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Multicellular spheroids (MCSs) are in vitro tissue models having important biomedical applications. The MCS generation is usually time-consuming because most MCS fabrication methods exploit the inherent ability of cells to self-assemble to form spheroids. Here we tried to accelerate the MCS generation by chemical pre-aggregation of the cells. We first developed a method to chemically aggregate cells, which involves a first treatment of cells with NaIO 4 to produce surface aldehyde functionalities, and then incubation with acrylic acid-modified chitosan (chitosan-AA), a new inter-cellular linker. Biocompatibility test indicates chitosan-AA is non-toxic to cells, even at a high concentration. When incubated in the presence of chitosan-AA, the NaIO 4 -treated cells aggregate quickly, because of the reaction between the amino groups on chitosan-AA and the aldehyde groups on cell surface. In addition, the cells in the resulting aggregates remain a high viability. The pre-aggregated cells were then seeded into an in situ-formed hydrogel to generate MCSs. While it takes several days to form MCSs in the control groups, it takes only 1 day for the cells to form compact spheroids in the pre-aggregation group. The spheroids formed in the pre-aggregation group (231 ± 74 μm at Day 4) are bigger than those obtained in the control groups (70 ± 17 μm at Day 4). In addition, the cells in the pre-aggregation group grow and proliferate faster (P

Hydrogels are three-dimensional (3D) polymeric networks that can confine a substantial fraction of water within their structure. Photopolymerization is one of the efficient methods to prepare hydrogels, by which polymers undergo a photocrosslinking process upon light exposure for a few minutes in the presence of an initiator. In comparison to other crosslinking methods (e.g. physical crosslinking and chemical addition/condensation crosslinking), photopolymerization has many advantages including fast and effective polymerization and good spatio-temporal control of hydrogel formation, and can occur under ambient reaction conditions at room temperature in physiological solutions. For these reasons, photocurable hydrogels have been extensively utilized for biomedical applications such as 3D hydrogel scaffold fabrication, drug delivery systems, and 3D bio-printing. This chapter begins with the introduction of photoinitiators, which play an important role in the preparation of photocurable hydrogels. Subsequently, two types of photocurable hydrogels and their preparation methods are described; the first section focuses on photocurable hydrogels made from synthetic materials, followed by the second section on those from natural materials.

This paper demonstrates the essential and efficient methods to design, and fabricate optimal vascular network for tissue engineering structures based on their physiological conditions. Comprehensive physiological requirements in both micro and macro scales were considered in developing the optimisation design for complex vascular vessels. The optimised design was then manufactured by stereolithography process using materials that are biocompatible, elastic and surface bio-coatable. The materials are self-developed photocurable resin consist of BPA-ethoxylated-diacrylate, lauryl acrylate and isobornylacrylate with Irgacure® 184, the photoinitiator. The optimised vascular vessel offers many advantages: 1) it provides the maximum nutrient supply; 2) it minimises the recirculation areas and 3) it allows the wall shear stress on the vessel in a healthy range. The stereolithography manufactured vascular vessels were then embedded in the hydrogel seeded with cells. The results of in vitro studies show that the optimised vascular network has the lowest cell death rate compared with a pure hydrogel scaffold and a hydrogel scaffold embedded within a single tube in day seven. Consequently, these design and manufacture routes were shown to be viable for exploring and developing a high range complex and specialised artificial vascular networks.

A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. However, the main focus in research and clinical application lies on dermal and epidermal substitutes whereas the development of a subcutaneous replacement (hypodermis) is often disregarded. In this study we used fibrin sealant as hydrogel scaffold to generate a three-layered skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes were embedded in the fibrin hydrogel and were combined with another fibrin clot with fibroblasts for the construction of the dermal layer. Keratinocytes were added on top of the two-layered construct to form the epidermal layer. The three-layered construct was cultivated for up to 3 weeks. Our results show that ASCs and fibroblasts were viable, proliferated normally, and showed physiological morphology in the skin substitute. ASCs were able to differentiate into mature adipocytes during the course of four weeks and showed morphological resemblance to native adipose tissue. On the surface keratinocytes formed an epithelial-like layer. For the first time we were able to generate a three-layered skin substitute based on a fibrin hydrogel not only serving as a dermal and epidermal substitute but also including the hypodermis.

