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Gelatin-based injectable hydrogels capable of encapsulating cells are pivotal in tissue engineering because they can conform to any geometry and exhibit physical properties similar to those of living tissues. However, the slow gelation process observed in these cell-encapsulating hydrogels often causes an uneven dispersion of cells. This study proposes an approach for achieving fast gelation of unmodified gelatin under physiological conditions through gelatin preclustering. By using tetrafunctional succinimidyl-terminated poly(ethylene glycol) as a clustering agent, the gelation process is successfully expedited fivefold without requiring chemical modifications, effectively addressing the associated challenges of uneven cell distribution., (© 2024 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Injectable hydrogels are gaining prominence as a biocompatible, minimally invasive, and adaptable platform for cartilage tissue engineering. Commencing with their synthesis, this review accentuates the tailored matrix formulations and cross-linking techniques essential for fostering three-dimensional cell culture and melding with complex tissue structures. Subsequently, it spotlights the hydrogels' enhanced properties, highlighting their augmented functionalities and broadened scope in cartilage tissue repair applications. Furthermore, future perspectives are advocated, urging continuous innovation and exploration to surmount existing challenges and harness the full clinical potential of hydrogels in regenerative medicine. Such advancements are crucial for validating the long-term efficacy and safety of hydrogels, positioning them as a promising direction in regenerative medicine to address cartilage-related ailments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recently, injectable hydrogels have attracted much interest in tissue engineering (TE) applications because of their controlled flowability, adaptability, and easy handling properties. This work emphasizes the synthesis and characterizations of bioactive glass (BAG) nanoparticle-reinforced poly(ethylene glycol) (PEG)- and poly( N -vinylcarbazole) (pNVC)-based minimally invasive composite injectable hydrogel suitable for bone regeneration. First, the copolymer was synthesized from a combination of PEG and pNVC through reversible addition-fragmentation chain-transfer (RAFT) polymerization and nanocomposite hydrogel constructs were subsequently prepared by conjugating BAG particles at varying loading concentrations. Gel permeation chromatography (GPC) analysis confirmed the controlled nature of the polymer. Various physicochemical characterization results confirmed the successful synthesis of copolymer and nanocomposite hydrogels that showed good gelling and injectability properties. Our optimal nanocomposite hydrogel formulation showed excellent swelling properties in comparison to the copolymeric hydrogel due to the presence of hydrophilic BAG particles. The bone cell proliferation rate was found to be evidently higher in the nanocomposite hydrogel than in the copolymeric hydrogel. Moreover, the enhanced level of ALP activity and apatite mineralization for the nanocomposite in comparison to that for the copolymeric hydrogel indicates accelerated in vitro osteogenesis. Overall, our study findings indicate BAG particle-conjugated nanocomposite hydrogels can be used as promising grafting materials in orthopedic reconstructive surgeries complementary to conventional bone graft substitutes in cancellous bone defects due to their 3D porous framework, minimal invasiveness, and ability to form any desired shape to match irregular bone defects.

