Nano-biomaterials for designing functional bioinks towards complex tissue and organ regeneration in 3D bioprinting
Introduction
Additive manufacturing, specially three dimentional (3D) printing (a subset of additive manufacturing, which does not include other techniques like repair and reconstruction of existing parts) is gaining popularity in medical applications and in cell culture systems. During 3D printing, the layer by layer deposition of a computer designed structure has precise control over the fabrication of large and complex biological components with controlled distribution of multiple biomaterials [1]. The advantages of cell-laden 3D printing over cell-free scaffolding attract tissue engineers towards 3D bioprinting for last few years [2]. Compared to the conventional additive manufacturing techniques, the bioprinting process is limited by the handling of cells in terms of both materials (bioink formulation) and methods (pressure, temperature and resolution). Cell tolerance, the physical, chemical and biological stresses on the encapsulated cells during and after processing should be in optimum level to induce desired cellular growth and proliferation without any adverse biological responses [3]. Thus, the major focus in this research area is to create a successful bioink with suitable biomechanical properties to maintain the structural integrity of the printed tissue or organ scaffolds till the neo-cellular architecture starts functioning. Building a bigger and complex structure with multiple layers is a matter of concern towards organ printing [4]. For this, nanomaterials are extensively researched by the scientists as viscosity modifier to improve the 3D printability of the bioink as well as to enhance the cellular activities (including differentiation of stem cells) leading to the formation of functional tissues [5].
Section snippets
3D bioprinting
Most of the 3D printing techniques like inkjet, laser-assisted, micro valve and extrusion printing are tried for bioprinting [6], [7]. Inkjet printing is suitable for small sized defects but has limitations of shear and thermal stress on encapsulated cells. Laser-assisted bioprinting has concerns on cell damage by UV exposure or photo-initiator [8]. But cell stress is lower in laser-based systems, showing better cell viability [9]. Laser-assisted in situ 3D bioprinting was successfully carried
Nano-biomaterials for functional bioinks
Though most of the cases, the purpose of using nano-biomaterials is to reinforce and improve the structural stability, functional applications such as improving cell proliferation, stimulating ECM production, enhancing cell-to-cell communication are also equally important [43]. Several researchers have also observed stem cell differentiation in the presence of nano-biomaterials after bioprinting with nanocomposite bioinks.
Cellular and physiological interactions of nano-biomaterials
Fig. 2 summarizes the physiological and cellular consequences of nano-biomaterials once they are released inside the body after implantation. Nano-biomaterials used in bioinks can be grossly classified as biodegradable and non-biodegradable. Pure cellulose, carbon (CNT, CNF and graphene) and noble metal based nanoparticles (gold and silver) are not easy to degrade in human physiological system and classified as non-biodegradable [130], [131], [132]. Till optimum doses, they accumulate and
Complex tissues and organ printing
Realizing the immense potential of 3D bioprinting, researches have focused towards the bioprinting of fully vascularized functional organs with neural networks. Vascularization or angiogenesis in the tissue construct is of utmost importance for the functioning of large, thick and complex bioprinted tissues [183]. Fig. 4 shows different large 3D bioprinted constructs developed by leading research groups using nanocomposite bioinks. The cell requirement is very high for a large organ bioprinting,
Future prospects
The multifunctional properties of nanocomposite hydrogels open the potential future path. The shape memory or stimuli-responsive polymers in conjugation with conducting nanofillers like CNT, carbon nanofiber or graphene are potential bioinks for 4D bioprinting where time-dependent transformation of the printed construct can be achieved [188], [189]. The nanoparticles not only improve the physical and chemical properties of hydrogel materials, they also enhance cellular activities [190].
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
The work is part of the project supported under Brain Pool Fellowship (NRF-2019H1D3A2A01061141) and research grant (2019R1H1A2101084) by National Research Foundation of Korea.
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