The ability to noninvasively assess skeletal muscle microstructure, which predicts function and disease, would be of significant clinical value. One method that holds this promise is diffusion tensor magnetic resonance imaging (DT-MRI), which is sensitive to the microscopic diffusion of water within tissues and has become ubiquitous in neuroimaging as a way of assessing neuronal structure and damage. However, its application to the assessment of changes in muscle microstructure associated with injury, pathology, or age remains poorly defined, because it is difficult to precisely control muscle microstructural features in vivo. However, recent advances in additive manufacturing technologies allow precision-engineered diffusion phantoms with histology informed skeletal muscle geometry to be manufactured. Therefore, the goal of this study was to develop skeletal muscle phantoms at relevant size scales to relate microstructural features to MRI-based diffusion measurements. A digital light projection based rapid 3D printing method was used to fabricate polyethylene glycol diacrylate based diffusion phantoms with (1) idealized muscle geometry (no geometry; fiber sizes of 30, 50, or 70 μm or fiber size of 50 μm with 40% of walls randomly deleted) or (2) histology-based geometry (normal and after 30-days of denervation) containing 20% or 50% phosphate-buffered saline (PBS). Mean absolute percent error (8%) of the printed phantoms indicated high conformity to templates when "fibers" were >50 μm. A multiple spin-echo echo planar imaging diffusion sequence, capable of acquiring diffusion weighted data at several echo times, was used in an attempt to combine relaxometry and diffusion techniques with the goal of separating intracellular and extracellular diffusion signals. When fiber size increased (30-70 μm) in the 20% PBS phantom, fractional anisotropy (FA) decreased (0.32-0.26) and mean diffusivity (MD) increased (0.44 × 10-3 mm2/s-0.70 × 10-3 mm2/s). Similarly, when fiber size increased from 30 to 70 μm in the 50% PBS diffusion phantoms, a small change in FA was observed (0.18-0.22), but MD increased from 0.86 × 10-3 mm2/s to 1.79 × 10-3 mm2/s. This study demonstrates a novel application of tissue engineering to understand complex diffusion signals in skeletal muscle. Through this work, we have also demonstrated the feasibility of 3D printing for skeletal muscle with relevant matrix geometries and physiologically relevant tissue characteristics.

Regenerative peripheral-nerve interfaces are a novel method for integrating with the peripheral nervous system. These devices have the potential to isolate and transduce both afferent (sensory) and efferent (motor) neural signals to produce fine control of advanced prosthetics. We have developed a novel regenerative device comprised of microfabricated polyimide electrode threads supported by a hydrogel scaffold containing methacrylated hyaluronic acid, collagen I, and laminin to enable intimate contact with regenerating axons. While this advanced device holds theoretical promise for establishing a stable chronic neural interface, it also requires a novel surgical approach in comparison to current existing methods of peripheral neural interface technologies. Here we describe the development of the surgical methodology required for successful chronic implantation of the TEENI device in the rat sciatic nerve.

Hydrogel scaffolds, both synthetic and biological, are an important component for microscale and macroscale tissue fabrication. Owing to their high water content, hydrogel scaffolds enable the distribution of nutrients and oxygen to support cells in larger constructs. However, thickness of hydrogel scaffolds is still limited by the diffusion rate of nutrients and oxygen, versus the metabolic rate of the cell culture. The creation of microbore conduits within a hydrogel scaffold can overcome these limitations. Here, controlled perfusion through a hydrogel scaffold is demonstrated with a microfluidic manifold device. The flow profile was simulated to aid in the device design, and flow control was validated experimentally. We used this system to determine the diffusion coefficient of two model solutes, one with a small molecular weight and one with a large molecular weight, through the hydrogel scaffold.

