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REVIEW ARTICLE

Using Spheroids as Building Blocks Towards 3D

Bioprinting of Tumor Microenvironment

Pei Zhuang, Yi-Hua Chiang, Maria Serafim Fernanda, Mei He*

Department of Pharmaceutics, University of Florida, Gainesville, Florida, 32610, USA

Abstract: Cancer still ranks as a leading cause of mortality worldwide. Although considerable efforts have been dedicated
to anticancer therapeutics, progress is still slow, partially due to the absence of robust prediction models. Multicellular tumor
spheroids, as a major three-dimensional (3D) culture model exhibiting features of avascular tumors, gained great popularity
in pathophysiological studies and high throughput drug screening. However, limited control over cellular and structural
organization is still the key challenge in achieving in vivo like tissue microenvironment. 3D bioprinting has made great strides
toward tissue/organ mimicry, due to its outstanding spatial control through combining both cells and materials, scalability,
and reproducibility. Prospectively, harnessing the power from both 3D bioprinting and multicellular spheroids would likely
generate more faithful tumor models and advance our understanding on the mechanism of tumor progression. In this review,
the emerging concept on using spheroids as a building block in 3D bioprinting for tumor modeling is illustrated. We begin
by describing the context of the tumor microenvironment, followed by an introduction of various methodologies for tumor
spheroid formation, with their specific merits and drawbacks. Thereafter, we present an overview of existing 3D printed
tumor models using spheroids as a focus. We provide a compilation of the contemporary literature sources and summarize
the overall advancements in technology and possibilities of using spheroids as building blocks in 3D printed tissue modeling,
with a particular emphasis on tumor models. Future outlooks about the wonderous advancements of integrated 3D spheroidal
printing conclude this review.

Keywords: 3D bioprinting; Tumor microenvironment; Spheroid

*Correspondence to: Mei He, at the Department of Pharmaceutics, University of Florida, Gainesville, Florida, 32610, USA; mhe@cop.ufl.edu
Received: September 6, 2021; Accepted: October 2, 2021; Published Online: October 21, 2021

Citation: Zhuang P, Chiang YH, Fernanda MS, et al., 2021, Using Spheroids as Building Blocks Towards 3D Bioprinting of Tumor
Microenvironment. Int J Bioprint, 7(4):444. http://doi.org/10.18063/ijb.v7i4.444

1. Introduction processes. Addressing these issues requires a wide range
of tumor models, including in vivo, ex vivo, and in vitro
Cancer accounts for about 1 in every 6 deaths and is (two-dimensional [2D] and three-dimensional [3D])
the second leading cause of deaths worldwide. In 2020, models with various complexities, developed specifically
cancer was estimably affecting 18.3 million people for studying cancer pathology and progressing with
globally, causing nearly 10 million deaths . Despite anticancer therapeutics.
[1]
the soaring investment in the development of anticancer Various types of mouse models, including cancer
therapeutics in past decades, positive outcomes are still cell line-derived and patient-derived tumor xenograft
far from satisfactory. The journey of an anticancer drug (PDX) models, have been generated by transplanting
from lab-to-shelf could take years (~15 years): Before cell lines, or a fraction of human tumors heterotopically
entering a clinical trial, drugs are heavily interrogated and/or orthotopically to immunocompromised mice.
through required sets of in vivo and in vitro tests. However, Cancer cell line-derived models fail in fully capturing the
a reliable in vitro model for accurate prediction of drug histopathological features exhibited in a clinical setting,
responses is lacking. Such shortfalls directly result in although PDXs models largely preserves the genetic
increased cost and time on developmental study, and and epigenetic abnormalities of the original tumors
overuse of animal models with slackening drug discovery when compared to patients in clinical trials . Despite
[2]
© 2021 Zhuang, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution and
reproduction in any medium, provided the original work is cited.
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