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Abstract

Hydrogels have captivated the attention of several research and industry segments, including bioengineering, tissue engineering, implantable/wearable sensors and actuators, bioactive agent delivery, food processing, and industrial processes optimization. A common limitation of these systems is their fixed shape. The concept of hydrogel moldability is often assigned to the injectability potential of liquid precursors, and this feature is often lost right after hydrogel formation. Hydrogel modulation is a recent trend that advocates the importance of designing materials with shape fitting ability targeting on-demand responses or defect filling purposes. Here, we present a compliant and cell encapsulation-compatible hydrogel prepared from unmodified natural origin polymers with the ability to undergo extreme sequential shape alterations with high recovery of its mechanical properties. Different fragments of these hydrogels could be bonded together in spatiotemporally-controlled shape- and formulation-morphing structures. This material is prepared with affordable off-the-shelf polysaccharides of natural origin using a mild and safe processing strategy, based solely on polyelectrolyte complexation followed by an innovative partial coacervate compactation and dehydration step. These unique hydrogels hold potential for multifield industrial and healthcare applications. In particular, they may find application as defect filling agents or highly compliant wound healing patches for cargo release and/or cell delivery for tissue regeneration and cell-based therapies.

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... Moreover, hydrogels formed with non-covalent bonds may be moldable, permitting a better defect filling ability. This leads to an increased demand of physically crosslinked hydrogels in the field of biomaterials and tissue engineering [18]. ...
... These hydrogels do not dissolve in any solvent until the covalent crosslinked points are weakened. The chemically crosslinked hydrogels are mechanically strong and depend upon the nature of chemical bonds existing between building blocks and crosslinks [18]. Different methods to develop such hydrogels are discussed below: a) Radical polymerization: Swelling is an important characteristic of the hydrogel system and it can be regulated by the number of crosslinking agents incorporated into the system. ...
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Injectable biomaterials scaffolds play a pivotal role for dental tissue regeneration, as such materials are highly applicable in the dental field, particularly when compared to pre-formed scaffolds. The defects in the maxilla-oral area are normally small, confined and sometimes hard to access. This narrative review describes different types of biomaterials for dental tissue regeneration, and also discusses the potential use of nanofibers for dental tissues. Various studies suggest that tissue engineering approaches involving the use of injectable biomaterials have the potential of restoring not only dental tissue function but also their biological purposes.
... Os hidrogéis são materiais constituídos por polímeros sintéticos ou naturais que foram concebidos para imitar as propriedades naturais da matriz extracelular (ECM), nomeadamente o suporte mecânico e a libertação de fatores de crescimento (GF) implicados na regeneração tecidual. Estes materiais encerram a vantagem de poderem ser produzidos à medida pretendida, ou mesmo polimerizados in situ (Oliveira, M. B., Bastos, H. X. S. & Mano, J. F., 2018). ...
... As referências bibliográficas deverão ser citadas no seguinte modelo (Dinis- Oliveira et al., 2018). As referências bibliográficas não incluem dados não publicados, podendo ser incorporada a informação ao longo do texto, entre parêntesis. ...
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The main aim of the present study was to perform a literature review on the use of xenogenic and synthetic bomaterials for tissue healing. Regarding ceramic materials, hybrid hydroxyapatite and β-TCP (60-70/40-30 wt%), apatite carbonate, demineralized bovine bone mineral (DBBM) are ordinary bone graft materials. However, the absorption rate and biologic response of synthetics is slower than those for xenogenic graft materials. Regarding several polymers, xenogenic materials (e.g. collagen, chitosan) have shown a biologic response proper for tissue healing when compared to synthetic polymers (e.g. PLGA, PLDLA). Thus, the bone healing involves cell migration, protein and mineral adsorption, angiogenesis, and the tissue formation. The development of synthetic polymers with a bio-absorption rate in synergism with the tissue healing and angiogenesis has been the focus of recent studies. Therefore, the combination of synthetic and xenogeneic graft materials become a strategy for enhanced tissue healing. https://revsalus.racslusofonia.org/wp-content/uploads/2019/11/RevSALUS-Volume-2.pdf
... Hydrogels can be obtained from complexing CH and oppositely charged polysaccharides. 94 Such highly moldable and versatile systems could be explored in the future in the context of the delivery of therapeutic biomolecules. Currently, there are some examples of the delivery of bioactive compounds via CH hydrogels. ...
... Porous chitosan/alginate gels were also prepared by controlling the ionic strength, using different sodium chloride contents (0, 0.15, and 0.5 M) at pH 4.0 to guarantee ionized polysaccharides in aqueous solutions. The ionic strength significantly influences the Zeta potential due to electrostatic screening [172]. Porous chitosan/chondroitin sulfate coacervates (hydrogels) were prepared by dropping an aqueous chondroitin sulfate solution (25% w/v) into 1.6% w/v chitosan solution created in 0.57 M aqueous hydrochloric acid solution. ...