This study demonstrated a novel injectable-thermoreversible hydrogel scaffold composing of PLuronic F127, carboxymethyl hexanoyl chitosan (CA) and glyoxal (Gx) for encapsulating human osteosarcoma MG-63 cells. The hydrogel was prepared by simply mixing CA, F127 and Gx. In so doing, this system exhibited short gelation time and higher gelation temperature. In addition, this hydrogel exhibited thermo-reversibility, that is, the hydrogel can liquefy at room temperature and revert to gel state at body temperature. The encapsulated cells in this hydrogel proliferated more than 400% in the 5-day incubation. Based on these results, these F127/CA/Gx hydrogels can be used to encapsulate cells for tissue engineering applications.

This paper presents a novel strategy for fabricating hydrogel scaffold at ambient temperature by 3D printing supplemented with an ultrasonic spraying which involves crosslink reaction. The contradictory between the rheological properties and solidification of natural biological material for machinability and formability respectively at ambient temperature was solved. The gelled fraction and porosity were measured respectively to study the influence of crosslinking agent. The results showed that the two subjects appear a parabolic trend with the concentration of CaCl2 from 2% to 4%, but the tolerance of aperture decreases monotone.

The regeneration of articular cartilage consisting of hyaline cartilage and hydrogel scaffolds has been generally used in tissue engineering. However, success in in vivo studies has been rarely reported. The hydrogel scaffolds implanted into articular cartilage defects are mechanically unstable and it is difficult for them to integrate with the surrounding native cartilage tissue. Therefore, it is needed to regenerate cartilage and bone tissue simultaneously. We developed hybrid scaffolds with hydrogel scaffolds for cartilage tissue and with ceramic scaffolds for bone tissue. For in vivo study, hybrid scaffolds were press-fitted into osteochondral tissue defects in a rabbit knee joints and the cartilage tissue regeneration in blank, hydrogel scaffolds, and hybrid scaffolds was compared. In 12th week after implantation, the histological and immunohistochemical analyses were conducted to evaluate the cartilage tissue regeneration. In the blank and hydrogel scaffold groups, the defects were filled with fibrous tissues and the implanted hydrogel scaffolds could not maintain their initial position; in the hybrid scaffold group, newly generated cartilage tissues were morphologically similar to native cartilage tissues and were smoothly connected to the surrounding native tissues. This study demonstrates hybrid scaffolds containing hydrogel and ceramic scaffolds can provide mechanical stability to hydrogel scaffolds and enhance cartilage tissue regeneration at the defect site.

Internal Grant Agency, Tomas Bata University in Zlin, Czech Republic [IGA/CPS/2018/008]; Ministry of Education, Youth, and Sports of The Czech Republic-NPU Program I [LO1504]

Corneal damage is the second cause of blindness in the world due to limitation of high quality corneal from donor. This condition promote rapid development of biodegradable and biocompatible scaffold for corneal tissue because it can reduce the patient's dependence on the cornea donor. The purpose of this research is to synthesize chitosan-based hydrogel scaffold with glutaraldehyde (GA) as crosslink agent and observe the influence of concentration chitosan and GA to transparency and mechanical properties of the scaffold. Scaffolds were prepared by solution casting combined with salt leaching method. Among all of chitosan-based scaffolds that have been prepared, sample with 6.7% of chitosan and 0.0% of GA possess the highest transparency (85%), while sample with 6.7% of chitosan and 0.3% of GA gave the highest Young's modulus (3.09 MPa). However, sample with 6.7% of chitosan and 0.1% of GA might possess the highest potency as corneal tissue implant because of its transparency fulfill the minimum value of corneal tissue (80%) and its Young's modulus (1.41 MPa) is higher than any chitosan-based scaffold with minimum transparency 80%.

Different hydrogel materials have been prepared to investigate the effects of culture substrate on the behaviour of pluripotent cells. In particular, genipin-crosslinked gelatin-silk fibroin hydrogels of different compositions have been prepared, physically characterized and used as substrates for the culture of pluripotent cells. Pluripotent cells cultured on hydrogels remained viable and proliferated. Gelatin and silk fibroin promoted the proliferation of cells in the short and long term, respectively. Moreover, cells cultured on genipin-crosslinked gelatin-silk fibroin blended hydrogels were induced to an epithelial ectodermal differentiation fate, instead of the neural ectodermal fate obtained by culturing on tissue culture plates. This work confirms that specific culture substrates can be used to modulate the behaviour of pluripotent cells and that our genipin-crosslinked gelatin-silk fibroin blended hydrogels can induce pluripotent cells differentiation to an epithelial ectodermal fate. Copyright © 2014 John Wiley & Sons, Ltd.

