Hydrogels For Cartilage Tissue Engineering Research Articles

Antioxidant hydrogels for the treatment of osteoarthritis: mechanisms and recent advances

Articular cartilage has limited self-healing ability, resulting in injuries often evolving into osteoarthritis (OA), which poses a significant challenge in the medical field. Although some treatments exist to reduce pain and damage, there is a lack of effective means to promote cartilage regeneration. Reactive Oxygen Species (ROS) have been found to increase significantly in the OA micro-environment. They play a key role in biological systems by participating in cell signaling and maintaining cellular homeostasis. Abnormal ROS expression, caused by internal and external stimuli and tissue damage, leads to elevated levels of oxidative stress, inflammatory responses, cell damage, and impaired tissue repair. To prevent excessive ROS accumulation at injury sites, biological materials can be engineered to respond to the damaged microenvironment, release active components in an orderly manner, regulate ROS levels, reduce oxidative stress, and promote tissue regeneration. Hydrogels have garnered significant attention due to their excellent biocompatibility, tunable physicochemical properties, and drug delivery capabilities. Numerous antioxidant hydrogels have been developed and proven effective in alleviating oxidative stress. This paper discusses a comprehensive treatment strategy that combines antioxidant hydrogels with existing treatments for OA and explores the potential applications of antioxidant hydrogels in cartilage tissue engineering.

A review of advanced hydrogels for cartilage tissue engineering.

With the increase in weight and age of the population, the consumption of tobacco, inappropriate foods, and the reduction of sports activities in recent years, bone and joint diseases such as osteoarthritis (OA) have become more common in the world. From the past until now, various treatment strategies (e.g., microfracture treatment, Autologous Chondrocyte Implantation (ACI), and Mosaicplasty) have been investigated and studied for the prevention and treatment of this disease. However, these methods face problems such as being invasive, not fully repairing the tissue, and damaging the surrounding tissues. Tissue engineering, including cartilage tissue engineering, is one of the minimally invasive, innovative, and effective methods for the treatment and regeneration of damaged cartilage, which has attracted the attention of scientists in the fields of medicine and biomaterials engineering in the past several years. Hydrogels of different types with diverse properties have become desirable candidates for engineering and treating cartilage tissue. They can cover most of the shortcomings of other treatment methods and cause the least secondary damage to the patient. Besides using hydrogels as an ideal strategy, new drug delivery and treatment methods, such as targeted drug delivery and treatment through mechanical signaling, have been studied as interesting strategies. In this study, we review and discuss various types of hydrogels, biomaterials used for hydrogel manufacturing, cartilage-targeting drug delivery, and mechanosignaling as modern strategies for cartilage treatment.

Zwitterionic Granular Hydrogel for Cartilage Tissue Engineering.

Zwitterionic hydrogels have high potential for cartilage tissue engineering due to their ultra-hydrophilicity, nonimmunogenicity, and superior antifouling properties. However, their application in this field has been limited so far, due to the lack of injectable zwitterionic hydrogels that allow for encapsulation of cells in a biocompatible manner. Herein, a novel strategy is developed to engineer cartilage employing zwitterionic granular hydrogels that are injectable, self-healing, in situ crosslinkable and allow for direct encapsulation of cells with biocompatibility. The granular hydrogel is produced by mechanical fragmentation of bulk photocrosslinked hydrogels made of zwitterionic carboxybetaine acrylamide (CBAA), or a mixture of CBAA and zwitterionic sulfobetaine methacrylate (SBMA). The produced microgels are enzymatically crosslinkable using horseradish peroxidase, to quickly stabilize the construct, resulting in a microporous hydrogel. Encapsulated human primary chondrocytes are highly viable and able to proliferate, migrate, and produce cartilaginous extracellular matrix (ECM) in the zwitterionic granular hydrogel. It is also shown that by increasing hydrogel porosity and incorporation of SBMA, cell proliferation and ECM secretion are further improved. This strategy is a simple and scalable method, which has high potential for expanding the versatility and application of zwitterionic hydrogels for diverse tissue engineering applications.