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Polysaccharide-based materials created by physical processes have received considerable attention for biomedical applications. These structures are often made by associating charged polyelectrolytes in aqueous solutions, avoiding toxic chemistries (crosslinking agents). We review the principal polysaccharides (glycosaminoglycans, marine polysaccharides, and derivatives) containing ionizable groups in their structures and cellulose (neutral polysaccharide). Physical materials with high stability in aqueous media can be developed depending on the selected strategy. We review strategies, including coacervation, ionotropic gelation, electrospinning, layer-by-layer coating, gelation of polymer blends, solvent evaporation, and freezing–thawing methods, that create polysaccharide-based assemblies via in situ (one-step) methods for biomedical applications. We focus on materials used for growth factor (GFs) delivery, scaffolds, antimicrobial coatings, and wound dressings.
... This is a procedure analogous to that reported for the compaction of PECs constituted of alginate and chitosan which allows for the preparation of highly hydrated hydrogels in the presence of salt. 24,25 After centrifugation (compaction stage), and removing the supernatant, the precipitates from all the samples presented a hydrogel-like aspect as can be observed in Fig. 3. Except for sample C, the SR (%) of all hydrogels increased after being immersed in water for 24 h. The negative SR (%) value obtained for sample C implied partial dissolution of the sample in water. ...
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The creation of flexible and high strength hydrogel materials from natural polymers as low cost and safe solid electrolytes is an area of intense research nowadays. We present a novel approach for the preparation of gelatin and chondroitin sulfate hydrogel complexes by using a simple centrifugation process. The innovative dual-bio-gel-network is able to swell and shrink upon changes on the pH and NaCl concentration. The solid bio-gels sandwiched between two macroporous carbon electrode materials are assembled in symmetric cells and their electrochemical properties are evaluated by cyclic voltammetry, galvanostatic, and impedance spectroscopy measurements. The cells exhibit areal capacitance values up to 2.74 mF cm−2 (3.1 F g−1) and a low resistance value of 12 Ohm cm2 for graphene electrode materials. These properties are the consequence of the successful infiltration of the solid gel inside the porous structure of the carbon electrode that boosts the charge transfer at the biopolymer/carbon electrode interphase. The results obtained may provide additional inspiration in the emerging field of bioelectronics, where biocompatible and powered systems are of the utmost importance.
... Smart bio-hydrogel actuators possess excellent biocompatibility and biodegradation, and are able to exhibit desired and programmable three-dimensional (3D) shape transformations, and thus mechanical property changes under external stimuli including pH, temperature, light, electric and magnetic. They can also function as soft actuators, such as grippers, smart capsules and bioinspired lenses with great application potentials in various fields, such as biomedicine, biomimetic machines, and so on [113]. Polymer actuators have been developed for significant deformations by repetitive molecular motions. ...
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The abilities of intelligent polymer hydrogels to change their structure and volume phase in response to external stimuli have provided new possibilities for various advanced technologies and great research and application potentials in medical field. The natural polymer-based hydrogels have the advantages of environment-friendliness, rich sources and good biocompatibility. Based on their responsiveness to external stimuli, the natural polymer-based hydrogels can be classified into temperature-responsive hydrogel, pH-responsive hydrogel, light-responsive hydrogel, electric-responsive hydrogel, redox-responsive hydrogel, enzyme-responsive hydrogel, magnetic-responsive hydrogel, multi-responsive hydrogel, etc. In this review, we have compiled some recent studies on natural polymer-based stimuli-responsive hydrogels, especially the hydrogels prepared from polysaccharides. The preparation methods, properties and applications of these hydrogels in medical field are highlighted.
... Natural polymers, which are divided into proteins and polysaccharides, are among the first biomaterials investigated in tissue regeneration because of their inviting characteristics; they are hydrophilic [52], have good cell recognition, and are highly biocompatible [53]. Because of these qualities, natural polymers are mostly studied as hydrogels in cell encapsulation in tissue engineering, demonstrating great final results [54][55][56][57]. Hydrogels are three-dimensional networks produced through physical or chemical cross-linking of polymers [58] that can swell by absorbing large amounts of, but do not [59]. ...
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Polyelectrolyte hydrogels are emerging materials for tissue engineering and regenerative medicine applications due to their tunable biochemical properties, electrical conductivity, biocompatibility and similar network structure to the extracellular matrix in mammalian bodies. In this review, representative polyelectrolyte hydrogels carrying anionic, cationic, ampholytic, zwitterionic and ionic liquid moieties are systemically cataloged to express their chemical structures and preparation strategies. Recent advance of polyelectrolyte hydrogels in tissue engineering and regenerative medicine for drug delivery, skin healing, bone regeneration, cardiac tissue repair and anti‐biofouling coating are also highlighted. Eventually, the outlook and challenges of polyelectrolyte hydrogels and their biomedical material applications are also discussed to offer future directions.
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Hydrogels are a recurrent platform for Tissue Engineering (TE) strategies. Their versatility and the variety of available methods for tuning their properties highly contribute to hydrogels’ success. As a result, the design of advanced hydrogels has been thoroughly studied, in the quest for better solutions not only for drugs‐ and cell‐based therapies but also for more fundamental studies. The wide variety of sources, crosslinking strategies, and functionalization methods, and mostly the resemblance of hydrogels to the natural extracellular matrix, make this 3D hydrated structures an excellent tool for TE approaches. The state‐of‐the‐art information regarding hydrogel design, processing methods, and the influence of different hydrogel formulations on the final cell‐biomaterial interactions are overviewed herein. This article is protected by copyright. All rights reserved
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Chapter
This chapter presents a brief introduction of the chitosan hydrogels and introduces advances in chitosan‐based hydrogels with emphasis on their preparation, characterization, properties, and possible applications. It introduces the multilayered chitosan‐based hydrogels formed by chitosan in acidic solution and chitosan/chitin physical hydrogels based on alkali/urea solvent system. The chapter briefly summarizes the problems, challenges, and prospects in the formation of chitosan‐based hydrogels with unique structures and distinctive functions. It also presents some currently typical technologies for fabricating multilayered chitosan‐based hydrogels. The chapter exhibits the unique character and classical applications of the resultant structured hydrogels and their corresponding dry products. It discusses chitin and chitosan physical hydrogels based on novel alkali/urea solvent system differing from traditional acidic solvent system. The chapter discusses the chitosan‐based superabsorbent hydrogels, providing a brief overview of their preparation methods, capacity, and promising applications.