Currently there are no potential curative therapies that can improve the central nervous system (CNS) regeneration after traumatic injuries or diseases. Indeed, the regeneration of CNS is greatly impaired by limited drug penetration across the blood brain barrier (BBB), poor drug targeting, deficient progenitor neural cells and limited proliferation of mature neural cells. To overcome these limitations, bioengineered injectable hydrogels in combination with drug and cell therapy have been proposed to mimic the complexity of the CNS microenvironment and architecture. Additionally, to enhance relevant CNS regeneration, proper biophysical and biochemical cues are needed. Recently, great efforts have been devoted to tailor stimuli-responsive hydrogels as novel carrier systems which are able to guide neural tissue regeneration. This review provides an extensive overview on the most promising injectable hydrogels for neural tissue engineering. A special emphasis is made to highlight the ability of these hydrogels to deliver bioactive compounds/cells upon the exposure to internal and external stimuli. Bioactive injectable hydrogels have a broad application in central nervous system's (CNS) regeneration. This review gives an overview of the latest pioneering approaches in CNS recovery using stimuli-responsive hydrogels for several neurodegenerative disorders. STATEMENT OF SIGNIFICANCE: This review summarizes the latest innovations on bioactive injectable hydrogels, focusing on tailoring internal/external stimuli-responsive hydrogels for the new injectable systems design, able to guide neural tissue response. The purpose is to highlight the advantages and the limitations of thermo-responsive, photo responsive, magnetic responsive, electric responsive, ultrasound responsive and enzymes-triggered injectable hydrogels in developing customizable neurotherapies. We believe that this comprehensive review will help in identifying the strengths and gaps in the existing literature and to further support the use of injectable hydrogels in stimulating CNS regeneration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Recently, injectable conducting polymer-based hydrogels (CPHs) have received increasing attention in tissue engineering owing to their controlled conductivity and minimally invasive procedures. Conducting polymers (CPs) are introduced into hydrogels to improve the electrical integration between hydrogels and host tissues and promote the repair of damaged tissues. Furthermore, endowing CPHs with in situ gelation or shear-thinning properties can reduce the injury size and inflammation caused by implanted surgery materials, which approaches the clinical transformation target of conductive biomaterials. Notably, functional CPs, including hydrophilic CP complexes, side-chain modified CPs, and conducting graft polymers, improve the water-dispersible and biocompatible properties of CPs and exhibit significant advantages in fabricating injectable CPHs under physiological conditions. This review discusses the recent progress in designing injectable hydrogels based on functional CPs. Their potential applications in neurological treatment, myocardial repair, and skeletal muscle regeneration are further highlighted. STATEMENT OF SIGNIFICANCE: Conducting polymer-based hydrogels (CPHs) have broad application prospects in the biomedical field. However, the low water dispersibility and processability of conducting polymers (CPs) make them challenging to form injectable CPHs uniformly. For the first time, this review summarizes the functionalization strategies to improve the hydrophilicity and biocompatibility of CPs, which provides unprecedented advantages for designing and fabricating the physical/chemical crosslinked injectable CPHs. Besides, future challenges and prospects for further clinical transformation of injectable CPHs for tissue engineering are presented. This review's content is of great significance for the treatment of electroactive tissues with limited self-regeneration, including neurological treatment, myocardial repair, and skeletal muscle regeneration.  Therefore, it is inspiring for the tissue engineering research of biomaterials and medical practitioners., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Injectable scaffolds made of biodegradable biomaterials can stabilize a myocardial infarct and promote cardiac repair. Here, we describe an injectable, citrate-containing polyester hydrogel which can release citrate as a cell regulator via hydrogel degradation and simultaneously show sustained release of an encapsulated myeloid-derived growth factor (Mydgf). Xu et al. described the synthesis of hydrogel with biocompatible starting chemicals including citric acid and poly(ethylene glycol) diol. The characterization of materials demonstrated that the developed hydrogels possess tunable degradation and mechanical properties and exhibit sustained drug release. The authors also observed improved postmyocardial infarction (MI) heart repair in a rat MI model through coupling the therapeutic effect of the hydrogel degradation product (citrate) with encapsulated Mydgf. In their study, hematoxylin and eosin (H&E) staining and Masson's trichrome staining were performed on heart samples to evaluate the change in heart structure. Furthermore, immunohistochemistry was used to study neovascularization. Their results showed that the intramyocardial injection of Mydgf-loaded citrate-containing hydrogel significantly reduced scar formation and infarct size, increased wall thickness and neovascularization, and improved heart function., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Injectable chitosan hydrogels exhibit excellent biological properties for application in biomedical engineering, however most of these hydrogels have limited applicability because "Swelling" can induce volume expansion of conventional hydrogels implanted in the body damages the surrounding tissues. Here, we report a new "Nonswelling" pentenyl chitosan (PTL-CS) hydrogel via N‒acylation reaction to graft an UV crosslinkable short hydrophobic alkyl chain (n‒pentenyl groups). The incorporated pentenyl groups can be crosslinked by UV irradiation to form hydrophobic chains via combination termination, which generate strong hydrophobic effect to extrude the excess water in hydrogel, resulting in a "Nonswelling" state at biological temperature. Furthermore, the PTL-CS solution showed no cytotoxicity in vitro and minimally invasive treatment in vivo demonstrated the PTL-CS hydrogel no adverse effects in a rat model. The nonswelling injectable and UV crosslinkable chitosan hydrogel hold potential applications in smart biomaterials and biological engineering as well as providing a new natural hydrogel in minimally invasive tissue engineering.., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Thermo-sensitive injectable hydrogels that spontaneously react to physiological temperature have been widely studied to be used in biomedical fields. However, several challenges on their unstable structures with large-sized pores and low mechanical strength under physiological conditions must be addressed to enable their practical applications. We synthesized the hydroxybutyl methacrylated chitosan (HBC-MA) hydrogel that possesses both thermo-sensitive and photo-crosslinkable properties. The HBC-MA showed effective sol-gel transition under physiological temperature as well as a sensitive photo-crosslinkable property with visible light capable of skin penetration. The co-nonsolvency property and thermo-sensitivity of HBC-MA prevented unintended loss of the hydrogel graft after being subcutaneously injected in mice. Subsequently applied visible light on the skin beneath which the hydrogel was injected significantly improved the mechanical strength and stability of the graft. The injectable HBC-MA hydrogel developed in this study can be applicable to a wide range of biomedical fields such as drug delivery system and tissue engineering., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Injectable hydrogels with conductivity are highly desirable as scaffolds for the engineering of various electrical stimuli-responsive tissues, including nerve, muscle, retina, and bone. However, oxygen deprivation within scaffolds can lead to failure by causing cell necrosis. Therefore, an oxygen release conductive injectable hydrogel can serve as a promising support for the regeneration of such tissues. In the present study, H 2 O 2 -loaded polylactic acid microparticles were fabricated. Then, gelatin-graft-polypyrrole with various pyrrole contents and periodate-oxidized pectin were synthesized, and consequently, injectable conductive hydrogel/microparticle scaffolds, inside which catalase was grafted and trapped, were obtained. The results revealed that spherical particles with a mean diameter of 60.39 μm and encapsulation efficiency of 49.64 %, which persistently provided oxygen up to 14 days, were achieved. Investigations on hydrogels revealed that with the increase of pyrrole content of gelatin-graft-polypyrrole from 0 to 15 %, the swelling ratio, pore size, porosity, and conductivity were increased from 6.5 to 11.8, 173.13 μm-295.96 μm, 79.7%-93.8%, and from 0.06 mS/m to 2.14 mS/m, respectively. On the other hand, the crosslinking degree and compressive modulus of hydrogels were shown to decrease from 67.24%-27.35%, and from 214.1 kPa to 64.4 kPa, respectively. Moreover, all formulations supported cell viability and attachment. Overall, the hydrogel/particle scaffold with the merits of electrical conductivity, injectability, compatibility, and sustained oxygen release can be used as a tissue engineering scaffold, promoting the regeneration of electricity responsive tissues. Considering all the aforementioned characteristics and behavior of the fabricated scaffolds, they may be promising candidates for bone tissue engineering applications., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, 6-(6-aminohexyl) amino-6-deoxy-β-cyclodextrin-gellan gum complex hydrogel (HCD-GG) was developed to enhance the affinity of anti-inflammatory drug dexamethasone (Dx), improve chondrogenesis, and decrease the inflammatory response. The modified chemical structure was confirmed by NMR and FTIR. Mechanical and physicochemical properties were characterized by performing viscosity study, compression test, injection force test, swelling kinetic, weight loss, and morphological study. The release profile of the drug-loaded hydrogels was analyzed to confirm the affinity of the hydrophobic drugs and the matrix and characterize cumulative release. In vitro test was carried out with MTT assay, live/dead staining, glycosaminoglycan (GAGs) content, double-stranded DNA (dsDNA) content, morphological analysis, histology, and gene expression. In vivo experiment was conducted by implanting the samples under a subcutaneous area of SPD rat and cartilage defected rabbit model. The results displayed successfully synthesized HCD-GG. The gelation temperature of the modified hydrogels was decreased while the mechanical property was improved when the drug was loaded in the modified hydrogel. Swelling and degradation kinetics resulted in a higher level compared to the pristine GG but was a sufficient level to support drugs and cells. The affinity and release rate of the drug was higher in the HCD-GG group which shows an improved drug delivery system of the GG-based material. The microenvironment provided a suitable environment for cells to grow. Also, chondrogenesis was affected by the existence of Dx and microenvironment, resulting in higher expression levels of cartilage-related genes while the expression of the inflammation mediators decreased when the Dx was loaded. In vivo study showed an improved anti-inflammatory response in the drug-loaded hydrogel. Furthermore, the cartilage defected rabbit model showed an enhanced regenerative effect when the Dx@HCD-GG was implanted. These results suggest that HCD-GG and Dx@HCD-GG have the potential for cartilage regeneration along with multiple applications in tissue engineering and regenerative medicine., (Copyright © 2020. Published by Elsevier B.V.)

Cardiovascular disease (CVD) remains the leading cause of death in Western countries. Post-myocardial infarction heart failure can be considered a degenerative disease where myocyte loss outweighs any regenerative potential. In this scenario, regenerative biology and tissue engineering can provide effective solutions to repair the infarcted failing heart. The main strategies involve the use of stem and progenitor cells to regenerate/repair lost and dysfunctional tissue, administrated as a suspension or encapsulated in specific delivery systems. Several studies demonstrated that effectiveness of direct injection of cardiac stem cells (CSCs) is limited in humans by the hostile cardiac microenvironment and poor cell engraftment; therefore, the use of injectable hydrogel or pre-formed patches have been strongly advocated to obtain a better integration between delivered stem cells and host myocardial tissue. Several approaches were used to refine these types of constructs, trying to obtain an optimized functional scaffold. Despite the promising features of these stem cells' delivery systems, few have reached the clinical practice. In this review, we summarize the advantages, and the novelty but also the current limitations of engineered patches and injectable hydrogels for tissue regenerative purposes, offering a perspective of how we believe tissue engineering should evolve to obtain the optimal delivery system applicable to the everyday clinical scenario.

Injectable hydrogels have unique advantages for the repair of irregular tissue defects. In this study, we report a novel injectable carbon nanotube (CNT) and black phosphorus (BP) gel with enhanced mechanical strength, electrical conductivity, and continuous phosphate ion release for tissue engineering. The gel utilized biodegradable oligo(poly(ethylene glycol) fumarate) (OPF) polymer as the cross-linking matrix, with the addition of cross-linkable CNT-poly(ethylene glycol)-acrylate (CNTpega) to grant mechanical support and electric conductivity. Two-dimensional (2D) black phosphorus nanosheets were also infused to aid in tissue regeneration through the steady release of phosphate that results from environmental oxidation of phosphorus in situ. This newly developed BP-CNTpega-gel was found to enhance the adhesion, proliferation, and osteogenic differentiation of MC3T3 preosteoblast cells. With electric stimulation, the osteogenesis of preosteoblast cells was further enhanced with elevated expression of several key osteogenic pathway genes. As monitored with X-ray imaging, the BP-CNTpega-gel demonstrated excellent in situ gelation and cross-linking to fill femur defects, vertebral body cavities, and posterolateral spinal fusion sites in the rabbit. Together, these results indicate that this newly developed injectable BP-CNTpega-gel owns promising potential for future bone and broad types of tissue engineering applications.

