Biomaterials for 3D Tumor Modeling

Subhas C. Kundu, Rui L. Reis

• Publisher: Elsevier
• Year: 2020
• ISBN:
  9780128181294
• Topic: Technology & Engineering
• Subtopic: Materials Science
• Index: Technology & Engineering

Biomaterials for 3D Tumor Modeling reviews the fundamentals and most relevant areas of the latest advances of research of 3D cancer models, focusing on biomaterials science, tissue engineering, drug delivery and screening aspects. The book reviews advanced fundamental topics, including the causes of cancer, existing cancer models, angiogenesis and inflammation during cancer progression, and metastasis in 3D biomaterials. Then, the most relevant biomaterials are reviewed, including methods for engineering and fabrication of biomaterials. 3D models for key biological systems and types of cancer are also discussed, including lung, liver, oral, prostate, pancreatic, ovarian, bone and pediatric cancer.

This book is suitable for those working in the disciplines of materials science, biochemistry, genetics, molecular biology, drug delivery and regenerative medicine.

• Reviews key biomaterials topics, including synthetic biomaterials, hydrogels, e-spun materials and nanoparticles
• Provides a comprehensive overview of 3D cancer models for key biological systems and cancer types
• Includes an overview of advanced fundamental concepts for an interdisciplinary audience in materials science, biochemistry, regenerative medicine and drug delivery

Section I

Engineering biomaterials for 3D cancer modelling

Outline

• Chapter 1 Trends in biomaterials for three-dimensional cancer modeling
• Chapter 2 Bioinspired biomaterials to develop cell-rich spherical microtissues for 3D in vitro tumor modeling
• Chapter 3 Biofabrication of 3D tumor models in cancer research
• Chapter 4 Biomatrices that mimic the cancer extracellular environment
• Chapter 5 3D neuroblastoma in vitro models using engineered cell-derived matrices
• Chapter 6 3D culture systems as models for solid tumors and cancer metabolism
• Chapter 7 Biomaterials as ECM-like matrices for 3D in vitro tumor models
• Chapter 8 Three-dimensional in vitro models of angiogenesis
• Chapter 9 Metastasis in three-dimensional biomaterials
• Chapter 10 3D cancer spheroids and microtissues
• Chapter 11 Biomaterial-based in vitro models for pancreatic cancer
• Chapter 12 In vitro three-dimensional modeling for prostate cancer
• Chapter 13 3D in vitro cutaneous melanoma models
• Chapter 14 3D scaffold materials for skin cancer modeling

Chapter 1

Trends in biomaterials for three-dimensional cancer modeling

David Caballero^1,2, Rui L. Reis^1,2 and Subhas C. Kundu^1,2, ¹13B’s Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal, ²2ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

Abstract

Cancer remains a major burden in our modern society. A significant amount of resources and efforts is invested in new approaches to better understand and treat this disease. During the last years, the development of novel biomaterials with advanced capabilities, together with modern tissue engineering techniques and nanotechnology tools permits a significant advance in the field of three-dimensional (3D) platforms for cancer modeling. These new platforms copycat the 3D architecture, biochemical complexity, mechanical properties, and cellular content of the native tumor microenvironment. Therefore, they are the ideal tools for cancer modeling. Further, when combined with cutting-edge fabrication technologies, such as 3D bioprinting or microfluidics, results in the development of advanced 3D tumor models that better reproduce the dynamic and mechanochemical properties of the in vivo scenario. Overall, 3D biomaterials will bring a broad range of applications in the field of 3D tumor modeling and drug screening. This will pave the way toward their adoption into the clinic for an improved cancer detection, diagnosis, and treatment.

Keywords

Biomaterial; cancer; three-dimensional; tumor microenvironment; tumor model

Abbreviations

2D Two-dimensions

3D Three-dimensions

4D Four-dimensions

ADMET Adsorption, distribution, metabolism, excretion, and toxicity

CAFs Cancer-associated fibroblasts

CDMs Cell-derived matrices

CTCs Circulating tumor cells

ECM Extracellular matrix

EMEA European Medicines Agency

EMT Epithelial-to-mesenchymal transition

EPR Enhanced permeability and retention

FDA Federal drug agency

HA Hyaluronic acid

HUVEC Human umbilical vein endothelial cells

MMPs Matrix metalloproteases

PDMS Polydimethylsiloxane

PEG Poly(ethylene glycol)