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We present here a synthetic strategy for the preparation of melt-processable shape-memory hydrogels with self-healing ability. The supramolecular hydrogel with a water content of 60-80 wt % consists of poly(acrylic acid) chains containing 20-50 mol % crystallizable n-octadecyl acrylate (C18A) segments together with surfactant micelles. The key of our approach to render the hydrogel melt-processable is the absence of chemical cross-links and the presence of surfactant micelles. At temperatures above the melting temperature T-m of the crystalline domains of alkyl side chains, the hydrogel liquefies due to the presence of surfactant micelles effective for solubilizing the hydrophobic C18A segments. At this stage, it can easily be shaped into any desired form by pouring into molds. Cooling below Tm and removing the surfactant from the gel network results in a hydrogel of any permanent shape with a particularly high compressive strength of 90 MPa and a Young's modulus of 26 MPa. If the hydrogel was damaged on purpose e.g. by cutting into two pieces, the extraordinary mechanical properties can completely be recovered via temperature-induced healing process. The hydrogel also exhibits a complete shape fixity ratio and a shape recovery ratio of 97 +/- 2%.
Article
Hydrogels are polymeric materials which have a relatively high capacity for holding water. Recently, a double network (DN) technique was developed to fabricate hydrogels with a toughness comparable to rubber. The mechanical properties of DN hydrogels may be attributed to the brittle sacrificial bonding network of one hydrogel, facilitating stress dispersion, combined with ductile polymer chains of a second hydrogel. Herein, we report a novel class of tuneable DN hydrogels composed of a polyurethane (PU) hydrogel and a stronger, dipole-dipole and H-bonding interaction reinforced (DHIR) hydrogel. Compared to conventional DN hydrogels, these materials show remarkable improvements in mechanical recovery, modulus and yielding, with excellent self-healing and self-gluing properties. In addition, the new DN hydrogels exhibit excellent tensile and compression strength and possess shape memory properties, which make them promising for applications in engineering, biomedicine and other domains where load-bearing is required.
Article
Over the past few years, there has been a great deal of interest in the development of hydrogel materials with tunable structural, mechanical, and rheological properties, which exhibit rapid and autonomous self-healing and self-recovery for utilization in a broad range of applications, from soft robotics to tissue engineering. However, self-healing hydrogels generally either possess mechanically robust or rapid self-healing properties but not both. Hence, the development of a mechanically robust hydrogel material with autonomous self-healing on the time scale of seconds is yet to be fully realized. Here, the current advances in the development of autonomous self-healing hydrogels are reviewed. Specifically, methods to test self-healing efficiencies and recoveries, mechanisms of autonomous self-healing, and mechanically robust hydrogels are presented. The trends indicate that hydrogels that self-heal better also achieve self-healing faster, as compared to gels that only partially self-heal. Recommendations to guide future development of self-healing hydrogels are offered and the potential relevance of self-healing hydrogels to the exciting research areas of 3D/4D printing, soft robotics, and assisted health technologies is highlighted.
Article
Statement of significance: Methacrylated gellan gum (GG-MA) is here suggested for the first time as a widely available polysaccharide to easily prepare hydrogels with cell adhesion properties and capability of inducing the autonomous osteogenic differentiation of human adipose-derived stem cells (hASCs). GG-MA was processed as stand-alone hydrogels or in different combinations with collage type I. All hydrogel formulations elicited the osteogenic differentiation of hASCs, independently of the addition of any osteoconductive or osteogenic stimuli, i.e. in basal/growth medium. Effective cellular adhesion to methacrylated gellan gum hydrogels in the absence of any cell-ligand peptide/protein was here proved for the first time. Moreover, we showed that the encapsulated hASCs underwent osteogenic differentiation due to a mechanotransduction phenomenon dependent on the actin-myosin contractility pathway.
Article
Stimuli-responsive hydrogels with high mechanical strength, programmable deformation, and simple preparation are essential for their practical applications. Here the preparation of tough hydrogels with programmable and complex shape deformations is reported. Janus hydrogels with different compositions and hydrophilic natures on the two surfaces are first prepared, and they exhibit reversible bending/unbending upon swelling/deswelling processes. More impressively, the deformation rate and extent of the hydrogels can further be easily controlled through an extremely simple and versatile ion dip-dyeing (IDD) and/or ion transfer printing (ITP) method. By selectively printing proper patterns on 1D gel strips, 2D gel sheets and 3D gel structures, the transformations from 1D to 2D, 2D to 3D, and 3D to more complicated 3D shapes can be achieved after swelling the ion-patterned hydrogels in water. The swelling-deformable Janus and ion-patterned hydrogels with high mechanical strengths and programmable deformations can find many practical applications, such as soft machines.