Despite tremendous advances in the field of tissue engineering, a number of obstacles are still hindering its successful translation to the clinic. One of these challenges has been to design cell-laden scaffolds that can provide an appropriate environment for cells to successfully synthesize new tissue while providing a mechanical support that can resist physiological loads at the early stage of in situ implementation. A solution to this problem has been to balance tissue growth and scaffold degradation by creating new hydrogel systems that possess both hydrolytic and enzymatic degradation behaviors. Very little is known, however, about the complex behavior of these systems, emphasizing the need for a rigorous mathematical approach that can eventually assist and guide experimental advances. This paper introduces a mathematical and numerical formulation based on mixture theory, to describe the degradation, swelling, and transport of extracellular matrix (ECM) molecules released by cartilage cells (chondrocytes) within a hydrogel scaffold. The model particularly investigates the relative roles of hydrolytic and enzymatic degradations on ECM diffusion and their impacts on two important outcomes: the extent of ECM transport (and deposition) and the evolution of the scaffold's mechanical integrity. Numerical results based on finite element show that if properly tuned, enzymatic degradation differs from hydrolytic degradation in that it can create a degradation front that is key to maintaining scaffold stiffness while allowing ECM deposition. These results therefore suggest a hydrogel design that could enable successful in situ cartilage tissue engineering.

OBJECTIVE: This experimental study aimed to evaluate the biological performance of poly (l-co-D, l-lactic acid)-co-trimetilene carbonate/poly (vinyl alcohol) (PLDLA-co TMC/PVA), hydrogel scaffolds, as an implant in the filling (and not in the repair) of osteochondral defects in New Zealand rabbits, assessing the influence of the material in tissue protection in vivo. METHODS: Twelve rabbits were divided into groups of nine and 16 weeks. In each animal, an osteochondral defect was created in both medial femoral condyles. In one knee, a hydrogel scaffold was implanted (pin group) and in the other, the defect was maintained (control group). A histological analysis of the material was performed after euthanasia. RESULTS: The condyles of the pin group showed no inflammatory reaction and were surrounded by a fibrous capsule. The control group presented higher bone growth in the areas of the defect, but with disorganized articular cartilage, evident fibrosis, bone exposure, atrophy, and proliferation of synovial membrane. CONCLUSION: The hydrogel pins are promising in filling osteochondral defects, generally do not cause inflammatory reactions, and are not effective in the repair of osteochondral defects. RESUMO OBJETIVO: Trabalho experimental para avaliar o desempenho biológico de arcabouços de hidrogel poli (L-co-D, L ácido lático)-co-trimetileno carbonato/poli (álcool vinílico) (PLDLA-co-TMC/PVA) como implante no preenchimento, e não no reparo, de defeito osteocondral em coelhos Nova Zelândia e verificar a influência do material na proteção tecidual in vivo. MÉTODOS: Foram usados 12 coelhos divididos em grupos de nove e 16 semanas. Em cada animal foi criado um defeito osteocondral em ambos os côndilos femorais mediais, em um foi implantado um arcabouço de hidrogel (grupo pino) e no outro foi mantido o defeito (grupo controle). Após o sacrifício dos animais, foi feita análise histológica do material. RESULTADOS: Os côndilos do grupo pino não evidenciaram reação inflamatória e estavam rodeados por cápsula fibrosa. Já no grupo controle, uma maior proliferação óssea foi observada nas áreas do defeito, porém com cartilagem articular desorganizada, fibrose evidente, atrofia com exposição óssea e proliferação de membrana sinovial. CONCLUSÃO: Os pinos de hidrogel são promissores na função de preenchimento de defeitos osteocondrais, não ocasionam, de modo geral, reação inflamatória e não são eficazes no reparo de defeitos osteocondrais.

