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3D Cell Culture Systems: Tumor Application, Advantages, and Disadvantages

Ola Habanjar, Mona Diab-Assaf, Florence Caldefie-Chezet and 1 more

International Journal of Molecular Sciences · 2021 · Review · CC BY

doi:10.3390/ijms222212200

Abstract

The traditional two-dimensional (2D) in vitro cell culture system (on a flat support) has long been used in cancer research. However, this system cannot be fully translated into clinical trials to ideally represent physiological conditions. This culture cannot mimic the natural tumor microenvironment due to the lack of cellular communication (cell-cell) and interaction (cell-cell and cell-matrix). To overcome these limitations, three-dimensional (3D) culture systems are increasingly developed in research and have become essential for tumor research, tissue engineering, and basic biology research. 3D culture has received much attention in the field of biomedicine due to its ability to mimic tissue structure and function. The 3D matrix presents a highly dynamic framework where its components are deposited, degraded, or modified to delineate functions and provide a platform where cells attach to perform their specific functions, including adhesion, proliferation, communication, and apoptosis. So far, various types of models belong to this culture: either the culture based on natural or synthetic adherent matrices used to design 3D scaffolds as biomaterials to form a 3D matrix or based on non-adherent and/or matrix-free matrices to form the spheroids. In this review, we first summarize a comparison between 2D and 3D cultures. Then, we focus on the different components of the natural extracellular matrix that can be used as supports in 3D culture. Then we detail different types of natural supports such as matrigel, hydrogels, hard supports, and different synthetic strategies of 3D matrices such as lyophilization, electrospiding, stereolithography, microfluid by citing the advantages and disadvantages of each of them. Finally, we summarize the different methods of generating normal and tumor spheroids, citing their respective advantages and disadvantages in order to obtain an ideal 3D model (matrix) that retains the following characteristics: better biocompatibility, good mechanical properties corresponding to the tumor tissue, degradability, controllable microstructure and chemical components like the tumor tissue, favorable nutrient exchange and easy separation of the cells from the matrix.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Cell culture systems, applied in biology, have contributed to reducing laboratory animal use and ensured the progression of research, pharmaceutical discovery, and the evolution of medicine. Initially, cells were grown in two dimensions and attached to polystyrene utensils or flat adherent surfaces (2D) but then researchers started to grow them with attachment proteins in a synthesized extracellular matrix (ECM) (3D). The two-dimensional (2D) in vitro cell culture system is a traditional application on flat support for cell growth in a monolayer. Historically, this system has been applied in research since the early 1900s, specifically in the co-culturing of cellular heterogeneity, and in oncological research as a tool to evaluate the biological performance of bioactive molecules. On the other hand, this type of culture has many limitations since it cannot ideally mimic physiological conditions and the natural microenvironment such as structure, physiology, biological signals of living tissues, and cell-matrix interactions. Indeed, the communication of cells with their ECM, which is absent in 2D, controls the cell growth, proliferation, and function. Cells cultured in 2D have been forced to modify various complex biological functions such as cell invasion, apoptosis, transcriptional regulation and receptor expression, cell proliferation and anti-apoptosis. To overcome these limitations, researchers are currently providing and developing new in vitro 3D cell culture systems to boost research (healthy and tumor). The first 3D cell culture model was provided in 1992 by Petersen and Bissell, who described 3D organotypic structures to mimic breast structures in cancerous and non-cancerous cases. This 3D system mimics the natural physiological properties and conditions, as well as enhances the development of new treatments at the preclinical stage in the future. It overcomes the problems associated with traditional 2D in vitro culture, provides more valuable information about 3D cell-cell and cell-matrix interactions and presents a more clinically representative response to therapeutic agents. Moreover, such a new type of culture will progressively evolve to have broader objectives to better assess the biological and molecular pathways during malignant transformation. The main role of 3D culture is therefore to imitate the structure of the ECM of the tissue. ECM is a scaffolding of non-cellular fibrillary proteins, various structural macromolecules (accessory proteins), and adhesive molecules that provide structural and biochemical support to cells and are essential to many basic processes. In addition, it forms cell-binding sites that control cell adhesion and migration. From a structural point of view, it is composed of:Interstitial ECM (stromal) contains biomolecules that can be organized into two main classes (proteins, glycoproteins) and proteoglycans (polysaccharides). It consists mainly of several protein molecules such as collagen I and III, self-arranged polysaccharides in fiber networks of glycosaminoglycans (GAG) such as hyaluronic acid (HA), proteoglycan (PG) and fibronectin;Basement membrane located at the basal side of epithelial or endothelial cells in normal tissues providing a physical barrier between epithelial cells and connective tissue (stroma) of the organ (always allow gas diffusion and transport of signaling molecules).

Interstitial ECM (stromal) contains biomolecules that can be organized into two main classes (proteins, glycoproteins) and proteoglycans (polysaccharides). It consists mainly of several protein molecules such as collagen I and III, self-arranged polysaccharides in fiber networks of glycosaminoglycans (GAG) such as hyaluronic acid (HA), proteoglycan (PG) and fibronectin;

Basement membrane located at the basal side of epithelial or endothelial cells in normal tissues providing a physical barrier between epithelial cells and connective tissue (stroma) of the organ (always allow gas diffusion and transport of signaling molecules).

These characteristics and ECM composition can be reached by 3D culture, and 3D culture can be achieved either via scaffold-free structures (i.e., spheroids) or scaffold-based structures (i.e., hydrogel-based supports and hard polymer material-based supports). Thus, in this review, we will be explaining the different techniques to reach 3D culture system, their advantages, and disadvantages.

2. 2D versus 3D Cell Culture

Cell-cell and cell-matrix interactions cannot be studied in 2D models in contrast to 3D models that are able to mimic these conditions in vitro. So, 3D culture provides a pragmatic pathophysiological microenvironment and plays a potential role in cancer drug discovery due to the lack of preclinical models relevant to 2D cultures. Inserts can be made up of biomaterials with properties like the ECM, and cells can also produce certain ECM proteins like collagen. Differences in physical and physiological properties between 2D and 3D cultures make 2D cells more sensitive to the effects of drugs than 3D cells since 2D cells are unable to maintain normal morphology as 3D cells can, and due to the difference in the organization of surface receptors on the cell. It should be noted that there is growing evidence suggesting that cells cultured in a 3D system behave differently from those cultured in a 2D system and retain important signals from the ECM. Appropriate 3D culture thus provides a more physiologically relevant approach for the analysis of gene function and cell phenotype ex vivo. In recent years, reconstructed 3D culture has become a method of choice for summarizing the tissue architecture of benign and malignant tumors. Thus, 3D culture can provide an important tool for better understanding changes, interactions, and cellular and molecular signaling during malignant transformation. Table 1 summarizes the differences between the characteristics of 2D and 3D culture models.

3. Extracellular Matrix Composition

The ECM forms the non-cellular physical support for the cellular constituents of all tissues and organs. The components of the ECM encompass cellular and biomechanical signals that maintain morphogenesis, differentiation, tissue homeostasis, integrity, and elasticity.

The ECM is divided into two main parts: the structural interstitial matrix surrounding the cells (collagen I and fibronectin) and the basement membrane (collagen IV, VIII and X, laminins, nidogen, perlecan, and integrin receptors) separating the epithelium from the surrounding stroma. In mammals, ECM contains about 300 proteins (central matrisome), having 43 collagen subunits, 36 proteoglycans (PG), and about 200 complex glycoproteins. The PG glycosaminoglycan (GAG) (proteoglycans that form the intercellular interstitial gel) and fibrous proteins (collagen, elastin, fibronectins, laminins) form the essential macromolecules of ECM. The shape and structure of PGs vary according to their functions in ECM. Three parameters allow the classification of PGs: central proteins, their localization, and their GAG composition (unbranched polysaccharide chains, sulfated or not sulfated). Normal glandular epithelial tissues, including the breast, are composed of a simple layer of epithelial cells that cover the internal cavity of the canal, their apical pole that is in contact with the light-filled with liquid, and their basal pole that rests on the basement membrane. Then, at the limit with the interstitial ECM (stroma), the layer of myoepithelial basal cells rests. Then the homeostasis of this epithelial tissue depends on communication and reciprocal interactions with the stromal microenvironment. Moreover, ECM is a rich reservoir of growth factors and other bioactive molecules (metabolic precursors). It is due to the signaling of this reserve that, on the one hand, cell proliferation, cell differentiation, and delay of apoptosis take place, and on the other hand, the reciprocal interaction of cells and the microenvironment is possible. In addition, ECM plays a basic role in the development and maintenance of epithelial tissues. For example, the ECM of human breast tissue is composed of protein fibril complexes intertwined in a network of carbohydrate chains of GAGs.

From a structural point of view, protein components, including laminins, fibronectin, and collagens, resist tensile forces, while carbohydrates, composed mainly of hyaluronan chains, chelate water, and resist compressive forces. Thus, the ECM is a key regulator of normal homeostasis and tissue phenotype.

Collagen is the most abundant structural protein in human tissues and constitutes about 30% of the body’s total protein mass. Generally, collagens, formed of 28 unique subtypes discovered, can be grouped either in fibrillar collagen (collagens I-III, V, and XI) or non-fibrillary. They regulate adhesion, cell migration, and tensile strength to maintain homeostasis. Basically, interstitial collagen is secreted by fibroblasts, being able by this to organize the alignment of collagen fibrils (I and III) in the fibronectin, hyaluronic acid, metalloproteinases (MMP), growth factors promoting cell differentiation, growth, and migration.

Hyaluronic acid (HA) is a non-sulfated linear GAG polysaccharide with hydrophilic characteristics and is resistant to high compressive forces. HA adopts very extensive conformations for the formation of hydrogels. It is a natural component essential for ECM to maintain compliance with compression and ensure ideal homeostasis in combination with collagen. In addition, its abnormal accumulation in ECM may promote tumor migration.

Fibronectin is a multidomain protein that interacts with different components of ECM to facilitate cell-ECM connection, thus forming a fibrillary network. It is involved first in guiding the direction of the organization of interstitial ECM through its reciprocal assembly with type I collagen and second in cell migration during development and tumor metastases.

Laminins are glycoproteins involved in adhesion, differentiation, migration, phenotype maintenance, and have resistance to apoptosis. It ensures the assembly of the basement membrane as well as ECM-cell interactions.

4. Three-Dimensional Cell Culture Scales

Various methods have been developed to address the growing demand for cell culture due to the lack of a single technology that fulfills the needs of all 3D cell cultures. 2D culture omits the effect of ECM molecules. Yet, its density and packaging contribute significantly to the creation of a 3D atmosphere. The 3D model is an in vitro reconstitution of the ECM after being inspired by the native microenvironment. It keeps the geometric, mechanical, and biochemical properties of the ECM. It consists of different cells integrated into a specialized environment arranged in a way that forms 3D tissues similar to the natural tissue structure. 3D culture models then make it possible to study the morphology and cellular organization shaped by ECM interactions, which are altered during oncogenic transformation. This makes the 3D models of in vitro tumors essential tools to study the mechanisms of cancer growth and metastasis. They are most useful when they support tissue growth from primary human cells and include defined and physiologically relevant components. Appropriate 3D culture thus provides a more physiologically relevant approach for the analysis of gene function and cell phenotype ex vivo. The engineering of 3D culture is based on different main principles: the nature of the cells (the selected, isolated, appropriate strain cell line, primary cells, and tissue origin), 3D artificial microenvironment (ECM imitation) in which they are grown, scaffold-based of biomaterials (natural, synthetic, or hard), signaling molecules (proteins and growth factors) and bioreactors (cell culture) that support a cellular environment that is biologically active. For these reasons, these parameters must be evaluated before choosing the most relevant technique and appropriate model. Culture systems can be either scaffold-based on natural or artificial solid scaffolding or scaffold-free, such as spheroids (non-scaffold based). The details of scaffold-based 3D techniques overview with these attributes are described in Table 2.

4.1. 3D Scaffolding Structures

In these techniques, the cells are grown in the presence of support which can be hydrogel-based supports and hard polymer material-based supports, natural or synthetic, of animal or vegetable origin. The polymer scaffolding offers a three-dimensionality favorable to cellular behavior in the microenvironment. It is the most used model, especially collagen-based hydrogel, due to the major constituent elements of the basement membrane. Hydrogels are cross-linked networks formed of hydrophilic polymers attached through physical, ionic, or covalent interactions. Their hydrophilic character allows them to absorb water that penetrates successively between the polymeric chains and causes swelling and thus the formation of the hydrogel. Hydrogels can be natural (natural polymers), synthetic (synthetic polymers) or hybrid (natural and synthetic) depending on the biocompatibility advantage or the physico-chemical nature, respectively (Table 2). These polymer-modified structures can be used as a matrix for cell culture in vitro or to make 3D spheroids. The main advantage of hydrogels is that their physico-chemical properties are adjustable and could appropriately mimic the biochemical and mechanical properties of the true native ECM. Cells can be deeply seeded into a porous hydrogel and easily recapitulate nutrition and oxygen (by diffusion).

4.1.1. Hydrogels

Some used hydrogels such as those of collagen are expensive, present a lack of reproducibility, and require extensive handling and specific equipment but present the opportunity of cellular heterogeneity as well as spontaneous cell organization (can be heterogeneous) (Table 2). Another option is to work with other scaffolding products, such as Hydrogel, which is a synthetic nanofiber peptide scaffolding. The stiffness of the 3D culture can be controlled by adjusting the hydrogel concentration. Above all, this system could be applied to study the interaction between any type of neoplastic cells. It may even be possible to design more complex systems using more than two different cell types. Hydrogels are unique because of their ability to mimic ECM while allowing soluble factors such as cytokines and growth factors to travel through tissue-like gel. There are different types of hydrogels: natural and synthetic. Natural gels (natural polymers) are, for example, fibrinogen, HA, collagen, Matrigel, gelatin, chitosan, and alginate. The hydrogels are, by definition, networks composed of hydrophilic polymers that are not cross-linked, and this allows them to swell widely by covalent bonds or to be held together by intramolecular and intermolecular physical attractions, maintaining their 3D structure. Due to their hydrophilic and hydrated character, they can absorb a large amount (thousands of percent) of water or biological fluids and inflater easily without dissolving, thus mimicking the structures and physical properties of soft tissue ECM. They are then soft and rubbery after swelling and resembling living tissues. On the other hand, gels differ from hydrogels since they are semi-solid materials (can appear more solid than liquid) consisting of hydrophilic polymers comprising small amounts of solids, dispersed in relatively large quantities of liquid. Depending on the nature of the polymer, hydrogels can be classified into different natural or synthetic categories and interconnected by physical and ionic interactions and even covalent bonds (hydrogels based on ECM proteins, natural hydrogels, and synthetic hydrogels) with distinct biochemical, physical and mechanical properties. For this, they were also explored as 3D models for cancer research. The use of 3D scaffolding models based on scaffolding expands the range of options available to researchers.

Protein-based EMC

These naturally formed biomaterials from biological polymers have been used in the manufacture of 3D platforms for breast cancer culture, including Matrigel®, collagen, HA, alginate, and gelatin (Table 2).

The Matrigel® is the gold standard. It is a tissue formed of a mixture of gelatinous proteins derived from the basement membrane isolated from the mouse sarcoma Engelberth–Holm–Swarm (EHS) and commercially available under the brand name Matrigel® (BD Biosciences) (Table 2). This extract is liquid at 4 °C and turns into a gel at 37 °C under physiological pH and ionic strength. It is then a ready-to-use solution that allows user-defined use. Recently, it has been widely used in 3D experiments in cell biology to assess cell migration, cancer cell behavior, and to create organoids in vitro, as it produces a large amount of ECM rich in type I collagen, laminin-111, heparin sulfate proteoglycans (perlecan) and nidogen. Matrigel® is considered the best product on the market used in the production of most 3D tests performed in cell biology. The success of Matrigel® is also due to its biological activity, which allows under normal culture conditions the differentiation of several cell types and the formation of complex structures such as mammary glands of acinous structures. In addition, the bioactivity of Matrigel® is due to the presence of soluble growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), transformative growth factor-β (TGF-β), and matrix metalloproteinases (MMP), including MMP-2 and -9. Although easy to use, the presence of these growth factors in unknown and uncontrollable quantities can have an impact on research (positively or negatively) which is why many researchers may prefer to manufacture their hydrogel systems using defined concentrations. In addition, as Matrigel® is produced and purified from an animal, there is a lack of control over its exact composition and batch-to-batch variability in its contents. Similarly, it presents difficulties of handling when it is in a refrigerated liquid state. Although the drawbacks of Matrigel® are significant, Matrigel® is a widely available model for studying many fundamental questions in cell biology, cell adhesion, and cancer research as a versatile platform for in vitro 3D cell culture.

Most natural polymers are structural molecules derived from mammalian ECM. Many different materials were used to develop in vitro 3D breast cancer scaffolding. They were first used as a coating of tissue culture boxes to promote cell adhesion and spread after they are incorporated into 3D materials in different forms (hydrogels, freeze-dried materials, and surface coating of bulk inorganic materials such as elastin, collagens, fibronectin, laminin (mainly laminin-111), GAGs (chondroitin sulfate and heparan sulfate, hyaluronan, alginate, and gelatin.

Classically, they are purified from ECM-rich animal tissues such as dermis and tendons (collagen type I, elastin), cartilage (collagen type II and GAGs), tumors (laminins and collagen IV), or directly from the blood (fibrin and fibronectin). On the other hand, with progress, it is now possible to obtain some of these molecules from recombinant DNA sources, which makes it possible to work with human ECM molecules, produced with a high degree of purity and free of many pathogens, but they are more expansive. Non-mammalian ECM molecules are also widely used in the design of biomaterials, mainly for their ability to self-assemble in 3D structures, but due to their origin, they lack many aspects of cell adhesion on their structures and should most often be supplemented with adhesive molecules or peptides to obtain a biologically active material. These polymers are hydrogels based on chitin/chitosan (polysaccharide purified from the exoskeleton of fungi or arthropods), agarose, or alginate (both polysaccharides purified from algae), and fibroin (cocoon protein from silkworms and spiders).