Article
Injectable hydrogels are investigated for cell encapsulation and delivery as they can shield cells from high shear forces. One of the approaches to obtain injectable hydrogels is to reinforce polymeric networks with high aspect ratio nanoparticles such as two-dimensional (2D) nanomaterials. 2D nanomaterials are emerging class of ultrathin materials with a high degree of anisotropy and strongly interacts with polymers resulting in formation of shear-thinning hydrogels. Here, we present a 2D nanosilicate reinforced kappa-Carrageenan (κCA) hydrogels for cellular delivery. κCA is a natural polysaccharide that resembles native glycosaminoglycans and can form brittle hydrogels via ionic crosslinking. The chemical modification of κCA with photocrosslinkable methacrylate groups render formation of covalently crosslinked network (MκCA). Reinforcing the MκCA with 2D nanosilicates result in shear-thinning characteristics, enhanced mechanical stiffness, elastomeric properties, and physiological stability. The shear-thinning characteristics of nanocomposite hydrogels was investigated for human mesenchymal stem cells (hMSCs) delivery. The hMSCs showed high cell viability after injection. In addition, encapsulated hMSCs showed circular morphology, indicating that these nanocomposite hydrogels can be used for cartilage regeneration.
Article
There is growing appreciation of the role that the extracellular environment plays in regulating cell behavior. Mechanical, structural, and compositional cues, either alone or in concert, can drastically alter cell function. Biomaterials, and particularly hydrogels, have been developed and implemented to present defined subsets of these cues for investigating countless cellular processes as a means of understanding morphogenesis, aging, and disease. Although most scientists concede that standard cell culture materials (tissue culture plastic and glass) do a poor job of recapitulating native cellular milieus, there is currently a knowledge barrier for many researchers in regard to the application of hydrogels for cell culture. Here, we introduce hydrogels to those who may be unfamiliar with procedures to culture and study cells with these systems, with a particular focus on commercially available hydrogels.
Article
Shape-morphing systems can be found in many areas, including smart textiles, autonomous robotics, biomedical devices, drug delivery and tissue engineering. The natural analogues of such systems are exemplified by nastic plant motions, where a variety of organs such as tendrils, bracts, leaves and flowers respond to environmental stimuli (such as humidity, light or touch) by varying internal turgor, which leads to dynamic conformations governed by the tissue composition and microstructural anisotropy of cell walls. Inspired by these botanical systems, we printed composite hydrogel architectures that are encoded with localized, anisotropic swelling behaviour controlled by the alignment of cellulose fibrils along prescribed four-dimensional printing pathways. When combined with a minimal theoretical framework that allows us to solve the inverse problem of designing the alignment patterns for prescribed target shapes, we can programmably fabricate plant-inspired architectures that change shape on immersion in water, yielding complex three-dimensional morphologies.
Article
The regeneration of soft biological tissues requires new substitutes that exhibit mechanical properties similar to the native tissue. Herein, thin saloplastic membranes with tunable physical properties are prepared by complexation of chitosan and alginate solutions containing different concentrations of sodium chloride. Polyelectrolyte complexes (PECs) are transferred to flat Petri dishes for compaction into membrane shapes by sedimentation and solvent evaporation. All membranes are resistant to degradation by lysozyme and are stable in solutions with pH values between 1 and 13. Immersing the different membranes in new doping solutions of increasing salt concentrations triggers the typical saloplastic behavior, with a high water absorption and decrease of the rigidity and ultimate tensile strength. The range of such variations is tuned by the sodium chloride amount used in the synthesis: high salt concentrations increase water uptake and tensile moduli, while decreasing the ultimate strength. Cellular assays demonstrate high proliferation rates and viability of L929 fibroblasts seeded onto the most rigid membranes. The results validate the use of saloplastic membranes as soft tissue substitutes for future biomedical applications.
Article
We investigated the pH-dependent properties of multilayered films made of chitosan (CHI) and alginate (ALG) and focused on their post-assembly response to different pH environments usingquartz crystal microbalance with dissipation monitoring (QCM-D), swelling studies, zeta potential measurements and dynamic mechanical analysis (DMA). In an acidic environment, the multilayers presented lower dissipation values and, consequently, higher moduli when compared with the values obtained for the pH used during the assembly (5.5). When the multilayers were exposed to alkaline environments the opposite behavior occurred. These results were further corroborated with the ability of this multilayered system to exhibit a reversible swelling-deswelling behavior within the pH range from 3 to 9. The changes of the physicochemical properties of the multilayer system were gradual and different from the ones of individual solubilized polyelectrolytes. This behavior is related to electrostatic interactions between the ionizable groups combined with hydrogen-bonding and hydrophobic interactions. Beyond the pH range of 3-9 the multilayers were stabilized by genipin cross-linking. The multilayered films also became more rigid while preserving the pH-responsiveness conferred by the ionizable moieties of the polyelectrolytes. This work demonstrates the versatility and feasibility of LbL methodology to generate inherently pH stimuli-responsive nanostructured films. Surface functionalization using pH-repsonsiveness endows abilities for several biomedical applications such as drug delivery, diagnostics, microfluidics, biosensing or biomimetic implantable membranes.