Enhancement of the mechanical as well as functional properties of the perspective mineralized PVP-CMC-CaCO3 hydrogel scaffold applicable for bone tissue engineering is quite essential. Therefore, the incorporation feasibility of chitin, a bioactive, antibacterial and biodegradable material, was examined in order to test its ability to enchance mechanical properties of the PVP-CMC- CaCO3 hydrogel scaffold. Chitin based PVP-CMC hydrogels were prepared and characterized both as non-mineralized and mineralized (CaCO3) form of hydrogel scaffolds. Both α-chitin (commercially bought) and β-chitin (isolated from the cuttlebone) were individually tested. It was observed that at 1% strain all hydrogel scaffolds have linear trend, with highly pronounced elastic properties in comparison to viscous ones. The complex viscosity has directly proportional behavior with negative slope against angular frequency within the range of ω = 0.1 − 100 rad.s−1. Incorporation of β-chitin increased storage modulus of all mineralized samples, making it interesting for further research.

3D in vitro culture systems may yield physiological outcomes that more closely approximate in vivo behavior. A number of fabrication techniques and hydrogel scaffold materials are available to researchers, but often their implementation is complex and seemingly prohibitive. Herein, we describe a simplistic and adaptable dual hydrogel photolithography method utilized to engineer advanced in vitro systems for studies of neuronal development and characterization.

Detection of reactive oxygen species (ROS) is important in varied biological processes, disease diagnostics, and chemotherapeutic drug screening. We constructed a ROS sensor comprising an ascorbic-acid-based hydrogel encapsulating luminescent amphiphilic carbon-dots (C-dots). The sensing mechanism is based upon ROS-induced oxidation of the ascorbic acid units within the hydrogel scaffold; as a consequence, the hydrogel framework collapses resulting in aggregation of the C-dots and quenching of their luminescence. The C-dot-hydrogel platform exhibits high sensitivity and detected ROS generated chemically in solution and in actual cell environments. We demonstrate application of the C-dot-hydrogel for evaluating the efficacy of a chemotherapeutic substance, underscoring the potential of the system for drug screening applications.

The anodophilic bacteria in the anodes of microbial fuel cells (MFCs) used to catalyze carbon oxidation are anaerobes and require anaerobic conditions; their bioelectrocatalytic activity will be greatly suppressed upon direct exposure to O2. In this study, an aerotolerant bioanode was fabricated for the first time by immobilization of anodophilic bacteria for use in MFCs operating under aerobic conditions. The fabrication of the aerotolerant bioanode was realized through the electrochemically induced penetration and propagation of anodophilic bacteria in a three-dimensional hydrogel scaffold. Under the protection of the hydrogel scaffold, the anodophilic bacteria exhibited excellent bioelectrocatalytic activity under continuous O2 aeration and delivered a current density comparable to that under anaerobic conditions. The MFC equipped with the aerotolerant bioanode has the potential to be applied to traditionally aerobic wastewater treatment (WWT) technology. This study offers new insight into the applicat...

Although a variety of scaffolds have been developed in recent years for a range of applications, the repair of load-bearing tissues, such as articular cartilage in the knee, is still in its infancy due to the exceptional demands on mechanical strength and stiffness. Unfortunately, rigorous in vitro mechanical characterisation has often been superseded by in vivo testing in animals, where the loading scenarios often bear little resemblance to those in human, which has significantly restricted the potential range of clinical applications. A comprehensive mechanical characterisation is essential if scaffolds are to be used for load-bearing applications. In this chapter, we report the characterisation of viscoelastic behaviour of hydrogel scaffolds. The key factors, including the effects of constraint, strain rate and sample microstructure, on the mechanical properties of a hydrogel scaffold will be investigated. Some of the latest techniques such as micro-CT imaging, in situ image-guided failure assessment and digital volume correlation (DVC) will be explored in the characterisation of the hydrogel scaffold under uniaxial compression.