Natural polysaccharide-based hydrogel bioprinting for articular cartilage repair

Tissue engineering represents a promising approach for impaired articular cartilage tissue regeneration. 3D printed hydrogels have become an emerging tissue engineering strategy because they closely mimic the physical and biochemical characteristics of the extracellular matrix. The formulation of hydrogel ink holds significant importance in attaining a precisely defined scaffold, which could exhibit excellent shape fidelity post-printing. Natural polysaccharide-based hydrogels are a highly promising class of scaffold biomaterials for articular cartilage regeneration in the field of material science and tissue engineering. These hydrogels are particularly advantageous due to their exceptional water absorption capacity, biodegradability, adjustable porosity, and biocompatibility, which closely resemble those of the natural extracellular matrix. This review aims to provide a comprehensive overview of the key characteristics, functions, and research progress in 3D printing technology for natural polysaccharide-based hydrogels. Specifically, this review categorizes the commonly used natural polysaccharide-based hydrogel materials in cartilage tissue engineering, and summarizes the classic literature in this area. In the end, we provide a comprehensive analysis of the challenges and potential applications of natural polysaccharide-based hydrogels in cartilage tissue engineering.

Self-healing interpenetrating network hydrogel based on GelMA/alginate/nano-clay

Today, tissue engineering strategies need the improvement of advanced hydrogels with biological and mechanical properties similar to natural cartilage for joint regeneration. In this study, an interpenetrating network (IPN) hydrogel composed of gelatin methacrylate (GelMA)/alginate (Algin)/nano-clay (NC) with self-healing ability was developed with particular consideration to balancing of the mechanical properties and biocompatibility of bioink material. Subsequently, the properties of the synthesized nanocomposite IPN, including the chemical structure, rheological behavior, physical properties (i.e. porosity and swelling), mechanical properties, biocompatibility, and self-healing performance were evaluated to investigate the potential application of the developed hydrogel for cartilage tissue engineering (CTE). The synthesized hydrogels showed highly porous structures with dissimilar pore sizes. The results revealed that the NC incorporation improved the properties of GelMA/Algin IPN, such as porosity, and mechanical strength (reached 170 ± 3.5 kPa), while the NC incorporation decreased the degradation (63.8 %) along with retaining biocompatibility. Therefore, the developed hydrogel showed a promising potential for the treatment of tissue defects in cartilage.

Anatomy, molecular structures, and hyaluronic acid - Gelatin injectable hydrogels as a therapeutic alternative for hyaline cartilage recovery: A review.

Cartilage damage caused by trauma or osteoarthritis is a common joint disease that can increase the social and economic burden in society. Due to its avascular characteristics, the poor migration ability of chondrocytes, and a low number of progenitor cells, the self-healing ability of cartilage defects has been significantly limited. Hydrogels have been developed into one of the most suitable biomaterials for the regeneration of cartilage because of its characteristics such as high-water absorption, biodegradation, porosity, and biocompatibility similar to natural extracellular matrix. Therefore, the present review article presents a conceptual framework that summarizes the anatomical, molecular structure and biochemical properties of hyaline cartilage located in long bones: articular cartilage and growth plate. Moreover, the importance of preparation and application of hyaluronic acid - gelatin hydrogels for cartilage tissue engineering are included. Hydrogels possess benefits of stimulating the production of Agc1, Col2α1-IIa, and SOX9, molecules important for the synthesis and composition of the extracellular matrix of cartilage. Accordingly, they are believed to be promising biomaterials of therapeutic alternatives to treat cartilage damage.

Injectable, In Situ Self-cross-linking, Self-healing Poly(l-glutamic acid)/Polyethylene Glycol Hydrogels for Cartilage Tissue Engineering.