Article
Objectives: The clinical translation of cell-based therapies for ischemic heart disease has been limited because of low cell retention (<1%) within, and poor targeting to, ischemic myocardium. To address these issues, we developed an injectable hyaluronic acid (HA) shear-thinning hydrogel (STG) and endothelial progenitor cell (EPC) construct (STG-EPC). The STG assembles as a result of interactions of adamantine- and β-cyclodextrin-modified HA. It is shear-thinning to permit delivery via a syringe, and self-heals upon injection within the ischemic myocardium. This directed therapy to the ischemic myocardial border zone enables direct cell delivery to address adverse remodeling after myocardial infarction. We hypothesize that this system will enhance vasculogenesis to improve myocardial stabilization in the context of a clinically translatable therapy. Methods: Endothelial progenitor cells (DiLDL(+) VEGFR2(+) CD34(+)) were harvested from adult male rats, cultured, and suspended in the STG. In vitro viability was quantified using a live-dead stain of EPCs. The STG-EPC constructs were injected at the border zone of ischemic rat myocardium after acute myocardial infarction (left anterior descending coronary artery ligation). The migration of the enhanced green fluorescent proteins from the construct to ischemic myocardium was analyzed using fluorescent microscopy. Vasculogenesis, myocardial remodeling, and hemodynamic function were analyzed in 4 groups: control (phosphate buffered saline injection); intramyocardial injection of EPCs alone; injection of the STG alone; and treatment with the STG-EPC construct. Hemodynamics and ventricular geometry were quantified using echocardiography and Doppler flow analysis. Results: Endothelial progenitor cells demonstrated viability within the STG. A marked increase in EPC engraftment was observed 1-week postinjection within the treated myocardium with gel delivery, compared with EPC injection alone (17.2 ± 0.8 cells per high power field (HPF) vs 3.5 cells ± 1.3 cells per HPF, P = .0002). A statistically significant increase in vasculogenesis was noted with the STG-EPC construct (15.3 ± 5.8 vessels per HPF), compared with the control (P < .0001), EPC (P < .0001), and STG (P < .0001) groups. Statistically significant improvements in ventricular function, scar fraction, and geometry were noted after STG-EPC treatment compared with the control. Conclusions: A novel injectable shear-thinning HA hydrogel seeded with EPCs enhanced cell retention and vasculogenesis after delivery to ischemic myocardium. This therapy limited adverse myocardial remodeling while preserving contractility.
Article
Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any post-processing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side.
Article
Injectable hydrogels can provide a scaffold for in situ tissue regrowth and regeneration, yet gel degradation before tissue reformation limits the gels' ability to provide physical support. Here, we show that this shortcoming can be circumvented through an injectable, interconnected microporous gel scaffold assembled from annealed microgel building blocks whose chemical and physical properties can be tailored by microfluidic fabrication. In vitro, cells incorporated during scaffold formation proliferated and formed extensive three-dimensional networks within 48 h. In vivo, the scaffolds facilitated cell migration that resulted in rapid cutaneous-tissue regeneration and tissue-structure formation within five days. The combination of microporosity and injectability of these annealed gel scaffolds should enable novel routes to tissue regeneration and formation in vivo.
Article
The role of Platelet Lysates (PLs) as a source of growth factors (GFs) and as main element of three-dimensional (3D) hydrogels has been previously described. However, the resulting hydrogels usually suffer from high degree of contraction, limiting their usefulness. This work describes the development of a stable biomimetic 3D hydrogel structure based on PLs, through the spontaneous assembling of a high concentration of chitosan-chondroitin sulfate nanoparticles (CH/CS NPs) with PLs loaded by adsorption. The interactions between the NPs and the lysates resemble the ones observed in the extracellular matrix (ECM) native environment between glycosaminoglycans and ECM proteins. In vitro release studies were carried out focusing on the quantification of PDGF-BB and TGF-β1 GFs. Human adipose derived stem cells (hASCs) were entrapped in these 3D hydrogels and cultured in vitro under chondrogenic stimulus, in order to assess their potential use for cartilage regeneration. Histological, immunohistological and gene expression analysis demonstrated that the PLs-assembled constructs entrapping hASCs exhibited results similar to the positive control (hASCS cultured in pellets), concerning the levels of collagen II expression and immunolocalisation of collagen type I and II and aggrecan. Moreover, the deposition of new cartilage ECM was detected by alcian blue and safranin-O positive stainings. This work demonstrates the potential of PLs to act simultaneously as a source/carrier of GFs and as a 3D structure of support, through the application of a "bottom-up" approach involving the assembly of NPs, resulting in an enriched construct for cartilage regeneration applications. Copyright © 2015. Published by Elsevier Ltd.