Background: Meniscal injury repair with tissue engineering technique is promising. Among various scaffolds, the thermosensitive injectable hydrogel has recently attracted much attention., Purpose: (1) Evaluate the biocompatibility of thermosensitive, injectable, in situ crosslinked hydrogel and (2) determine whether the hydrogel with or without transforming growth factor β1 (TGF-β1) could support the fibrochondrogenic differentiation of bone mesenchymal stromal cells (BMSCs) and promote the repair of a critical-sized defect in rabbit meniscus., Study Design: Controlled laboratory study., Methods: The rheological and sustained release properties of the hydrogel were demonstrated. BMSCs were isolated and cultured. Cell viability, quantitative polymerase chain reaction (qPCR), and Western blot were tested in vitro. In vivo, a critical-sized defect was introduced into the meniscus of 30 rabbits. Each defect was randomly assigned to be implanted with either phosphate-buffered saline (PBS); BMSC-laden hydrogel; or BMSC-laden, TGF-β1-incorporated hydrogel. Histological and immunohistochemical analyses were performed at 8 weeks after surgery. The Ishida scoring system was adopted to evaluate the healing quantitatively., Results: The elastic modulus of the hydrogel was about 1000 Pa. The hydrogel demonstrated a sustained-release property and could promote proliferation and induce fibrochondrogenic differentiation of BMSCs after the incorporation of TGF-β1 ( P < .001). At 8 weeks after surgery, a large amount of fibrocartilaginous tissue, which was positive on safranin-O staining and expressed strong type II collagen intermingled with weak type I collagen, was observed in the defect region of the BMSC-laden, TGF-β1-incorporated hydrogel group. In the BMSC-laden hydrogel group, the defect was filled with fibrous tissue together with a small amount of fibrocartilage. The mean ± SD quantitative scores obtained for the 3 groups-PBS; BMSC-laden hydrogel; and BMSC-laden, TGF-β1-incorporated hydrogel-were 1.00, 3.20 ± 0.84, and 5.00 ± 0.71, respectively ( P < .001)., Conclusion: The hydrogel was biocompatible and could stimulate strong fibrochondrogenic differentiation of BMSCs after the incorporation of TGF-β1. The local administration of the BMSC-laden, TGF-β1-incorporated hydrogel could promote the healing of rabbit meniscal injury., Clinical Relevance: This hydrogel is an alternative scaffold for meniscus tissue engineering.

Osteoarthritis (OA) is the most common form of the joint disease associated with age, obesity, and traumatic injury. It is a disabling degenerative disease that affects synovial joints and leads to cartilage deterioration. Despite the prevalence of this disease, the understanding of OA pathophysiology is still incomplete. However, the onset and progression of OA are heavily associated with the inflammation of the joint. Therefore, studies on OA treatment have sought to intra-articularly deliver anti-inflammatory drugs, proteins, genes, or cells to locally control inflammation in OA joints. These therapeutics have been delivered alone or increasingly, in delivery vehicles for sustained release. The use of hydrogels in OA treatment can extend beyond the delivery of anti-inflammatory components to have inherent immunomodulatory function via regulating immune cell polarization and activity. Currently, such immunomodulatory biomaterials are being developed for other applications, which can be translated into OA therapy. Moreover, anabolic and proliferative levels of OA chondrocytes are low, except initially, when chondrocytes temporarily increase anabolism and proliferation in response to structural changes in their extracellular environment. Therefore, treatments need to restore matrix protein synthesis and proliferation to healthy levels to reverse OA-induced damage. In conjugation with injectable and/or adhesive hydrogels that promote cartilage tissue regeneration, immunomodulatory tissue engineering solutions will have robust potential in OA treatment. This review describes the disease, its current and future immunomodulatory therapies as well as cartilage-regenerative injectable and adhesive hydrogels., Competing Interests: The authors declare no conflicts of interest.

Novel injectable thermosensitive PNIPAM/hyaluronic acid hydrogels containing various amounts of chitosan-g-acrylic acid coated PLGA (ACH-PLGA) micro/nanoparticles were synthesized and designed to facilitate the regeneration of cartilage tissue. The ACH-PLGA particles were used in the hydrogels to play a triple role: first, the allyl groups on the chitosan-g-acrylic acid shell act as crosslinkers for PNIPAM and improved the mechanical properties of the hydrogel to mimic the natural cartilage tissue. Second, PLGA core acts as a carrier for the controlled release of chondrogenic small molecule melatonin. Third, they could reduce the syneresis of the thermosensitive hydrogel during gelation. The optimum hydrogel with the minimum syneresis and the maximum compression modulus was chosen for further evaluations. This hydrogel showed a great integration with the natural cartilage during the adhesion test, and also, presented an interconnected porous structure in scanning electron microscopy images. Eventually, to evaluate the cytotoxicity, mesenchymal stem cells were encapsulated inside the hydrogel. MTT and Live/Dead assay showed that the hydrogel improved the cells growth and proliferation as compared to the tissue culture polystyrene. Histological study of glycosaminoglycan (GAG) showed that melatonin treatment has the ability to increase the GAG synthesis. Overall, due to the improved mechanical properties, low syneresis, the ability of sustained drug release and also high bioactivity, this injectable hydrogel is a promising material system for cartilage tissue engineering., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The goal of tissue engineering scaffolds is to simulate the physiological microenvironment, in which the electrical microenvironment is an important part. Hydrogel is an ideal material for tissue engineering scaffolds because of its soft, porous, water-bearing, and other extracellular matrix-like properties. However, the hydrogel matrix is usually not conductive and can hinder the communication of electrical signals between cells, which promotes researchers' attention to conductive hydrogels. Conductive hydrogels can promote the communication of electrical signals between cells and simulate the physiological microenvironment of electroactive tissues. Hydrogel formation is an important step for the application of hydrogels in tissue engineering. In situ forming of injectable hydrogels and customized forming of three-dimensional (3D) printing hydrogels represent two most potential advanced forming processes, respectively. In this review, we discuss (i) the classification, properties, and advantages of conductive hydrogels, (ii) the latest development of conductive hydrogels applied in myocardial, nerve, and bone tissue engineering, (iii) advanced forming processes, including injectable conductive hydrogels in situ and customized 3D printed conductive hydrogels, (iv) the challenges and opportunities of conductive hydrogels for tissue engineering. Impact Statement Biomimetic construction of electro-microenvironment is a challenge of tissue engineering. The development of conductive hydrogels provides possibility for the construction of biomimetic electro-microenvironment. However, the importance of conductive hydrogels in tissue engineering has not received enough attention so far. Herein, various conductive hydrogels and their tissue engineering applications are systematically reviewed. Two potential methods of conductive hydrogel forming, in situ forming of injectable conductive hydrogels and customized forming of three-dimensional printing conductive hydrogels, are introduced. The current challenges and future development directions of conductive hydrogels are comprehensively overviewed. This review provides a guideline for tissue engineering applications of conductive hydrogels.