Injectable hydrogels have drawn much attention in the field of tissue engineering because of advantages such as simple operation, strong plasticity, and good biocompatibility and biodegradability. Herein, we propose the novel design of injectable hydrogels via a Schiff base cross-linking reaction between adipic dihydrazide (ADH)-modified poly(l-glutamic acid) (PLGA-ADH) and benzaldehyde-terminated poly(ethylene glycol) (PEG-CHO). The effects of the mass fraction and the molar ratio of -CHO/-NH2 on the gelation time, mechanical properties, equilibrium swelling, and in vitro degradation of the hydrogels were examined. The PLGA/PEG hydrogels cross-linked by dynamic Schiff base linkages exhibited good self-healing ability. Additionally, the PLGA/PEG hydrogels had good biocompatibility with bone marrow-derived mesenchymal stem cells (BMSCs) and could effectively support BMSC proliferation and deposition of glycosaminoglycans and upregulate the expression of cartilage-specific genes. In a rat cartilage defect model, PLGA/PEG hydrogels significantly promoted new cartilage formation. The results suggest the prospect of the PLGA/PEG hydrogels in cartilage tissue engineering.

Advances in Mechanical Properties of Hydrogels for Cartilage Tissue Defect Repair.

Numerous factors, such as degeneration and accidents, frequently cause cartilage deterioration. Owing to the absence of blood vessels and nerves in cartilage tissue, the ability of cartilage tissue to heal itself after an injury is relatively low. Hydrogels are beneficial for cartilage tissue engineering owing to their cartilage-like structure and advantageous properties. Due to the disruption of its mechanical structure, the bearing capacity and shock absorption of cartilage are diminished. The tissue should possess excellent mechanical properties to ensure the efficacy of cartilage tissue repair. This paper discusses the application of hydrogels in the fields of cartilage repair, the mechanical properties of hydrogels used for cartilage repair, and the materials used for hydrogels in cartilage tissue engineering. In addition, the challenges faced by hydrogels and future research directions are discussed.

Designing functional hyaluronic acid-based hydrogels for cartilage tissue engineering.

Damage to cartilage tissues is often difficult to repair owing to chronic inflammation and a lack of bioactive factors. Therefore, developing bioactive materials, such as hydrogels acting as extracellular matrix mimics, that can inhibit the inflammatory microenvironment and promote cartilage repair is crucial. Hyaluronic acid, which exists in cartilage and synovial fluid, has been extensively investigated for cartilage tissue engineering because of its promotion of cell adhesion and proliferation, regulation of inflammation, and enhancement of cartilage regeneration. However, hyaluronic acid-based hydrogels have poor degradation rates and unfavorable mechanical properties, limiting their application in cartilage tissue engineering. Recently, various multifunctional hyaluronic acid-based hydrogels, including alkenyl, aldehyde, thiolated, phenolized, hydrazide, and host-guest group-modified hydrogels, have been extensively studied for use in cartilage tissue engineering. In this review, we summarize the recent progress in the multifunctional design of hyaluronic acid-based hydrogels and their application in cartilage tissue engineering. Moreover, we outline the future research prospects and directions in cartilage tissue regeneration. This would provide theoretical guidance for developing hyaluronic acid-based hydrogels with specific properties to satisfy the requirements of cartilage tissue repair.

Electrically Conductive Hydrogels for Articular Cartilage Tissue Engineering

Articular cartilage is a highly specialized tissue found in diarthrodial joints, which is crucial for healthy articular motion. Despite its importance, articular cartilage has limited regenerative capacities, and the degeneration of this tissue is a leading cause of disability worldwide, with hundreds of millions of people affected. As current treatment options for cartilage degeneration remain ineffective, tissue engineering has emerged as an exciting approach to create cartilage substitutes. In particular, hydrogels seem to be suitable candidates for this purpose due to their biocompatibility and high customizability, being able to be tailored to fit the biophysical properties of native cartilage. Furthermore, these hydrogel matrices can be combined with conductive materials in order to simulate the natural electrochemical properties of articular cartilage. In this review, we highlight the most common conductive materials combined with hydrogels and their diverse applications, and then present the current state of research on the development of electrically conductive hydrogels for cartilage tissue engineering. Finally, the main challenges and future perspectives for the application of electrically conductive hydrogels on articular cartilage repair strategies are also discussed.

Advanced injectable hydrogels for cartilage tissue engineering.