Article
The spontaneous formation of coacervate microdroplet-laden photo-crosslinked hydrogels derived from the simple mixing of oxidized, methacrylated alginate (OMA) and methacrylated gelatin (GelMA) enables simultaneous creation of drug-laden microdroplets and encapsulation of stem cells in photopolymerized coacervate hydrogels under physiological conditions. This can be utilized as a novel platform for in situ formation of localized, sustained bioactive molecule delivery to encapsulate stem cells for therapeutic applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Article
Biofabrication is an emerging and rapidly expanding field of research in which additive manufacturing techniques in combination with cell printing are exploited to generate hierarchical tissue-like structures. Materials that combine printability with cytocompatibility, so called bioinks, are currently the biggest bottleneck. Since recombinant spider silk proteins are non-immunogenic, cytocompatible, and exhibit physical crosslinking, their potential as a new bioink system was evaluated. Cell-loaded spider silk constructs can be printed by robotic dispensing without the need for crosslinking additives or thickeners for mechanical stabilization. Cells are able to adhere and proliferate with good viability over at least one week in such spider silk scaffolds. Introduction of a cellbinding motif to the spider silk protein further enables finetuned control over cell–material interactions. Spider silk hydrogels are thus a highly attractive novel bioink for biofabrication.
Article
Stem cell transplantation via direct injection is a minimally invasive strategy being explored for treatment of a variety of injuries and diseases. Injectable hydrogels with shear moduli <50 Pa can mechanically protect cells during the injection process; however, these weak gels typically biodegrade within 1–2 weeks, which may be too fast for many therapeutic applications. To address this limitation, an injectable hydrogel is designed that undergoes two different physical crosslinking mechanisms. The first crosslinking step occurs ex vivo through peptide-based molecular recognition to encapsulate cells within a weak gel that provides mechanical protection from injection forces. The second crosslinking step occurs in situ to form a reinforcing network that significantly retards material biodegradation and prolongs cell retention time. Human adipose-derived stem cells are transplanted into the subcutaneous space of a murine model using hand-injection through a 28-gauge syringe needle. Cells delivered within the double-network hydrogel are significantly protected from mechanical damage and have significantly enhanced in vivo cell retention rates compared to delivery within saline and single network hydrogels. These results demonstrate that in situ formation of a reinforcing network within an already existing hydrogel can greatly improve transplanted cell retention, thereby enhancing potential regenerative medicine therapies.
Article
Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics—too fast leads to delivery failure, too slow limits material retention. To overcome this challenge, supramolecular assembly is exploited to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels are designed through the separate pendant modifications of hyaluronic acid (HA) by the guest–host pair cyclodextrin and adamantane, enabling shear-thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurs via addition of thiols and Michael-acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increases hydrogel moduli (E = 25.0 ± 4.5 kPa) and stability (>3.5 fold in vivo at 28 d). Application of the dual-crosslinking hydrogel to a myocardial infarct model shows improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired.
Article
Polyelectrolyte complex (PEC) membrane of cationic chitosan and anionic sodium alginate with fiber structure were prepared by freeze-drying method. Chitosan and sodium alginate were blended in different concentration and frozen at different temperature. Freeze-dried fiber membrane were extensively characterized for their inter-molecular interaction, the solution property, morphology and biocompatibility by using FTIR, XRD, Zeta (ζ) potentials, SEM and Cytotoxicity assay, respectively. The study of swelling property showed that PEC membrane with the fiber structure cross-linked with glutaraldehyde exhibited pH and ionic strength-dependent swelling in aqueous media, which might have a potential application in tissue engineering or drug controlled release. Furthermore, chitosan-sodium alginate samples showed better cell adhesion and proliferation than pure chitosan. The results indicated that two natural polyelectrolyte complex nanofibers were prepared by freeze-drying method and fitted for tissue engineering or drug carrier.
Article
Origami can turn a sheet of paper into complex three-dimensional shapes, and similar folding techniques can produce structures and mechanisms. To demonstrate the application of these techniques to the fabrication of machines, we developed a crawling robot that folds itself. The robot starts as a flat sheet with embedded electronics, and transforms autonomously into a functional machine. To accomplish this, we developed shape-memory composites that fold themselves along embedded hinges. We used these composites to recreate fundamental folded patterns, derived from computational origami, that can be extrapolated to a wide range of geometries and mechanisms. This origami-inspired robot can fold itself in 4 minutes and walk away without human intervention, demonstrating the potential both for complex self-folding machines and autonomous, self-controlled assembly.
Article
Application of Raman spectroscopy in determination of the acetylation degree (DA) of chitosan has been developed. The spectra of several chitosan samples characterized by different DD (degree of deacetylation) in the range 50-100% have been measured. The integral intensities of the bands assigned to the vibrations of amine group and glucosidic ring were used to calculate the DA from the intensity ratio. The assignment of the bands to the respective normal modes of chitosan was based on the DFT quantum chemical calculations. This method has a number of advantages over other techniques. It is fast and does not require purification of the sample nor require dissolution of the chitosan in any solvent.
Article
Free-standing films have increasing applications in the biomedical field as drug delivery systems, for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce thick membrane, to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any post-processing step. They dry thickness was varied over a large range from 4 to 35 µm. A two-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the FS membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side.
Article
Liquified capsules featuring (i) an external shell by layer-by-layer assembly of poly(L-lysine), alginate and chitosan, and encapsulating (ii) surface functionalized poly(L-lactic acid) (PLLA) microparticles were developed. We hypothesize that, while the liquified environment enhances the diffusion of essential molecules for cell survival, microparticles dispersed in the liquified core of capsules provide the physical support required for cellular functions of anchorage-dependent cells. The influence of the incorporation of PLL on the regime growth, thickness and stability was analyzed. Results show a more resistant and thicker film with an exponential build-up growth regime. Moreover, capsules ability to support cell survival was assessed. Capsules containing microparticles revealed an enhanced biological outcome in cell metabolic activity and proliferation, suggesting their potential to boost the development of innovative biomaterials designs for bioencapsulation systems and tissue engineering products.