Scaffolds for tissue engineering of specific sites such as cardiac, nerve, and bone tissues need a comprehensive design of three dimensional materials that covers all aspects of chemical composition and physical structures, required for regeneration of desired cells. Hydrogels, possessing highly hydrated and interconnected structures, are promising materials for tissue engineering applications. Improvement of an injectable hydrogel from biocompatible polysaccharides and poly‑N‑isopropyl acryl amide enriched with Au nanoparticles are the main goal of this study. Two main enhancements in this study are included mixture design of the components and addition of Au nanoparticles to access a homogeneous mixture that have potential application in tissue engineering. Chemical and physical properties of the injectable hydrogel are fully characterized. Addition of Au nanoparticles as a conductive component to enhance cell growth and attachment is investigated through MG-63 cell viability assay., (Copyright © 2018. Published by Elsevier B.V.)

The in-situ forming injectable hydrogels have received much attention as scaffolds in the biomedical field, providing a minimally invasive surgical procedure to fill the damaged area. In the present work, carboxymethyl chitin (CMCH) synthesized homogenously was further functionalized with tyramine, resulted in a new injectable enzymatically crosslinked in-situ forming hydrogel under physiological conditions. This new tyramine-modified carboxymethyl chitin (CMCH-Tyr) hydrogel showed much better mechanical properties than those of the thermosensitive in-situ forming physical-crosslinking CMCH hydrogel. The CMCH-Tyr hydrogels remained stable under physiological conditions and could be degraded by lysozyme. The gelation time, strength and biodegradation rate of the CMCH-Tyr hydrogels can be adjusted by varying the concentrations of the horseradish peroxidase and H 2 O 2 in the certain range. In vitro cytotoxicity assays and in vivo in-situ injection study showed non-toxicity, favorable gel formation, and good tissue biocompatibility of the enzyme-catalyzed CMCH-Tyr hydrogel. Thus, the biodegradable and biocompatible CMCH-Tyr hydrogels may hold great potential for three dimensional cell culture and tissue engineering., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Drug-loaded injectable hydrogels have been proven to possess huge potential for applications in tissue engineering. However, increasing the drug loading capacity and regulating the release system to adapt to the microenvironment after myocardial infarction face a huge challenge. In this research, an ROS-sensitive injectable hydrogel strengthened by self-nanodrugs was constructed. A hyperbranched ROS-sensitive macromer (HB-PBAE) with multiacrylate end groups was synthesized through dynamic controlled Michael addition. Meanwhile, a simple protocol based on dopamine polymerization was employed to generate a polydopamine (PDA) layer deposited on the tanshinone IIA (TIIA) nanoparticles (NPs) formed from spontaneous hydrophobic self-assembly. The HB-PBAE reacted with thiolate-modified hyaluronic acid (HA-SH) to form an in situ hydrogel, where TIIA@PDA NPs can be conveniently entrapped through the chemical cross-link between thiolate and quinone groups on PDA, which doubles the modulus of hydrogels. The in vivo degradation behavior of the hydrogels was characterized by MRI, exhibiting a much slower degradation behavior that is markedly different from that of in vitro. Importantly, a significant improvement of cardiac functions was achieved after hydrogel injection in terms of increased ejection fraction and decreased infarction size, accompanied by inhibition of the expression of inflammation factors, such as IL-1β, IL-6, and TNF-α.

Injectable hydrogels are attractive and alternative scaffolds for cell delivery because they could form in situ, simulate natural tissue and fill any shape of defect. This study aimed at fabricating injectable, self-crosslinkable and biomimetic hydrogels based on collagen type II (Col II) and activated chondroitin sulfate (CS-sNHS) under physiological conditions without the addition of any catalysts or crosslinking agents. The inner morphology of hydrogels was detected by scanning electron microscopy, and it showed that fibrous structure formed in the hydrogels. The gelation time, water absorption capacity and the mechanical property of hydrogels were closely related to the weight ratio of Col II and CS-sNHS in hydrogels. Chondrocytes were encapsulated into these hydrogels, and the effect of hydrogels on survival, proliferation, morphology of cells and remolding of extracellular matrix was investigated. The results demonstrated that chondrocytes survived well and showed round or oval morphology in these hydrogels, in addition, the matrix in hydrogels had been remolded and the collagen fibers displayed periodic alternation of light and shade. These results implied that the injectable and self-crosslinkable hydrogels were alternative carriers for chondrocyte delivery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bone disease is a public health problem around the word, and it is urgent to develop novel tissue engineering scaffolds for the complicated cranial bone regeneration. The present work developed a novel triple crosslinked polysaccharides based injectable hydrogel to composite bio-glass (BG) for cranial bone repair. Dynamic mechanical analysis showed the storage modulus (G') of the hydrogel reached to ∼4000Pa. While after compositing BG, G' exceeded 4500Pa. The degradation behavior of the hydrogel is influenced by hydrogel composition, crosslinking methods and degradation environment. Through compositing BG for rat cranial bone repair, excellent bone regeneration effect was achieved (chunks of "white" new tissue was detected in the defected site, HE histopathological analysis confirmed the new tissue was bone tissue). Thus, the hydrogel is suitable as the carrier of BG for bone repair, demonstrating the prepared triple crosslinked hydrogel is potential for bone tissue engineering applications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as autologous bone grafting. While many bone tissue engineering approaches have traditionally focused on synthetic materials (such as polymers or hydrogels), there has been a lot of excitement surrounding the use of natural materials due to their biologically inspired properties. Fibrin is a natural scaffold formed following tissue injury that initiates hemostasis and provides the initial matrix useful for cell adhesion, migration, proliferation, and differentiation. Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient's own blood, enable the fabrication of completely autologous scaffolds. In this article, we highlight the unique properties of fibrin as a scaffolding material to treat bone defects. Moreover, we emphasize its role in bone tissue engineering nanocomposites where approaches further emulate the natural nanostructured features of bone when using fibrin and other nanomaterials. We also review the preparation methods of fibrin glue and then discuss a wide range of fibrin applications in bone tissue engineering. These include the delivery of cells and/or biomolecules to a defect site, distributing cells, and/or growth factors throughout other pre-formed scaffolds and enhancing the physical as well as biological properties of other biomaterials. Thoughts on the future direction of fibrin research for bone tissue engineering are also presented. In the future, the development of fibrin precursors as recombinant proteins will solve problems associated with using multiple or single-donor fibrin glue, and the combination of nanomaterials that allow for the incorporation of biomolecules with fibrin will significantly improve the efficacy of fibrin for numerous bone tissue engineering applications., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In the present work, a thermosensetive copolymer with a low gelation concentration under 37°C, F127@ChS (F127 crosslinked chondroitin sulfate) was synthesized via DA click chemistry between F127-AMI (maleimido terminated F127) and ChS-furan (furfurylamine grafted chondroitin sulfate). Then, dual crosslinked hydrogels were prepared based on F127@ChS and PEG-AMI (maleimido terminated polyethylene glycol). The physical crosslinking of F127@ChS affords the hydrogel fast gelation behavior, while in situ DA click reaction occurred between F127@ChS and PEG-AMI affords the hydrogel system covalent crosslinking. The dual crosslinked injectable hydrogel was applied as scaffold to load BMP-4 for rat cranial defect repair. As indicated by X-ray imaging, cranial digital images and histological (HE and Masson) staining analysis, new bone tissues were formed in the defected area after 12 weeks repair. The results demonstrate that the novel dual crosslinked injectable hydrogel offer an interesting option for cranial bone tissue engineering., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In the present study, we developed a biomimetic injectable hydrogel system based on hyaluronic acid-adipic dihydrazide and the oligopeptide G 4 RGDS-grafted oxidized pectin, in which their hydrazide and aldehyde-derivatives enable covalent hydrazone crosslinking of polysaccharides. The hydrazone crosslinking strategy is simple, while circumventing toxicity, making this injectable system feasible, minimally invasive and easily translatable for regenerative purposes. By varying their weight ratios, the physicochemical properties of the mechanically stable hydrogel system were easily adjustable. Additionally, the preliminary studies demonstrated that chondrocyte behavior was dependent on HA/pectin composition and the presence of integrin binding moieties. Specifically, the incorporation of a certain amount of G 4 RGDS oligopeptide into HA/pectin-based hydrogels could serve as a biologically active microenvironment that supported chondrocyte phenotype and facilitated chondrogenesis. Furthermore, the hydrogel system exhibited acceptable tissue compatibility by using a mouse subcutaneous implantation model. Overall, the novel injectable multicomponent hydrogel presented here is expected to be useful biomaterial scaffold for cartilage tissue regeneration., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Photocrosslinked hydrogels are being investigated for many tissue engineering applications because of the ability to form these materials in-situ in a minimally invasive manner by injection of aqueous solution under physiological conditions. In this work, carboxymethyl chitin (CMCH) synthesized homogenously was further modified with methacrylic anhydride and photocrosslinked into hydrogel with tunable degradation and mechanical properties. This new methacrylated carboxymethyl chitin (Me-CMCH) hydrogel formed in-situ photocrosslinked under UV irradiation showed much higher storage modulus than that of the thermosensitive in-situ forming physical-crosslinking CMCH hydrogel. The Me-CMCH hydrogels remained stable under physiological conditions and could be degraded by lysozyme. Cytotoxicity test indicated that the photo-induced Me-CMCH hydrogels were non-cytotoxic. The mechanical property, morphology, swelling and biodegradation behavior of the Me-CMCH hydrogels could be tuned by controlling the degree of methacrylation of Me-CMCH. These biodegradable photocrosslinkable Me-CMCH hydrogels may hold great promises for various biomedical applications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Hydrogels prepared from poly(ethylene glycol) (PEG) are widely applied in tissue engineering, especially those derived from a combination of functional multi-arm star PEG and linear crosslinker, with an expectation to form a structurally ideal network. However, the poor mechanical strength still renders their further applications. Here we examined the relationship between the dynamics of the pre-gel solution and the mechanical property of the resultant hydrogel in a system consisting of 4-arm star PEG functionalized with vinyl sulfone and short dithiol crosslinker. A method to prepare mechanically strong hydrogel for cartilage tissue engineering is proposed. It is found that when gelation takes place at the overlap concentration, at which a slow relaxation mode just appears in dynamic light scattering (DLS), the resultant hydrogel has a local maximum compressive strength ∼20 MPa, while still keeps ultralow mass concentration and Young's modulus. Chondrocyte-laden hydrogel constructed under this condition was transplanted into the subcutaneous pocket and an osteochondral defect model in SCID mice. The in vivo results show that chondrocytes can proliferate and maintain their phenotypes in the hydrogel, with the production of abundant extracellular matrix (ECM) components, formation of typical chondrocyte lacunae structure and increase in Young's modulus over 12 weeks, as indicated by histological, immunohistochemistry, gene expression analyses and mechanical test. Moreover, newly formed hyaline cartilage was observed to be integrated with the host articular cartilage tissue in the defects injected with chondrocytes/hydrogel constructs. The results suggest that this hydrogel is a promising candidate scaffold for cartilage tissue engineering., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