The rapid development of tissue engineering makes it an effective strategy for repairing cartilage defects. The significant advantages of injectable hydrogels for cartilage injury include the properties of natural extracellular matrix (ECM), good biocompatibility, and strong plasticity to adapt to irregular cartilage defect surfaces. These inherent properties make injectable hydrogels a promising tool for cartilage tissue engineering. This paper reviews the research progress on advanced injectable hydrogels. The cross-linking method and structure of injectable hydrogels are thoroughly discussed. Furthermore, polymers, cells, and stimulators commonly used in the preparation of injectable hydrogels are thoroughly reviewed. Finally, we summarize the research progress of the latest advanced hydrogels for cartilage repair and the future challenges for injectable hydrogels.

3D printed hydrogel for articular cartilage regeneration

Tissue engineering is a promising strategy for damaged cartilage tissue repair. Three-dimensional (3D) printed hydrogel exhibits great potential in cartilage tissue engineering for fabricating 3D cell culture scaffolds, owing to its similarity to the extracellular matrix (ECM). Numerous hydrogels have been tested for 3D printing in vitro articular cartilage tissues, including natural and synthetic hydrogels that mimic their in vivo counterparts. The advancement of materials science and 3D printing techniques enables a wide range of fabrication strategies that produce cartilage tissues with delicate structures and on multiple scales. Stimuli-responsive hydrogels, which rely on the external environment to transform to a desired structure or dimension, have likewise been widely studied in tissue engineering. This review summarizes the characteristics, functions, and research conducted on 3D printed hydrogels by categorizing cutting-edge hydrogel materials commonly used in cartilage tissue engineering and their complexes. The challenges and application prospects of hydrogels in cartilage tissue engineering are described. Novel composite hydrogels must be investigated to meet the requirements of native articular cartilage in the aspects of structure, scale, mechanical properties, among others. Combining stimuli-responsive hydrogels with biological scaffolds also shows great potential in various applications, including but not limited to articular cartilage, vascularization, and osteochondral repair.

Advanced Nanocomposite Hydrogels for Cartilage Tissue Engineering.

Tissue engineering is becoming an effective strategy for repairing cartilage damage. Synthesized nanocomposite hydrogels mimic the structure of natural cartilage extracellular matrices (ECMs), are biocompatible, and exhibit nano–bio effects in response to external stimuli. These inherent characteristics make nanocomposite hydrogels promising scaffold materials for cartilage tissue engineering. This review summarizes the advances made in the field of nanocomposite hydrogels for artificial cartilage. We discuss, in detail, their preparation methods and scope of application. The challenges involved for the application of hydrogel nanocomposites for cartilage repair are also highlighted.

Incorporation of a Collagen-Binding Chondroitin Sulfate Molecule to a Collagen Type I and II Blend Hydrogel for Cartilage Tissue Engineering.

Adding chondroitin sulfate (CS) to collagen scaffolds has been shown to improve the outcomes for articular cartilage tissue engineering. Instead of physical entrapment or chemical crosslinking of CS within a scaffold, this study investigated the use of CS with attached collagen-binding peptides (termed CS-SILY). This method better recapitulates the aspects of native cartilage while retaining CS within a collagen type I and II blend (Col I/II) hydrogel. CS retention, average fibril diameter, and mechanical properties were altered by varying the number of SILY peptides attached to the CS backbone. When mesenchymal stromal cells (MSCs) were encapsulated within the scaffolds, the addition of CS-SILY molecules resulted in higher sulfated glycosaminoglycan production, and these results suggest that CS-SILY promotes MSC differentiation into chondrocytes. Taken together, our study shows the promise of adding a CS-SILY molecule to a Col I/II hydrogel with encapsulated MSCs to promote cartilage repair.

Advanced Hydrogels for Cartilage Tissue Engineering: Recent Progress and Future Directions.

