular Network Formation in Left Ventricle Decellularized Extracellular Matrix Hydrogels
Gels 2022, 8(11), 729; https://doi.org/10.3390/gels8110729 - 10 Nov 2022
Cited by 2 | Viewed by 1543
Abstract
Background: Angiogenesis is a crucial process in physiological maintenance and tissue regeneration. To understand the contribution of angiogenesis, it is essential to replicate this process in an environment that reproduces the biochemical and physical properties which are largely governed by the extracellular matrix [...] Read more.
Background: Angiogenesis is a crucial process in physiological maintenance and tissue regeneration. To understand the contribution of angiogenesis, it is essential to replicate this process in an environment that reproduces the biochemical and physical properties which are largely governed by the extracellular matrix (ECM). We investigated vascularization in cardiac left ventricular ECM hydrogels to mimic post-myocardial repair. We set out to assess and compare different destructive and non-destructive methods, optical as well as non-optical, to visualize angiogenesis and associated matrix remodeling in myocardial ECM hydrogels. Methods: A total of 100,000, 300,000, and 600,000 Human Pulmonary Microvascular Endothelial Cells (HPMEC) were seeded in left ventricular cardiac ECM hydrogel in 48-well plates. After 1, 7, and 14 days of culture, the HPMEC were imaged by inverted fluorescence microscopy and 3D confocal laser scanning microscopy (Zeiss Cell Discoverer 7). In addition, cell-seeded ECM hydrogels were scanned by optical coherence tomography (OCT). Fixed and paraffin-embedded gels were thin-sectioned and assessed for ECM components via H&E, picrosirius red histochemical staining, and immunostaining for collagen type I. ImageJ-based densitometry was used to quantify vascular-like networks and GraphPad was used for statistical analyses. Results: Qualitative analyses were realized through fluoromicrographs obtained by the confocal laser scanning microscope which allowed us to visualize the extensive vascular-like networks that readily appeared at all seeding densities. Quantification of networks was only possible using fluoromicrographs from inverted microscopy. These showed that, after three days, the number of master junctions was seeding density-dependent. The resolution of optical coherence tomography was too low to distinguish between signals caused by the ECM and cells or networks, yet it did show that gels, irrespective of cells, were heterogeneous. Interestingly, (immuno)histochemistry could clearly distinguish between the cast cardiac-derived matrix and newly deposited ECM in the hydrogels. The H&E staining corroborated the presence of vascular-like network structures, albeit that sectioning inevitably led to the loss of 3D structure. Conclusions: Except for OCT, all methods had complementary merit and generated qualitative and quantitative data that allowed us to understand vascular network formation in organ-derived ECM hydrogels. Full article
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19 pages, 2831 KiB  
Article
Bioprinting of 3D Adipose Tissue Models Using a GelMA-Bioink with Human Mature Adipocytes or Human Adipose-Derived Stem Cells
Gels 2022, 8(10), 611; https://doi.org/10.3390/gels8100611 - 25 Sep 2022
Cited by 9 | Viewed by 2496
Abstract
Adipose tissue is related to the development and manifestation of multiple diseases, demonstrating the importance of suitable in vitro models for research purposes. In this study, adipose tissue lobuli were explanted, cultured, and used as an adipose tissue control to evaluate in vitro [...] Read more.
Adipose tissue is related to the development and manifestation of multiple diseases, demonstrating the importance of suitable in vitro models for research purposes. In this study, adipose tissue lobuli were explanted, cultured, and used as an adipose tissue control to evaluate in vitro generated adipose tissue models. During culture, lobule exhibited a stable weight, lactate dehydrogenase, and glycerol release over 15 days. For building up in vitro adipose tissue models, we adapted the biomaterial gelatin methacryloyl (GelMA) composition and handling to homogeneously mix and bioprint human primary mature adipocytes (MA) and adipose-derived stem cells (ASCs), respectively. Accelerated cooling of the bioink turned out to be essential for the homogeneous distribution of lipid-filled MAs in the hydrogel. Last, we compared manual and bioprinted GelMA hydrogels with MA or ASCs and the explanted lobules to evaluate the impact of the printing process and rate the models concerning the physiological reference. The viability analyses demonstrated no significant difference between the groups due to additive manufacturing. The staining of intracellular lipids and perilipin A suggest that GelMA is well suited for ASCs and MA. Therefore, we successfully constructed physiological in vitro models by bioprinting MA-containing GelMA bioinks. Full article
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17 pages, 2476 KiB  
Article
Gellan Gum Is a Suitable Biomaterial for Manual and Bioprinted Setup of Long-Term Stable, Functional 3D-Adipose Tissue Models
Gels 2022, 8(7), 420; https://doi.org/10.3390/gels8070420 - 05 Jul 2022
Cited by 7 | Viewed by 2601
Abstract
Due to its wide-ranging endocrine functions, adipose tissue influences the whole body’s metabolism. Engineering long-term stable and functional human adipose tissue is still challenging due to the limited availability of suitable biomaterials and adequate cell maturation. We used gellan gum (GG) to create [...] Read more.