One of the major problems in the treatment of cardiovascular diseases is the inability of myocardium to self-regenerate. Current therapies are unable to restore the heart's function after myocardial infarction. Myocardial tissue engineering is potentially a key approach to regenerate damaged heart muscle. Myocardial patches are applied surgically, whereas injectable hydrogels provide effective minimally invasive approaches to recover functional myocardium. These hydrogels are easily administered and can be either cell free or loaded with bioactive agents and/or cardiac stem cells, which may apply paracrine effects. The aim of this review is to investigate the advantages and disadvantages of injectable stem cell-laden hydrogels and highlight their potential applications for myocardium repair., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A robust synthetic strategy of biopolymer-based hydrogels has been developed where hyaluronic acid derivatives reacted through aqueous Diels-Alder chemistry without the involvement of chemical catalysts, allowing for control and sustain release of dexamethasone. To conjugate the hydrogel, furan and maleimide functionalized hyaluronic acid were synthesized, respectively, as well as furan functionalized dexamethasone, for the covalent immobilization. Chemical structure, gelation time, morphologies, swelling kinetics, weight loss, compressive modulus and dexamethasone release of the hydrogel system in PBS at 37°C were studied. The results demonstrated that the aqueous Diels-Alder chemistry provides an extremely selective reaction and proceeds with high efficiency for hydrogel conjugation and covalent immobilization of dexamethasone. Cell culture results showed that the dexamethasone immobilized hydrogel was noncytotoxic and preserved proliferation of entrapped human adipose-derived stem cells. This synthetic approach uniquely allows for the direct fabrication of biologically functionalized gel scaffolds with ideal structures for adipose tissue engineering, which provides a competitive alternative to conventional conjugation techniques such as copper mediated click chemistry., (Copyright © 2015. Published by Elsevier B.V.)

Glycopolypeptides are an emerging class of bioinspired polymers that mimic naturally occurring glycopeptides or glycoproteins, and therefore are expected to exhibit great potential for biomedical applications. In this study, a glycopolypeptide was synthesized by conjugation of poly(γ-propargyl-l-glutamate) (PPLG) with azido-modified mannose and 3-(4-hydroxyphenyl) propanamide (HPPA), via click chemistry. Injectable hydrogels based on the glycopolypeptide were developed through enzymatic crosslinking reaction in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The physicochemical properties of the hydrogels, such as gelation time, storage modulus, swelling and degradation time, could be controlled by varying the concentrations of HRP and H2O2. The glycopolypetide copolymer as well as the extracts of the glycopolypetide hydrogels displayed good cytocompatibility in vitro. After subcutaneous injection into rats, the glycopolypeptide hydrogels were rapidly formed in situ, and exhibited acceptable biocompatibility accompanying the degradation of the hydrogels in vivo. The rabbit chondrocytes inside the glycopolypeptide hydrogels showed spherical morphology with high viability during the incubation period of 3 weeks in vitro, and exhibited a higher proliferation rate than within the hydrogel counterparts of PPLG grafted with 2-(2-(2-methoxyethoxy)ethoxy)ethane (MEO3) and HPPA. Biochemical analysis demonstrated that the production of glycosaminoglycans (GAG) and type II collagen were significantly enhanced after incubation for 2 and 3 weeks in vitro. Moreover, the chondrocyte-containing glycopolypeptide hydrogels in subcutaneous model of nude mice maintained chondrocyte phenotype and produced the cartilaginous specific matrix. These results indicated that the biomimetic glycopolypeptide-based hydrogels hold potential as three-dimensional scaffolds for cartilage tissue engineering., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Injectable, biodegradable scaffolds are required for soft tissue reconstruction owing to its minimally invasive approach. Such a scaffold can mimic the native extracellular matrix (ECM), provide uniform distribution of cells and overcome limitations like donor site morbidity, volume loss, etc. So, here we report two classes of biocompatible and biodegradable hydrogel blend systems namely, Alginate/O-carboxymethyl chitosan (O-CMC) and Alginate/poly (vinyl alcohol) (PVA) with the inclusion of fibrin nanoparticles in each. The hydrogels were prepared by ionic cross-linking method. The developed hydrogels were compared in terms of its swelling ratio, degradation profile, compressive strength and elastic moduli. From these preliminary findings, it was concluded that Alginate/O-CMC formed a better blend for tissue engineering applications. The potential of the formed hydrogel as an injectable scaffold was revealed by the survival of adipose derived stem cells (ADSCs) on the scaffold by its adhesion, proliferation and differentiation into adipocytes. Cell differentiation studies of fibrin incorporated hydrogel scaffolds showed better differentiation was confirmed by Oil Red O staining technique. These injectable gels have potential in soft tissue regeneration., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This chapter describes the preparation of tissue engineered constructs by immobilizing chondrocytes in hydrogel with independently tunable porosity and mechanical properties. This chapter also presents the methods to characterize these tissue engineered constructs. The resulting tissue engineered constructs can be useful for the generation of cartilage tissue both in vitro and in vivo.