Natural hydrogels

Collagen-based hydrogels are natural hydrogels. Collagen, as the main component of ECM, plays a key role in the development and spread of cancer. It affects the tumor microenvironment especially in breast cancer signaling, differentiation and migration through cell-matrix interactions (Table 2). Depending on the type of tissue, collagen fibrils organize themselves in a variety of ways to form collagen fibers suitable for the specific functions and properties of tissues. The mechanical properties, architecture, and biodegradability of collagen hydrogels can be finely modulated by adjusting their concentrations and preparation parameters. Thanks to its specificity of spatial organization and self-assembly of collagen in acid solutions, the architecture of hydrogels can be controlled by the manipulation of ionic force, pH, and temperature during frost polymerization. The concentration of collagen increases gradually with the regulated evaporation of the solvent, as well as modifies the organization of collagen molecules. The original collagen solution to a solid hydrogel structure (i.e., the so-called “soil/frost transition”) retains the tissue-like molecular organization of collagen molecules (Figure 1a). In addition, an increase in collagen concentration (i.e., the ionic strength of gels) leads to an increase in fiber density and a reduction in pore size but has no effect on fiber diameter. In contrast, increasing temperature and pH accelerates polymerization, reduces fiber diameter and pore size, and also increases the mechanical properties of hydrogel (Table 3). As a result, many collagen-based 3D models of in vitro cancer culture have been developed.

Polysaccharide-based hydrogels are natural hydrogels. Proteoglycans (PGs) have a protein that is covalently bound to GAG chains. Thanks to the polyanionic profile of GAGs (due to the sulfate groups), they attract water, thus causing the swelling of the GAG (Figure 1b). This swelling can then open pathways of invasion and migration of cells that resemble the state of invasion and cancer metastases (Table 2). These PGs are directly involved in cellular functions and the release of active molecules (growth factors, cytokines). Hyaluronic acid (HA) is a major category of structural macromolecular components of ECM. It is an unsulfated GAG. The polyanionic nature of GAG attracts water, causing GAG to swell. Concerning HA hydrogel, this natural polysaccharide can be chemically modified to similarly mimic native tumor tissue by adding acrylate or thiol groups that have cross-linked to form a network with a pore size of 70 to 100 nm. Similarly, their sulfation pattern contributes to the binding of growth factors to GAGs. Indeed, GAGs provide hydration and compressive strength by binding to water as well as are involved in different biological processes such as tumor progression, angiogenesis, and cell development. It is not only a structural component of the tumor ECM but also a biologically active molecule that has been used extensively in the formation of 3D in vivo tumor models. This use is because of its biodegradable, non-immunogenic, non-inflammatory hydrodynamic and swelling characteristics to fill most of the extracellular interstitial spaces of tissues in the form of hydrated gels and promote cancer progression (Table 3). These properties make HA an ideal matrix for preparing 3D tumor models. HA gels are formed by covalent cross-linking (reaction with carboxylic acid groups) with hydrazide derivatives. They carry inherent biological properties such as protein grafting, but they are mechanically poor. HA is most often incorporated into the constituent materials of hydrogels. Recent studies have demonstrated the usefulness of HA-based scaffolding for improving adipose tissue development in vivo and in vitro. Table 4 summarizes the differences between scaffolds made with pure collagen vs. collagen-HA-based ones.

Dextran is a bacterial polysaccharide, consisting mainly of a glucosidic-1,6 bond of D-glucopyranose residues, used for more than 60 years in the medical and biomedical fields. Dextran is widely used for biomedical applications. Its advantages are its biocompatibility, low cost, good water solubility, ease of modification, antifouling properties. Dextran glucose must be oxidized in duplicate and then followed by a freeze-drying step.

Chitosan is the second most abundant natural polymer. It is a linear polysaccharide derived from chitin in the form of a deacetylated derivative. Its advantages are its structure (D-glucosamine bound in (1-4) + N-acetyl-glucosamine) that mimics the structural characteristic of the GAGs of ECM. It’s a biomaterial widely used in biomedical, biocompatible, biodegradable, and can be produced on a large-scale, easily transformed (simple freeze-drying). It shows a disadvantage of solubility in neutral solutions (it adds cysteine); no gel is formed without the grafting of cysteine, and poor mechanical properties of the gel are observed.

Synthetic hydrogels

Most synthetic hydrogels are synthesized by polymerization of synthetic polymers, which exhibit versatile biophysical, mechanical, and biological properties in 3D breast cultures to study the relationship between the microenvironment and malignant tumors in vitro. They are formed of synthetic polymers comprising poly-ε-caprolactone (PCL), polyethylene glycol oxide (PEG), polyvinyl alcohol or in a mixed solution or a combination of copolymer with poly-lactide-co-glycolide (PLGA) (PLG). In addition, their use is more preponderant in 3D culture of many cell types including neural, bone, cartilaginous, muscle, and renal cells. Synthetic organic polymers offer a wide range of creativity to produce 3D materials. Although they inherently lack basic biological activity, they have great flexibility in treatment and are easier to be produced (Table 2). The diversity of synthetic polymers used in biomaterials is great as they can be transformed into 3D materials with many types of techniques (electro piping, foaming, hydrogel, and sheets), some of which are not bearable by biological polymers. Polyesters and polyhydroxy acids can be biodegradable thanks to the presence of hydrolyzable bonds in their skeleton, while polyacrylamides and polyacrylates are almost unbreakable in cell culture. Synthetic polymers have the inherent properties to form a 3D scaffolding by which they contain active chemical groups (amine, acid, or alcohol functions) sensitive to chemical reactions, thus providing an ECM model with well-defined characteristics. Physiologically, they are irrelevant and can release toxic degradation products to cells (Table 3). Similarly, they are unable to provide the biochemical signals necessary to “communicate” with the cell. To overcome this limitation, synthetic polymers can be functionalized by adding signaling biomolecules, such as peptides, growth factors, and glycans.

Cells embedded in natural biopolymers take advantage of the signaling already present inside the matrix, while synthetic polymers lack signaling patterns capable of modulating the cellular outcome. The stiffness of biomaterials is also very important for cell proliferation and behavior, but an increase in the stiffness of a matrix (PEG gels) acts as a physical barrier for 3D cells, preventing their proliferation and migration. Similarly, studies have already shown that changes in the cross-linking density of PEG-based hydrogel cause changes in cell growth and morphology. For all these reasons, their applications are limited in the engineering of tumors in vitro. Levenberg et al. (2003) used PLGA and PLA to form porous scaffolding to create a 3D artificial microenvironment for human embryonic stem cell differentiation. While this was partly successful, they also demonstrated the difficulties in getting cells to infiltrate throughout the scaffolding. Similarly, the biodegradation of scaffolding based on poly-lactic acid, poly-glycolic acid, and their copolymer PLGA can lead to the release of by-products such as lactic acid. For these reasons, biodegradable materials are not practical for routine 3D cell culture where issues such as storage life, storage, and product consistency need to be taken into consideration (Table 3).

Nanofibrous scaffolding is a thin sheet composed of synthetic polymer fibers (PLGA or PLGA-PEG) of nanometric size randomly aligned. It forms a fibrous support for ECM and provides topographic features necessary for cell adhesion and growth. These nanofibers can be manufactured by several techniques such as electrospiding, phase separation, and self-assembly with varying chemical properties, diameters, lengths, porosities, and mechanical properties. In addition, the authors evaluated the usefulness of this model for drug testing by growing a tumor biopsy on 3D scaffolding and determining the effect of the drug on it. These nanofiber-based models have several key features; for example, providing topographic characteristics to cancer cells for 3D tumoroid development and reproducibility with the ease of tumoroid imaging could make it an elegant approach for drug testing.

Alvetex® hard-base scaffolding (Figure 2) provides a large internal volume and 3D space that cells can occupy and form a tissue. Cells find a more physiological shape because they are not seeded on a flat surface but in the presence of fibers or sponge-shaped structures with high consistency and reproducibility. These scaffolds are composed of non-degradable inert materials (polystyrene or polycaprolactone PCL) to avoid the formation of by-products. They can be manufactured by electrospinning or by gas foam technology to improve their application in cell culture, but very few have been developed into a commercially successful process for 3D culture (Table 2). They are important tools in the study of cell-ECM interactions due to the ability of the scaffolding to reproduce the structure of the ECM and high porosity. Moreover, it is less affected by cytotoxic compounds. Polystyrene is a familiar substrate to the user in 3D cell culture since it is inert and does not degrade during normal use (Table 3). On the other hand, polystyrene has some disadvantages: it is rigid (its rigidity must be controlled), does not have the biomechanical properties found in soft tissues, can display cytotoxicity, and a lack of biochemical stimuli (for example, molecules dependent on cell anchorage). However, these can be solved by adding known ECM proteins. In this case, a balance must be found between the needs of the model and the objective of the study.

The advantages and disadvantages of the described hydrogel-based scaffolds are summarized in Table 3.

4.1.2. Synthetic Strategies

Porous material

Despite the good biocompatibility of hydrogels due to their water content, they most often have low mechanical properties and high degradation rates. For this, porous materials have been designed with interconnected pore networks and surfaces or fibers to support cell adhesion. These materials are discriminated against 3D models of ECM of nano porous scaffolding where pore structures are in the range of cell diameter (about 10 μm) (Figure 3a). Nevertheless, microporous structures allow more efficient cell penetration and migration into the material but with specific pore sizes since a micro-size can represent a barrier to cellular colonization of the material and limit cellular interactions at the edges of the material. Like hydrogels, porous materials can be prepared with natural and synthetic polymers by different techniques, including electrospinning, phase separation, model creation, and vapor polymerization. The porosity based is mainly used with synthetic polymers (PLA/glycolic acid and PCL) but is also suitable for natural polymers such as collagen and silk fibroin. For example, porous collagen materials, due to their high porous structures, make so-called “collagen sponges”, by thermally induced phase separation. The phase separation of collagen molecules from the water-based solvent is due to the freezing of acidic collagen solution, which induces one that is then eliminated by freeze-drying. Pore size and interconnectivity can be altered by modulating collagen concentration and phase separation temperature or by mixing collagen solutions with other natural polymers such as GAG or synthetic polymers such as PLA. The low mechanical properties of freeze-dried collagen materials are often enhanced by the addition of GAG by cross-linking them with chemical species (aldehydes) using dehydrothermal processes.

Hydrogel technology

The cross-linking of natural hydrogels such as agarose, fibrin, and especially collagen and HA with high water content is one of the popular options in 3D culture that ensures the encapsulation of cells in a hydrogel comprising a loose scaffolding structure. Considerable progress has been made in the preparation of hydrogels called smart hydrogels to better mimic the artificial ECM protein microenvironment. However, these hydrogels may undergo unusual changes in the structure, mechanical characteristics, and swelling behavior of the network (support, cell growth), as a result of variations in pH, temperature, light, ionic, and force or electric field or enzymes. Regarding freeze-drying, its main purpose is to regulate porosity and form a collagen sponge. Changing the porosity of hydrogels (the number, size, shape, and interconnectivity of pores) will promote cell growth and homogeneous cell seeding in cell culture. Pore size is also a very important parameter to avoid inhibition of cell penetration. However, the diameters of all cells are less than 200 μm (for nutrition and oxygenation). To do this, it is necessary to choose the optimal size suitable for each cell type. A resume of this method, its advantages and disadvantages are summarized in Table 5.

Collagen Hydrogel by Freeze-Drying (Lyophilization)

Porosity is an amount of open pore volume in a scaffold that provides suitable support for cell colonization, ECM production, and subsequent spheroid formation. Highly porous scaffolding is then essential for the transport of nutrients and the disposal of waste. Pore size (diameter of circular pores or the longest length for non-circular pores) is one of the major factors that affect cellular behavior in the porous matrix, such as migration, adhesion in pores, and interaction with neighboring cells. Lyophilization is a dehydration technique that results in the formation of an interconnected circular/dry oval porous microstructure (Figure 3b). The solution is frozen before undergoing a vacuum drying process leading to the sublimation of ice crystals. This technique is currently the most used for the manufacture of collagen-based scaffolding due to the easy control of the architecture and mechanical properties. In addition, this architecture can be affected by collagen concentration, temperature, and freezing speed. It has also been shown that a decrease in the final freezing temperature reduces the size of the ice crystal and consequently the size of the pores even for the freezing speed, which must be slow and controlled to result in homogeneous scaffolding (pore shape and size). Variation in collagen concentration affects the stiffness, size and porosity of scaffolding pores since an increase in collagen concentration from 0.5% to 1% (w/v) increases pore size and reduces scaffold porosity. To address the complexity of component alignment observed in the ECM, Campbell et al. used a polycarbonate mold, cylindrical wells, and sharp copper inserts (coated with PTFE). The inserts were thermally insulated from the freeze dryer shelf by a thin 1 mm rubber mat. In a recent study, Hume et al. used 1% (w/v) of collagen (bovine Achilles’ tendon) solubilized in 0.05 M acetic acid followed by custom freeze-drying to produce reticulated anisotropic scaffolding (reticulated DAC/NHS). Samples of xenograft mammary tumors and fragment co-culture with 3T3-L1 pre-adipocyte cell line have been successfully cultured in collagen scaffolding (pore size 100 μm), highlighting the promise of ex-vivo application. This is commonly used as a gel for adipose tissue engineering, noting that adipocytes increased the migration of tumor cells into scaffolding on day 10. A resume of this method, its advantages and disadvantages are summarized in Table 5.

Electrospinning Hydrogel

The electrospinning technique uses electrical forces to form a network of fibers that offer a large surface area from polymer solutions or melts (Figure 3c). This technique is fast, efficient, relatively inexpensive, versatile, and produces microfibers with a diameter of less than 100 nm. The diameter of the fibers increases with increasing concentration/viscosity of the polymer. This creates uniform fibers and reduces the incidence of fiber defects such as beading (low concentration or surface tension problems). Fiber thickness generally increases pore size (space between fibers), while fibers with a smaller diameter exhibit the opposite effect due to the higher density of the fiber network inside the scaffolding. Noting that manufacturing parameters should be adjusted to avoid overly dense and tight fibrous networks as dense fibrous networks can prevent cellular infiltration into the scaffolding; high porosity is then essential. In addition, its limited control of porosity and relatively poor mechanical properties reduces its use in a 3D culture based on hydrogel scaffolding (Table 5).

Collagen-based scaffolding manufactured by electrospiding uses 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), trifluoroethanol (TFE) solvents, although these nanofibrous scaffolds were wrung out using a more benign water/salt/alcohol solvent system. The diameter of the fibers in these collagen-based scaffolds ranged from 100 to 900 nm, with differences obtained by changing the specific electrospiding parameters. On the other hand, crosslinking agents can be used to increase the mechanical properties of electrospirated scaffolding. Highlighting the potential of collagen-based scaffolding in 3D in vitro culture model, excellent cell proliferation and viability has been observed in many manufactured models. Szot et al. used this model to assess cellular behavior on electrospirated collagen/PCL fibers manufactured in terms of growth, proliferation, adhesion, and infiltration (fiber diameters ~400 nm (5%) to 2250 μm (15%) depending on concentration). Recently created (2021) by Malakpour-Permlid et al., a 3D culture model is based on a PCL fiber network resembling the collagen network of ECM due to its involvement in the main tissues and organs of the body. And as collagen is one of the most widely used biopolymers in tissue engineering, this fiber network is applied in the culture of normal and cancer cells by mimicking the collagen structure that ensures the 3D fixation and growth of cells. Despite the advantageous bio-activity in vitro and in vivo of collagen-based hydrogels and biomaterials, the major problem of clinical translation and therapeutic use remains related to the animal origin of collagen (i.e., bovine collagen, of porcine origin type I), with potential pathogenic content (disease transmission) and lack of growth factor (addition of TGF-B).

3D-Printing Scaffolding for 3D cell Culture via Stereolithography

Stereolithography is another method commonly used for imitation of complex structures in vitro of the intestine artificial 3DP models such as microvilli. It is an excellent candidate for studying homeostasis regeneration mechanisms in vitro. It is based on a construction of the different layers that harden to visible light or infrared (Figure 3d). Each layer will be superimposed after the next layer has dried (generally by UV). These layers are printed by a specific thin sheet material: The Installation Multiresolution 3D Printer (Dilase 3D, Kloe France), layer by layer until the scaffolding is finished; it is then placed under UV light where it is post-cured. This support can be combined with a polymerizable photo hydrogel (PCL fibers, PCL/gelatin) that promotes cell line growth with 3D-printing stereolithography and produce different scaffolds size from mm to cm. However, the manufactured scaffolding is usually limited to a few tens of microns of resolution and needs specific end expensive equipment (Table 5).

Micro Fluid

The microfluid support consists of silicon/elastomer-based devices. It creates a dynamic microenvironment presenting micro-channels with proportions from 1 to 1000 μm which are responsible for the exploitation of a small volume of fluids generally in the range of 10–9 to 10–18 (Figure 3e). In this system, the flow of the fluid is strictly laminar (in parallel layers) rather than turbulent (parallel and no strong). This support is normally applied in complex 3D structures or to synthesize matrices used in human transplantation. The generation of aggregates of different forms and the coculture of several cells reconstitute a more physiologically relevant tumor. It simulates cell-cell contacts and biological signals controlled by spatial and temporal gradients of soluble biological factors, progression, invasion, angiogenesis as well as treatment efficacy since the continuous flow of nutrients and therapeutic agents establishes a physiological profile such as that of blood circulation and intravenous injections. In fact, this system saves labor and the reagents used since it works automatically and consumes low cellular usage. According to its manufacturing complexity, this system requires professional equipment and special design and a higher budget than other strategies applied. The different synthetic strategies are summarized in Table 5.