Hydrogel scaffolds based on poly(vinyl alcohol) (PVA) collagen films were prepared by a chemical cross-linking method. The effects of the contents of PVA and cross-linker on compressive strength and swelling ratio were studied, and the effect of the pH value of the immersion medium on the swelling ratio was also investigated. The results showed that the introduction of PVA improved the compressive strength of PVA/collagen hydrogel, and the swelling ratio of the hydrogel scaffold increased with increasing PVA content in the blends. With increasing cross-linker content, the swelling ratio decreased; however, the compressive strength increased. The swelling ratio of PVA/collagen scaffold increased when pH was decreased. In conclusion, swelling ratio and compressive strength in PVA/collagen blends can be controlled by variation of their contents, cross-linking agent content, and pH value.

The objective of this work was to create 3D hydrogel with tunable degradability for use in tissue regeneration. Therefore, we reported the synthesis and characterization of a novel degradable hydrogel based on poly (amic acid) (PAA). Unlike previously reported degradable hydrogel, these materials contained two kind of cleavable bonds to adjust their degradation. FTIR was employed to characterize the structure of PAA and hydrogels. Swelling ratio and degradation time correlated with the molar ratio of two cross-linkers and cross-linked density. The surface microstructure of hydrogels during degradation was observed by SEM. These properties changed predictably as degradation.

To develop a biomaterial composite for promoting proliferation and migration of neural stem cells (NSCs), as well as angiogenesis on the materials, to rescue central nervous system (CNS) injuries.A delivery system was constructed based on cross-linked hyaluronic acid (HA) hydrogels, containing embedded BDNF and VEGF-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery and support for NSCs in the CNS. The surface morphologies were evaluated by SEM and AFM, mechanical property was investigated by rheological tests, and release kinetics were performed by ELISA. Bioactivity of released BDNF and VEGF was assessed by neuron and endothelial cell culture, respectively. Compatibility with NSCs was studied by immunofluorescent staining.Release kinetics showed the delivery of BDNF and VEGF from PLGA microspheres and HA hydrogel composite were sustainable and stable, releasing ~20-30% within 150 h. The bioactivities preserved well to promote survival and growth of the cells. Evaluation of structure and mechanical properties showed the hydrogel composite possessed an elastic scaffold structure. Biocompatibility assay showed NSCs adhered and proliferated well on the hydrogel.Our created HA hydrogel/PLGA microsphere systems have a good potential for controlled delivery of varied biofactors and supporting NSCs for brain repair and implantation.

Basic fibroblast growth factor (bFGF) and growth and differentiation factor (GDF)-5 stimulate the healing of medial collateral ligament (MCL) injury. However, the effect of isolated and combined use of bFGF/GDF-5 remains still unclear. We investigated cellular proliferation and migration responding to bFGF/GDF-5 using rabbit MCL fibroblasts. Rabbit MCL injury was treated by bFGF and/or GDF-5 with peptide hydrogels. Gene expression and deposition of collagens in healing tissues were evaluated. bFGF/GDF-5 treatment additively enhanced cell proliferation and migration. bFGF/GDF-5 hydrogels stimulated Col1a1 expression without increasing Col3a1 expression. Combined use of bFGF/GDF-5 stimulated type I collagen deposition and the reorganization of fiber alignment, and induced better morphology of fibroblasts in healing MCLs. Our study indicates that combined use of bFGF/GDF-5 might enhance MCL healing by increasing proliferation and migration of MCL fibroblasts, and by regulating collagen synthesis and connective fiber alignment.