Due to its wide-ranging endocrine functions, adipose tissue influences the whole body’s metabolism. Engineering long-term stable and functional human adipose tissue is still challenging due to the limited availability of suitable biomaterials and adequate cell maturation. We used gellan gum (GG) to create manual and bioprinted adipose tissue models because of its similarities to the native extracellular matrix and its easily tunable properties. Gellan gum itself was neither toxic nor monocyte activating. The resulting hydrogels exhibited suitable viscoelastic properties for soft tissues and were stable for 98 days in vitro. Encapsulated human primary adipose-derived stem cells (ASCs) were adipogenically differentiated for 14 days and matured for an additional 84 days. Live-dead staining showed that encapsulated cells stayed viable until day 98, while intracellular lipid staining showed an increase over time and a differentiation rate of 76% between days 28 and 56. After 4 weeks of culture, adipocytes had a univacuolar morphology, expressed perilipin A, and secreted up to 73% more leptin. After bioprinting establishment, we demonstrated that the cells in printed hydrogels had high cell viability and exhibited an adipogenic phenotype and function. In summary, GG-based adipose tissue models show long-term stability and allow ASCs maturation into functional, univacuolar adipocytes. Full article
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26 pages, 4564 KiB  
Article
An Engineered Protein-Based Building Block (Albumin Methacryloyl) for Fabrication of a 3D In Vitro Cryogel Model
Gels 2022, 8(7), 404; https://doi.org/10.3390/gels8070404 - 25 Jun 2022
Cited by 5 | Viewed by 1730
Abstract
Drug-induced liver injury (DILI) is a leading cause of attrition in drug development or withdrawal; current animal experiments and traditional 2D cell culture systems fail to precisely predict the liver toxicity of drug candidates. Hence, there is an urgent need for an alternative [...] Read more.
Drug-induced liver injury (DILI) is a leading cause of attrition in drug development or withdrawal; current animal experiments and traditional 2D cell culture systems fail to precisely predict the liver toxicity of drug candidates. Hence, there is an urgent need for an alternative in vitro model that can mimic the liver microenvironments and accurately detect human-specific drug hepatotoxicity. Here, for the first time we propose the fabrication of an albumin methacryloyl cryogel platform inspired by the liver’s microarchitecture via emulating the mechanical properties and extracellular matrix (ECM) cues of liver. Engineered crosslinkable albumin methacryloyl is used as a protein-based building block for fabrication of albumin cryogel in vitro models that can have potential applications in 3D cell culture and drug screening. In this work, protein modification, cryogelation, and liver ECM coating were employed to engineer highly porous three-dimensional cryogels with high interconnectivity, liver-like stiffness, and liver ECM as artificial liver constructs. The resulting albumin-based cryogel in vitro model provided improved cell–cell and cell–material interactions and consequently displayed excellent liver functional gene expression, being conducive to detection of fialuridine (FIAU) hepatotoxicity. Full article
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14 pages, 4053 KiB  
Article
A Novel Method for the Preparation of Poly (Acrylamide-co-Acrylonitrile) Upper Critical Solution Temperature Thermosensitive Hydrogel by the Partial Dehydration of Acrylamide Grafted Polypropylene Sheets
Gels 2022, 8(6), 345; https://doi.org/10.3390/gels8060345 - 31 May 2022
Cited by 3 | Viewed by 1770
Abstract
In an attempt to find a potential application of cell culture harvesting, a novel method for the preparation of an upper critical solution temperature (UCST) thermosensitive hydrogel was studied. An electron accelerator was used as the electron beam (EB) radiation source, and acrylamide [...] Read more.