4.2. Scaffold-Free Spheroids

Self-assembly is a natural phenomenon that occurs during morphogenesis and organogenesis. In culture, these techniques are considered the least complicated to apply because of the absence of a fastening surface or scaffolding that allows cell colonies to self-assemble and form aggregates of non-adherent 3D microtissues called spheroids. According to a general definition, spheroids are aggregates of cells growing in a 3D way in suspension; they can be mono or multicellular (homo or heterotypic). The cells form hard spherical structures with a well-balanced morphology of variable size (50 to 150 μm), formed by a necrotic nucleus and a peripheral layer. Historically, Holt Freter was the first to use spheroids as a morphogenic model in his investigation of skin behavior during development in 1944. Then this mode was considered a powerful tool in research and clinical applications and is the best in vitro cellular model for high-throughput screening. Recent advances in tissue engineering and regeneration have provided new techniques for the generation of tumor 3D spheroids for a variety of cancer types in vitro. This model of multicellular tumor spheroid was initially created in the early 1970s by radiobiologists, and then it was managed to be used for a wide variety of cancer cell lines. Nowadays, a multitude of techniques are used for the production of spheroids because cells are unable to adhere to the support, either in the adhesion-free gel of the micro-well with superposition of cellular suspensions (e.g., agarose gel or alginate gel) or by other techniques as pellet culture, suspended goutte and filature culture.

Spheroids have been widely used by a simple, high-yield, inexpensive application protocol that allows the production of more spheroids to mimic the architectural and functional characteristics of native tissues, and to assemble models of different types of cancer in vitro such as breast cancer (spherical shape of the breast canal). On the other hand, this culture requires intense and precise work and presents a risk of the formation of spheroids of uniform size and shape. Noting that this variation may be at the origin of the gel used but, in general, the gels (agarose, alginate, chitosan) used in the spheroid formations have benign characteristics such as plant origin that do not present a risk of animal contamination, significant stability at room temperature (but are biodegradable) and non-toxicity. In contrast, agarose gels were formed by heating (near the boiling temperature) the solution that freezes with cooling. For these reasons, different porous architectures and mechanical properties can be constructed according to the modulation of agarose concentration. For alginate citing a commercial product AlgiMatrix™ ready to use, it looks like a highly porous sponge (>90%), ready to use (freeze-dried alginate), stable at room temperature with long-term viability, non-toxic, biodegradable, and can easily be degraded by a dissolution buffer in a few minutes leaving cell aggregates intact for analysis (spheroids 50 to 150 μm). Similarly for chitosan (derived from crustaceans) has no binding domain to human cells therefore favorable to spheroids. Table 6 summarizes the advantages and disadvantages of spheroid culture.

4.2.1. Technical Methods of Spheroid Formation

Pellet Culture

In this system, cells are concentrated at the conical bottom of a tube by centrifugal force (500 g, 5 min) to maximize cell-to-cell adhesions (Figure 4a). After that, the supernatants are removed, and cell pellets are resuspended in a spheroid formation cell culture medium. We noted that shear stress due to centrifugation could damage cells, so to optimize results, the suspension can be incubated on an agitator for one hour before centrifugation (Table 7).

Hanging drop

Hanging drop is a spheroid culture technique that uses surface tension and gravitational force to form definite size spheroids in the form of droplets that rely on gravity self-disassembly. It allows single cells to aggregate and fabricate spheroids in the form of droplets (Figure 4b). By controlling the volume of the drop or density of cell suspension, it is possible to control the spheroid size. We prepare a cell suspension at desired density distribution in the wells of a mini-plateau, then it will be placed on the mini-tray, and the entire mini-tray is overturned upside down. The drop remains fixed on the mini tray on the inverted surface (surface tension). Therefore, this technique is mostly used due to the defined and controlled size of the spheroid (drop volume and suspension density) with inexpensive equipment. Despite high amount production (384 spheroids in a single network), heterotypic spheroids can appear with narrow size distribution (Table 7).

Cultivation of Molded Lozenges and Liquid Overlay (Static Suspension)

The cultivation of molded lozenges and liquid overlay (static suspension) are culture technique that forms spheroids by interrupting the adhesion of cells on non-adherent culture plates or gel with non-adherent properties such as agarose with micro-well (agar) gel or pHEMA with superposition of cellular suspensions (Figure 4c). It is a simple method to monitor the formation and growth of spheroids. Since the cell binding to the support is inhibited, cells spontaneously form spheroids. It is forced to aggregate by continuous agitation with/without centrifugation. Despite the excellent non-adherent properties of agarose, this biomaterial has drawbacks in terms of producing heterogeneous spheroids in size and shape (Table 7).

Spinner Culture Technique

It refers to the technique wherein the cell suspension in spinner centrifugal flask bioreactor, generated by a magnetic stirring wheel container, and which is continuously mixed by convection force stirring (Figure 4d). It adds the uniform and well-mixed single-celled suspension with constant continuous stirring to form the spheroid (may not be useful for cells with low cohesion; they have the risk of apoptosis). The stirring rate must be constant because a high stirring rate induces damage to the spheroid cells and a slow speed makes the cells sink to the bottom of the container (blocks the spheroids). In addition, it is difficult to follow the spheroids during formation (Table 7).

Table 7 summarizes the technical methods of spheroid formation.

4.2.2. Technical Methods of Tumor Spheroid Formation

Due to their particular interest, spheroids are the most applied 3D models in oncogenic research. They form an effective tool capable of studying the variation in morphology, topography, size, cell organization, protein expression, and genes in the invasive and metastatic potential of cancer cells. These tumor spheroids have a heterogeneous distribution with active cells proliferating on the surface of spheroid cells (oxygen and nutrients) and resting cells in the center. Tumor spheroids may be homotypic formed only of cancer cells or heterotypic consisting of cancer cells with other cell types. Spherical cancers can be classified into four groups:Multicellular tumor spheroids are obtained after aggregation and compaction of the cultured cell suspension (1–7 days) under non-adherent conditions (well plates, vials or boxes + agar gel, agarose or polyH + a traditional culture medium depending on the cell line).Tumorospheres (floating sphere): Tumors are formed from a single cell capable of giving rise to a sphere by clonal expansion (5–7 days up to 1–2 months) under conditions of low adhesion (plastic with low adhesion) and with a stem cell medium (depending on the type of cancer, growth factors may be preferentially added).Tissue-derived tumor spheres (endoscopic biopsy): Tumor spheres derived from cut (scalpel blade) and minced partially dissociated cancerous tissues are generated by partial dissociation of tumor tissue and compaction/remodeling (2–5 days up to 12–18 days) in conventional FBS-supplemented medium.Organotypic multicellular spheroids are formed from the cutting of partially dissociated tumor tissue (mechanically or enzymatically) under non-adherent conditions (plastic treated in culture and then non-adherent conditions) that have rounded during culture (1–3 days).

Multicellular tumor spheroids are obtained after aggregation and compaction of the cultured cell suspension (1–7 days) under non-adherent conditions (well plates, vials or boxes + agar gel, agarose or polyH + a traditional culture medium depending on the cell line).

Tumorospheres (floating sphere): Tumors are formed from a single cell capable of giving rise to a sphere by clonal expansion (5–7 days up to 1–2 months) under conditions of low adhesion (plastic with low adhesion) and with a stem cell medium (depending on the type of cancer, growth factors may be preferentially added).

Tissue-derived tumor spheres (endoscopic biopsy): Tumor spheres derived from cut (scalpel blade) and minced partially dissociated cancerous tissues are generated by partial dissociation of tumor tissue and compaction/remodeling (2–5 days up to 12–18 days) in conventional FBS-supplemented medium.

Organotypic multicellular spheroids are formed from the cutting of partially dissociated tumor tissue (mechanically or enzymatically) under non-adherent conditions (plastic treated in culture and then non-adherent conditions) that have rounded during culture (1–3 days).

5. Conclusions

Standard cell culture studies are widely used to delineate biological, chemical, and molecular pathways, first by traditional 2D culture and then by enhanced 3D culture. According to 2D cell limitations in some practices, recent advances in tissue engineering and regeneration then provided new techniques for a variety of 3D in vitro models. Cells develop in an organized three-dimensional (3D) matrix, and their behavior depends on interactions with immediate neighbors and ECM. The 3D culture can provide an important tool for better understanding changes, interactions, and cellular and molecular signaling during malignant transformation and metastasis. Three-dimensional (3D) cellular scaffolding is then essential for tissue engineering. So far, various natural and synthetic polymer hydrogels have been used to design 3D scaffolding as biomaterials. This is a barrier to mimicking the native ECM microenvironment, and therefore synthetic scaffolds may be more useful for investigations of specific tumorigenic steps. We provide here characteristics, advantages, and disadvantages of 3D cell culture compared to 2D types, different types of 3D matrices such as natural, synthetics hydrogel, and spheroids—the best rational classification of the most used 3D strategies models in cancer research. Finally, depending on the specific objectives, the most relevant 3D models must be carefully selected.

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    Weaver V.M., Fischer A.H., Peterson O.W., Bissell M.J. The Importance of the Microenvironment in Breast Cancer Progression: Recapitulation of Mammary Tumorigenesis Using a Unique Human Mammary Epithelial Cell Model and a Three-Dimensional Culture Assay. Biochem. Cell Biol. 1996;74:833-851.

    Not in our library10.1139/o96-089

  59. 59.

    Kenny P.A., Lee G.Y., Myers C.A., Neve R.M., Semeiks J.R., Spellman P.T., Lorenz K., Lee E.H., Barcellos-Hoff M.H., Petersen O.W., et al. The Morphologies of Breast Cancer Cell Lines in Three-Dimensional Assays Correlate with Their Profiles of Gene Expression. Mol. Oncol. 2007;1:84-96.

    Not in our library10.1016/j.molonc.2007.02.004

  60. 60.

    Järveläinen H., Sainio A., Koulu M., Wight T.N., Penttinen R. Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy. Pharmacol. Rev. 2009;61:198-223.

    Not in our library10.1124/pr.109.001289

  61. 61.

    Bonnans C., Chou J., Werb Z., Bonnans C., Chou J., Werb Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014;15:786-801.

    Not in our library10.1038/nrm3904

  62. 62.

    Lu P., Weaver V.M., Werb Z. The Extracellular Matrix: A Dynamic Niche in Cancer Progression. J. Cell Biol. 2012;196:395-406.

    Not in our library10.1083/jcb.201102147

  63. 63.

    Ricard-Blum S. The Collagen Family. Cold Spring Harbor Perspect. Biol. 2011;3:a004978.

    Not in our library10.1101/cshperspect.a004978

  64. 64.

    Hashmi S., Marinkovich M.P. Molecular Organization of the Basement Membrane Zone. Clin. Dermatol. 2011;29:398-411.

    Not in our library10.1016/j.clindermatol.2011.01.009

  65. 65.

    Hohenester E., Yurchenco P.D. Laminins in Basement Membrane Assembly. Cell Adhes. Migr. 2013;7:56-63.

    Not in our library10.4161/cam.21831

  66. 66.

    Mouw J.K., Ou G., Weaver V.M. Extracellular Matrix Assembly: A Multiscale Deconstruction. Nat. Rev. Mol. Cell Biol. 2014;15:771-785.

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    Hynes R.O., Naba A. Overview of the Matrisome-An Inventory of Extracellular Matrix Constituents and Functions. Cold Spring Harbor Perspect. Biol. 2012;4:1-16.

    Not in our library10.1101/cshperspect.a004903

  68. 68.

    Iozzo R.V., Schaefer L. Proteoglycan Form and Function: A Comprehensive Nomenclature of Proteoglycans. Matrix Biol. 2015;42:11-55.

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    Schaefer L., Schaefer R.M. Proteoglycans: From Structural Compounds to Signaling Molecules. Cell Tissue Res. 2010;339:237-246.

    Not in our library10.1007/s00441-009-0821-y

  70. 70.

    Roberts K., Alberts B., Johnson A., Lewis J., Morgan D., Raff M., Walter P., Wilson J., Hunt T. Molecular Biology of the Cell. 2015.

    Not in our library10.1201/9781315735368

  71. 71.

    Barsky S.H., Karlin N.J. Myoepithelial Cells: Autocrine and Paracrine Suppressors of Breast Cancer Progression. J. Mammary Gland Biol. Neoplasia. 2005;10:249-260.

    Not in our library10.1007/s10911-005-9585-5

  72. 72.

    Tsang K.Y., Cheung M.C.H., Chan D., Cheah K.S.E. The Developmental Roles of the Extracellular Matrix: Beyond Structure to Regulation. Cell Tissue Res. 2010;339:93-110.

    Not in our library10.1007/s00441-009-0893-8

  73. 73.

    Huveneers S., Danen E.H.J. Adhesion Signaling—Crosstalk between Integrins, Src and Rho. J. Cell Sci. 2009;122:1059-1069.

    Not in our library10.1242/jcs.039446

  74. 74.

    Discher D.E., Mooney D.J., Zandstra P.W. Growth Factors, Matrices, and Forces Combine and Control Stem Cells. Science. 2009;324:1673-1677.

    Not in our library10.1126/science.1171643

  75. 75.

    Calvo F., Ege N., Grande-Garcia A., Hooper S., Jenkins R.P., Chaudhry S.I., Harrington K., Williamson P., Moeendarbary E., Charras G., et al. Mechanotransduction and YAP-Dependent Matrix Remodelling Is Required for the Generation and Maintenance of Cancer-Associated Fibroblasts. Nat. Cell Biol. 2013;15:637-646.

    Not in our library10.1038/ncb2756

  76. 76.

    Varelas X. The Hippo Pathway Effectors TAZ and YAP in Development, Homeostasis and Disease. Development. 2014;141:1614-1626.

    Not in our library10.1242/dev.102376

  77. 77.

    Bissell M.J., Radisky D.C., Rizki A., Weaver V.M., Petersen O.W. The Organizing Principle: Microenvironmental Influences in the Normal and Malignant Breast. Differ. Res. Biol. Divers. 2002;70:537-546.

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  78. 78.

    Myllyharju J., Kivirikko K.I. Collagens, Modifying Enzymes and Their Mutations in Humans, Flies and Worms. TIG. 2004;20:33-43.

    Not in our library10.1016/j.tig.2003.11.004

  79. 79.

    Ricard-Blum S., Ruggiero F. The Collagen Superfamily: From the Extracellular Matrix to the Cell Membrane. Pathologie-Biologie. 2005;53:430-442.

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    Camenisch T.D., Spicer A.P., Brehm-Gibson T., Biesterfeldt J., Augustine M.L., Calabro A.J., Kubalak S., Klewer S.E., McDonald J.A. Disruption of Hyaluronan Synthase-2 Abrogates Normal Cardiac Morphogenesis and Hyaluronan-Mediated Transformation of Epithelium to Mesenchyme. J. Clin. Investig. 2000;106:349-360.

    Not in our library10.1172/jci10272

  81. 81.

    Chen X., Thibeault S.L. Response of Fibroblasts to Transforming Growth Factor-Β1 on Two-Dimensional and in Three-Dimensional Hyaluronan Hydrogels. Tissue Eng. Part A. 2012;18:2528-2538.

    Not in our library10.1089/ten.tea.2012.0094

  82. 82.

    De Wever O., Demetter P., Mareel M., Bracke M. Stromal Myofibroblasts Are Drivers of Invasive Cancer Growth. Int. J. Cancer. 2008;123:2229-2238.

    Not in our library10.1002/ijc.23925

  83. 83.

    Hynes R.O. The Extracellu. Science. 2009;326:1216-1219.

    Not in our library10.1126/science.1176009

  84. 84.

    Schaefer L., Iozzo R.V. Biological Functions of the Small Leucine-Rich Proteoglycans: From Genetics to Signal Transduction. J. Biol. Chem. 2008;283:21305-21309.

    Not in our library10.1074/jbc.r800020200

  85. 85.

    Josefsson A., Adamo H., Hammarsten P., Granfors T., Stattin P., Egevad L., Laurent A.E., Wikström P., Bergh A. Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome. Am. J. Pathol. 2011;179:1961-1968.

    Not in our library10.1016/j.ajpath.2011.06.005

  86. 86.

    McAtee C.O., Barycki J.J., Simpson M.A. Emerging Roles for Hyaluronidase in Cancer Metastasis and Therapy. Adv. Cancer Res. 2014;123:1-34.

    Not in our library10.1016/b978-0-12-800092-2.00001-0

  87. 87.

    Singh P., Carraher C., Schwarzbauer J.E. Assembly of Fibronectin Extracellular Matrix. Annu. Rev. Cell Dev. Biol. 2010;26:397-419.

    Not in our library10.1146/annurev-cellbio-100109-104020

  88. 88.

    Dallas S.L., Sivakumar P., Jones C.J.P., Chen Q., Peters D.M., Mosher D.F., Humphries M.J., Kielty C.M. Fibronectin Regulates Latent Transforming Growth Factor-Beta (TGF Beta) by Controlling Matrix Assembly of Latent TGF Beta-Binding Protein-1. J. Biol. Chem. 2005;280:18871-18880.

    Not in our library10.1074/jbc.m410762200

  89. 89.

    Sottile J., Hocking D.C. Fibronectin Polymerization Regulates the Composition and Stability of Extracellular Matrix Fibrils and Cell-Matrix Adhesions. Mol. Biol. Cell. 2002;13:3546-3559.

