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International Journal of Bioprinting Medical regenerative in situ bioprinting

VML injuries (Figure 3B). They used laponite nanoclay to situ bioprinter utilizes a coaxial extrusion strategy, but the
control the release of vascular endothelial growth factor. method does not guarantee uniform mixing of the bioink.
The in vivo experimental results suggested that the bioink Ultrasound can enhance ink adhesion and facilitate instant
can promote functional muscle recovery and reduce mixing of two inks when deposited, thereby ensuring the
fibrosis. Mostafavi et al. introduced a hand bioprinter that mechanical strength of the printed structure.
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can deposit melt-spun materials directly within the bone The tissue repair ability of the printed structure can
defect site (Figure 3C). The printed scaffolds displayed be enhanced by improving its mechanical strength and
promising adhesion and biocompatibility in mouse ensuring that the structure possesses a certain level of
models. To improve the effect of tissue repair, it is generally porosity. Optimal porosity facilitates efficient transport
necessary to add bioactive factors and cells to the bioink. of nutrients and metabolic waste, thereby promoting
In the case of photo-crosslinked bioinks, the handheld improved cell activity. Ying et al. developed an aqueous
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printer deposits the bioink and cells into the tissue defect, two-phase emulsion bioink to produce microscale pores
and the photoinitiator reduces the activity of the cells. To via in situ photo-crosslinking. Mostafavi et al. prepared
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address this issue, current handheld printers typically use a porous bioink by high-speed stirring foaming and
a core-shell structure that is coaxially extruded from the reported significantly enhanced viscosity of the bioink
bioink and cell components, isolating the photoinitiator for promoting skeletal muscle regeneration in a rat
from the cell. Duchi et al. reported a co-axial core-shell VML model.
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handheld device to repair cartilage defects (Figure 3D).
Moreover, this strategy maintains high cell viability and 2.2.3. Challenges
has great potential for in situ surgical cartilage engineering. While HISBS is appropriate for regenerating superficial
Di Bella et al. also introduced a handheld bioprinter trauma and minor damage, handheld devices are limited
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featuring a core-shell structure. Their experiment using a in treating more severe damage and accessing internal
full-layer cartilage injury model in sheep demonstrated the trauma. This limitation can potentially increase the risk
feasibility of printing cartilage scaffolds using this device. of infection. Furthermore, several challenges still need
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In addition to reducing the toxicity of the photoinitiator to be addressed, such as low resolution, poor repeatability,
to the cell, the core-shell structure of the handheld printer high dependence on operator skills, and difficulty in
can also be used to construct multi-layer structures with rapidly covering large areas of tissue defects. Notably,
gradient properties. Besides photo-crosslinked bioinks, most handheld printers only have simple extrusion and
there have also been reports utilizing ion- and enzyme- coating functions. For repairing tissue defects, the accurate
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crosslinked bioinks (Figure 3E). Hakimi et al. reported a construction of scaffolds is essential for wound healing and
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similar design, but their device incorporates a microfluidic functional recovery. To address these challenges, several
printhead, enabling rapid repair of large skin defects. In strategies can be employed. For example, reducing the
addition, the roller is also installed to enhance the stability speed of the printhead movement and using thinner print
of the printing process and improve the printing efficiency, needles can improve resolution. Introducing programmed
and the flow rate of the two ink tanks can be controlled design and stepper motors enables controlled movement
separately. However, this device has its limitations. For of the printhead, reducing reliance on human influence.
instance, it utilizes a pneumatic extrusion, whereby Additionally, multi-channel printhead enables rapid
changes in bioink or ambient temperature will affect coverage of large wounds. Taken together, HISBS has
the rheological properties of the material, necessitating significant potential for further development in addressing
immediate adjustments to the extrusion pressure to these challenges. 55,91
maintain a constant flow rate. Therefore, the incorporation
of an active temperature control device should be 2.3. Minimally invasive in situ bioprinting
considered. Pagan et al. used a hydraulic-driven injection Minimally invasive in situ bioprinting utilizes human-
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pump that is separate from the device to maintain constant controlled robotic systems for in vivo tissue repair.
extrusion flow. Automated in situ bioprinting systems can be combined
with minimally invasive surgery to enhance printing
Handheld in situ bioprinting systems (HISBS) can accuracy and flexibility. Minimally invasive in situ
be loaded with functional modules, such as a UV light bioprinting is crucial as it can mitigate the risk of infection
source, positioning device, and ultrasound, to improve associated with traditional surgical procedures. Minimally
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the adhesion of printed structures and tissues. Zhou et invasive bioprinting can be achieved by integrating non-
al. introduced an ultrasound module into HISBS and invasive surgical tools with automated strategies, such as
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reported significantly enhanced bio-adhesive performance extrusion bioprinting 29,60,51 and SLA. 44,45 To clinically apply
of the bioink in a diabetic wound model. Their handheld in minimally invasive in situ bioprinting, two issues need to

Volume 10 Issue 5 (2024) 55 doi: 10.36922/ijb.3366