Cartilage, a remarkable viscoelastic connective tissue, undergoes formation during the embryonic phase of human development, preceding the initiation of bone formation (Camarero-Espinosa et al., 2016). In the realm of mammals, this resilient cartilaginous framework plays a crucial role as a blueprint for bone maturation, beginning in the embryonic stage and persisting throughout skeletal development in select regions of the body. Cartilage exhibits remarkable variations in its structural characteristics throughout its depth, showcasing divergent orientations of its constituents, unique compositions of the extracellular matrix (ECM), and intricate arrangements of chondrocytes. Moreover, chondrocytes residing in different zones exhibit distinct morphological features and selectively express markers that are inherently characteristic of each specific zone. The development of this stratified architecture occurs during maturation, arising from the interplay of externally applied and internally generated hydrostatic forces within the tissue. Consequently, the articular cartilage can be classified into distinct zones, namely: 1) the uppermost layer, often referred to as the superficial or tangential zone, 2) the intermediate or transitional zone, 3) the deep or radial zone, and 4) the calcified zone (Temenoff and Mikos, 2000; Williams et al., 2008). These zones have been extensively studied and characterized. Furthermore, articular cartilage exhibits a secondary microstructure that varies in relation to the radial distance from the chondrocytes. Hyaline cartilage is a crucial nonlinear, inhomogeneous, anisotropic, poro-viscoelastic connective tissue, which is usually referred to as articular cartilage. It plays a pivotal role as a friction-reducing and load-bearing cushion within synovial joints, facilitating smooth skeletal movements in mammal. Following the process of maturation, hyaline cartilage undergoes structural and compositional changes that establish it as a crucial component of articular joints, offering a remarkable interface with low friction while effectively supporting and transferring loads. The predominant constituents of hyaline cartilage include water (comprising approximately 70%–80% of its weight) that interacts synergistically with essential ECM components, such as proteoglycans, collagens, and other minor proteins and macromolecules. This intricate interplay of constituents contributes to the unique properties and functionality of hyaline cartilage.

The effective management of articular cartilage defects remains a significant and enduring clinical hurdle for orthopaedic surgeons. Articular cartilage is a highly specialized and structurally intricate tissue characterized by remarkable durability. However, owing to its avascular and aneural properties, it exhibits a limited intrinsic ability to self-repair (Setton et al., 1999; Jackson et al., 2001; Makris et al., 2015; Antich et al., 2020; Sang et al., 2023). Chronic joint pain and functional impairment are commonly observed in individuals who have experienced tissue damage due to either traumatic injury or degenerative pathology. Such conditions often give rise to a gradual deterioration of tissue, ultimately resulting in reduced joint function and mobility (Lories and Luyten, 2011). Failure to repair extensive focal chondral lesions and other cartilage injuries can result in the deterioration of the entire tissue, thus increasing an individual’s susceptibility to developing osteoarthritis (OA), a debilitating condition that is a major contributor to global disability (Hunter and Bierma-Zeinstra, 2019). Due to the simultaneous impact of population ageing, rising obesity rates, and an upsurge in joint injuries, the prevalence of this syndrome, which is already burdensome, is on the rise. Global estimates indicate that approximately 250 million individuals are currently affected by this condition. OA is a chronic condition that frequently manifests in individuals with untreated traumatic osteochondral lesions (Glyn-Jones et al., 2015). The manifestation of OA can be observed through various clinical indicators such as joint stiffness, pain, swelling, and restricted range of motion (Lespasio et al., 2017). Due to the limited availability of effective repair treatments, individuals with end-stage OA frequently undergo joint replacement procedures (Kloppenburg and Berenbaum, 2020). Thus, the timely management of articular cartilage lesions is imperative in order to mitigate or postpone the onset and progression of OA. The primary reparative approaches, namely microfracture, osteochondral transplantation, and autologous chondrocyte implantation, are associated with significant limitations, including the formation of fibrocartilage (Bae et al., 2006; Kreuz et al., 2006), limited donor sources, two operations required, etc. Consequently, it is imperative to expedite the development of a viable alternative approach to facilitate the regeneration of articular cartilage (Zhang et al., 2019).