    Not in our library10.1091/mbc.e02-01-0048

  90. 90.

    Dzamba B.J., Wu H., Jaenisch R., Peters D.M. Fibronectin Binding Site in Type I Collagen Regulates Fibronectin Fibril Formation. J. Cell Biol. 1993;121:1165-1172.

    Not in our library10.1083/jcb.121.5.1165

  91. 91.

    Colombi M., Zoppi N., De Petro G., Marchina E., Gardella R., Tavian D., Ferraboli S., Barlati S. Matrix Assembly Induction and Cell Migration and Invasion Inhibition by a 13-Amino Acid Fibronectin Peptide. J. Biol. Chem. 2003;278:14346-14355.

    Not in our library10.1074/jbc.m211997200

  92. 92.

    Domogatskaya A., Rodin S., Tryggvason K. Functional Diversity of Laminins. Annu. Rev. Cell Dev. Biol. 2012;28:523-553.

    Not in our library10.1146/annurev-cellbio-101011-155750

  93. 93.
    Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer · 2015
    No notice
  94. 94.

    Banerji S., Wright A.J., Noble M., Mahoney D.J., Campbell I.D., Day A.J., Jackson D.G. Structures of the Cd44-Hyaluronan Complex Provide Insight into a Fundamental Carbohydrate-Protein Interaction. Nat. Struct. Mol. Biol. 2007;14:234-239.

    Not in our library10.1038/nsmb1201

  95. 95.

    Nelson J., McFerran N.V., Pivato G., Chambers E., Doherty C., Steele D., Timson D.J. The 67 KDa Laminin Receptor: Structure, Function and Role in Disease. Biosci. Rep. 2008;28:33-48.

    Not in our library10.1042/bsr20070004

  96. 96.

    Harburger D.S., Calderwood D.A. Integrin Signalling at a Glance. J. Cell Sci. 2009;122:159-163.

    Not in our library10.1242/jcs.018093

  97. 97.

    Holen I., Nutter F., Wilkinson J.M., Evans C.A., Avgoustou P., Ottewell P.D. Human Breast Cancer Bone Metastasis in Vitro and in Vivo: A Novel 3D Model System for Studies of Tumour Cell-Bone Cell Interactions. Clin. Exp. Metastasis. 2015;32:689-702.

    Not in our library10.1007/s10585-015-9737-y

  98. 98.

    Egeblad M., Nakasone E.S., Werb Z. Tumors as Organs: Complex Tissues That Interface with the Entire Organism. Dev. Cell. 2010;18:884-901.

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  99. 99.

    Aumailley M., Gayraud B. Structure and Biological Activity of the Extracellular Matrix. J. Mol. Med. 1998;76:253-265.

    Not in our library10.1007/s001090050215

  100. 100.

    Cukierman E., Pankov R., Stevens D.R., Yamada K.M. Taking Cell-Matrix Adhesions to the Third Dimension. Science. 2001;294:1708-1712.

    Not in our library10.1126/science.1064829

  101. 101.

    Sethi T., Rintoul R.C., Moore S.M., MacKinnon A.C., Salter D., Choo C., Chilvers E.R., Dransfield I., Donnelly S.C., Strieter R., et al. Extracellular Matrix Proteins Protect Small Cell Lung Cancer Cells against Apoptosis: A Mechanism for Small Cell Lung Cancer Growth and Drug Resistance in Vivo. Nat. Med. 1999;5:662-668.

    Not in our library10.1038/9511

  102. 102.

    Pal A., Kleer C.G. Three Dimensional Cultures: A Tool to Study Normal Acinar Architecture vs. Malignant Transformation of Breast Cells. JoVE. 2014;86:51311.

    Not in our library10.3791/51311

  103. 103.

    Espinoza-Sánchez N.A., Chimal-Ramírez G.K., Fuentes-Pananá E.M. Analyzing the Communication Between Monocytes and Primary Breast Cancer Cells in an Extracellular Matrix Extract (ECME)-Based Three-Dimensional System. JoVE. 2018;131:56589.

    Not in our library10.3791/56589

  104. 104.
    Advances in 3D cell culture technologies enabling tissue‐like structures to be created in vitro · 2014
    No notice
  105. 105.

    Moroni L., Burdick J.A., Highley C., Lee S.J., Morimoto Y., Takeuchi S., Yoo J.J. Biofabrication Strategies for 3D in Vitro Models and Regenerative Medicine. Nat. Rev. Mater. 2021;3:21-37.

    Not in our library10.1038/s41578-018-0006-y

  106. 106.

    El-Sherbiny I.M., Yacoub M.H. Hydrogel Scaffolds for Tissue Engineering: Progress and Challenges. Glob. Cardiol. Sci. Pract. 2013;2013:38.

    Not in our library10.5339/gcsp.2013.38

  107. 107.

    Benton G., Arnaoutova I., George J., Kleinman H.K., Koblinski J. Matrigel: From Discovery and ECM Mimicry to Assays and Models for Cancer Research. Adv. Drug Deliv. Rev. 2014;79–80:3-18.

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  108. 108.

    Baharvand H., Hashemi S.M., Ashtiani S.K., Farrokhi A. Differentiation of Human Embryonic Stem Cells into Hepatocytes in 2D and 3D Culture Systems in Vitro. Int. J. Dev. Biol. 2006;50:645-652.

    Not in our library10.1387/ijdb.052072hb

  109. 109.
    Analysis of Contractility and Invasion Potential of Two Canine Mammary Tumor Cell Lines · 2017
    Not checked
  110. 110.

    Mulfaul K., Giacalone J.C., Voigt A.P., Riker M.J., Ochoa D., Han I.C., Stone E.M., Mullins R.F., Tucker B.A. Stepwise Differentiation and Functional Characterization of Human Induced Pluripotent Stem Cell-Derived Choroidal Endothelial Cells. Stem Cell Res. Ther. 2020;11:409.

    Not in our library10.1186/s13287-020-01903-4

  111. 111.

    Chen D., Qu Y., Hua X., Zhang L., Liu Z., Pflugfelder S.C., Li D.-Q. A Hyaluronan Hydrogel Scaffold-Based Xeno-Free Culture System for Ex Vivo Expansion of Human Corneal Epithelial Stem Cells. Eye. 2017;31:962-971.

    Not in our library10.1038/eye.2017.8

  112. 112.

    Devarasetty M., Wang E., Soker S., Skardal A. Mesenchymal Stem Cells Support Growth and Organization of Host-Liver Colorectal-Tumor Organoids and Possibly Resistance to Chemotherapy. Biofabrication. 2017;9:21002.

    Not in our library10.1088/1758-5090/aa7484

  113. 113.

    Mannino R.G., Santiago-Miranda A.N., Pradhan P., Qiu Y., Mejias J.C., Neelapu S.S., Roy K., Lam W.A. 3D Microvascular Model Recapitulates the Diffuse Large B-Cell Lymphoma Tumor Microenvironment in Vitro. Lab. Chip. 2017;17:407-414.

    Not in our library10.1039/c6lc01204c

  114. 114.

    Chen X., Thibeault S.L. Cell-Cell Interaction between Vocal Fold Fibroblasts and Bone Marrow Mesenchymal Stromal Cells in Three-Dimensional Hyaluronan Hydrogel. J. Tissue Eng. Regen. Med. 2016;10:437-446.

    Not in our library10.1002/term.1757

  115. 115.

    Engel B.J., Constantinou P.E., Sablatura L.K., Doty N.J., Carson D.D., Farach-Carson M.C., Harrington D.A., Zarembinski T.I. Multilayered, Hyaluronic Acid-Based Hydrogel Formulations Suitable for Automated 3D High Throughput Drug Screening of Cancer-Stromal Cell Cocultures. Adv. Healthc. Mater. 2015;4:1664-1674.

    Not in our library10.1002/adhm.201500258

  116. 116.

    Zhang N., Milleret V., Thompson-Steckel G., Huang N.-P., Vörös J., Simona B.R., Ehrbar M. Soft Hydrogels Featuring In-Depth Surface Density Gradients for the Simple Establishment of 3D Tissue Models for Screening Applications. SLAS Discov. Adv. Life Sci. R&D. 2017;22:635-644.

    Not in our library10.1177/2472555217693191

  117. 117.

    Saha K., Pollock J.F., Schaffer D.V., Healy K.E. Designing synthetic materials to control stem cell phenotype. Curr. Opin. Chem. Biol. 2008;11:381-387.

    Not in our library10.1016/j.cbpa.2007.05.030

  118. 118.

    Seal B., Otero T.C., Panitch A. Polymeric Biomaterials for Tissue and Organ Regeneration. Mater. Sci. Eng. R Rep. 2001;34:147-230.

    Not in our library10.1016/s0927-796x(01)00035-3

  119. 119.

    Haycock J.W. 3D Cell Culture: A Review of Current Approaches and Techniques. Methods Mol. Biol. 2011;695:1-15.

    Not in our library10.1007/978-1-60761-984-0_1

  120. 120.

    Sun T., Norton D., McKean R.J., Haycock J.W., Ryan A.J., MacNeil S. Development of a 3D Cell Culture System for Investigating Cell Interactions with Electrospun Fibers. Biotechnol. Bioeng. 2007;97:1318-1328.

    Not in our library10.1002/bit.21309

  121. 121.

    Aydin H.M., El Haj A.J., Pişkin E., Yang Y. Improving Pore Interconnectivity in Polymeric Scaffolds for Tissue Engineering. J. Tissue Eng. Regen. Med. 2009;3:470-476.

    Not in our library10.1002/term.187

  122. 122.

    Bokhari M., Carnachan R.J., Przyborski A., Cameron N.R. Emulsion-Templated Porous Polymers as Scaffolds for Three Dimensional Cell Culture: Effect of Synthesis Parameters on Scaffold Formation and Homogeneity. J. Mater. Chem. 2007;17:4088-4094.

    Not in our library10.1039/b707499a

  123. 123.

    Salerno A., Oliviero M., Di Maio E., Iannace S., Netti P.A. Design of Porous Polymeric Scaffolds by Gas Foaming of Heterogeneous Blends. J. Mater. Sci. Mater. Med. 2009;20:2043-2051.

    Not in our library10.1007/s10856-009-3767-4

  124. 124.

    Bai C., Yang M., Fan Z., Li S., Gao T., Fang Z. Associations of Chemo- and Radio-Resistant Phenotypes with the Gap Junction, Adhesion and Extracellular Matrix in a Three-Dimensional Culture Model of Soft Sarcoma. J. Exp. Clin. Cancer Res. CR. 2015;34:58.

    Not in our library10.1186/s13046-015-0175-0

  125. 125.

    Zhang M., Rose B., Lee C.S., Hong A.M. In Vitro 3-Dimensional Tumor Model for Radiosensitivity of HPV Positive OSCC Cell Lines. Cancer Biol. Ther. 2015;16:1231-1240.

    Not in our library10.1080/15384047.2015.1056410

  126. 126.

    Elisseeff J. Hydrogels: Structure Starts to Gel. Nat. Mater. 2008;7:271-273.

    Not in our library10.1038/nmat2147

  127. 127.

    Slaughter B.V., Khurshid S.S., Fisher O.Z., Khademhosseini A., Peppas N.A. Hydrogels in Regenerative Medicine. Adv. Mater. 2009;21:3307-3329.

    Not in our library10.1002/adma.200802106

  128. 128.

    Martínez-Ramos C., Lebourg M. Three-Dimensional Constructs Using Hyaluronan Cell Carrier as a Tool for the Study of Cancer Stem Cells. J. Biomed. Mater. Research. Part B Appl. Biomater. 2015;103:1249-1257.

    Not in our library10.1002/jbm.b.33304

  129. 129.

    Hamdi D.H., Barbieri S., Chevalier F., Groetz J.-E., Legendre F., Demoor M., Galera P., Lefaix J.-L., Saintigny Y. In Vitro Engineering of Human 3D Chondrosarcoma: A Preclinical Model Relevant for Investigations of Radiation Quality Impact. BMC Cancer. 2015;15:579.

    Not in our library10.1186/s12885-015-1590-5

  130. 130.

    Tibbitt M.W., Anseth K.S. Hydrogels as Extracellular Matrix Mimics for 3D Cell Culture. Biotechnol. Bioeng. 2009;103:655-663.

    Not in our library10.1002/bit.22361

  131. 131.

    Fischbach C., Chen R., Matsumoto T., Schmelzle T., Brugge J.S., Polverini P.J., Mooney D.J. Engineering Tumors with 3D Scaffolds. Nat. Methods. 2007;4:855-860.

    Not in our library10.1038/nmeth1085

  132. 132.
    Peptide Hydrogels – Versatile Matrices for 3D Cell Culture in Cancer Medicine · 2015
    No notice
  133. 133.

    Dhaliwal A. 3D Cell Culture: A Review. Mater. Methods. 2012;2:162.

    Not in our library10.13070/mm.en.2.162

  134. 134.

    Le V.-M., Lang M.-D., Shi W.-B., Liu J.-W. A Collagen-Based Multicellular Tumor Spheroid Model for Evaluation of the Efficiency of Nanoparticle Drug Delivery. Artif. Cells Nanomed. Biotechnol. 2016;44:540-544.

    Not in our library10.3109/21691401.2014.968820

  135. 135.

    Haisler W.L., Timm D.M., Gage J.A., Tseng H., Killian T.C., Souza G.R. Three-Dimensional Cell Culturing by Magnetic Levitation. Nat. Protoc. 2013;8:1940-1949.

    Not in our library10.1038/nprot.2013.125

  136. 136.

    Lee K.Y., Mooney D.J. Hydrogels for Tissue Engineering. Chem. Rev. 2001;101:1869-1879.

    Not in our library10.1021/cr000108x

  137. 137.

    Hoffman A.S. Hydrogels for Biomedical Applications. Adv. Drug Deliv. Rev. 2012;64:18-23.

    Not in our library10.1016/j.addr.2012.09.010

  138. 138.

    Caliari S.R., Burdick J.A. A Practical Guide to Hydrogels for Cell Culture. Nat. Methods. 2016;13:405-414.

    Not in our library10.1038/nmeth.3839

  139. 139.

    Domb A., Khan W. Biodegradable Polymers as Drug Carrier Systems. Encyclopedia of PHARMACEUTICAL TECHNOLOGY. 2013;Volume 1:135-176.

    Not in our library

  140. 140.

    Zhang J., Yun S., Du Y., Zannettino A.C.W., Zhang H. Fabrication of a Cartilage Patch by Fusing Hydrogel-Derived Cell Aggregates onto Electrospun Film. Tissue Eng. Part A. 2020;26:863-871.

    Not in our library10.1089/ten.tea.2019.0318

  141. 141.

    Jeon O., Marks R., Wolfson D., Alsberg E. Dual-Crosslinked Hydrogel Microwell System for Formation and Culture of Multicellular Human Adipose Tissue-Derived Stem Cell Spheroids. J. Mater. Chem. B. 2016;4:3526-3533.

    Not in our library10.1039/c6tb00064a

  142. 142.

    Pradhan S., Clary J.M., Seliktar D., Lipke E.A. A Three-Dimensional Spheroidal Cancer Model Based on PEG-Fibrinogen Hydrogel Microspheres. Biomaterials. 2017;115:141-154.

    Not in our library10.1016/j.biomaterials.2016.10.052

  143. 143.

    Wu Y., Zhao Z., Guan Y., Zhang Y. Galactosylated Reversible Hydrogels as Scaffold for HepG2 Spheroid Generation. Acta Biomater. 2014;10:1965-1974.

    Not in our library10.1016/j.actbio.2013.12.044

  144. 144.

    Tseng T.-C., Wong C.-W., Hsieh F.-Y., Hsu S. Biomaterial Substrate-Mediated Multicellular Spheroid Formation and Their Applications in Tissue Engineering. Biotechnol. J. 2017;12:1700064.

    Not in our library10.1002/biot.201700064

  145. 145.

    Lee B.H., Kim M.H., Lee J.H., Seliktar D., Cho N.-J., Tan L.P. Modulation of Huh7.5 Spheroid Formation and Functionality Using Modified PEG-Based Hydrogels of Different Stiffness. PLoS ONE. 2015;10:e0118123.

    Not in our library10.1371/journal.pone.0118123

  146. 146.

    Carvalho M.P., Costa E.C., Miguel S.P., Correia I.J. Tumor Spheroid Assembly on Hyaluronic Acid-Based Structures: A Review. Carbohydr. Polym. 2016;150:139-148.

    Not in our library10.1016/j.carbpol.2016.05.005

  147. 147.

    Yamada Y., Yoshida C., Hamada K., Kikkawa Y., Nomizu M. Development of Three-Dimensional Cell Culture Scaffolds Using Laminin Peptide-Conjugated Agarose Microgels. Biomacromolecules. 2020;21:3765-3771.

    Not in our library10.1021/acs.biomac.0c00871

  148. 148.

    Barros A.S., Costa E.C., Nunes A.S., de Melo-Diogo D., Correia I.J. Comparative Study of the Therapeutic Effect of Doxorubicin and Resveratrol Combination on 2D and 3D (Spheroids) Cell Culture Models. Int. J. Pharm. 2018;551:76-83.

    Not in our library10.1016/j.ijpharm.2018.09.016

  149. 149.
    A Comprehensive Panel of Three-Dimensional Models for Studies of Prostate Cancer Growth, Invasion and Drug Responses · 2010
    No notice
  150. 150.

    Poincloux R., Collin O., Lizárraga F., Romao M., Debray M., Piel M., Chavrier P. Contractility of the Cell Rear Drives Invasion of Breast Tumor Cells in 3D Matrigel. Proc. Natl. Acad. Sci. USA. 2011;108:1943-1948.

    Not in our library10.1073/pnas.1010396108

  151. 151.