Cartilage is a tension- and load-bearing tissue and has a limited capacity for intrinsic self-healing. While microfracture and arthroplasty are the conventional methods for cartilage repair, these methods are unable to completely heal the damaged tissue. The need to overcome the restrictions of these therapies for cartilage regeneration has expanded the field of cartilage tissue engineering (CTE), in which novel engineering and biological approaches are introduced to accelerate the development of new biomimetic cartilage to replace the injured tissue. Until now, a wide range of hydrogels and cell sources have been employed for CTE to either recapitulate microenvironmental cues during a new tissue growth or to compel the recovery of cartilaginous structures via manipulating biochemical and biomechanical properties of the original tissue. Towards modifying current cartilage treatments, advanced hydrogels have been designed and synthesized in recent years to improve network crosslinking and self-recovery of implanted scaffolds after damage in vivo. This review focused on the recent advances in CTE, especially self-healing hydrogels. The article firstly presents the cartilage tissue, its defects, and treatments. Subsequently, introduces CTE and summarizes the polymeric hydrogels and their advances. Furthermore, characterizations, the advantages, and disadvantages of advanced hydrogels such as multi-materials, IPNs, nanomaterials, and supramolecular are discussed. Afterward, the self-healing hydrogels in CTE, mechanisms, and the physical and chemical methods for the synthesis of such hydrogels for improving the reformation of CTE are introduced. The article then briefly describes the fabrication methods in CTE. Finally, this review presents a conclusion of prevalent challenges and future outlooks for self-healing hydrogels in CTE applications.

3D Bioprinting of Hydrogels for Cartilage Tissue Engineering.

Three-dimensional (3D) bioprinting is an emerging technology based on 3D digital imaging technology and multi-level continuous printing. The precise positioning of biological materials, seed cells, and biological factors, known as “additive biomanufacturing”, can provide personalized therapy strategies in regenerative medicine. Over the last two decades, 3D bioprinting hydrogels have significantly advanced the field of cartilage and bone tissue engineering. This article reviews the development of 3D bioprinting and its application in cartilage tissue engineering, followed by a discussion of the current challenges and prospects for 3D bioprinting. This review presents foundational information on the future optimization of the design and manufacturing process of 3D additive biomanufacturing.

Enhanced efficacy of transforming growth factor-β1 loaded an injectable cross-linked thiolated chitosan and carboxymethyl cellulose-based hydrogels for cartilage tissue engineering

Growth factors (GFs) are soluble proteins extracellular that control a wide range of cellular processes as well as tissue regeneration. While transforming growth factor beta-1 (TGF-β1) promotes chondrogenesis, its medical use is restricted by its potential protein instability, which necessitates high doses of the protein, which can result in adverse side effects such as inefficient cartilage formation. In this work, we have developed a novel hydrogel composite based on the polymer, cross-linked thiolated chitosan; TCS and carboxymethyl cellulose; CMC (TCS/CMC) hydrogel system was utilized as injectable TGF-β1 carriers for cartilage tissue engineering applications. Rheological measurements showed that the elastic modulus of TCS/CMC hydrogels with an optimized CMC concentration could reach around 2.5 kPa or higher than their respective viscous modulus, indicating that they behaved like strong hydrogels. Crosslinking significantly alters the overall network distribution, surface morphology, pore size, porosity, gelation time, swelling ratio, water content, and in vitro degradation of the TCS/CMC hydrogels. TCS/CMC hydrogels maintain more than 90% of their weight and retain their original form after 21 days. TGF-β1 released marginally from TCS/CMC hydrogels as incubation time increased, up to 21 days, with around 18.6 ± 0.9% of the drug stored inside the TCS/CMC hydrogels. On day 21, BMSC treated with TGF-β1 in medium or TGF-β1-loaded TCS/CMC hydrogels grew faster than the other groups. For in vivo cartilage repair, full-thickness cartilage defects were induced on rat knees for 8 weeks. The optimal ability of this novel TGF-β1-loaded TCS/CMC hydrogel system was further demonstrated by histological analysis, resulting in a novel therapeutic strategy for repairing articular cartilage defects.

Development and Evaluation of Gellan Gum/Silk Fibroin/Chondroitin Sulfate Ternary Injectable Hydrogel for Cartilage Tissue Engineering.

