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International Journal of Bioprinting                           3D-Printed GelMA biomaterials in cartilage repair




            tissues directly, but it may improve tissue integration   physical properties of GelMA hydrogels, specifically the
            by promoting the synthesis and deposition of ECM   stiffness, play an important role in maintaining chondrocyte
            components, such as glycosaminoglycans and collagen.   phenotypes.  Additionally,  the  microporous  structure  of
            Zhan  fabricated the PEGDA into GelMA hydrogels and   gelatin hydrogels was found to have varying effects on
                [24]
            obtained hydrogels with different ligand adhesion densities   chondrocytes, with non-microporous gelatin hydrogels
            and stiffness properties. PEGDA is a hydrophilic polymer   being beneficial for maintaining the cartilage phenotype
            that attracts water molecules and forms a hydrated layer   of chondrocytes and microporous GelMA hydrogels being
            on its surface. This hydrated layer can help to promote   more suitable for chondrocyte proliferation . Hyaluronic
                                                                                                 [29]
            cell  adhesion by  mimicking  the ECM  of  living  tissues.   acid methacrylate (HAMA) is also an excellent material
            Brown  et al.  incorporated thiolated heparin (HepSH)   for cartilage regeneration and is added to GelMA for
                      [25]
            into GelMA hydrogel containing chondrocytes. HepSH is   biomimetic approach. Costantini et al.  prepared GelMA,
                                                                                             [30]
            able to bind to various biomolecules and surfaces, allowing   GelMA+CS-AEMA (chondroitin sulfate amino ethyl
            it for easy conjugation to other biomaterials, creating   methacrylate), and GelMA+CS-AEMA+HAMA, three
            a stable and biologically active material. Introducing   kinds of bioinks containing BMSCs. The incorporation of
            HepSH promoted cell differentiation and cartilage matrix   chondroitin sulfate (CS) and HAMA enhanced cell viability
            deposition in vitro. Wang et al.  introduced GelMA with   and chondrogenesis of BMSCs, showing the potential for
                                    [26]
            ε-polylysine (EPL) and phenylboronic acid (PBA) to create   advanced engineering of cartilage tissue. Shopperly et al.
                                                                                                           [31]
            a modified Gel-EPL/PBA hydrogel. EPL can interact with   chose HAMA and GelMA as bioinks to mimic the zonal
            negatively charged cell surfaces and ECM components,   structure of articular cartilage. They discovered that cell-
            making it a potential material for tissue engineering and   laden constructs supported the growth and secretion of
            drug delivery systems. These GelMA hydrogels modified   proteoglycans and type II collagen of chondrocytes.
            by  EPL  and PBA  enhanced  the  growth  of  chondrocytes   In summary, GelMA with modifications shows
            and the chondrogenesis of stem cells, as well as promoted   promising results for cartilage repair, and thus, they are
            the cartilage defects repair. PBA has the ability to bind   extensively applied in cartilage tissue engineering.
            to sugars and other molecules that contain diols, such as
            glucose. Overall, the use of these approaches that improve   The incorporation of different materials to GelMA
            the adhesive properties of GelMA hydrogels significantly   hydrogels showed potential in developing “smart” scaffolds
            enhances cell differentiation and cartilage matrix   that regulate cell behavior and controlled drug release.
            deposition, and promotes tissue integration, broadening   Further modifications and improvements to GelMA-based
            the application of GelMA hydrogels in cartilage tissue   inks are needed to enable the fabrication of 3D constructs
            engineering.                                       with multiple components and organized structures that
                                                               can  better  mimic  the  complex  properties  of  articular
               The RGD peptide family is a unique recognition site
            for integrin receptors, which play a vital role in cell–cell   cartilage.
            and cell–extracellular communication. To promote tissue
            regeneration, researchers have explored using RGD   5. Application of GelMA-based materials in
            peptides-PFS (peptide sequence PFSSTKT) to create   the 3D printing cartilage tissue engineering
            functional GelMA/ECM-PFS hydrogels that enhance the
            mechanical properties of GelMA, recruit BMSCs, and   The good biocompatibility and flexible characteristics
            improve hyaline cartilage repair in rabbits .      of GelMA hydrogels make them suitable as scaffolds to
                                             [27]
                                                               explore cell–matrix and cell–cell interactions and serve
               In summary, improving the integration between   as 3D supports for soft tissue regeneration. Moreover, the
            GelMA  and  in situ  cartilage  tissues  can  substantially   unique properties make the GelMA hydrogels widely used
            bolster the regeneration of neocartilage. Nonetheless, there   biological inks for 3D printing, allowing for the creation of
            are no methods identified thus far that could be deemed   customized patterns, components, and architectures that
            flawless. This underscores the necessity for the exploration   can be tailored to specific tissue engineering applications .
                                                                                                           [13]
            of innovative strategies in future.
                                                                  Articular cartilage defects often involve the regeneration
            4.3. Cell behavior regulation                      of multiple tissues, including hydroline cartilage, calcified
            In addition, the physical properties of GelMA hydrogels   cartilage, and subchondral bone, and this highly organized
            have varying effects in maintaining chondrocyte    tissue is specialized for its function. With advancements
            phenotypes, which play a crucial role in cartilage repair. Li    in 3D printing technology, it is now possible to fabricate
            et al.  conducted studies to investigate the effects of GelMA   tissue constructs that closely resemble target tissues in
               [28]
            hydrogels on chondrocyte phenotypes. They found that the   both  structure  and  composition,  which  is  a  significant

            Volume 9 Issue 6 (2023)                        245                         https://doi.org/10.36922/ijb.0116
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