    Dolega M.E., Abeille F., Picollet-D’hahan N., Gidrol X. Controlled 3D Culture in Matrigel Microbeads to Analyze Clonal Acinar Development. Biomaterials. 2015;52:347-357.

    Not in our library10.1016/j.biomaterials.2015.02.042

  152. 152.

    Chen L., Xiao Z., Meng Y., Zhao Y., Han J., Su G., Chen B., Dai J. Biomaterials The Enhancement of Cancer Stem Cell Properties of MCF-7 Cells in 3D Collagen Scaffolds for Modeling of Cancer and Anti-Cancer Drugs. Biomaterials. 2012;33:1437-1444.

    Not in our library10.1016/j.biomaterials.2011.10.056

  153. 153.

    Campbell J.J., Husmann A., Hume R.D., Watson C.J., Cameron R.E. Biomaterials Development of Three-Dimensional Collagen Scaffolds with Controlled Architecture for Cell Migration Studies Using Breast Cancer Cell Lines. Biomaterials. 2017;114:34-43.

    Not in our library10.1016/j.biomaterials.2016.10.048

  154. 154.

    Liverani C., De Vita A., Minardi S., Kang Y., Mercatali L., Bongiovanni A., La Manna F., Ibrahim T., Tasciotti E. Open a Biomimetic 3D Model of Hypoxia-Driven Cancer Progression. Sci. Rep. 2019;9:12263.

    Not in our library10.1038/s41598-019-48701-4

  155. 155.

    Liverani C., Mercatali L., Cristofolini L., Giordano E., Minardi S., Della Porta G., De Vita A., Miserocchi G., Spadazzi C., Tasciotti E., et al. Investigating the Mechanobiology of Cancer Cell–ECM Interaction Through Collagen-Based 3D Scaffolds. Cell. Mol. Bioeng. 2017;10:223-234.

    Not in our library10.1007/s12195-017-0483-x

  156. 156.

    Egeblad M., Rasch M.G., Weaver V.M. Dynamic Interplay between the Collagen Scaffold and Tumor Evolution. Curr. Opin. Cell Biol. 2010;22:697-706.

    Not in our library10.1016/j.ceb.2010.08.015

  157. 157.

    O’Connor S.M., Andreadis J.D., Shaffer K.M., Ma W., Pancrazio J.J., Stenger D.A. Immobilization of Neural Cells in Three-Dimensional Matrices for Biosensor Applications. Biosens. Bioelectron. 2000;14:871-881.

    Not in our library10.1016/s0956-5663(99)00055-x

  158. 158.

    Cross V.L., Zheng Y., Won Choi N., Verbridge S.S., Sutermaster B.A., Bonassar L.J., Fischbach C., Stroock A.D. Dense Type I Collagen Matrices That Support Cellular Remodeling and Microfabrication for Studies of Tumor Angiogenesis and Vasculogenesis in Vitro. Biomaterials. 2010;31:8596-8607.

    Not in our library10.1016/j.biomaterials.2010.07.072

  159. 159.

    Suggs L.J., Mikos A.G. Development of Poly(Propylene Fumarate-Co-Ethylene Glycol) as an Injectable Carrier for Endothelial Cells. Cell Transplant. 1999;8:345-350.

    Not in our library10.1177/096368979900800402

  160. 160.

    Model D., Cancer B., Subia B., Dey T., Sharma S., Kundu S.C. Target Specific Delivery of Anticancer Drug in Silk Fibroin Based 3D Target Specific Delivery of Anticancer Drug in Silk Fibroin Based 3D Distribution Model of Bone−Breast Cancer Cells. ACS Appl. Mater. Interfaces. 2015;7:2269-2279.

    Not in our library10.1021/am506094c

  161. 161.

    Talukdar S., Kundu S.C. A Non-Mulberry Silk Fibroin Protein Based 3D In Vitro Tumor Model for Evaluation of Anticancer Drug Activity. Adv. Funct. Mater. 2012;22:4778-4788.

    Not in our library10.1002/adfm.201200375

  162. 162.

    Talukdar S., Mandal M., Hutmacher D.W., Russell P.J., Soekmadji C., Kundu S.C. Biomaterials Engineered Silk Fi Broin Protein 3D Matrices for in vitro Tumor Model. Biomaterials. 2011;32:2149-2159.

    Not in our library10.1016/j.biomaterials.2010.11.052

  163. 163.

    Gurski L.A., Jha A.K., Zhang C., Jia X., Farach-Carson M.C. Hyaluronic Acid-Based Hydrogels as 3D Matrices for in Vitro Evaluation of Chemotherapeutic Drugs Using Poorly Adherent Prostate Cancer Cells. Biomaterials. 2009;30:6076-6085.

    Not in our library10.1016/j.biomaterials.2009.07.054

  164. 164.

    Wang Y., Mirza S., Wu S., Zeng J., Shi W. 3D Hydrogel Breast Cancer Models for Studying the Effects of Hypoxia on Epithelial to Mesenchymal Transition. Oncotarget. 2018;9:32191-32203.

    Not in our library10.18632/oncotarget.25891

  165. 165.

    Xu W., Qian J., Zhang Y., Suo A., Cui N., Wang J., Yao Y., Wang H. Acta Biomaterialia A Double-Network Poly (Ne-Acryloyl L-Lysine)/Hyaluronic Acid Hydrogel as a Mimic of the Breast Tumor Microenvironment. Acta Biomater. 2016;33:131-141.

    Not in our library10.1016/j.actbio.2016.01.027

  166. 166.

    Fisher S.A., Anandakumaran P.N., Owen S.C., Shoichet M.S. Tuning the Microenvironment: Click-Crosslinked Hyaluronic Acid-Based Hydrogels Provide a Platform for Studying Breast Cancer Cell Invasion. Adv. Funct. Mater. 2015;25:7163-7172.

    Not in our library10.1002/adfm.201502778

  167. 167.

    Cavo M., Caria M., Pulsoni I., Beltrame F., Fato M., Scaglione S. A New Cell-Laden 3D Alginate-Matrigel Hydrogel Resembles Human Breast Cancer Cell Malignant Morphology, Spread and Invasion Capability Observed “ in vivo”. Sci. Rep. 2018;8:5333.

    Not in our library10.1038/s41598-018-23250-4

  168. 168.

    Qiao S., Zhao Y., Li C., Yin Y., Meng Q., Lin F., Liu Y., Hou X., Guo K., Chen X., et al. Acta Biomaterialia An Alginate-Based Platform for Cancer Stem Cell Research. Acta Biomater. 2016;37:83-92.

    Not in our library10.1016/j.actbio.2016.04.032

  169. 169.
    Directing the Self-assembly of Tumour Spheroids by Bioprinting Cellular Heterogeneous Models within Alginate/Gelatin Hydrogels · 2017
    Not checked
  170. 170.

    Arya A.D., Hallur P.M., Karkisaval A.G., Gudipati A., Rajendiran S., Dhavale V., Ramachandran B., Jayaprakash A., Gundiah N., Chaubey A. Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro. ACS Appl. Mater. Interfaces. 2016;8:22005-22017.

    Not in our library10.1021/acsami.6b06309

  171. 171.

    Charmsaz S., Hughes É., Bane F.T., Tibbitts P., Mcilroy M., Byrne C., Cocchiglia S., Mcbryan J., Hennessy B.T., Dwyer R.M., et al. S100 β as a Serum Marker in Endocrine Resistant Breast Cancer. BMC Med. 2017;15:79.

    Not in our library10.1186/s12916-017-0836-2

  172. 172.

    Benton G., Kleinman H.K., George J., Arnaoutova I. Multiple Uses of Basement Membrane-like Matrix (BME/Matrigel) In Vitro and In Vivo with Cancer Cells. Int. J. Cancer. 2011;128:1751-1757.

    Not in our library10.1002/ijc.25781

  173. 173.

    Ghajar C.M., Bissell M.J. Extracellular Matrix Control of Mammary Gland Morphogenesis and Tumorigenesis: Insights from Imaging. Histochem. Cell Biol. 2008;130:1105-1118.

    Not in our library10.1007/s00418-008-0537-1

  174. 174.

    Raub C.B., Unruh J., Suresh V., Krasieva T., Lindmo T., Gratton E., Tromberg B.J., George S.C. Image Correlation Spectroscopy of Multiphoton Images Correlates with Collagen Mechanical Properties. Biophys. J. 2008;94:2361-2373.

    Not in our library10.1529/biophysj.107.120006

  175. 175.

    Fridman R., Giaccone G., Kanemoto T., Martin G.R., Gazdar A.F., Mulshine J.L. Reconstituted Basement Membrane (Matrigel) and Laminin Can Enhance the Tumorigenicity and the Drug Resistance of Small Cell Lung Cancer Cell Lines. Proc. Natl. Acad. Sci. 1990;87:6698-6702.

    Not in our library10.1073/pnas.87.17.6698

  176. 176.

    Xu S., Jia Z.-F., Kang C., Huang Q., Wang G., Liu X., Zhou X., Xu P., Pu P. Upregulation of SEPT7 Gene Inhibits Invasion of Human Glioma Cells. Cancer Investig. 2010;28:248-258.

    Not in our library10.3109/07357900903179609

  177. 177.

    Arnaoutova I., George J., Kleinman H.K., Benton G. The Endothelial Cell Tube Formation Assay on Basement Membrane Turns 20: State of the Science and the Art. Angiogenesis. 2009;12:267-274.

    Not in our library10.1007/s10456-009-9146-4

  178. 178.

    Manuscript A. Modular Extracellular Matrices: Solutions for the Puzzle. Methods. 2009;45:93-98.

    Not in our library10.1016/j.ymeth.2008.01.010

  179. 179.

    Jafari M., Paknejad Z., Rad M.R., Motamedian S.R., Eghbal M.J., Nadjmi N., Khojasteh A. Polymeric Scaffolds in Tissue Engineering: A Literature Review. J. Biomed. Mater. Res. Part B Appl. Biomater. 2017;105:431-459.

    Not in our library10.1002/jbm.b.33547

  180. 180.

    Nagaoka M., Jiang H.L., Hoshiba T., Akaike T., Cho C.S. Application of Recombinant Fusion Proteins for Tissue Engineering. Ann. Biomed. Eng. 2010;38:683-693.

    Not in our library10.1007/s10439-010-9935-3

  181. 181.

    Kapoor S., Kundu S.C. Acta Biomaterialia Silk Protein-Based Hydrogels: Promising Advanced Materials for Biomedical Applications. Acta Biomater. 2016;31:17-32.

    Not in our library10.1016/j.actbio.2015.11.034

  182. 182.

    Conklin M.W., Keely P.J. Why the stroma matters in breast cancer. Cell Adhes. Migr. 2012;6:249-260.

    Not in our library10.4161/cam.20567

  183. 183.

    Acerbi Cassereau I., Weaver V.M. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integrative Biology. 2015;7:1120-1134.

    Not in our library10.1039/c5ib00040h

  184. 184.

    Singh D., Singh D., Han S.S. 3D Printing of Scaffold for Cells Delivery: Advances in Skin Tissue Engineering. Polymers. 2016;8:19.

    Not in our library10.3390/polym8010019

  185. 185.

    Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F.T., Csiszar K., Giaccia A., Weninger W., et al. Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell. 2009;139:891-906.

    Not in our library10.1016/j.cell.2009.10.027

  186. 186.
    Collagen as a double-edged sword in tumor progression · 2013
    No notice
  187. 187.

    Gelse K., Pöschl E., Aigner T. Collagens-Structure, Function, and Biosynthesis. Adv. Drug Deliv. Rev. 2003;55:1531-1546.

    Not in our library10.1016/j.addr.2003.08.002

  188. 188.

    Gordon M.K., Hahn R.A. Collagens. Cell Tissue Res. 2009;339:247.

    Not in our library10.1007/s00441-009-0844-4

  189. 189.

    Shoulders M.D., Raines R.T. Collagen Structure and Stability. Annu. Rev. Biochem. 2009;78:929-958.

    Not in our library10.1146/annurev.biochem.77.032207.120833

  190. 190.

    Ramtani S., Helary C. Mechanical Behavior under Unconfined Compression Loading of Dense Fibrillar Collagen Matrices Mimetic Living Tissues Compression Loadings of Dense. J. Mech. Med. Biol. 2010;10:35-55.

    Not in our library10.1142/s0219519410003290

  191. 191.

    Tierney C.M., Haugh M.G., Liedl J., Mulcahy F., Hayes B., O’Brien F.J. The Effects of Collagen Concentration and Crosslink Density on the Biological, Structural and Mechanical Properties of Collagen-GAG Scaffolds for Bone Tissue Engineering. J. Mech. Behav. Biomed. Mater. 2009;2:202-209.

    Not in our library10.1016/j.jmbbm.2008.08.007

  192. 192.

    Ahmed E.M. Hydrogel: Preparation, Characterization, and Applications: A Review. J. Adv. Res. 2015;6:105-121.

    Not in our library10.1016/j.jare.2013.07.006

  193. 193.

    Antoine E.E., Vlachos P.P., Rylander M.N. Review of Collagen I Hydrogels for Bioengineered Tissue Microenvironments: Characterization of Mechanics, Structure, and Transport. Tissue Eng. Part B Rev. 2014;20:683-696.

    Not in our library10.1089/ten.teb.2014.0086

  194. 194.

    Martin R., Farjanel J., Eichenberger D., Colige A., Kessler E., Hulmes D.J.S., Giraud-Guille M.M. Liquid Crystalline Ordering of Procollagen as a Determinant of Three-Dimensional Extracellular Matrix Architecture. J. Mol. Biol. 2000;301:11-17.

    Not in our library10.1006/jmbi.2000.3855

  195. 195.

    Achilli M., Mantovani D. Tailoring Mechanical Properties of Collagen-Based Scaffolds for Vascular Tissue Engineering: The Effects of PH, Temperature and Ionic Strength on Gelation. Polymers. 2010;2:664-680.

    Not in our library10.3390/polym2040664

  196. 196.

    Hyllested J.L., Veje K., Ostergaard K. Histochemical Studies of the Extracellular Matrix of Human Articular Cartilage—A Review. Osteoarthr. Cartil. 2002;10:333-343.

    Not in our library10.1053/joca.2002.0519

  197. 197.
    Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment. · 2012
    Not checked
  198. 198.

    James-Bhasin M., Siegel P.M., Nazhat S.N. A Three-Dimensional Dense Collagen Hydrogel to Model Cancer Cell/Osteoblast Interactions. J. Funct. Biomater. 2018;9:72.

    Not in our library10.3390/jfb9040072

  199. 199.

    Tom E., Jonathan B. Collagen substrata for studies on cell behavior. J. Cell Biol. 1972;54:626-637.

    Not in our library10.1083/jcb.54.3.626

  200. 200.

    Folkman J., Haudenschild C. Angiogenesis in Vitro. Nature. 1980;288:551-556.

    Not in our library10.1038/288551a0

  201. 201.

    Krause S., Maffini M.V., Soto A.M., Sonnenschein C. The Microenvironment Determines the Breast Cancer Cells’ Phenotype: Organization of MCF7 Cells in 3D Cultures. BMC Cancer. 2010;10:263.

    Not in our library10.1186/1471-2407-10-263

  202. 202.

    Millerot-Serrurot E., Guilbert M., Fourré N., Witkowski W., Said G., Van Gulick L., Terryn C., Zahm J.-M., Garnotel R., Jeannesson P. 3D Collagen Type I Matrix Inhibits the Antimigratory Effect of Doxorubicin. Cancer Cell Int. 2010;10:26.

    Not in our library10.1186/1475-2867-10-26

  203. 203.

    Patterson D.M., Nazarova L.A., Prescher J.A. Finding the Right (Bioorthogonal) Chemistry. ACS Chem. Biol. 2014;9:592-605.

    Not in our library10.1021/cb400828a

  204. 204.

    Lutolf M.P., Hubbell J.A. Synthetic Biomaterials as Instructive Extracellular Microenvironments for Morphogenesis in Tissue Engineering. Nat. Biotechnol. 2005;23:47-55.

    Not in our library10.1038/nbt1055

  205. 205.

    Lokeshwar V.B., Cerwinka W.H., Isoyama T., Lokeshwar B.L. HYAL1 Hyaluronidase in Prostate Cancer: A Tumor Promoter and Suppressor. Cancer Res. 2005;65:7782-7789.

    Not in our library10.1158/0008-5472.can-05-1022

  206. 206.

    Murphy A.R., Laslett A., O’Brien C.M., Cameron N.R. Scaffolds for 3D in Vitro Culture of Neural Lineage Cells. Acta Biomater. 2017;54:1-20.

    Not in our library10.1016/j.actbio.2017.02.046

  207. 207.

    Burdick J.A., Anseth K.S. Photoencapsulation of Osteoblasts in Injectable RGD-Modified PEG Hydrogels for Bone Tissue Engineering. Biomaterials. 2002;23:4315-4323.

    Not in our library10.1016/s0142-9612(02)00176-x

  208. 208.

    Burdick J.A., Mason M.N., Hinman A.D., Thorne K., Anseth K.S. Delivery of Osteoinductive Growth Factors from Degradable PEG Hydrogels Influences Osteoblast Differentiation and Mineralization. J. Control. Release. 2002;83:53-63.

    Not in our library10.1016/s0168-3659(02)00181-5

  209. 209.

    Bryant S.J., Durand K.L., Anseth K.S. Manipulations in Hydrogel Chemistry Control Photoencapsulated Chondrocyte Behavior and Their Extracellular Matrix Production. J. Biomed. Mater. Res. Part A. 2003;67:1430-1436.

    Not in our library10.1002/jbm.a.20003

  210. 210.