The effects of a recombinant human bone morphogenetic protein-2/7 (rhBMP-2/7) heterodimer and a RADA16 (Ac-RADARADARADARADA-CONH2) hydrogel scaffold on bone formation during distraction osteogenesis were evaluated.Forty New Zealand white rabbits, which underwent mandibular lengthening, were randomly divided into 5 groups. One group served as the control group. The others received 2 μg of rhBMP-2 homodimer, 2 μg of rhBMP-2/7 heterodimer, 100 μL of RADA16, or 100 μL of RADA16 plus 2 μg of rhBMP-2/7 heterodimer in the mandibular distraction gap at the beginning of distraction. Fluorine-18-labeled fluoride positron emission tomography was used to assess osteogenesis both after distraction and at the end of consolidation. Dual-energy x-ray absorptiometry (DEXA) examination and bone histologic findings were also evaluated.At the end of distraction, the radioactivity concentration in the distracted area was significantly greater in the RADA16 plus rhBMP-2/7 heterodimer group than in the other groups (P .01). The differences among the other 4 groups were also statistically significant in the following order: rhBMP-2/7 heterodimer group greater than the rhBMP-2 homodimer group, which was greater than the RADA16 group (or control group; P .05). However, the radioactivity concentration of the RADA16 group was slightly greater than that of the control group with a nonsignificant difference (P .05). By the end of consolidation, the activity in the control group, RADA16 group, rhBMP-2 homodimer group, and rhBMP-2/7 heterodimer group had significantly diminished (P .05). However, the activity in the RADA16 plus rhBMP-2/7 heterodimer group remained at the same level (P .05). The DEXA results and bone histologic findings indicated that more callus regeneration was noted in the RADA16 plus rhBMP-2/7 heterodimer group than in any other group.The use of rhBMP-2/7 heterodimer and RADA16 hydrogel scaffold significantly promoted mandibular distraction osteogenesis.

Wang, C., Wang, J. et al. show that local injection of a hydrogel scaffold degraded by reactive oxygen species in the tumour microenvironment releases chemotherapy and an immune checkpoint inhibitor with kinetics that increase antitumour responses.

In this study, a two-step crosslinking method derived from commercial rapid prototyping equipment was used to fabricate a gradient hydrogel scaffold in vitro. This system contained two types of nozzles; one was double-nozzle unit, used for relatively simple gradient hydrogel scaffold composed of two nonmiscible hydrogel materials. The other was single nozzle that was used for mixing a gradient hydrogel scaffold composed of two types of hydrogel materials. Different types of scaffolds were formed by modifying the gradient in one of the relevant nozzles. To improve the extrusion controlling effect, accessorial parameters were introduced. A 3D gradient construct containing neuron cells and Schwann cells was fabricated and cultured for 7 days. This construct was helpful in designing a gradient mode to observe the relationship between different cells in vitro. This work has improved tissue-engineering techniques for later manufacturing of very complicated organ analogs.

Encapsulating cells in biodegradable hydrogels offers numerous attractive features for tissue engineering, including ease of handling, a highly hydrated tissue-like environment for cell and tissue growth, and the ability to form in vivo. Many properties important to the design of a hydrogel scaffold, such as swelling, mechanical properties, degradation, and diffusion, are closely linked to the crosslinked structure of the hydrogel, which is controlled through a variety of different processing conditions. Degradation may be tuned by incorporating hydrolytically or enzymatically labile segments into the hydrogel or by using natural biopolymers that are susceptible to enzymatic degradation. Because cells are present during the gelation process, the number of suitable chemistries and formulations are limited. In this review, we describe important considerations for designing biodegradable hydrogels for cell encapsulation and highlight recent advances in material design and their applications in tissue engineering.

Recently, understanding of the extracellular matrix (ECM) has expanded rapidly due to the accessibility of cellular and molecular techniques and the growing potential and value for hydrogels in tissue engineering. The fabrication of hydrogel-based cellular scaffolds for the generation of bioengineered tissues has been based on knowledge of the composition and structure of ECM. Attempts at recreating ECM have used either naturally-derived ECM components or synthetic polymers with structural integrity derived from hydrogels. Due to their increasing use, their biocompatibility has been questioned since the use of these biomaterials needs to be effective and safe. It is not surprising then that the evaluation of biocompatibility of these types of biomaterials for regenerative and tissue engineering applications has been expanded from being primarily investigated in a laboratory setting to being applied in the multi-billion dollar medicinal industry. This review will aid in the improvement of design of non-invasive, smart hydrogels that can be utilized for tissue engineering and other biomedical applications. In this review, the biocompatibility of hydrogels and design criteria for fabricating effective scaffolds are examined. Examples of natural and synthetic hydrogels, their biocompatibility and use in tissue engineering are discussed. The merits and clinical complications of hydrogel scaffold use are also reviewed. The article concludes with a future outlook of the field of biocompatibility within the context of hydrogel-based scaffolds.