The current study aims to prepare and compare three injectable hydrogels consisting of chitosan, hyaluronic acid, and hydroxyapatite in different combinations using two solvents and homoginizer that can be employed in bone tissue engineering (BTE) for remodelling and healing bones. The hydrogel structures were well characterized by FT-IR, XRD and SEM analyses. Surface study, porosity, percolation capacity, bone cell adhesion and proliferation, and swelling properties were tested and was found that these hydrogels are better candidates for BTE. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) analysis showed better compatibility with mononuclear cells derived from human peripherals. Our findings suggest that these hydrogels can be efficiently used as injectable hydrogels in BTE applications. [ABSTRACT FROM AUTHOR]

Irreversible fibrosis following myocardial infarction (MI) stiffens the infarcted myocardium, which remains challenging to restore. This study aimed to investigate whether the injectable RLP12 hydrogel, derived from recombinant resilin protein, could serve as a vehicle for stem cells to enhance the function of the infarcted myocardium. The RLP12 hydrogel was prepared and injected into the myocardium of rats with MI, and brown adipose-derived mesenchymal stem cells (BADSCs) were loaded. The survival and differentiation of BADSCs in vivo were investigated using immunofluorescence one week and four weeks after treatment, respectively. The heart function, MI area, collagen deposition, and microvessel density were further assessed four weeks after treatment through echocardiography, histology, immunohistochemistry, and immunofluorescence. The RLP12 hydrogel was prepared with a shear modulus of 10–15 kPa. Four weeks after transplantation, the RLP12 hydrogel significantly improved cardiac function by increasing microvessel density and reducing infarct area size and collagen deposition in MI rats. Furthermore, the distribution ratio of collagen III to I increased in both the centre and edge areas of the MI, indicating the improved compliance of the infarct heart. Moreover, the RLP12 hydrogel also promoted the survival and differentiation of BADSCs into cardiac troponin T- and α-smooth muscle-positive cells. The RLP12 hydrogel can be utilised as an injectable vehicle of BADSCs for treating MI and regulating collagen I and III expression profiles to improve the mechanical microenvironment of the infarct site, thereby restoring heart function. The study provides novel insights into the mechanical interactions between the hydrogel and the infarct microenvironment. [ABSTRACT FROM AUTHOR]

The primary request nowadays is for innovative and superior scaffold designs that mimic the characteristics of native tissue in cartilage tissue engineering. GelMA/Alginate (G/A) interpenetrating polymer network (IPN) has become a popular hydrogel material for tissue engineering because of its superior mechanical and biological properties. Here, to balance the properties, a hydrogel composed of G/A and covalent organic frameworks (COF) nanoparticles is specially designed. In this study, a hydrogel of GelMA/Alginate/COF (G/A/C) with improved properties such as pore size, swelling, mechanical strength, shear‐thinning behavior, and biocompatibility is produced. Furthermore, the G/A/C hydrogel facilitate the printing of complex three dimensional (3D) scaffolds. The test result demonstrates that the addition of COF up to 1% (w/w) enhances the porosity and decreases pore size (0.2 times), improves the compression strength (six times), and decreases the degradation ratio (0.05 times) and the swelling (0.3 times) compared to the G/A hydrogel sample. Besides, the cell viability test confirms the cell growth during the incubation and great biological behavior (more than 98%). The suitable performance of the G/A hydrogel containing 1% COF and its shape fidelity during the injection by 3D printer is confirmed. Nanocomposite IPN hydrogel based on G/A/C could be useful in tissue engineering applications. [ABSTRACT FROM AUTHOR]

The tissue engineering field is currently advancing towards minimally invasive procedures to reconstruct soft tissue defects. In this regard, injectable hydrogels are viewed as excellent scaffold candidates to support and promote the growth of encapsulated cells. Cross-linked gelatin methacryloyl (GelMA) gels have received substantial attention due to their extracellular matrix-mimicking properties. In particular, GelMA microgels were recently identified as interesting scaffold materials since the pores in between the microgel particles allow good cell movement and nutrient diffusion. The current work reports on a novel microgel preparation procedure in which a bulk GelMA hydrogel is ground into powder particles. These particles can be easily transformed into a microgel by swelling them in a suitable solvent. The rheological properties of the microgel are independent of the particle size and remain stable at body temperature, with only a minor reversible reduction in elastic modulus correlated to the unfolding of physical cross-links at elevated temperatures. Salts reduce the elastic modulus of the microgel network due to a deswelling of the particles, in addition to triple helix denaturation. The microgels are suited for clinical use, as proven by their excellent cytocompatibility. The latter is confirmed by the superior proliferation of encapsulated adipose tissue-derived stem cells in the microgel compared to the bulk hydrogel. Moreover, microgels made from the smallest particles are easily injected through a 20G needle, allowing a minimally invasive delivery. Hence, the current work reveals that powdered cross-linked GelMA is an excellent candidate to serve as an injectable hydrogel for adipose tissue engineering. [ABSTRACT FROM AUTHOR]