    Bryant S.J., Anseth K.S. Hydrogel Properties Influence ECM Production by Chondrocytes Photoencapsulated in Poly(Ethylene Glycol) Hydrogels. J. Biomed. Mater. Res. 2002;59:63-72.

    Not in our library10.1002/jbm.1217

  211. 211.

    Adelöw C., Segura T., Hubbell J.A., Frey P. The Effect of Enzymatically Degradable Poly(Ethylene Glycol) Hydrogels on Smooth Muscle Cell Phenotype. Biomaterials. 2008;29:314-326.

    Not in our library10.1016/j.biomaterials.2007.09.036

  212. 212.

    Strutz F., Zeisberg M., Renziehausen A., Raschke B., Becker V., van Kooten C., Müller G. TGF-Beta 1 Induces Proliferation in Human Renal Fibroblasts via Induction of Basic Fibroblast Growth Factor (FGF-2). Kidney Int. 2001;59:579-592.

    Not in our library10.1046/j.1523-1755.2001.059002579.x

  213. 213.

    Engler A.J., Sen S., Sweeney H.L., Discher D.E. Matrix Elasticity Directs Stem Cell Lineage Specification. Cell. 2006;126:677-689.

    Not in our library10.1016/j.cell.2006.06.044

  214. 214.

    Hayward A.S., Sano N., Przyborski S.A., Cameron N.R. Acrylic-Acid-Functionalized PolyHIPE Scaffolds for Use in 3D Cell Culture. Macromol. Rapid Commun. 2013;34:1844-1849.

    Not in our library10.1002/marc.201300709

  215. 215.

    Brown T.E., Anseth K.S. Spatiotemporal Hydrogel Biomaterials for Regenerative Medicine. Chem. Soc. Rev. 2017;46:6532-6552.

    Not in our library10.1039/c7cs00445a

  216. 216.

    Sell S.A., Wolfe P.S., Garg K., McCool J.M., Rodriguez I.A., Bowlin G.L. The Use of Natural Polymers in Tissue Engineering: A Focus on Electrospun Extracellular Matrix Analogues. Polymers. 2010;2:522-553.

    Not in our library10.3390/polym2040522

  217. 217.

    Liu J., He X., Corbett S.A., Lowry S.F., Graham A.M., Fässler R., Li S. Integrins Are Required for the Differentiation of Visceral Endoderm. J. Cell Sci. 2009;122:233-242.

    Not in our library10.1242/jcs.037663

  218. 218.

    El-Sherbiny I.M., Smyth H.D.C. Poly(Ethylene Glycol)-Carboxymethyl Chitosan-Based PH-Responsive Hydrogels: Photo-Induced Synthesis, Characterization, Swelling, and in Vitro Evaluation as Potential Drug Carriers. Carbohydr. Res. 2010;345:2004-2012.

    Not in our library10.1016/j.carres.2010.07.026

  219. 219.

    Davidenko N., Campbell J.J., Thian E.S., Watson C.J., Cameron R.E. Acta Biomaterialia Collagen–Hyaluronic Acid Scaffolds for Adipose Tissue Engineering. Acta Biomater. 2010;6:3957-3968.

    Not in our library10.1016/j.actbio.2010.05.005

  220. 220.

    Pluen A., Boucher Y., Ramanujan S., McKee T.D., Gohongi T., di Tomaso E., Brown E.B., Izumi Y., Campbell R.B., Berk D.A., et al. Role of Tumor-Host Interactions in Interstitial Diffusion of Macromolecules: Cranial vs. Subcutaneous Tumors. Proc. Natl. Acad. Sci. USA. 2001;98:4628-4633.

    Not in our library10.1073/pnas.081626898

  221. 221.

    Toole B.P. Hyaluronan Promotes the Malignant Phenotype. Glycobiology. 2002;12:37R-42R.

    Not in our library10.1093/glycob/12.3.37r

  222. 222.

    Gallagher J.T. Heparan Sulfate: Growth Control with a Restricted Sequence Menu. J. Clin. Investig. 2001;108:357-361.

    Not in our library10.1172/jci13713

  223. 223.

    Guimond S., Maccarana M., Olwin B.B., Lindahl U., Rapraeger A.C. Activating and Inhibitory Heparin Sequences for FGF-2 (Basic FGF). Distinct Requirements for FGF-1, FGF-2, and FGF-4. J. Biol. Chem. 1993;268:23906-23914.

    Not in our library10.1016/s0021-9258(20)80471-2

  224. 224.

    Nikitovic D., Assouti M., Sifaki M., Katonis P., Krasagakis K., Karamanos N.K., Tzanakakis G.N. Chondroitin Sulfate and Heparan Sulfate-Containing Proteoglycans Are Both Partners and Targets of Basic Fibroblast Growth Factor-Mediated Proliferation in Human Metastatic Melanoma Cell Lines. Int. J. Biochem. Cell Biol. 2008;40:72-83.

    Not in our library10.1016/j.biocel.2007.06.019

  225. 225.

    Toole B.P. Hyaluronan: From Extracellular Glue to Pericellular Cue. Nat. Rev. Cancer. 2004;4:528-539.

    Not in our library10.1038/nrc1391

  226. 226.
    Targeting ECM Disrupts Cancer Progression · 2015
    No notice
  227. 227.

    Campbell J.C., Botos L.A., Sargeant T.J., Davidenko N., Cameron R.E., Watson C.J. A 3-D in vitro co-culture model of mammary gland involution. Integr. Biol (Camb). 2014;6:618-626.

    Not in our library10.1039/c3ib40257f

  228. 228.

    Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Department of Systems Pharmacology, UTokyo Graduate School of Medicine. The CUBIC Clearing Protocol with Reagent-1A (for Whole Mouse Brain). 2015.

    Not in our library

  229. 229.

    Monteiro J., Gaspar C., Richer W., Franken P.F., Sacchetti A., Joosten R., Idali A., Brandao J., Decraene C., Fodde R. Cancer Stemness in Wnt-Driven Mammary Tumorigenesis. Carcinogenesis. 2014;35:2-13.

    Not in our library10.1093/carcin/bgt279

  230. 230.

    Hemmrich K., Von Heimburg D., Rendchen R., Di C., Milella E., Pallua N. Implantation of Preadipocyte-Loaded Hyaluronic Acid-Based Scaffolds into Nude Mice to Evaluate Potential for Soft Tissue Engineering. Biomaterials. 2005;26:7025-7037.

    Not in our library10.1016/j.biomaterials.2005.04.065

  231. 231.

    Flynn L., Prestwich G.D., Semple J.L., Woodhouse K.A. Adipose Tissue Engineering in Vivo with Adipose-Derived Stem Cells on Naturally Derived Scaffolds. J. Biomed. Mater. Res. Part A. 2009;89:929-941.

    Not in our library10.1002/jbm.a.32044

  232. 232.

    Flynn L., Prestwich G.D., Semple J.L., Woodhouse K.A. Adipose Tissue Engineering with Naturally Derived Scaffolds and Adipose-Derived Stem Cells. Biomaterials. 2007;28:3834-3842.

    Not in our library10.1016/j.biomaterials.2007.05.002

  233. 233.

    Halbleib M., Skurk T., De Luca C., Von Heimburg D., Hauner H. Tissue Engineering of White Adipose Tissue Using Hyaluronic Acid-Based Scaffolds. I: In Vitro Differentiation of Human Adipocyte Precursor Cells on Scaffolds. Biomaterials. 2003;24:3125-3132.

    Not in our library10.1016/s0142-9612(03)00156-x

  234. 234.

    Offeddu G.S., Ashworth J.C., Cameron R.E., Oyen M.L. Multi-Scale Mechanical Response of Freeze-Dried Collagen Scaffolds for Tissue Engineering Applications. J. Mech. Behav. Biomed. Mater. 2015;42:19-25.

    Not in our library10.1016/j.jmbbm.2014.10.015

  235. 235.

    Hume R.D., Pensa S., Brown E.J., Kreuzaler P.A., Hitchcock J., Husmann A., Campbell J.J., Lloyd-thomas A.O., Cameron R.E., Watson C.J. Tumour Cell Invasiveness and Response to Chemotherapeutics in Adipocyte Invested 3D Engineered Anisotropic Collagen Scaffolds. Sci. Rep. 2018;1-15.

    Not in our library10.1038/s41598-018-30107-3

  236. 236.

    Wondraczek H., Elschner T., Heinze T. Synthesis of Highly Functionalized Dextran Alkyl Carbonates Showing Nanosphere Formation. Carbohydr. Polym. 2011;83:1112-1118.

    Not in our library10.1016/j.carbpol.2010.09.013

  237. 237.

    Nowakowska M., Zapotoczny S., Sterzel M., Kot E. Novel Water-Soluble Photosensitizers from Dextrans. Biomacromolecules. 2004;5:1009-1014.

    Not in our library10.1021/bm034506w

  238. 238.

    Cao B., Li L., Wu H., Tang Q., Sun B., Dong H., Zhe J., Cheng G. Zwitteration of Dextran: A Facile Route to Integrate Antifouling, Switchability and Optical Transparency into Natural Polymers. Chem. Commun. 2014;50:3234-3237.

    Not in our library10.1039/c3cc48878k

  239. 239.

    Perrino C., Lee S., Choi S.W., Maruyama A., Spencer N.D. A Biomimetic Alternative to Poly(Ethylene Glycol) as an Antifouling Coating: Resistance to Nonspecific Protein Adsorption of Poly(L-Lysine)-Graft-Dextran. Langmuir. 2008;24:8850-8856.

    Not in our library10.1021/la800947z

  240. 240.

    Zhang X., Yang Y., Yao J., Shao Z., Chen X. Strong Collagen Hydrogels by Oxidized Dextran Modification. ACS Sustain. Chem. Eng. 2014;2:1318-1324.

    Not in our library10.1021/sc500154t

  241. 241.

    Berillo D., Elowsson L., Kirsebom H. Oxidized Dextran as Crosslinker for Chitosan Cryogel Scaffolds and Formation of Polyelectrolyte Complexes between Chitosan and Gelatin. Macromol. Biosci. 2012;12:1090-1099.

    Not in our library10.1002/mabi.201200023

  242. 242.

    Wang T., Nie J., Yang D. Dextran and Gelatin Based Photocrosslinkable Tissue Adhesive. Carbohydr. Polym. 2012;90:1428-1436.

    Not in our library10.1016/j.carbpol.2012.07.011

  243. 243.

    Hoffmann B., Seitz D., Mencke A., Kokott A., Ziegler G. Glutaraldehyde and Oxidised Dextran as Crosslinker Reagents for Chitosan-Based Scaffolds for Cartilage Tissue Engineering. J. Mater. Sci. Mater. Med. 2009;20:1495-1503.

    Not in our library10.1007/s10856-009-3707-3

  244. 244.

    Khor E., Lim L.Y. Implantable Applications of Chitin and Chitosan. Biomaterials. 2003;24:2339-2349.

    Not in our library10.1016/s0142-9612(03)00026-7

  245. 245.

    Dash M., Federica C., Ottenbrite R., Chiellini E. Chitosan—A Versatile Semi-Synthetic Polymer in Biomedical Applications. Prog. Polym. Sci. 2011;36:981-1014.

    Not in our library10.1016/j.progpolymsci.2011.02.001

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    Madihally S.V., Matthew H.W. Porous Chitosan Scaffolds for Tissue Engineering. Biomaterials. 1999;20:1133-1142.

    Not in our library10.1016/s0142-9612(99)00011-3

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    Hornof M.D., Kast C.E., Bernkop-Schnürch A. In Vitro Evaluation of the Viscoelastic Properties of Chitosan-Thioglycolic Acid Conjugates. Eur. J. Pharm. Biopharm. 2003;55:185-190.

    Not in our library10.1016/s0939-6411(02)00162-5

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    Loscalzo D.E.H.R.C.J. NIH Public Access. Bone. 2011;23:1-7.

    Not in our library10.1002/jbm.a.32259.monocyte

  249. 249.

    Rabionet M., Yeste M. Electrospinning PCL Scaffolds Manufacture for Three-Dimensional Breast Cancer Cell Culture. Polymers. 2017;9:328.

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    Cdk2 silencing via a DNA/PCL electrospun scaffold suppresses proliferation and increases death of breast cancer cells. · 2012
    Not checked
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    Sims-Mourtada J., Niamat R.A., Samuel S., Eskridge C., Kmiec E.B. Enrichment of Breast Cancer Stem-like Cells by Growth on Electrospun Polycaprolactone-Chitosan Nanofiber Scaffolds. Int. J. Nanomed. 2014;9:995-1003.

    Not in our library10.2147/ijn.s55720

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    Ampuja M., Jokimäki R., Juuti-uusitalo K., Rodriguez-martinez A., Alarmo E., Kallioniemi A. BMP4 Inhibits the Proliferation of Breast Cancer Cells and Induces an MMP-Dependent Migratory Phenotype in MDA-MB-231 Cells in 3D Environment. BMC Cancer. 2013;13:429.

    Not in our library10.1186/1471-2407-13-429

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    Pradhan S., Hassani I., Seeto W.J., Lipke E.A. PEG-Fibrinogen Hydrogels for Three-Dimensional Breast Cancer Cell Culture. J. Biomed. Mater. Res. Part A. 2016;105:236-252.

    Not in our library10.1002/jbm.a.35899

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    Chang F.-C., Tsao C.-T., Lin A., Zhang M., Levengood S.L., Zhang M. PEG-Chitosan Hydrogel with Tunable Stiffness for Study of Drug Response of Breast Cancer Cells. Polymers. 2016;8:112.

    Not in our library10.3390/polym8040112

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    Pathi S.P., Lin D.D.W., Dorvee J.R., Estroff L.A., Fischbach C. Biomaterials Hydroxyapatite Nanoparticle-Containing Scaffolds for the Study of Breast Cancer Bone Metastasis. Biomaterials. 2011;32:5112-5122.

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    Bryant S.J., Anseth K.S., Lee D.A., Bader D.L. Crosslinking Density Influences the Morphology of Chondrocytes Photoencapsulated in PEG Hydrogels during the Application of Compressive Strain. J. Orthop. Res. 2004;22:1143-1149.

    Not in our library10.1016/j.orthres.2004.02.001

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    Bryant S.J., Chowdhury T.T., Lee D.A., Bader D.L., Anseth K.S. Crosslinking Density Influences Chondrocyte Metabolism in Dynamically Loaded Photocrosslinked Poly(Ethylene Glycol) Hydrogels. Ann. Biomed. Eng. 2004;32:407-417.

    Not in our library10.1023/b:abme.0000017535.00602.ca

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    Levenberg S., Huang N.F., Lavik E., Rogers A.B., Itskovitz-Eldor J., Langer R. Differentiation of Human Embryonic Stem Cells on Three-Dimensional Polymer Scaffolds. Proc. Natl. Acad. Sci. USA. 2003;100:12741-12746.

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    Mikos A.G., Sarakinos G., Leite S.M., Vacant J.P., Langer R. Laminated Three-Dimensional Biodegradable Foams for Use in Tissue Engineering. Biomaterials. 1993;14:323-330.

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    Ouyang A., Ng R., Yang S.-T. Long-Term Culturing of Undifferentiated Embryonic Stem Cells in Conditioned Media and Three-Dimensional Fibrous Matrices Without Extracellular Matrix Coating. Stem Cells. 2007;25:447-454.

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    Girard Y.K., Wang C., Ravi S., Howell M.C., Mallela J., Alibrahim M., Green R., Hellermann G., Mohapatra S.S., Mohapatra S. A 3D Fibrous Scaffold Inducing Tumoroids: A Platform for Anticancer Drug Development. PLoS ONE. 2013;8:e75345.

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    Vasita R., Katti D.S. Nanofibers and Their Applications in Tissue Engineering. Int. J. Nanomed. 2006;1:15-30.

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    Glass-Brudzinski J., Perizzolo D., Brunette D.M. Effects of Substratum Surface Topography on the Organization of Cells and Collagen Fibers in Collagen Gel Cultures. J. Biomed. Mater. Res. 2002;61:608-618.

    Not in our library10.1002/jbm.10243

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    Karuri N.W., Liliensiek S., Teixeira A.I., Abrams G., Campbell S., Nealey P.F., Murphy C.J. Biological Length Scale Topography Enhances Cell-Substratum Adhesion of Human Corneal Epithelial Cells. J. Cell Sci. 2004;117:3153-3164.

    Not in our library10.1242/jcs.01146

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    Dalby M.J. Cellular Response to Low Adhesion Nanotopographies. Int. J. Nanomed. 2007;2:373-381.

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    Maltman D.J., Przyborski S.A. Developments in Three-Dimensional Cell Culture Technology Aimed at Improving the Accuracy of in Vitro Analyses. Biochem. Soc. Trans. 2010;38:1072-1075.

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    Knight E., Murray B., Carnachan R., Przyborski S. Alvetex®: Polystyrene Scaffold Technology for Routine Three Dimensional Cell Culture. Methods Mol. Biol. 2011;695:323-340.

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    Hayman M.W., Smith K.H., Cameron N.R., Przyborski S.A. Growth of Human Stem Cell-Derived Neurons on Solid Three-Dimensional Polymers. J. Biochem. Biophys. Methods. 2005;62:231-240.

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    Hayman M.W., Smith K.H., Cameron N.R., Przyborski S.A. Enhanced Neurite Outgrowth by Human Neurons Grown on Solid Three-Dimensional Scaffolds. Biochem. Biophys. Res. Commun. 2004;314:483-488.

    Not in our library10.1016/j.bbrc.2003.12.135

  270. 270.

    Alayoubi A., Alqahtani S., Kaddoumi A., Nazzal S. Effect of PEG Surface Conformation on Anticancer Activity and Blood Circulation of Nanoemulsions Loaded with Tocotrienol-Rich Fraction of Palm Oil. AAPS J. 2013;15:1168-1179.

