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Mei, et al.
has high controllability as well as predictability in tuning nanoparticles. Then, the KGN-PLGA were incorporated
mechanical properties and maintaining cell viability. into photo-crosslinkable acrylated HA (m-HA), and this
system could form a hydrogel scaffold in situ under UV
2.3. Additives in photo-crosslinkable hydrogel light treatment. In vivo experiments demonstrated that the
systems regenerated tissue was close to the natural hyaline cartilage.

To fabricate functional hydrogel platforms, many (2) Cells
additives such as nanomaterials, functional cells, drugs,
and/or cytokine are introduced into the hydrogel systems, For bone engineering, BMSCs are the most widely used
bestowing on those hydrogels improved physical and cells since it possesses the ability to differentiate into
[52]
biological properties. functional bone cells . Meanwhile, articular cartilage-
resident chondroprogenitor cells (ACPCs) represent an
(1) Nanomaterials opportunity for cartilage regeneration . In addition,
[53]
The majority of human bone tissues range from some bone cells such as osteoblasts and chondrocytes
[54]
cancellous to cortical structures. It is difficult to design have also been introduced into hydrogels , while
an ideal scaffold by a single pure hydrogel material due other cells associated with bone growth such as human
to the diversity in geometric mechanics and mechanical umbilical vein EC (HUVECs) provide abundant
[55]
strength of bone tissues. Herein, nanomaterials can be opportunities for bone tissue repair . Vascularization
integrated into hydrogels with multiple gradients and is also essential for bone regeneration process especially
good mechanical properties, which may help solve this for large bone defects. ECs are the main cells with
challenge. Nanomaterials can control the micro- and nano- angiogenic ability. Three types of ECs, HUVECs, human
scale structures of hydrogel as well as regulate hydrogels’ dermal microvascular EC (HDMVECs), and endothelial
mechanical properties without hindering the exchange progenitor cells (EPC), have been reported to create vessel-
[56]
of nutrients with the surrounding environment . like structures in in vitro culture . Incorporating ECs in
[49]
Meanwhile, the nanomaterial itself can also work as a the hydrogel scaffolds could induce the regeneration of
drug delivery system. new blood vessels by creating capillary networks. These
For example, Zuo et al. combined GelMA with prevascularized constructs could provide nutrients to
hydroxyapatite (Hap) for osteon biofabrication . As the surrounding cells and reduce the time to anastomose with
[50]
main inorganic composite material of bone matrix, Hap host vasculature, which would promote angiogenesis
[57]
can guide and induce bone formation. Furthermore, the and osteogenesis for bone regeneration . To fabricate a
introduction of Hap into GelMA network could enhance suitable microenvironment, photo-polymerized hydrogels
the mechanical rigidity. The results demonstrated that can be used for cell transplantation, where the hydrogel
compared to the pure hydrogel, this composite hydrogel materials provide a cell-favorable environment which
showed a lower swelling behavior, higher mechanical allows for diffusion of nutrients, oxygen, and metabolic
modulus, and better biocompatibility, which had a products.
prospective application for bone reconstruction. In another For example, in a study of Zhai et al., the authors
example, Zhang et al. prepared a self-assembled metallic- developed a biodegradable two-channel 3D bioprinting
ion nanocomposite hydrogel . This hydrogel consisted ink consisting of both PEGDA and Laponite nanoclay
[49]
of bisphosphonate-grafted HA (HABP) and magnesium in channel A, and rat osteoblasts (ROBs)-laden HA
[58]
chloride (MgCl ). The coordination between BP and in channel B . The bio-ink A, composed of a PEG-
2
magnesium ions (Mg ) contributed to the formation of clay nanocomposite crosslinked hydrogel, was used to
2+
acrylated-BP-Mg-nanoparticles (Ac-BP-Mg NPs), which prepare 3D-bioprinting and effectively deliver oxygen
would stabilize the hydrogel network as multi-valent and nutrients to cells. Meanwhile, it could promote
4+
crosslinker, increasing the mechanical properties and osteogenesis due to the released silicon ions (Si ) and
contributing to the injectability as well as self-healing Mg , while the bio-ink B, ROBs-ladened HA, was
2+
characteristics. The acrylate groups could be crosslinked adopted to improve distribution uniformity, deposition
under UV irradiation, and allowed for better control efficiency and cell viability. The two inks were alternately
over stiffness. This nanocomposite hydrogel allowed for extruded through a two-channel 3D-bioprinting machine
encapsulation of stem cells, which could be used for bone to construct osteoblast-laden nanocomposite hydrogel for
engineering. In a study of Shi et al., the authors fabricated bone regeneration. The printed scaffolds showed excellent
a rapidly photo-crosslinkable hydrogel with Kartogenin osteogenic potential in in vivo experiments. In another
(KGN)-loaded nanoparticles to prepare cartilage . study, Annika et al. co-encapsulated EC (HDMVECs)
[51]
The small molecule KGN (which could induce bone and osteogenic cells (human adipose-derived stem cells)
marrow-derived MSCs [BMSCs]) into chondrocytes) was in GelMA hydrogel for engineering vascularized bone.
encapsulated into poly (lactic-co-glycolic acid) (PLGA) Results showed that this co-culture system could promote

International Journal of Bioprinting (2021)–Volume 7, Issue 3 41