In an attempt to find a potential application of cell culture harvesting, a novel method for the preparation of an upper critical solution temperature (UCST) thermosensitive hydrogel was studied. An electron accelerator was used as the electron beam (EB) radiation source, and acrylamide (AAm) was first grafted onto the pre-irradiated polypropylene (PP) sheet. Then, the grafting layer of poly (acrylamide-co-acrylonitrile) (P (AAm-co-AN)) was obtained by the partial dehydration of the acylamino group into the cyano group in the solution mixture of sulfoxide chloride (SOCl2) and dimethyl formamide (DMF). The effects of the absorbed dose, AAm concentration, reaction time, and temperature on the degree of grafting were studied, respectively. The effect of the SOCl2 concentration on the conversion degree of the cyano group from the acylamino group was studied, followed by the temperature of the UCST. The UCST properties of the grafted samples with P (AAm-co-AN) were studied by quartz crystal microbalance (QCM) and atomic force microscope (AFM), respectively. The cytotoxicities of the hydrogels against cells were verified by CCK-8 studies. Full article
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Review

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28 pages, 1257 KiB  
Review
Liquid Embolic Agents for Endovascular Embolization: A Review
Gels 2023, 9(5), 378; https://doi.org/10.3390/gels9050378 - 04 May 2023
Cited by 5 | Viewed by 2719
Abstract
Endovascular embolization (EE) has been used for the treatment of blood vessel abnormalities, including aneurysms, AVMs, tumors, etc. The aim of this process is to occlude the affected vessel using biocompatible embolic agents. Two types of embolic agents, solid and liquid, are used [...] Read more.
Endovascular embolization (EE) has been used for the treatment of blood vessel abnormalities, including aneurysms, AVMs, tumors, etc. The aim of this process is to occlude the affected vessel using biocompatible embolic agents. Two types of embolic agents, solid and liquid, are used for endovascular embolization. Liquid embolic agents are usually injectable and delivered into the vascular malformation sites using a catheter guided by X-ray imaging (i.e., angiography). After injection, the liquid embolic agent transforms into a solid implant in situ based on a variety of mechanisms, including polymerization, precipitation, and cross-linking, through ionic or thermal process. Until now, several polymers have been designed successfully for the development of liquid embolic agents. Both natural and synthetic polymers have been used for this purpose. In this review, we discuss embolization procedures with liquid embolic agents in different clinical applications, as well as in pre-clinical research studies. Full article
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20 pages, 2137 KiB  
Review
A Beginner’s Guide to the Characterization of Hydrogel Microarchitecture for Cellular Applications
Gels 2022, 8(9), 535; https://doi.org/10.3390/gels8090535 - 26 Aug 2022
Cited by 18 | Viewed by 3690
Abstract
The extracellular matrix (ECM) is a three-dimensional, acellular scaffold of living tissues. Incorporating the ECM into cell culture models is a goal of cell biology studies and requires biocompatible materials that can mimic the ECM. Among such materials are hydrogels: polymeric networks that [...] Read more.
The extracellular matrix (ECM) is a three-dimensional, acellular scaffold of living tissues. Incorporating the ECM into cell culture models is a goal of cell biology studies and requires biocompatible materials that can mimic the ECM. Among such materials are hydrogels: polymeric networks that derive most of their mass from water. With the tuning of their properties, these polymer networks can resemble living tissues. The microarchitectural properties of hydrogels, such as porosity, pore size, fiber length, and surface topology can determine cell plasticity. The adequate characterization of these parameters requires reliable and reproducible methods. However, most methods were historically standardized using other biological specimens, such as 2D cell cultures, biopsies, or even animal models. Therefore, their translation comes with technical limitations when applied to hydrogel-based cell culture systems. In our current work, we have reviewed the most common techniques employed in the characterization of hydrogel microarchitectures. Our review provides a concise description of the underlying principles of each method and summarizes the collective data obtained from cell-free and cell-loaded hydrogels. The advantages and limitations of each technique are discussed, and comparisons are made. The information presented in our current work will be of interest to researchers who employ hydrogels as platforms for cell culture, 3D bioprinting, and other fields within hydrogel-based research. Full article
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