Over the past few decades, substantial endeavors have been directed towards devising cartilage tissue engineering (CTE) methods as alternative therapeutic modalities to address the limitations of conventional clinical approaches. CTE techniques exhibit considerable promise for clinical implementation (Vinatier and Guicheux, 2016). CTE represents a highly encouraging avenue for restoring and rehabilitating articular cartilage, as it has the potential to stimulate tissue formation at the subchondral bone interface, thereby ameliorating the clinical manifestations of OA patients. Scaffolds constitute a fundamental constituent of CTE and exert a crucial impact on the regenerative potential of cartilage. Numerous scaffolding methodologies have been devised in the realm of tissue engineering (TE) (Ma et al., 1995; Mooney et al., 1996; Yang et al., 2002; Wu et al., 2006). The application of 3D bioprinting technology has emerged as a potent modality for fabricating scaffolds capable of providing cells with the necessary microenvironmental condition for TE (Murphy and Atala, 2014a; Patel et al., 2017). The hallmark of 3D bioprinting technologies is the generation of intricate structures through a process of layer-by-layer deposition, facilitated by computer-aided design (CAD). This method provides precise regulation over the shape and configuration of the scaffold, enabling the production of scaffolds with multiple layers, as well as the customized design of anatomically tailored implants (Lafuente-Merchan et al., 2022). The layer-by-layer deposition process facilitated by 3D bioprinting technology allows for the swift fabrication of scaffolds used in TE applications (Li et al., 2022). The material for deposition is commonly referred to as bio-ink, which comprises of cells and biomaterials. It has the potential to be supplemented with additional compounds such as medications, proteins, genetic matter, or growth factors (Ruiz-Alonso et al., 2021). These bio-inks have to meet certain requirements, such as biocompatility, biodegradability, printability, bioactivity and proper mechanical properties (Gungor-Ozkerim et al., 2018; Abdollahiyan et al., 2020). The mechanical properties of articular cartilage are mainly manifested in compressive properties, tensile and shear properties. The compressive aggregate modulus of articular cartilage in joint structures spans a range of 0.08–2 MPa, exhibiting depth-dependent variations within the tissue (Athanasiou et al., 1991; Schinagl et al., 1997). The Young’s modulus of articular cartilage displays zone-dependent variations within the tissue, with values ranging from 5 to 25 MPa. Notably, the superficial zone exhibits higher modulus values compared to the middle and deep zones (Kempson et al., 1968; Woo et al., 1979; Akizuki et al., 1986). Articular cartilage experiences shear stresses resulting from the translational and rotational movements of bones, relying predominantly on the solid phase of the tissue for support. Experimental measurements have determined the equilibrium shear modulus to range from 0.05 to 0.25 MPa. Moreover, calculations have indicated that the dynamic shear modulus varies from 0.1 to 4 MPa, while the loss angle is approximately 10° (Zhu et al., 1993; Wong and Sah, 2010).

In addition to the aforementioned requirements, it is essential for bioprinting ink demonstrate the capability to imitate the architecture and composition of the articular cartilage ECM to enable chondrogenic cell adhesion, migration, proliferation, and differentiation (Yang et al., 2017). Several investigations have demonstrated that hydrogel is regarded as a highly suitable material for addressing cartilage defects (Hunt et al., 2014; Xue et al., 2021). Hydrogels are polymer materials that exhibit water-swelling behavior and possess a 3D network structure. The formation of this structure is achieved through crosslinking reactions among hydrophilic polymers. Due to their ability to mimic the inner environment of the ECM, hydrogels have gained significant attention for their biomimetic properties (Grande et al., 1997; Chen et al., 2021). The excellent biocompatibility and biodegradability exhibited by hydrogels have made them a popular choice for the fabrication of in vitro tissues and organs (Correia et al., 2012; Gao et al., 2018). In addition, the hydrogel’s distinct properties of elevated moisture levels and porosity confer a significant advantage by creating a 3D crosslinking network that facilitates cellular retention, differentiation, migration, adhesion, and proliferation (Zhang et al., 2009). Hydrogels promote chondrocyte attachment similarly to the way cartilage ECM does, and unlike chondrocytes in other monolayer culture, chondrocytes embedded in hydrogels maintain their phenotype (Yamaoka et al., 2006; Aisenbrey and Bryant, 2016). The viscoelasticity of hydrogels allows transferring load effectively to chondrocytes, thereby ensuring their survival and controlling chondrogenic differentiation (Li J. et al., 2019a). Thus far, significant advancements have been made in the use of hydrogels and their composites for the repair of cartilage injuries, indicating promising prospects for potential clinical applications (Zhang et al., 2009).

