Elsevier

Additive Manufacturing

Volume 37, January 2021, 101639
Additive Manufacturing

Nano-biomaterials for designing functional bioinks towards complex tissue and organ regeneration in 3D bioprinting

https://doi.org/10.1016/j.addma.2020.101639Get rights and content

Abstract

The complexity of biological architectures (tissue or organ) attracts extensive use of additive manufacturing techniques for tissue engineering scaffolding. A step forward, to ensure precise control over the architecture-based distribution and activities of cells, cell-laden 3D bioprinting is in focused research at present for the regeneration of the tissue or organ. The process should ensure maximum viability and minimum stress for the encapsulated cells before, during and after printing. Thus, the printing properties of the bioinks are often compromised, and printing multilayered, large, complex organ with reasonably good resolution becomes a challenging task. Nanocomposite bioinks have caught scientists’ attention considering this aspect. Along with the structural stability and shape fidelity improvement during and after printing, the controlled use of nano-biomaterials induces differentiation, enhances cell growth, proliferation and extracellular matrix factor secretion. In this review, we have highlighted the significant importance of bioactive nanomaterials in bioinks for 3D bioprinting processes to overcome the limitations of native hydrogel-based bioinks. We have reviewed recent advances in the bioink components and compositions where different nano-biomaterials have been used to impart or improve physico-chemical, biological and printing properties. The designs of specific, functional nano-biomaterials -incorporated bioinks in regeneration of complex tissues, the steps towards large organ printing and future possibilities are addressed in the researchers’ interest.

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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