Article
The swelling of membranes of the polyelectrolyte complex (PEC) between chitosan and alginate shows a similar pattern to that of other PECs. However, if the swelled membranes are dried, a second swelling process is seen which exhibits Fickian behavior. The apparent activation energy was estimated to be 32.8 kJ · mol-1. The release rate of model solutes was highly dependent on their molecular weight and the pH of the medium.
Article
This study aims to examine mechanical properties and surface charge characteristics of chitosan/alginate-based films for biomedical applications. By varying the concentrations of chitosan and alginate, we have developed films with varying surface charge densities and mechanical characteristics. The surface charge densities of these films were determined by applying an analytical model on force curves derived from an atomic force microscope (AFM). The average surface charge densities of films containing 60% chitosan and 80% chitosan were found to be -0.46 mC/m(2) and -0.32 mC/m(2), respectively. The surface charge density of 90% chitosan containing films was found to be neutral. The elastic moduli and the water content were found to be decreasing with increasing chitosan concentration. The films with 60%, 80% and 90% chitosan gained 93.5 +/- 6.6%, 217.1 +/- 22.1% and 396.8 +/- 67.5% of their initial weight, respectively. Their elastic moduli were found to be 2.6 +/- 0.14 MPa, 1.9 +/- 0.27 MPa and 0.93 +/- 0.12 MPa, respectively. The trend observed in the mechanical response of these films has been attributed to the combined effect of the concentration of polyelectrolyte complexes (PEC) and the amount of water absorbed. The Fourier transform infrared spectroscopy experiments indicate the presence of higher alginate on the surface of the films compared to the bulk in all films. The presence of higher alginate on surface is consistent with negative surface charge densities of these films, determined from AFM experiments.
Article
Polyelectrolyte complexes (PECs) of alginate and chitosan were formed by addition of 0.1% alginate solution (pH ∼6.5) to 0.1% chitosan solution (pH ∼4.0), and by adding the chitosan solution to the alginate solution under high shearing conditions. Variations in the properties of the polymers and the preparation procedure were studied, and the resultant PEC size, zeta potential (Zp), and pH were determined using dynamic light scattering (DLS), electrophoresis and by measuring turbidity and pH. Tapping mode atomic force microscopy (AFM) was used to examine some of the complexes. The particle size was decreased as the speed and diameter of the dispersing element of the homogenizer was increased. The net charge ratio between chitosan and alginate, and the molecular weights (MW) of both the alginate and chitosan samples were the most significant parameters that influenced the particle size, Zp, and pH. The mixing order also influenced the size of the PECs, however, the Zp and pH were not affected by the mixing order. The stability of the complexes was investigated by incubation at an elevated temperature (37 °C), storage for one month at 4 °C, alteration of the pH of the PEC mixture, and addition of salt to physiological ionic strength (0.15 M NaCl). The properties of the PEC could be affected according to the molecular properties of the polyelectrolytes selected and the preparation procedures used. The resultant PEC sizes and properties of the complex were rationalised using a core-shell model for the structure of the complexes.
Article
Light-activated polymers are an exciting class of modern materials that respond mechanically when irradiated by light at particular wavelengths. While details of the mechanisms that connect the optical excitation to mechanical behavior are complex and differ from material to material, there is sufficient commonality among them to permit the development of a generalized modeling framework to describe the photomechanics. The features shared by light-activated polymers involve light interacting with the material, which triggers photochemical reactions that alter the structure of the crosslinked polymer network. Many such structural alterations result in an evolution of the polymer network, and subsequent macroscopic deformation. When this process is appropriately executed it can enable a photomechanical shape-memory effect. In this paper, we develop a three-dimensional finite-deformation modeling framework to describe the photomechanical response of light-activated polymer systems. This framework integrates four coupled phenomena that contribute to macroscopic photomechanical behavior: photophysics, photochemistry, chemomechanical coupling, and mechanical deformation. The chemomechanical coupling consists of chemically induced structural alterations of the crosslinked network that result in subsequent deformation. We describe this behavior through a decomposition of the crosslinked network into two components consisting of an original network and a photochemically altered network; both evolve during photomechanical deformation. The modeling framework presented in this paper is sufficiently general that it is applicable to light-activated polymer systems that operate with various mechanisms in each of the four areas. Using this modeling approach, we develop constitutive models for two recently developed light-activated polymer systems [Lendlein, A., Hongyan, J., Junger, O., Langer, R., 2005. Light-induced shape-memory polymers. Nature 434 (7035) 879; Scott, T.F., Schneider, A.D., Cook, W.D., Bowman, C.N., 2005. Photoinduced plasticity in crosslinked polymers. Science 308 (5728) 1615]. For the material developed by Scott and his co-workers we validate our model by measuring and numerically simulating photo-induced stress relaxation and bending deformation and obtain good agreement between measurements and predictions. Finally, we use the model to study the effects of photomechanical parameters (applied strain magnitude, irradiation time and intensity, and photoabsorber concentration) and the behavior of the network evolution rule on the material response.