Hydrogels can be classified as either natural or synthetic. Over the past several years, significant advancements have been made in the design of both types of hydrogels, with the specific goal of facilitating cartilage restoration. Such advancements involve the creation of 3D microenvironments that can effectively support the growth and proliferation of chondrocytes or stem cells (Bose et al., 2013). The natural hydrogel is primarily composed of proteins and polysaccharides derived from the ECM. This type of hydrogel exhibits properties that are similar to the ECM, including high water content, porosity, and softness (Gunatillake et al., 2003; Stoppel et al., 2015). The widespread usage of synthetic hydrogels in CTE can be attributed to several advantageous features they possess, which make them suitable for cartilage regeneration. These benefits include their ease of processing, high mechanical properties, and their ability to be controlled in terms of shape, porous structure, and degradation rate (Dang and Leong, 2006; Yao et al., 2015; Rao et al., 2018). Synthetic hydrogels possess certain properties that are unsuitable for the purpose of cartilage regeneration. These properties include inferior biocompatibility, low bioactivity, and the induction of aseptic inflammation due to the degradation products they release upon implantation into immunocompetent large animal models and human subjects. In light of recent research, synthetic hydrogels have been deemed suboptimal for the purpose of cartilage regeneration. In contrast, natural hydrogels are gaining favor as biomimetic scaffolds due to their exceptional biocompatibility, notable biological activity, minimal immunogenicity, and low cytotoxicity associated with their degradation byproducts (Diekjürgen and Grainger, 2017; Liu et al., 2017). Currently, natural hydrogel materials comprise polysaccharide-based hydrogels such as chitosan, hyaluronic acid, alginate, chondroitin sulfate and agarose, as well as protein-based hydrogels including gelatin, fibrin, elastin, silk fibroin, and collagen in addition to other materials derived from the extracellular matrix. Within the repertoire of biopolymers capable of constructing natural hydrogels, polysaccharides and their derivatives have gained increasing popularity for utilization in 3D bioprinting (Li N. et al., 2021a). Polysaccharides belong to the category of biopolymers that consist of monomeric units linked together via glycosidic bonds (Dai et al., 2019). Various polysaccharides, like chitosan, hyaluronic acid, alginate, chondroitin sulfate, and agarose have gained significant attention in the scientific community due to their wide availability, cost-effectiveness, and renewable nature. These polysaccharides have been extensively utilized in various applications, and their diverse physicochemical properties make them highly versatile and suitable for different uses (Teixeira et al., 2022). Polysaccharides are regarded as unique scaffold materials, owing to their beneficial characteristics such as biocompatibility, biodegradability, and customizable functionality, which position them among the most desirable choices for scaffold development. Moreover, these materials possess several appealing characteristics, such as facile derivatization/functionalization capabilities, a vast array of chemical structures with high diversity, and favorable rheological and mechanical properties (Oliveira and Reis, 2011). In addition, hydrogels based on natural polysaccharide-based hydrogels (NP-hydrogels) exhibit notable resemblances to the ECM of cartilage, thereby presenting them as a promising option for scaffold material in the context of CTE (Li P. et al., 2021b).

As previously discussed, 3D bioprinting offers a rapid means of manufacturing scaffolds used in CTE applications, utilizing a material known as bioprinting ink. Among the various options available in the realm of CTE, hydrogels have emerged as the most promising choice. Their injectability facilitates the delivery of stem cells, while their advantages in terms of minimally invasive surgery further bolster their appeal. As a result, hydrogels have found extensive application as bioprinting ink in the realm of 3D bioprinting. The procedure of 3D bioprinting can be typically classified into a tripartite process. Firstly, it involves acquiring relevant data pertaining to the characteristics of biological tissues or organs and creating 3D models through techniques such as CT and MRI. Subsequently, bioink must be prepared to facilitate tissue or organ repair. Lastly, 3D structures of natural tissues or organs are created through the application of a bio-printer (Heinrich et al., 2019). Categorized by their operational mechanisms, 3D bioprinting methodologies can be grouped into three types: extrusion-based, inkjet-based, and light-based 3D printing. Each of them has its own advantages and disadvantages (Table 1).