Injectable hydrogel provides an excellent substrate for bone tissue engineering (BTE) applications due to its water base, and capacity to encapsulate, manipulate, and easily reach to the adjacent tissue with minimal invasiveness. The purpose of the present study, is to develop an injectable hydrogel with a combination of chitosan, hyaluronic acid, and hydroxyapatite for enhanced bone regeneration and remodeling. Blend hydrogels have enough surface roughness and porosity that helps to attach bone cells. Hydrogel synthesis was confirmed with XRD, FTIR, EDX and TGA characterization. These hydrogels demonstrated adequate swelling and mechanical properties for its use in BTE applications. These hydrogels have the acceptable range of mechanical strength required for injectable hydrogels for bone regeneration. The synthesized hydrogel showed enough range of percolation capacity needed for the permeability of medicine, growth factors, and nutritional molecules. All these findings suggest the use of synthesized hydrogels for bone regeneration in biomedical engineering applications. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration is a leading cause of back pain and precursor to more severe conditions, including disc herniation and spinal stenosis. While traditional growth factor therapies (e.g., TGFβ) are effective at transiently reversing degenerated disc by stimulation of matrix synthesis, it is increasingly accepted that bioscaffolds are required for sustained, complete IVD regeneration. Current scaffolds (e.g., metal/polymer composites, non-mammalian biopolymers) can be improved in one or more IVD regeneration demands: biodegradability, noninvasive injection, recapitulated healthy IVD biomechanics, predictable crosslinking, and matrix repair induction. To meet these demands, tetrazine-norbornene bioorthogonal ligation was combined with gelatin to create an injectable bioorthogonal hydrogel (BIOGEL). The liquid hydrogel precursors remain free-flowing across a wide range of temperatures and crosslink into a robust hydrogel after 5–10 min, allowing a human operator to easily inject the therapeutic constructs into degenerated IVD. Moreover, BIOGEL encapsulation of TGFβ potentiated histological repair (e.g., tissue architecture and matrix synthesis) and functional recovery (e.g., high water retention by promoting the matrix synthesis and reduced pain) in an in vivo rat IVD degeneration/nucleotomy model. This BIOGEL procedure readily integrates into existing nucleotomy procedures, indicating that clinical adoption should proceed with minimal difficulty. Since bioorthogonal crosslinking is essentially non-reactive towards biomolecules, our developed material platform can be extended to other payloads and degenerative injuries.

Intervertebral disc (IVD) degeneration occurred with the increasing age or accidents has puzzled peoples in daily life. To seal IVD defect by injectable hydrogels is a promising method for slowing down IVD degeneration. Herein, we reported a rapidly in situ forming injectable chitosan/PEG hydrogel (CSMA-PEGDA-L) through integrating photo-crosslink of methacrylate chitosan (CSMA) with Schiff base reaction between CSMA and aldehyde polyethylene glycol (PEGDA). The CSMA-PEGDA-L possessed a stronger compressive strength than the photo-crosslinked CSMA-L hydrogel and Schiff-base-crosslinked CSMA-PEGDA hydrogel. This chitosan/PEG hydrogel showed low cytotoxicity from incubation experiments of nucleus pulpous cells. When implanted on the punctured IVD of rat's tail, the CSMA-PEGDA-L hydrogel could well retard the progression of IVD degeneration through physical plugging, powerfully proven by radiological and histological evaluations. This work demonstrated the strategy of in situ injectable glue may be a potential solution for prevention of IVD degeneration.

Introduction: Biocompatible and biodegradable scaffolds based on natural polymers such as gelatin and chitosan (CS) provide suitable microenvironments in dental tissue engineering. In the present study, we report on the synthesis of injectable thermosensitive hydrogel (PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel) for osteogenic differentiation of human dental pulp stem cells (hDPSCs). Methods: The CS-g-PNIPAAm was synthesized using the reaction of carboxyl terminated PNIPAAm with CS, which was then mixed with various amounts of gelatin solution in the presence of genipin as a chemical crosslinker to gain a homogenous solution. The chemical composition and microstructures of the fabricated hydrogels were confirmed by FT-IR and SEM analysis, respectively. To evaluate the mechanical properties (e.g., storage and loss modulus of the gels), the rheological analysis was considered. Calcium deposition and ALP activity of DPSCs were carried out using alizarin red staining and ALP test. While the live/dead assay was performed to study its toxicity, the real-time PCR was conducted to investigate the osteogenic differentiation of hDPSCs cultured on prepared hydrogels. Results: The hydrogels with higher gelatin incorporation showed a slightly looser network compared to the other ones. The hydrogel with less gelatin indicates a rather higher value of G', indicating a higher elasticity due to more crosslinking reaction of amine groups of CS via a covalent bond with genipin. All the hydrogels contained viable cells with negligible dead cells, indicating the high biocompatibility of the prepared hydrogels for hDPSCs. The quantitative results of alizarin red staining displayed a significant rise in calcium deposition in hDPSCs cultured on prepared hydrogels after 21 days. Further, hDPSCs cultured on hydrogel with more gelatin displayed the most ALP activity. The expression of late osteogenic genes such as OCN and BMP-2 were respectively 6 and 4 times higher on the hydrogel with more gelatin than the control group after 21 days. Conclusion: The prepared PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel presented great features (e.g., porous structure, suitable rheological behavior, and improved cell viability), and resulted in osteogenic differentiation necessary for dental tissue engineering.

Injectable hydrogels can be applied to treat damaged meniscus in minimally invasive conditions. Generally, injectable hydrogels can be prepared from various polymers such as polycaprolactone (PCL) and poly (N-isopropylacrylamide) (PNIPAAm). Poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer-diacrylate (PEO-PPO-PEO-DA) is an interesting polymer due to its biodegradability and can be prepared as water-insoluble injectable hydrogel after curing with UV light at low intensity. However, mechanical and cell adhesion properties are not optimal for these hydrogels. For the improved mechanical performance of the injectable hydrogel, cellulose nanofiber (CNF) extracted from cassava pulp was used as a reinforcing filler in this study. In addition, gelatin methacrylate (GelMA), the denatured form of collagen was used to enhance cell adhesion. PEO-PPO-PEO-DA/CNF/GelMA injectable hydrogels were prepared with 2-hydroxy-1-(4-(hydroxy ethoxy) phenyl)-2-methyl-1-propanone as a photoinitiator and then cured with UV light, 365 nm at 6 mW/cm2. Physicochemical characteristics of the hydrogels and hydrogels with CNF were studied in detail including morphology characterization, pore size diameter, porosity, mechanical properties, water uptake, and swelling. In addition, cell viability was also studied. CNF-reinforced injectable hydrogels were successfully prepared after curing with UV light within 10 min with a thickness of 2 mm. CNF significantly improved the mechanical characteristics of injectable hydrogels. The incorporation of GelMA into the injectable hydrogels improved the viability of human cartilage stem/progenitor cells. At optimum formulation, 12%PEO-PPO-PEO-DA/0.5%CNF/3%GelMA injectable hydrogels significantly promoted cell viability (>80%) and also showed good physicochemical properties, which met tissue engineering requirements. In summary, this work shows that these novel injectable hydrogels have the potential for meniscus tissue engineering. [ABSTRACT FROM AUTHOR]

The tissue engineering field is currently advancing towards minimally invasive procedures to reconstruct soft tissue defects. In this regard, injectable hydrogels are viewed as excellent scaffold candidates to support and promote the growth of encapsulated cells. Cross-linked gelatin methacryloyl (GelMA) gels have received substantial attention due to their extracellular matrix-mimicking properties. In particular, GelMA microgels were recently identified as interesting scaffold materials since the pores in between the microgel particles allow good cell movement and nutrient diffusion. The current work reports on a novel microgel preparation procedure in which a bulk GelMA hydrogel is ground into powder particles. These particles can be easily transformed into a microgel by swelling them in a suitable solvent. The rheological properties of the microgel are independent of the particle size and remain stable at body temperature, with only a minor reversible reduction in elastic modulus correlated to the unfolding of physical cross-links at elevated temperatures. Salts reduce the elastic modulus of the microgel network due to a deswelling of the particles, in addition to triple helix denaturation. The microgels are suited for clinical use, as proven by their excellent cytocompatibility. The latter is confirmed by the superior proliferation of encapsulated adipose tissue-derived stem cells in the microgel compared to the bulk hydrogel. Moreover, microgels made from the smallest particles are easily injected through a 20G needle, allowing a minimally invasive delivery. Hence, the current work reveals that powdered cross-linked GelMA is an excellent candidate to serve as an injectable hydrogel for adipose tissue engineering.