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    Han S., Nie K., Li J., Sun Q., Wang X., Li X., Li Q. 3D Electrospun Nanofiber-Based Scaffolds: From Preparations and Properties to Tissue Regeneration Applications. Stem Cells Int. 2021;2021:8790143.

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    Sancho A., Vazquez L., De Juan-Pardo E. Effect of Cold Storage on Collagen-Based Hydrogels for the Three-Dimensional Culture of Adipose-Derived Stem Cells. Biofabrication. 2014;6:35017.

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    Ghaedi M., Soleimani M., Shabani I., Duan Y., Lotfi A. Hepatic Differentiation from Human Mesenchymal Stem Cells on a Novel Nanofiber Scaffold. Cell. Mol. Biol. Lett. 2012;17:89-106.

    Not in our library10.2478/s11658-011-0040-x

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    Puppi D., Zhang X., Yang L., Chiellini F., Sun X., Chiellini E. Nano/Microfibrous Polymeric Constructs Loaded with Bioactive Agents and Designed for Tissue Engineering Applications: A Review. J. Biomed. Mater. Res. Part B Appl. Biomater. 2014;102:1562-1579.

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    Kundu B., Rajkhowa R., Kundu S.C., Wang X. Silk Fibroin Biomaterials for Tissue Regenerations. Adv. Drug Deliv. Rev. 2013;65:457-470.

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    O’Brien F.J., Harley B.A., Yannas I.V., Gibson L.J. The Effect of Pore Size on Cell Adhesion in Collagen-GAG Scaffolds. Biomaterials. 2005;26:433-441.

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    Zhu W., Holmes B., Glazer R.I., Zhang L.G. 3D Printed Nanocomposite Matrix for the Study of Breast Cancer Bone Metastasis. Nanomed. Nanotechnol. Biol. Med. 2016;12:69-79.

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    Yang Y., Yang X., Zou J., Jia C., Hu Y., Du H., Wang H. Evaluation of Photodynamic Therapy Efficiency Using an In Vitro Three-Dimensional Microfluidic Breast Cancer Tissue Model. Lab Chip. 2014;15:735-744.

    Not in our library10.1039/c4lc01065e

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    Rao S.S., DeJesus J., Short A.R., Otero J.J., Sarkar A., Winter J.O. Glioblastoma Behaviors in Three-Dimensional Collagen-Hyaluronan Composite Hydrogels. ACS Appl. Mater. Interfaces. 2013;5:9276-9284.

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    Friedl P., Maaser K., Klein C.E., Niggemann B., Krohne G., Zã K.S. Migration of Highly Aggressive MV3 Melanoma Cells in 3-Dimensional Collagen Lattices Results in Local Matrix Reorganization and Shedding of A2 and 131Integrins and CD441. Cancer Res. 1997;57:2061-2070.

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    Nyga A., Loizidou M., Emberton M., Cheema U. A Novel Tissue Engineered Three-Dimensional in Vitro Colorectal Cancer Model. Acta Biomater. 2013;9:7917-7926.

    Not in our library10.1016/j.actbio.2013.04.028

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    Heywood H.K., Sembi P.K., Lee D.A., Bader D.L. Cellular Utilization Determines Viability and Matrix Distribution Profiles in Chondrocyte-Seeded Alginate Constructs. Tissue Eng. 2004;10:1467-1479.

    Not in our library10.1089/ten.2004.10.1467

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    Jongpaiboonkit L., King W.J., Lyons G.E., Paguirigan A.L., Warrick J.W., Beebe D.J., Murphy W.L. An Adaptable Hydrogel Array Format for 3-Dimensional Cell Culture and Analysis. Biomaterials. 2008;29:3346-3356.

    Not in our library10.1016/j.biomaterials.2008.04.040

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    Gutowska A., Bae Y.H., Feijen J., Kim S.W. Heparin Release from Thermosensitive Hydrogels. J. Control. Release. 1992;22:95-104.

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    Ferreira L., Vidal M.M., Gil M.H. Evaluation of Poly(2-Hydroxyethyl Methacrylate) Gels as Drug Delivery Systems at Different PH Values. Int. J. Pharm. 2000;194:169-180.

    Not in our library10.1016/s0378-5173(99)00375-0

  286. 286.

    D’Emanuele A., Staniforth J.N. An Electrically Modulated Drug Delivery Device: I. Pharm. Res. 1991;8:913-918.

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  287. 287.

    Barbosa M.A., Chiesa R., Cigada A., Ginebra M.P., Leali P.T., Lewis A.L., Lloyd A.W., Merolli A., Montufar E.B., Pérez R.A., Santin M., Phillips G. Biomimetic, bioresponsive, and bioactive materials: An Introduction to Integrating Materials with Tissues. 2012.

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    Léon Y. León, C.A. New Perspectives in Mercury Porosimetry. Adv. Colloid Interface Sci. 1998;76–77:341-372.

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    Yang S., Leong K.F., Du Z., Chua C.K. The Design of Scaffolds for Use in Tissue Engineering. Part I. Traditional Factors. Tissue Eng. 2001;7:679-689.

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    Brauker J.H., Carr-Brendel V.E., Martinson L.A., Crudele J., Johnston W.D., Johnson R.C. Neovascularization of Synthetic Membranes Directed by Membrane Microarchitecture. J. Biomed. Mater. Res. 1995;29:1517-1524.

    Not in our library10.1002/jbm.820291208

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    Klawitter J.J., Hulbert S.F. Application of Porous Ceramics for the Attachment of Load Bearing Internal Orthopedic Applications. J. Biomed. Mater. Res. 1971;5:161-229.

    Not in our library10.1002/jbm.820050613

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    Levingstone T.J., Matsiko A., Dickson G.R., Brien F.J.O., Gleeson J.P. Acta Biomaterialia A Biomimetic Multi-Layered Collagen-Based Scaffold for Osteochondral Repair. Acta Biomater. 2014;10:1996-2004.

    Not in our library10.1016/j.actbio.2014.01.005

  293. 293.

    Haugh M.G., Murphy C.M., Mckiernan R.C., Altenbuchner C., Brien F.J.O. Cell Attachment, Proliferation, and Migration Within Collagen Glycosaminoglycan Scaffolds. Tissue Eng. Part A. 2011;17:1201-1208.

    Not in our library10.1089/ten.tea.2010.0590

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    Curtin C.M., Cunniffe G.M., Lyons F.G., Bessho K., Dickson G.R., Duffy G.P., Brien F.J.O. Innovative Collagen Nano-Hydroxyapatite Scaffolds Offer a Highly Efficient Non-Viral Gene Delivery Platform for Stem Cell-Mediated Bone Formation. Adv. Mater. 2012;24:749-754.

    Not in our library10.1002/adma.201103828

  295. 295.

    Ueda H., Hong L., Yamamoto M., Shigeno K., Inoue M., Toba T., Yoshitani M., Nakamura T., Tabata Y., Shimizu Y. Use of Collagen Sponge Incorporating Transforming Growth Factor-Β1 to Promote Bone Repair in Skull Defects in Rabbits. Biomaterials. 2002;23:1003-1010.

    Not in our library10.1016/s0142-9612(01)00211-3

  296. 296.

    Pawelec K.M., Husmann A., Best S.M., Cameron R.E. Understanding Anisotropy and Architecture in Ice-Templated Biopolymer Scaffolds. Mater. Sci. Eng. C. 2014;37:141-147.

    Not in our library10.1016/j.msec.2014.01.009

  297. 297.

    Haugh M.G., Murphy C.M., O’Brien F.J. Novel Freeze-Drying Methods to Produce a Range of Collagen–Glycosaminoglycan Scaffolds with Tailored Mean Pore Sizes. Tissue Eng. Part C Methods. 2009;16:887-894.

    Not in our library10.1089/ten.tec.2009.0422

  298. 298.

    O’Brien F.J., Harley B.A., Yannas I.V., Gibson L. Influence of Freezing Rate on Pore Structure in Freeze-Dried Collagen-GAG Scaffolds. Biomaterials. 2004;25:1077-1086.

    Not in our library10.1016/s0142-9612(03)00630-6

  299. 299.

    Szot C.S., Buchanan C.F., Gatenholm P., Nichole M., Freeman J.W. Investigation of Cancer Cell Behavior on Nano Fi Brous Scaffolds. Mater. Sci. Eng. C. 2011;31:37-42.

    Not in our library10.1016/j.msec.2009.12.005

  300. 300.

    Tran C., Kalra V. Fabrication of Porous Carbon Nanofibers with Adjustable Pore Sizes as Electrodes for Supercapacitors. J. Power Sources. 2013;235:289-296.

    Not in our library10.1016/j.jpowsour.2013.01.080

  301. 301.

    Phipps M.C., Clem W.C., Grunda J.M., Clines G.A., Bellis S.L. Increasing the Pore Sizes of Bone-Mimetic Electrospun Scaffolds Comprised of Polycaprolactone, Collagen I and Hydroxyapatite to Enhance Cell Infiltration. Biomaterials. 2012;33:524-534.

    Not in our library10.1016/j.biomaterials.2011.09.080

  302. 302.

    Blakeney B.A., Tambralli A., Anderson J.M., Andukuri A., Lim D., Dean D.R., Jun H. Biomaterials Cell in Fi Ltration and Growth in a Low Density, Uncompressed Three-Dimensional Electrospun Nano Fi Brous Scaffold. Biomaterials. 2011;32:1583-1590.

    Not in our library10.1016/j.biomaterials.2010.10.056

  303. 303.

    Zhang Y.Z., Feng Y., Huang Z.-M., Ramakrishna S., Lim C.T. Fabrication of Porous Electrospun Nanofibres. Nanotechnology. 2006;17:901-908.

    Not in our library10.1088/0957-4484/17/3/047

  304. 304.

    Kim T.G., Chung H.J., Park T.G. Macroporous and Nanofibrous Hyaluronic Acid/Collagen Hybrid Scaffold Fabricated by Concurrent Electrospinning and Deposition/Leaching of Salt Particles. Acta Biomater. 2008;4:1611-1619.

    Not in our library10.1016/j.actbio.2008.06.008

  305. 305.

    Li W.-J., Laurencin C.T., Caterson E.J., Tuan R.S., Ko F.K. Electrospun Nanofibrous Structure: A Novel Scaffold for Tissue Engineering. J. Biomed. Mater. Res. 2002;60:613-621.

    Not in our library10.1002/jbm.10167

  306. 306.

    Ma P.X. Biomimetic Materials for Tissue Engineering. Adv. Drug Deliv. Rev. 2008;60:184-198.

    Not in our library10.1016/j.addr.2007.08.041

  307. 307.

    Chen Z.G., Wang P.W., Wei B., Mo X.M., Cui F.Z. Electrospun Collagen–Chitosan Nanofiber: A Biomimetic Extracellular Matrix for Endothelial Cell and Smooth Muscle Cell. Acta Biomater. 2010;6:372-382.

    Not in our library10.1016/j.actbio.2009.07.024

  308. 308.

    Aras O., Kazanci M. Production of Collagen Micro- and Nanofibers for Potential Drug-Carrier Systems. J. Enzym. Inhib. Med. Chem. 2015;30:1013-1016.

    Not in our library10.3109/14756366.2014.976567

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    Fiorani A., Gualandi C., Panseri S., Montesi M., Marcacci M., Focarete M.L., Bigi A. Comparative Performance of Collagen Nanofibers Electrospun from Different Solvents and Stabilized by Different Crosslinkers. J. Mater. Sci. Mater. Med. 2014;25:2313-2321.

    Not in our library10.1007/s10856-014-5196-2

  310. 310.

    Dong B., Arnoult O., Smith M.E., Wnek G.E. Electrospinning of Collagen Nanofiber Scaffolds from Benign Solvents. Macromol. Rapid Commun. 2009;30:539-542.

    Not in our library10.1002/marc.200800634

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    Zhong S., Teo W.E., Zhu X., Beuerman R.W., Ramakrishna S., Yung L.Y.L. An Aligned Nanofibrous Collagen Scaffold by Electrospinning and Its Effects on in Vitro Fibroblast Culture. J. Biomed. Mater. Res. Part A. 2006;79:456-463.

    Not in our library10.1002/jbm.a.30870

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    Hartman O., Zhang C., Adams E.L., Farach-Carson M.C., Petrelli N.J., Chase B.D., Rabolt J.F. Microfabricated Electrospun Collagen Membranes for 3-D Cancer Models and Drug Screening Applications. Biomacromolecules. 2009;10:2019-2032.

    Not in our library10.1021/bm8012764

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    Eltom A., Zhong G., Muhammad A. Scaffold Techniques and Designs in Tissue Engineering Functions and Purposes: A Review. Adv. Mater. Sci. Eng. 2019;2019:3429527.

    Not in our library10.1155/2019/3429527

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    Creff J., Courson R., Mangeat T., Foncy J., Souleille S., Thibault C., Besson A., Malaquin L. Fabrication of 3D Scaffolds Reproducing Intestinal Epithelium Topography by High-Resolution 3D Stereolithography. Biomaterials. 2019;221:119404.

    Not in our library10.1016/j.biomaterials.2019.119404

  315. 315.

    Lee S.-J., Nowicki M., Harris B., Zhang L.G. Fabrication of a Highly Aligned Neural Scaffold via a Table Top Stereolithography 3D Printing and Electrospinning. Tissue Eng. Part A. 2016;23:491-502.

    Not in our library10.1089/ten.tea.2016.0353

  316. 316.

    Accardo A., Courson R., Riesco R., Raimbault V., Malaquin L. Direct Laser Fabrication of Meso-Scale 2D and 3D Architectures with Micrometric Feature Resolution. Addit. Manuf. 2018;22:440-446.

    Not in our library10.1016/j.addma.2018.04.027

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    Wang Y., Gunasekara D.B., Reed M.I., DiSalvo M., Bultman S.J., Sims C.E., Magness S.T., Allbritton N.L. A Microengineered Collagen Scaffold for Generating a Polarized Crypt-Villus Architecture of Human Small Intestinal Epithelium. Biomaterials. 2017;128:44-55.

    Not in our library10.1016/j.biomaterials.2017.03.005

  318. 318.

    Yu J., Peng S., Luo D., March J.C. In Vitro 3D Human Small Intestinal Villous Model for Drug Permeability Determination. Biotechnol. Bioeng. 2012;109:2173-2178.

    Not in our library10.1002/bit.24518

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    Guvendiren M., Molde J., Soares R.M.D., Kohn J. Designing Biomaterials for 3D Printing. ACS Biomater. Sci. Eng. 2016;2:1679-1693.

    Not in our library10.1021/acsbiomaterials.6b00121

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    Zhang Z., Nagrath S. Microfluidics and Cancer: Are We There Yet? Biomed. Microdevices. 2013;15:595-609.

    Not in our library10.1007/s10544-012-9734-8

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    Shimizu A., Goh W.H., Hashimoto M., Miura S., Onoe H. ECM-Based Stretchable Microfluidic System for in Vitro 3D Tissue Culture. Proceedings of the 2019 20th International Conference on Solid-State Sensors, Actuators and Microsystems & Eurosensors XXXIII (TRANSDUCERS & EUROSENSORS XXXIII). 752-755.

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    Hutmacher D.W., Loessner D., Rizzi S., Kaplan D.L., Mooney D.J., Clements J.A. Can Tissue Engineering Concepts Advance Tumor Biology Research? Trends Biotechnol. 2010;28:125-133.

    Not in our library10.1016/j.tibtech.2009.12.001

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    Ghajar C.M., Bissell M.J. Tumor Engineering: The Other Face of Tissue Engineering. Tissue Eng. Part A. 2010;16:2153-2156.

    Not in our library10.1089/ten.tea.2010.0135

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    Whitesides G.M. The Origins and the Future of Microfluidics. Nature. 2006;442:368-373.

    Not in our library10.1038/nature05058

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    El-Ali J., Sorger P.K., Jensen K.F. Cells on Chips. Nature. 2006;442:403-411.

    Not in our library10.1038/nature05063

  326. 326.

    Pisano M., Triacca V., Barbee K.A., Swartz M.A. An in Vitro Model of the Tumor-Lymphatic Microenvironment with Simultaneous Transendothelial and Luminal Flows Reveals Mechanisms of Flow Enhanced Invasion. Integr. Biol. 2015;7:525-533.

    Not in our library10.1039/c5ib00085h

  327. 327.

    Jeon J.S., Bersini S., Gilardi M., Dubini G., Charest J.L., Moretti M., Kamm R.D. Human 3D Vascularized Organotypic Microfluidic Assays to Study Breast Cancer Cell Extravasation. Proc. Natl. Acad. Sci. USA. 2015;112:214-219.

    Not in our library10.1073/pnas.1417115112

  328. 328.

    Chen Y., Gao D., Liu H., Lin S., Jiang Y. Drug Cytotoxicity and Signaling Pathway Analysis with Three-Dimensional Tumor Spheroids in a Microwell-Based Microfluidic Chip for Drug Screening. Anal. Chim. Acta. 2015;898:85-92.

    Not in our library10.1016/j.aca.2015.10.006

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    Kim J.-Y., Fluri D.A., Marchan R., Boonen K., Mohanty S., Singh P., Hammad S., Landuyt B., Hengstler J.G., Kelm J.M., et al. 3D Spherical Microtissues and Microfluidic Technology for Multi-Tissue Experiments and Analysis. J. Biotechnol. 2015;205:24-35.

    Not in our library10.1016/j.jbiotec.2015.01.003

  330. 330.

    Ruppen J., Wildhaber F.D., Strub C., Hall S.R.R., Schmid R.A., Geiser T., Guenat O.T. Towards Personalized Medicine: Chemosensitivity Assays of Patient Lung Cancer Cell Spheroids in a Perfused Microfluidic Platform. Lab Chip. 2015;15:3076-3085.