The application of 3D bioprinting technology enables the attainment of meticulous regulation over both the external shape and internal pore architecture of scaffolds (Jungst et al., 2016; Lai et al., 2019). Its capability to position cells and biomaterials with precision in a stratified manner enables the fabrication of constructs that possess controlled porosity, thus facilitating optimal diffusion of essential nutrients, oxygen, and metabolic waste products for the embedded cells (Murphy and Atala, 2014b; Turnbull et al., 2018). Furthermore, bioprinting methodologies enable the incorporation of elevated cell densities, which is unattainable by alternative techniques or necessitates the sequential inclusion of cells post-scaffold fabrication (Yang et al., 2022). Thus, 3D printing surpasses conventional techniques in the fields of TE. (Figure 1).

This article presents a comprehensive overview of the properties, roles, and recent advancements in NP-hydrogels and their composites for 3D printing of articular cartilage. The NP-hydrogel materials that are frequently utilized in CTE are systematically classified. We also present a detailed exposition of the benefits and limitations associated with each type of NP-hydrogel, with the aim of providing valuable guidance for the development of articular cartilage scaffolds. Finally, the article explores the existing obstacles and future prospects of NP-hydrogels in the context of CTE.

The principal NP-hydrogels employed in 3D printing for the regeneration of articular cartilage tissue comprise chitosan, hyaluronic acid, alginate, and chondroitin sulfate (Table 2).

This article begins with a succinct overview of the merits and limitations of widely used 3D printing methods. Subsequently, it presents a comprehensive summary of hydrogels produced through 3D printing with natural polysaccharides, delineating their distinctive features. Moreover, select prototypical instances are singled out to generate curiosity and enhance readers’ cognizance regarding the superior potential of NP-hydrogels in the field of CTE. In the presented examples, we provide a comprehensive overview of the diverse cell types employed in cartilage tissue engineering. It is worth noting that among these, MSCs derived from bone marrow or umbilical cord have emerged as the most promising candidates for advancing CTE applications. The intrinsic lack of vascularization, innervation, and inadequate chondrocyte differentiation in natural cartilage renders the tissue incapable of proficient self-restoration. However, the advent of bioprinting techniques has revolutionized TE by enabling the construction of customized artificial tissues that replicate the physiological characteristics of native tissues with precision. In comparison to traditional methodologies, 3D bioprinting provides several benefits, including the ability to incorporate intended micro/nanostructures into scaffolds at the intended location, efficient fabrication at a high throughput, and the capacity for achieving exceptional spatiotemporal resolution. The selection of a suitable bioink material assumes a critical role in the precise fabrication of 3D printed scaffolds designed for orthopedic applications. In light of this, hydrogels derived from natural polysaccharides exhibit tunable chemical properties, desirable processability, satisfactory cellular biocompatibility, biodegradability, low cytotoxicity, and an inherent structural similarity to the ECM of native cartilage. As a result, they have garnered considerable attention in the development of scaffolds for CTE. Nonetheless, the mechanical attributes of such hydrogels fall short of matching the requisite properties of native cartilage, thereby constraining their clinical utilization. By blending natural and synthetic hydrogels, it is feasible to harness the superior mechanical characteristics of the latter alongside the desirable biocompatibility of the former, thereby achieving an optimal composite hydrogel for diverse biomedical applications. Hence, the integration of natural and synthetic biomaterials utilizing state-of-the-art fabrication methodologies continues to constitute a prominent avenue for the development of in vitro cartilage constructs. However, it should be acknowledged that achieving a complete restoration of cartilage to its native composition, architecture, mechanics, and biofunctionality remains a formidable obstacle. Despite considerable advancements in the field of 3D bioprinting of natural polysaccharides for articular cartilage applications, successful clinical implementation remains a significant challenge. Enhancing the rheological and mechanical characteristics of natural polysaccharide-based inks and scaffolds represents a crucial area of focus to address this issue. Further efforts are necessary to improve the translational potential of this technology for clinical use.