Article
Self-folding broadly refers to self-assembly processes wherein thin films or interconnected planar templates curve, roll-up or fold into three dimensional (3D) structures such as cylindrical tubes, spirals, corrugated sheets or polyhedra. The process has been demonstrated with metallic, semiconducting and polymeric films and has been used to curve tubes with diameters as small as 2nm and fold polyhedra as small as 100nm, with a surface patterning resolution of 15nm. Self-folding methods are important for drug delivery applications since they provide a means to realize 3D, biocompatible, all-polymeric containers with well-tailored composition, size, shape, wall thickness, porosity, surface patterns and chemistry. Self-folding is also a highly parallel process, and it is possible to encapsulate or self-load therapeutic cargo during assembly. A variety of therapeutic cargos such as small molecules, peptides, proteins, bacteria, fungi and mammalian cells have been encapsulated in self-folded polymeric containers. In this review, we focus on self-folding of all-polymeric containers. We discuss the mechanistic aspects of self-folding of polymeric containers driven by differential stresses or surface tension forces, the applications of self-folding polymers in drug delivery and we outline future challenges.
Article
An elastomeric, healable, supramolecular polymer blend comprising a chain-folding polyimide and a telechelic polyurethane with pyrenyl end groups is compatibilized by aromatic pi-pi stacking between the pi-electron-deficient diimide groups and the pi-electron-rich pyrenyl units. This interpolymer interaction is the key to forming a tough, healable, elastomeric material. Variable-temperature FTIR analysis of the bulk material also conclusively demonstrates the presence of hydrogen bonding, which complements the pi-pi stacking interactions. Variable-temperature SAXS analysis shows that the healable polymeric blend has a nanophase-separated morphology and that the X-ray contrast between the two types of domain increases with increasing temperature, a feature that is repeatable over several heating and cooling cycles. A fractured sample of this material reproducibly regains more than 95% of the tensile modulus, 91% of the elongation to break, and 77% of the modulus of toughness of the pristine material.
Article
Myocardial regeneration using stem and progenitor cell transplantation in the injured heart has recently become a major goal in the treatment of cardiac disease. Experimental studies and clinical applications have generally been encouraging, although the functional benefits that have been attained clinically are modest and inconsistent. Low cell retention and engraftment after myocardial delivery is a key factor limiting the successful application of cell therapy, irrespective of the type of cell or the delivery method. To improve engraftment, accurate methods for tracking cell fate and quantifying cell survival need to be applied. Several laboratory techniques (histological methods, real-time quantitative polymerase chain reaction, radiolabeling) have provided invaluable information about cell engraftment. In vivo imaging (nuclear medicine modalities, bioluminescence, and MRI) has the potential to provide quantitative information noninvasively, enabling longitudinal assessment of cell fate. In the present review, we present several available methods for assessing cell engraftment, and we critically discuss their strengths and limitations. In addition to providing insights about the mechanisms mediating cell loss after transplantation, these methods can evaluate techniques for augmenting engraftment, such as tissue engineering approaches, preconditioning, and genetic modification, allowing optimization of cell therapies.
Article
Raman spectra of nine anomerically stable monosaccharides have been obtained in aqueous solution in the 700-1700 cm(-1) spectral range. Good-quality spectra are obtained of solutions with concentrations as low as 10 mM and volumes as small as 15 microL. Interestingly, the Raman spectra appear to be exquisitely sensitive to the configuration of the carbon centers; unique spectra are obtained of all nine monosaccharides. The unique Raman spectral fingerprint observed for each monosaccharide, and for each anomer of each monosaccharide, suggests that Raman spectroscopy may be a useful technique for the identification and characterization of biologically relevant oligosaccharides. To test this idea, Raman spectra of three unknown disaccharides were obtained in a single-blind study. Identification of the individual monosaccharide components and their anomeric configuration was completely successful. All of these results suggest that development of Raman spectroscopy as a fast, sensitive discovery tool in glycobiology and carbohydrate chemistry is straightforward.
Article
A series of semi-interpenetrating, polymer network (semi-IPN), hydrogel beads, composed of calcium alginate (Ca-alginate) and poly(N-isopropylacrylamide) (PNIPAAM), were prepared for a pH/temperature-sensitive drug delivery study. The equilibrium swelling showed the independent pH- and thermo- responsive nature of the developed materials. At pH=2.1, the release amount of indomethacin incorporated into these beads was about 10% within 400 min, while this value approached to 95% at pH=7.4. The release rate of the drug was higher at 37 degrees C than that at 25 degrees C and increased slightly with increasing PNIPAAM content. These results suggest that the Ca-alginate/PNIPAAM beads have the potential to be used as an effective pH/temperature sustainable delivery system of bioactive agents. [GRAPHS: SEE TEXT] A summary of the temperature- and pH-dependence on the release of the drug over a period of 450 min. The effect of the temperature on the swelling of the beads is shown in the inset.
Bioinspired Ultratough Hydrogel with Fast Recovery
  • S Azevedo
  • Ams Costa
  • A Andersen
  • I S Choi
  • H Birkedal
  • J F Mano
Azevedo S, Costa AMS, Andersen A, Choi IS, Birkedal H, Mano JF. Bioinspired Ultratough Hydrogel with Fast Recovery, Self-Healing, Injectability and Cytocompatibility. Mater Adv. 2017; 29