Hydrogel is in the spotlight as a useful biomaterial in the field of drug delivery and tissue engineering due to its similar biological properties to a native extracellular matrix (ECM). Herein, we proposed a ternary hydrogel of gellan gum (GG), silk fibroin (SF), and chondroitin sulfate (CS) as a biomaterial for cartilage tissue engineering. The hydrogels were fabricated with a facile combination of the physical and chemical crosslinking method. The purpose of this study was to find the proper content of SF and GG for the ternary matrix and confirm the applicability of the hydrogel in vitro and in vivo. The chemical and mechanical properties were measured to confirm the suitability of the hydrogel for cartilage tissue engineering. The biocompatibility of the hydrogels was investigated by analyzing the cell morphology, adhesion, proliferation, migration, and growth of articular chondrocytes-laden hydrogels. The results showed that the higher proportion of GG enhanced the mechanical properties of the hydrogel but the groups with over 0.75% of GG exhibited gelling temperatures over 40 °C, which was a harsh condition for cell encapsulation. The 0.3% GG/3.7% SF/CS and 0.5% GG/3.5% SF/CS hydrogels were chosen for the in vitro study. The cells that were encapsulated in the hydrogels did not show any abnormalities and exhibited low cytotoxicity. The biochemical properties and gene expression of the encapsulated cells exhibited positive cell growth and expression of cartilage-specific ECM and genes in the 0.5% GG/3.5% SF/CS hydrogel. Overall, the study of the GG/SF/CS ternary hydrogel with an appropriate content showed that the combination of GG, SF, and CS can synergistically promote articular cartilage defect repair and has considerable potential for application as a biomaterial in cartilage tissue engineering.

Recent Advancements in 3D Printing of Polysaccharide Hydrogels in Cartilage Tissue Engineering.

The application of hydrogels coupled with 3-dimensional (3D) printing technologies represents a modern concept in scaffold development in cartilage tissue engineering (CTE). Hydrogels based on natural biomaterials are extensively used for this purpose. This is mainly due to their excellent biocompatibility, inherent bioactivity, and special microstructure that supports tissue regeneration. The use of natural biomaterials, especially polysaccharides and proteins, represents an attractive strategy towards scaffold formation as they mimic the structure of extracellular matrix (ECM) and guide cell growth, proliferation, and phenotype preservation. Polysaccharide-based hydrogels, such as alginate, agarose, chitosan, cellulose, hyaluronan, and dextran, are distinctive scaffold materials with advantageous properties, low cytotoxicity, and tunable functionality. These superior properties can be further complemented with various proteins (e.g., collagen, gelatin, fibroin), forming novel base formulations termed “proteo-saccharides” to improve the scaffold’s physiological signaling and mechanical strength. This review highlights the significance of 3D bioprinted scaffolds of natural-based hydrogels used in CTE. Further, the printability and bioink formation of the proteo-saccharides-based hydrogels have also been discussed, including the possible clinical translation of such materials.

Alginate/cartilage extracellular matrix-based injectable interpenetrating polymer network hydrogel for cartilage tissue engineering.

In the present study, alginate/cartilage extracellular matrix (ECM)-based injectable hydrogel was developed incorporated with silk fibroin nanofibers (SFN) for cartilage tissue engineering. The in situ forming hydrogels were composed of different ionic crosslinked alginate concentrations with 1% w/v enzymatically crosslinked phenolized cartilage ECM, resulting in an interpenetrating polymer network (IPN). The response surface methodology (RSM) approach was applied to optimize IPN hydrogel's mechanical properties by varying alginate and SFN concentrations. The results demonstrated that upon increasing the alginate concentration, the compression modulus improved. The SFN concentration was optimized to reach a desired mechanical stiffness. Accordingly, the concentrations of alginate and SFN to have an optimum compression modulus in the hydrogel were found to be 1.685 and 1.724% w/v, respectively. The gelation time was found to be about 10 s for all the samples. Scanning electron microscope (SEM) images showed homogeneous dispersion of the SFN in the hydrogel, mimicking the natural cartilage environment. Furthermore, water uptake capacity, degradation rate, cell cytotoxicity, and glycosaminoglycan and collagen II secretions were determined for the optimum hydrogel to support its potential as an injectable scaffold for articular cartilage defects.