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Hydrogel based 3D-printing Bioinks for Cartilage Repair
orientated cells were also observed, indicating a process printed constructs can be tuned by manipulating their
of chondrogenesis and osteogenesis . printing process or crosslinking with other materials. In
[93]
addition, cells, drugs, and other bioactive factors such
3. Current clinical trials based on hydrogel as cytokines, can also be combined with 3D-printed
scaffold against cartilage damage tissue scaffolds to enhance the repair and regeneration of
cartilage (Table 3) .
[11]
Until now, articular cartilage scaffolds for commercial Generally, hydrogels lack mechanical strength and
use or clinical settings can be divided into three types: are incapable to bear long-term repetitive loading in vivo .
[23]
cell-laden constructs such as BioSeed®-C and CaReS® Thus, future directions of 3D-bioprinted cartilage tissue
with seeded chondrocytes, cell-free constructs such include developing tougher bioinks that can withstand the
as MaioRegen and TruFit with MSC derivates, and long-term compression and shear in joint environment .
[98]
scaffold-free constructs with degradability, such For example, interpenetrating network (IPN) hydrogels,
as Chondrosphere® . In addition, scientists have which are fabricated by combining multiple independent
[95]
performed a clinical trial comparing patients receiving but interdigitating polymer networks at molecular level,
microfracture treatment with those implanted with BST- has been shown to be an efficient way to enhance the
CarGel, an acellular scaffold containing polysaccharide mechanical properties of the biomaterial (Table 4) .
[99]
chitosan. It was shown that BST-CarGel with a debrided A recent study by Shojarazavi et al. developed an injectable
cartilage lesion could develop a more stable, voluminous, IPN hydrogel composed of ionic crosslinked alginate,
and adherent blood clot compared with the traditional enzymatically crosslinked phenolized ECM and silk
surgical strategy for full-thickness cartilage defects . fibrin nanofibers [100] . The results show that with optimized
[96]
Moreover, current ongoing clinical trials include a study concentration of alginate and silk fibrin nanofibers, the
to investigate the efficacy of decalcification bone scaffold compression modulus and the mechanical stiffness of the
when combined with microfracture in the clinical hydrogels could be both improved.
repairment of articular cartilage defects and another Developing functional scaffold is a new tendency
project comparing microfracture with COL scaffold laden for 3D-printing cartilage repair. A general idea of
with adipose-derived stem cells. functionalizing cartilage scaffolds is delivering drugs
However, challenges still lie in the way of hydrogel which target enzymes or cytokines that hinder cartilage
scaffolds’ application from bench to bedside. Firstly, none regeneration. For example, MMP-13 has been found
of the above products are 3D-bioprinted. The printing to be significant for the hypertrophy of BMSCs,
process of one tissue-based human scale scaffold may take thereby inhibiting the therapeutic effects of BMSCs for
several hours, leading to an extremely long fabrication cartilage repair [101] . Thus, hydrogel carriers of MMP-13
process and high costs if 3D-printed scaffolds are put inhibitors can be developed to reduce the hypertrophy
into large scale production ; Second, even if a rapid and of mesenchymal stem cells during chondrogenesis [102] .
[23]
automatic printing process is developed, it may still be Additionally, functional scaffolds with novel physical
difficult to find a material with biomimetic components properties can be fabricated to enhance the efficacy
and structure. In addition, underlying molecular of other existing treatments of osteochondral defects
mechanisms of cartilage regeneration are still unclear, as well. Pulsed electromagnetic fields, a therapy for
causing difficulties to navigate the regulatory pathways . bone repair of low-risk and low-cost, has been found
[95]
Therefore, the clinical application of 3D-printed cartilage to improve the growth and healing of engineered
scaffolds still has a long way to go unless more advance cartilage [103] . Thus, inks that are conductive and able to
is made in pathological studies, bioink development, and build electro-microenvironment can be developed and
customized 3D printing technologies. applied in the field of 3D-printing cartilage tissue repair.

4. Conclusion and future direction Functionalizing cartilage scaffolds with cell derivates
to avoid the side effects of cell-based therapies are also
As a technology that initially appeared at the end of the catching increasing attention. Previously, hydrogel
20 century, 3D printing can manipulate the structure scaffolds encapsulated with chondrocytes developed
th
of engineered tissue scaffolds with high resolution rapidly. However, the limited number of chondrocytes
and accuracy . In the recent decade, the 3D printing from donor sites and undesired effects, such as
[10]
technique has been increasingly applied in the repair chondrocyte dedifferentiation, hinder their clinical
of articular cartilage, which is usually unable to self- efficacy [104] . Thus, MSC-laden scaffolds began to appear.
regenerate as it lacks vessels and nerves. Hydrogels have Nevertheless, current clinical studies using engineered
become the most used resources for bioinks due to their articular cartilage with MSCs demonstrated problems
elastic property and ECM-mimetic crosslinked network such as undesired MSC dedifferentiation, tumorigenicity
structure. The mechanical and structural properties of and disease transmission [105] . To overcome these

24 International Journal of Bioprinting (2022)–Volume 8, Issue 3