Introduction: Biocompatible and biodegradable scaffolds based on natural polymers such as gelatin and chitosan (CS) provide suitable microenvironments in dental tissue engineering. In the present study, we report on the synthesis of injectable thermosensitive hydrogel (PNIPAAmg-CS copolymer/gelatin hybrid hydrogel) for osteogenic differentiation of human dental pulp stem cells (hDPSCs). Methods: The CS-g-PNIPAAm was synthesized using the reaction of carboxyl terminated PNIPAAm with CS, which was then mixed with various amounts of gelatin solution in the presence of genipin as a chemical crosslinker to gain a homogenous solution. The chemical composition and microstructures of the fabricated hydrogels were confirmed by FT-IR and SEM analysis, respectively. To evaluate the mechanical properties (e.g., storage and loss modulus of the gels), the rheological analysis was considered. Calcium deposition and ALP activity of DPSCs were carried out using alizarin red staining and ALP test. While the live/dead assay was performed to study its toxicity, the real-time PCR was conducted to investigate the osteogenic differentiation of hDPSCs cultured on prepared hydrogels. Results: The hydrogels with higher gelatin incorporation showed a slightly looser network compared to the other ones. The hydrogel with less gelatin indicates a rather higher value of G', indicating a higher elasticity due to more crosslinking reaction of amine groups of CS via a covalent bond with genipin. All the hydrogels contained viable cells with negligible dead cells, indicating the high biocompatibility of the prepared hydrogels for hDPSCs. The quantitative results of alizarin red staining displayed a significant rise in calcium deposition in hDPSCs cultured on prepared hydrogels after 21 days. Further, hDPSCs cultured on hydrogel with more gelatin displayed the most ALP activity. The expression of late osteogenic genes such as OCN and BMP-2 were respectively 6 and 4 times higher on the hydrogel with more gelatin than the control group after 21 days. Conclusion: The prepared PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel presented great features (e.g., porous structure, suitable rheological behavior, and improved cell viability), and resulted in osteogenic differentiation necessary for dental tissue engineering. [ABSTRACT FROM AUTHOR]

Hydrogels have been used as scaffolds for biomineralization in tissue engineering and regenerative medicine for the repair and treatment of many tissue types. In the present work, we studied an amino acid-based material that is attached to protecting groups and self-assembles into biocompatible and stable nanostructures that are suitable for tissue engineering applications. Specifically, the doubly protected aspartic residue (Asp) with fluorenyl methoxycarbonyl (Fmoc) protecting groups have been shown to lead to the formation of well-ordered fibrous structures. Many amino acids and small peptides which are modified with protecting groups display relatively fast self-assembly and exhibit remarkable physicochemical properties leading to three-dimensional (3D) networks, the trapping of solvent molecules, and forming hydrogels. In this study, the self-assembling fibrous structures are targeted toward calcium binding and act as nucleation points for the binding of the available phosphate groups. The cell viability, proliferation, and osteogenic differentiation of pre-osteoblastic cells cultured on the formed hydrogel under various conditions demonstrate that hydrogel formation in CaCl2 and CaCl2-Na2HPO4 solutions lead to calcium ion binding onto the hydrogels and enrichment with phosphate groups, respectively, rendering these mechanically stable hydrogels osteoinductive scaffolds for bone tissue engineering. [ABSTRACT FROM AUTHOR]

A number of stimuli-responsive-based hydrogels has been widely explored in biomedical applications in the last few decades because of their excellent biodegradability and biocompatibility. The development of synthetic chemistry and materials science leads to the emergence of in situ stimuli-responsive hydrogels. In this regard, several synthetic and natural polymers have been synthesized and utilized to prepare temperature-sensitive in situ forming hydrogels. This could be best used via injections as temperature stimulus could trigger in situ hydrogels gelation and swelling behaviors. There are many smart polymers available for the formulation of the in situ based thermoresponsive injectable hydrogel. Among these, poly (ε-caprolactone) (PCL) polymer has been recognized and approved by the FDA for numerous biomedical applications. More specifically, the PCL is coupled with polyethylene glycol (PEG) to obtain amphiphilic thermosensitive "smart" copolymers (PCL-PEG), to form rapid and reversible physical gelation behavior. However, the chemical structure of the copolymer is a critical aspect in determining water solubility, thermo-gelation behavior, drug release rate, degradation rate, and the possibility to deliver a diverse range of drugs. In this review, we have highlighted the typical PCL-PEG-based thermosensitive injectable hydrogels progress in the last decade for tissue engineering and localized drug delivery applications to treat various diseases. Additionally, the impact of molecular weight of PCL-PEG upon gelling behavior has also been critically highlighted for optimum hydrogels properties for potential pharmaceutical and biomedical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Tissue engineering is a triad involves three components of different types of cells, growth factor, small biomolecules and scaffold for the purpose of tissue restore, repair and regeneration. In tissue engineering, attachment, growth, proliferation and differentiation of cells require careful control of external factors such as the physical properties of the scaffold as extra cellular matrix (ECM), type and amount of biologically active molecules like small biomolecules, peptides and proteins. Therefore, the interaction of the synthetic and natural scaffolds with the cells must reflect the cellular microenvironment in the body. In this study, we describe a variety of in situ forming injectable hydrogels synthesis with the medical application and tissue regeneration that are crosslinked by chemical bonding or physical interactions. These types of hydrogels have attracted a lot of attention in tissue engineering applications because they can easily transfer the cells or delivered the biomolecules to the damaged tissue. Lack of severe toxicity, minimal injury and pain during surgery could be the other advantages of the injectable hydrogels. A wide variety of chemical methods have been used to crosslink the injectable hydrogels such as click chemistry, Michael addition, Schiff-base, enzymatic reaction and, etc. Some hydrogels can also be cross-linked using physical interactions such as ionic interactions, hydrogen bonding, supramolecular interaction, etc., without external factors in the physiological conditions of the body. In this study, in addition to various methods of synthesis, the practical aspects of hydrogels in regenerative medicine and their achievements in tissue engineering are discussed.

Hydrogels are encouraging for different clinical purposes because of their high water absorption and mechanical relation to native tissues. Injectable hydrogels can modify the invasiveness of utilization, which decreases recovery and surgical costs. Principal designs applied to create injectable hydrogels incorporate in situ formation owing to chemical or/and physical crosslinking. Here, we report nontoxic, thermosensitive, injectable hydrogels composed of gelatin (GEL) and oxidized alginate (OA) reinforced by silicon carbide nanoparticles (SiC NPs) and crosslinked with N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The mechanical characteristics of the hydrogels were examined via rheological analysis. The outcomes reveal that extending the SiC NPs contents enhances the mechanical properties around five times. The cross-sectional microstructure of the scaffolds comprising 0.25, 1.0, and 1.5% SiC NPs was scrutinized by FESEM, verifying porous structure with interconnected pores. Because of the smaller pore sizes in the hydrogels, the swelling rate has reduced at the higher content of SiC, which diminishes the water uptake. Additionally, the biodegradation study unveils that the hydrogels with SiC are more long-lasting than the hydrogel without SiC. By adding SiC NPs, a decrease is observed in the biodegradation and swelling ratio. The scaffold with a higher SiC NPs content (1.5%) manifested better cell attachment and was less cytotoxic than hydrogel without SiC. OA/GEL composites embedded SiC NPs have manifested excellent physical properties for tissue engineering in comparison with hydrogel without nanoparticles.