Creating a microenvironment that supports angiogenesis, cellular cross-talk, cell migration and differentiation is crucial in providing an optimal environment for tissue regeneration. Additionally, varying size and contour of the root canals play a critical role and should get into serious consideration in the context of pulp regeneration. Therefore, an ideal scaffold material for pulp regeneration should demonstrate the ability to easily incorporate growth factors and cells by simple mixing and to adapt to the varying contour of the pulp chamber and root canals following injection. Dental pulp stem cells is the predominant type of stem cells that holds the potential to be used in dental pulp regeneration for their ready availability, ease of harvesting and stemness properties. Encapsulation of DPSCs within an injectable hydrogel scaffold provides a favourable approach for pulp regeneration as it can be injected to any irregular-shaped defect eliminating the necessity for custom-made scaffold designs.

Hydrogels consisting of three-dimensional (3D) polymeric networks have found a wide range of applications in biotechnology due to their large water capacity, high biocompatibility, and facile functional versatility. The hydrogels with stimulus-responsive swelling properties have been particularly instrumental to realizing signal transduction in biosensors and bioelectronics. Graphenes are two-dimensional (2D) nanomaterials with unprecedented physical, optical, and electronic properties and have also found many applications in biosensors and bioelectronics. These two classes of materials present complementary strengths and limitations which, when effectively coupled, can result in significant synergism in their electrical, mechanical, and biocompatible properties. This report reviews recent advances made with hydrogel and graphene materials for the development of high-performance bioelectronics devices. The report focuses on the interesting intersection of these materials wherein 2D graphenes are hybridized with 3D hydrogels to develop the next generation biosensors and bioelectronics.

The in situ-forming colloidal hydrogels from the thermal gelation of poly(N-isopropylacrylamide) (PNIPAM) microgel dispersions have been exploited for 3D cell culture. The properties of the hydrogel scaffold need to be tuned to further improve its performance. In addition, cellular uptake of the microgel particles need to be reduced to avoid their potential undesired influence. For these purposes we systematically examined the effect of microgel particle size on the hydrogel scaffold. It was found that gel properties could be tuned via changing particle size. Increasing particle size reduces the gel strength and its syneresis degree, both of which are favorable for cell growth. Meanwhile increasing particle size could also reduce significantly the cellular uptake of the microgel particles. Microgel with a size of ~162 nm shows the highest cellular uptake, beyond which cellular uptake decreases with increasing particle size. Hydrogel scaffold from 300 nm microgel, with suitable physical properties and reduced cellular uptake, were successfully used for multicellular spheroid generation.

Due to its intrinsically poor repair potential, injuries to articular cartilage do not heal and clinical intervention is required. Osteochondral grafts may improve healing while promoting integration with host tissue. We report here the development of an osteochondral graft based on a hybrid of a hyrogel and a polymer-bioactive glass composite (PLAGA-BG) microsphere scaffold. This novel osteochondral construct consists of three regions: gel-only, gel/composite interface, and a composite-only-region. The three phases differ in calcium phospate (Ca-P) or BG content. The objective of the current study is to investigate the effects of scaffold composition on chondrocyte response, and to evaluate the effects of co-culture on osteoblasts and chondrocyte growh and differentiation on the hybrid scaffold. The PLAGA-BG microsphere scaffold supported the growth of chondrocytes and initial results indicate that in the presence of BG, chondrocyte-mediated mineralization may be stimulated. Co-culture of osteoblasts and chondrocytes on the multi-phased scaffold with varied Ca-P content facilitated the formation of multiple matrix zones: a GAGrich chondrocyte region, an interfacial matrix rich in GAG+collagen, and a mineralized collagen matrix with osteoblasts. In summary, chondrocyte response has been optimized as a function of scaffold composition and the novel osteochondral graft has the potential to support the simultaneous formation of multiple types of tissue in vitro.

A novel chitosan hydrogel with high porosity was fabricated by a crosslinking method. Cartilage tissue engineering formed after mesenchymal stem cells was cultured on this hydrogel scaffold for 12 weeks. The immunohistochemistry tests demonstrated that the obtained cartilage had the specific histological properties of natural cartilage. And the qPCR tests also proved that the genes for type II collagen in the obtained cartilage were expressed the same as in the natural one.