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Latest Scientific Pathways on Tissue Spheroids: Opportunities to Innovate
Extrusion, stereolithography and microvalve-based of the cells do not aggregate spontaneously in culture;
bioprinting present the less difficulties to operate while therefore, they need to be induced by some means .
[1]
laser-assisted involves more complex process and inkjet These cellular aggregates can be fabricated using a
process is even more complex. scaffold or scaffold-free .
[12]
The material that is printed is referred to as “bioink” The first time these multicellular spheroids were
and it consists of multiple types of cells and biomaterials. created was in 2003 by Garboc Forgacs at the University
Bioinks are analyzed in terms of their printability, of Missouri . Since then, several techniques have
[15]
biocompatibility, and bioactivity . The printing resolution been used for the generation of tissue spheroids. The
[6]
and dimensionality contribute to the overall shape fidelity most commonly used techniques rely solely on the self-
of the bioprinted construct. Its dimensionality can be arranging properties of cells using micromolded recessed
represented by z-resolution in printing and it mainly templates prepared in a non-adhesive hydrogel .
[16]
depends on specific printing parameters such as printing In general, the use of tissue spheroids serves two
path height, path space, and the nozzle diameter, while main purposes, as building blocks in tissue engineering
material properties as material contraction/swelling, or as tissue models used in the pharmaceutical industry .
[9]
thixotropy, and the crosslinking mechanism affect the Tissue engineering constitutes an important field of
z-resolution. The principle for deposition varies according regenerative medicine for tissue repair as it offers the
to the bioprinting technology to be applied which affects potential for developing patient-specific 3D tissue
the print resolution and dimensionality differently . constructs for the treatment of human diseases. It
[7]
To meet all mechanical and functional requirements represents a huge potential solution to overcome the
to produce biomimetic tissue-like constructs, current shortage of organs or tissues for transplantation.
multicomponent bioinks have been developed recently. On the other hand, 3D in vitro systems have significantly
Also known as multimaterials or multicelular bioinks, advanced the drug screening processes as 3D tissue
they include more than one biomaterial, cell, and additive models can closely mimic native tissues and, in some
material or biomolecule . Multicomponent bioinks can cases, the physiological response to the drugs, thus
[3]
be characterized as: improving the ability to predict the efficacy and toxicity
[17]
(i) Bioinks having combination of natural materials, for of drug candidates .
example, alginate with gelatin/fibrin, silk fibroin with This study was performed to analyze and describe
gelatin, agarose with collagen, chitosan with gelatin, the development of tissue spheroids, as these cell
cellulose with alginate, and hyaluronan with cellulose; aggregates can contribute significantly to the advancement
(ii) Bioinks comprising natural and synthetic and innovation of tissue engineering and regenerative
components; medicine.
(iii) Bioinks involving synthetic biomaterials;
(iv) Bioinks fabricated with hydrogels and particles; 2. Methodology
(v) Bioinks for 4D printing; and A scientometric analysis was performed as part of a
(vi) Bioinks with different type of cells and soluble Competitive Technology Intelligence (CTI) process to
factors. identify current applications and newly emerging areas
Moreover, materials innano scale can also be added related to tissue spheroids for regenerative medicine
to improve structure and functionality . and tissue engineering. CTI is a cyclical process used
[3]
One crucial element to succeed in 3D bioprinting is to collect, analyze, and interpret data from different
the right selection of cells to print. Cells can be used as sources legally and ethically to produce valuable
individually encapsulated, as cells in scaffolds or as cell information for decision-making purposes pertaining to
aggregates (spheroids) [3,8] . As mentioned by Hospodiuk research and development (R&D) and innovation within
et al. and Rezende et al. , tissue spheroids are a type an organization . In this research, this process was
[10]
[9]
[18]
of scaffold-free bioink that has a small-sized and ideal conducted using the CTI hybrid model developed by
geometric shape for bioprinting. This novel bioink Rodríguez-Salvador et al. , which comprises ten main
[19]
enhances cell-cell interaction, growth, differentiation, steps: (i) process planning, (ii) primary and secondary
and resistance to the environment because of the high cell source identification, (iii) establishment of the information
density in the assembly . collection strategy, (iv) information collection, (v) expert
[11]
Tissue spheroids consist of 3D cell clusters that validation and adjustments, (vi) scientometric analysis,
represent the intricacy of healthy and unhealthy human (vii) expert validation and adjustments, (viii) verification
tissues [12,13] . One important characteristic of these of the final results, (ix) results delivery, and (x) decision-
cell aggregates is their self-assembly, which mimics making. Execution of CTI implies the collection of
developing tissue by fusion and reorganization . the most relevant information instead of collecting the
[14]
Conversely, a major disadvantage is that the majority largest number of documents. From this perspective, the
136 International Journal of Bioprinting (2021)–Volume 7, Issue 1