TAMs Tumor-associated macrophages

TME Tumor microenvironment

ToC Tumor-on-a-chip

VEGF Vascular endothelial growth factor

1.1 A historical introduction

1.1.1 In vitro and in vivo models: an overview

During the last decade, the type of biological assays that are used for extracting information about the efficiency of drugs (including cancer-related compounds) have dramatically changed. The reason is that a large amount of these drugs fail when they are tested in pre-clinical assays. This is because most pre-clinical drug evaluations rely on simplified in vitro assays based on flat two-dimensional (2D) surfaces. This type of assay poorly correlates with the human disease state. Therein, the cells display artificial phenotypes and perturbed gene expressions. In general, the drugs respond differently than in vivo. Ex vivo (e.g., biopsies) and in vivo (e.g., animal) models are also employed for drug evaluation. In cancer research, these models display certain advantages over 2D surfaces, such as a greater biological complexity. This makes the drugs to produce native-like responses. However, ex vivo models typically lack perfusion and are not representative of the heterogeneity of the tumor. In contrast, in vivo (animal) models are highly dynamic systems, but they are very costly, lack the human immune system, and are ethically controversial. In addition, regardless of the type of animal model, it is extremely difficult to investigate cellular and physiological interactions on this type of models. More advanced tumor models are patient-derived xenografts, where a surgically resected tumor sample of a patient is engrafted into an immunodeficient mice. However, these models are extremely expensive and time-consuming, they are associated with ethical concerns, and individual parameters cannot be isolated [1].

1.1.2 A paradigm shift

To resolve the abovementioned issues, a paradigm shift has occurred since the late 1990s about how the cells are studied [2,3]. Indeed, there is a huge difference between cells cultured on flat surfaces and/or on three-dimensional (3D) environments. Indeed, seminal works using 3D in vitro models have demonstrated the important differences in the phenotypes and activities between cells grown in 2D surfaces and 3D cultures. The latter recapitulate the important interactions between—healthy and malignant—cells and the surrounding 3D environment [4,5]. As a result, the cancer research community, including academic researchers, pharma/biotech industries, and clinicians, have started to move toward the third dimension. In this regard, 2D assays in the form of traditional tissue culture flasks or Petri dishes, are being replaced by more sophisticated 3D tissue-engineered cell culture microenvironments. Therein, the cells display several similarities with the native scenario, and therefore, are considered as physiologically relevant environments that bridge the gap between obsolete flat materials and the native scenario. In particular, the early events of cancer progression can closely be reproduced in 3D culture platforms, where the cells display phenotypes, morphodynamics, and gene expression patterns much closer to the in vivo physiological microenvironment. In addition, as previously mentioned, this is of upmost importance during the development of drugs, where the cells respond to compounds as they do in vivo.

Finally, the combination of cutting-edge nanotechnologies with advances in materials science and tissue engineering tools, have created a powerful toolbox in the field of biomedical and health sciences capable to create a new generation of 3D biomaterials with unprecedented possibilities in cancer research. These biomaterials are capable (1) to copycat the tremendous complexity (physical, biological, structural, biochemical, and rheological) of the natural tumor microenvironment (TME); (2) to investigate in a physiologically relevant environment the pathogenesis of tumors; and (3) to screen the efficiency and pharmacokinetics/pharmacodynamics of drugs in a reliable manner. All these advanced capabilities make this new generation of 3D biomaterials ideal candidates for 3D tumor modeling.

1.1.3 Three-dimensional biomaterials for cancer modeling

The pioneering work by the Bissell lab in this field changed completely the vision and paradigm of how cancer cells need to be cultured in vitro [6]. The third dimension reproduces the physiological behavior of cells in the human body. As an example, the inhibition of β1 integrin in human breast cancer cells seeded in a 3D model reversed the malignant phenotype of cells resulting into normal morphologies and functional phenotypes; cells lost their abnormal shapes and patterns of growth. This work shows clearly that the context (i.e., environment) where cells are cultured influences the phenotype and response of cells, and in particular, cancerous cells. Similarly, the way how tumors are cultured in vitro also influences the migration capacity of cells and their motility mechanism [7]. In this regard, new migration modes, which are not observed in 2D, are revealed when tumor cells are seeded in 3D. In this case, the cells switch to an amoeba-like form of migration. This new type of migration mechanism enhances the capacity of cancer cells to squeeze to physical constrictions of the extracellular matrix (ECM) and invade the tumor stroma.

Cancer researchers have focused in developing biomimetic 3D platforms with controlled composition, bioactive functional groups, architecture, mechanical properties, and degradation rates, capable to reproduce the mechanochemical and hydrodynamic properties of the TME, overcoming the limitations of standard biomaterials. These biomaterials may also display “smart” character...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Section I: Engineering biomaterials for 3D cancer modelling
• Section II: Advanced models for cancer research
• Section III: Tumor models for drug discovery and therapeutics
• Section IV: Point-of-care applications
• Index