    Not in our library10.1039/c5lc00454c

  331. 331.

    McMillan K.S., Boyd M., Zagnoni M. Transitioning from Multi-Phase to Single-Phase Microfluidics for Long-Term Culture and Treatment of Multicellular Spheroids. Lab Chip. 2016;16:3548-3557.

    Not in our library10.1039/c6lc00884d

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    Fu C.-Y., Tseng S.-Y., Yang S.-M., Hsu L., Liu C.-H., Chang H.-Y. A Microfluidic Chip with a U-Shaped Microstructure Array for Multicellular Spheroid Formation, Culturing and Analysis. Biofabrication. 2014;6:15009.

    Not in our library10.1088/1758-5082/6/1/015009

  333. 333.
    Drug testing and flow cytometry analysis on a large number of uniform sized tumor spheroids using a microfluidic device · 2016
    No notice
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    Ramanujan S., Pluen A., McKee T.D., Brown E.B., Boucher Y., Jain R.K. Diffusion and Convection in Collagen Gels: Implications for Transport in the Tumor Interstitium. Biophys. J. 2002;83:1650-1660.

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    Lintz M., Muñoz A., Reinhart-King C.A. The Mechanics of Single Cell and Collective Migration of Tumor Cells. J. Biomech. Eng. 2017;139:210051-210059.

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    Hollister S.J., Maddox R.D., Taboas J.M. Optimal Design and Fabrication of Scaffolds to Mimic Tissue Properties and Satisfy Biological Constraints. Biomaterials. 2002;23:4095-4103.

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    Conklin M.W., Eickhoff J.C., Riching K.M., Pehlke C.A., Eliceiri K.W., Provenzano P.P., Friedl A., Keely P.J. Aligned Collagen Is a Prognostic Signature for Survival in Human Breast Carcinoma. Am. J. Pathol. 2011;178:1221-1232.

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    Collagen reorganization at the tumor-stromal interface facilitates local invasion · 2006
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    Brabrand A., Kariuki I.I., Engstrøm M.J., Haugen O.A., Dyrnes L.A., Åsvold B.O., Lilledahl M.B., Bofin A.M. Alterations in Collagen Fibre Patterns in Breast Cancer. A Premise for Tumour Invasiveness? APMIS. 2015;123:1-8.

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    Lee C.H., Singla A., Lee Y. Biomedical Applications of Collagen. Int. J. Pharm. 2001;221:1-22.

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    Schindelin J., Arganda-carreras I., Frise E., Kaynig V., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., Tinevez J., et al. Fiji—An Open Source Platform for Biological Image Analysis. Nat. Methods. 2019;9:10-38.

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    Hilliou F., Pairault J., Dominice J., Redziniak G. Growth and Differentiation of 3T3-F442A Preadipocytes in Three-Dimensional Gels of Native Collagen. Exp. Cell Res. 1988;177:372-381.

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    Huss F.R.M., Kratz G. Mammary Epithelial Cell and Adipocyte Co-Culture in a 3-D Matrix: The First Step towards Tissue-Engineered Human Breast Tissue. Cells Tissues Organs. 2001;169:361-367.

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    Jha B.S., Ayres C.E., Bowman J.R., Telemeco T.A., Sell S.A., Bowlin G.L., Simpson D.G. Electrospun Collagen: A Tissue Engineering Scaffold with Unique Functional Properties in a Wide Variety of Applications. J. Nanomater. 2011;2011:348268.

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    Zeng J., Xu X., Chen X., Liang Q., Bian X., Yang L., Jing X. Biodegradable Electrospun Fibers for Drug Delivery. J. Control. Release. 2003;92:227-231.

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    Chaurey V., Chiang P.-C., Polanco C., Su Y.-H., Chou C.-F., Swami N.S. Interplay of Electrical Forces for Alignment of Sub-100 Nm Electrospun Nanofibers on Insulator Gap Collectors. Langmuir. 2010;26:19022-19026.

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    Beachley V., Wen X. Effect of Electrospinning Parameters on the Nanofiber Diameter and Length. Mater. Sci. Eng. C. 2009;29:663-668.

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    Zong X., Kim K., Fang D., Ran S., Hsiao B.S., Chu B. Structure and Process Relationship of Electrospun Bioabsorbable Nanofiber Membranes. Polymer. 2002;43:4403-4412.

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    Deitzel J.M., Kleinmeyer J., Harris D., Beck Tan N.C. The Effect of Processing Variables on the Morphology of Electrospun Nanofibers and Textiles. Polymer. 2001;42:261-272.

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    Nezarati R.M., Eifert M.B., Cosgriff-Hernandez E. Effects of Humidity and Solution Viscosity on Electrospun Fiber Morphology. Tissue Eng. Part C: Methods. 2013;19:810-819.

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    Tarus B., Fadel N., Al-Oufy A., El-Messiry M. Effect of Polymer Concentration on the Morphology and Mechanical Characteristics of Electrospun Cellulose Acetate and Poly (Vinyl Chloride) Nanofiber Mats. Alex. Eng. J. 2016;55:2975-2984.

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    Rnjak-Kovacina J., Weiss A.S. Increasing the Pore Size of Electrospun Scaffolds. Tissue Eng. Part B Rev. 2011;17:365-372.

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    Shields K.J., Beckman M.J., Bowlin G.L., Wayne J.S. Mechanical Properties and Cellular Proliferation of Electrospun Collagen Type II. Tissue Eng. 2004;10:1510-1517.

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    Malakpour-Permlid A., Buzzi I., Hegardt C., Johansson F., Oredsson S. Identification of Extracellular Matrix Proteins Secreted by Human Dermal Fibroblasts Cultured in 3D Electrospun Scaffolds. Sci. Rep. 2021;11:6655.

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    Yamada D., Kobayashi S., Wada H., Kawamoto K., Marubashi S., Eguchi H., Ishii H., Nagano H., Doki Y., Mori M. Role of Crosstalk between Interleukin-6 and Transforming Growth Factor-Beta 1 in Epithelial–Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. Eur. J. Cancer. 2013;49:1725-1740.

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    Pankov R., Yamada K.M. Fibronectin at a Glance. J. Cell Sci. 2002;115:3861-3863.

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    Lee M.P., Cooper G.J.T., Hinkley T., Gibson G.M., Padgett M.J., Cronin L. Development of a 3D Printer Using Scanning Projection Stereolithography. Sci. Rep. 2015;5:9875.

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    Achilli T.-M., Meyer J., Morgan J.R. Advances in the Formation, Use and Understanding of Multi-Cellular Spheroids. Expert Opin. Biol. Ther. 2012;12:1347-1360.

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    Duguay D., Foty R.A., Steinberg M.S. Cadherin-Mediated Cell Adhesion and Tissue Segregation: Qualitative and Quantitative Determinants. Dev. Biol. 2003;253:309-323.

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    Spheroid Culture System Methods and Applications for Mesenchymal Stem Cells · 2019
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    Moscona A., Moscona H. The Dissociation and Aggregation of Cells from Organ Rudiments of the Early Chick Embryo. J. Anat. 1952;86:287-301.

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    Advanced Cell Culture Techniques for Cancer Drug Discovery · 2014
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    Kang A., Seo H.I., Chung B.G., Lee S.-H. Concave Microwell Array-Mediated Three-Dimensional Tumor Model for Screening Anticancer Drug-Loaded Nanoparticles. Nanomed. Nanotechnol. Biol. Med. 2015;11:1153-1161.

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    Development of an Innovative 3D Cell Culture System to Study Tumour - Stroma Interactions in Non-Small Cell Lung Cancer Cells · 2014
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    Mueller-Klieser W. Three-Dimensional Cell Cultures: From Molecular Mechanisms to Clinical Applications. Am. J. Physiol. Physiol. 1997;273:C1109-C1123.

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    Dhiman H.K., Ray A.R., Panda A.K. Three-Dimensional Chitosan Scaffold-Based MCF-7 Cell Culture for the Determination of the Cytotoxicity of Tamoxifen. Biomaterials. 2005;26:979-986.

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    Ong S.-M., Zhao Z., Arooz T., Zhao D., Zhang S., Du T., Wasser M., van Noort D., Yu H. Engineering a Scaffold-Free 3D Tumor Model for in Vitro Drug Penetration Studies. Biomaterials. 2010;31:1180-1190.

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    AlgiMatrix™ Based 3D Cell Culture System as an In-Vitro Tumor Model for Anticancer Studies · 2013
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    Holtfreter J. A Study of the Mechanics of Gastrulation. J. Exp. Zool. 1944;95:171-212.

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    Laschke M.W., Menger M.D. Life Is 3D: Boosting Spheroid Function for Tissue Engineering. Trends Biotechnol. 2017;35:133-144.

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    Li L., Neaves W.B. Normal Stem Cells and Cancer Stem Cells: The Niche Matters. Cancer Res. 2006;66:4553-4557.

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    Mesenchymal Stem Cell Spheroids Retain Osteogenic Phenotype Through α2β1 Signaling · 2016
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    Fennema E., Rivron N., Rouwkema J., van Blitterswijk C., de Boer J. Spheroid Culture as a Tool for Creating 3D Complex Tissues. Trends Biotechnol. 2013;31:108-115.

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    Costa E.C., Gaspar V.M., Coutinho P., Correia I.J. Optimization of Liquid Overlay Technique to Formulate Heterogenic 3D Co-Cultures Models. Biotechnol. Bioeng. 2014;111:1672-1685.

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    Metzger W., Sossong D., Bächle A., Pütz N., Wennemuth G., Pohlemann T., Oberringer M. The Liquid Overlay Technique Is the Key to Formation of Co-Culture Spheroids Consisting of Primary Osteoblasts, Fibroblasts and Endothelial Cells. Cytotherapy. 2011;13:1000-1012.

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    Wang X., Zhen X., Wang J., Zhang J., Wu W., Jiang X. Doxorubicin Delivery to 3D Multicellular Spheroids and Tumors Based on Boronic Acid-Rich Chitosan Nanoparticles. Biomaterials. 2013;34:4667-4679.

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    Gunay G., Kirit H.A., Kamatar A., Baghdasaryan O., Hamsici S., Acar H. The Effects of Size and Shape of the Ovarian Cancer Spheroids on the Drug Resistance and Migration. Gynecol. Oncol. 2020;159:563-572.

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    Torisawa Y., Takagi A., Nashimoto Y., Yasukawa T., Shiku H., Matsue T. A Multicellular Spheroid Array to Realize Spheroid Formation, Culture, and Viability Assay on a Chip. Biomaterials. 2007;28:559-566.

    Not in our library10.1016/j.biomaterials.2006.08.054

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    Sarisozen C., Dhokai S., Tsikudo E.G., Luther E., Rachman I.M., Torchilin V.P. Nanomedicine Based Curcumin and Doxorubicin Combination Treatment of Glioblastoma with ScFv-Targeted Micelles: In Vitro Evaluation on 2D and 3D Tumor Models. Eur. J. Pharm. Biopharm. 2016;108:54-67.

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    Perche F., Patel N.R., Torchilin V.P. Accumulation and Toxicity of Antibody-Targeted Doxorubicin-Loaded PEG-PE Micelles in Ovarian Cancer Cell Spheroid Model. J. Control. Release. 2012;164:95-102.

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    Zhang Y.S., Duchamp M., Oklu R., Ellisen L.W., Langer R., Khademhosseini A. Bioprinting the Cancer Microenvironment. ACS Biomater. Sci. Eng. 2016;2:1710-1721.

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    Foty R. A Simple Hanging Drop Cell Culture Protocol for Generation of 3D Spheroids. JoVE. 2011;51:e2720.

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    High-Throughput 3D Screening Reveals Differences in Drug Sensitivities between Culture Models of JIMT1 Breast Cancer Cells · 2013
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    Fukuda J., Nakazawa K. Orderly Arrangement of Hepatocyte Spheroids on a Microfabricated Chip. Tissue Eng. 2005;11:1254-1262.

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    Desroches B.R., Zhang P., Choi B.-R., King M.E., Maldonado A.E., Li W., Rago A., Liu G., Nath N., Hartmann K.M., et al. Functional Scaffold-Free 3-D Cardiac Microtissues: A Novel Model for the Investigation of Heart Cells. Am. J. Physiol. Circ. Physiol. 2012;302:H2031-H2042.

    Not in our library10.1152/ajpheart.00743.2011

  387. 387.
    Three-Dimensional Lung Tumor Microenvironment Modulates Therapeutic Compound Responsiveness In Vitro – Implication for Drug Development · 2014
    No notice
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    Perets A., Baruch Y., Weisbuch F., Shoshany G., Neufeld G., Cohen S. Enhancing the Vascularization of Three-Dimensional Porous Alginate Scaffolds by Incorporating Controlled Release Basic Fibroblast Growth Factor Microspheres. J. Biomed. Mater. Res. 2003;65:489-497.

    Not in our library10.1002/jbm.a.10542

  389. 389.

    Huang G.-S., Dai L.-G., Yen B.L., Hsu S. Spheroid Formation of Mesenchymal Stem Cells on Chitosan and Chitosan-Hyaluronan Membranes. Biomaterials. 2011;32:6929-6945.

    Not in our library10.1016/j.biomaterials.2011.05.092

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    Cheng N.-C., Wang S., Young T.-H. The Influence of Spheroid Formation of Human Adipose-Derived Stem Cells on Chitosan Films on Stemness and Differentiation Capabilities. Biomaterials. 2012;33:1748-1758.

    Not in our library10.1016/j.biomaterials.2011.11.049

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    Maritan S.M., Lian E.Y., Mulligan L.M. An Efficient and Flexible Cell Aggregation Method for 3D Spheroid Production. JoVE. 2017;121:55544.

    Not in our library10.3791/55544

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    Li J., He F., Pei M. Creation of an in Vitro Microenvironment to Enhance Human Fetal Synovium-Derived Stem Cell Chondrogenesis. Cell Tissue Res. 2011;345:357-365.

    Not in our library10.1007/s00441-011-1212-8

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    Carpenedo R.L., Sargent C.Y., McDevitt T.C. Rotary Suspension Culture Enhances the Efficiency, Yield, and Homogeneity of Embryoid Body Differentiation. Stem Cells. 2007;25:2224-2234.

    Not in our library10.1634/stemcells.2006-0523

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    Bosnakovski D., Mizuno M., Kim G., Ishiguro T., Okumura M., Iwanaga T., Kadosawa T., Fujinaga T. Chondrogenic Differentiation of Bovine Bone Marrow Mesenchymal Stem Cells in Pellet Cultural System. Exp. Hematol. 2004;32:502-509.

    Not in our library10.1016/j.exphem.2004.02.009

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    Giovannini S., Diaz-Romero J., Aigner T., Heini P., Mainil-Varlet P., Nesic D. Micromass Co-Culture of Human Articular Chondrocytes and Human Bone Marrow Mesenchymal Stem Cells to Investigate Stable Neocartilage Tissue Formation in Vitro. Eur. Cells Mater. 2010;20:245-259.

    Not in our library10.22203/ecm.v020a20

  396. 396.

    Qihao Z., Xigu C., Guanghui C., Weiwei Z. Spheroid Formation and Differentiation into Hepatocyte-like Cells of Rat Mesenchymal Stem Cell Induced by Co-Culture with Liver Cells. DNA Cell Biol. 2007;26:497-503.

    Not in our library10.1089/dna.2006.0562

  397. 397.

    Bartosh T.J., Ylostalo J.H. Preparation of Anti-Inflammatory Mesenchymal Stem/Precursor Cells (MSCs) through Sphere Formation Using Hanging-Drop Culture Technique. Curr. Protoc. Stem Cell Biol. 2014;28.

    Not in our library10.1002/9780470151808.sc02b06s28

  398. 398.

    Tung Y.-C., Hsiao A.Y., Allen S.G., Torisawa Y., Ho M., Takayama S. High-Throughput 3D Spheroid Culture and Drug Testing Using a 384 Hanging Drop Array. Analyst. 2011;136:473-478.

    Not in our library10.1039/c0an00609b

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    Kelm J.M., Timmins N.E., Brown C.J., Fussenegger M., Nielsen L.K. Method for Generation of Homogeneous Multicellular Tumor Spheroids Applicable to a Wide Variety of Cell Types. Biotechnol. Bioeng. 2003;83:173-180.

    Not in our library10.1002/bit.10655

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    Timmins N.E., Nielsen L.K. Generation of Multicellular Tumor Spheroids by the Hanging-Drop Method. Methods Mol. Med. 2007;140:141-151.

    Not in our library10.1007/978-1-59745-443-8_8

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    Generation of Multicellular Tumor Spheroids with Microwell-Based Agarose Scaffolds for Drug Testing · 2015
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  402. 402.

    Dahlmann J., Kensah G., Kempf H., Skvorc D., Gawol A., Elliott D.A., Dräger G., Zweigerdt R., Martin U., Gruh I. The Use of Agarose Microwells for Scalable Embryoid Body Formation and Cardiac Differentiation of Human and Murine Pluripotent Stem Cells. Biomaterials. 2013;34:2463-2471.

    Not in our library10.1016/j.biomaterials.2012.12.024

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    Carlsson J., Yuhas J.M. Liquid-Overlay Culture of Cellular Spheroids. Recent Results Cancer Res. 1984;95:1-23.

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    Costa E.C., de Melo-Diogo D., Moreira A.F., Carvalho M.P., Correia I.J. Spheroids Formation on Non-Adhesive Surfaces by Liquid Overlay Technique: Considerations and Practical Approaches. Biotechnol. J. 2018;13:1700417.

    Not in our library10.1002/biot.201700417

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    Enmon R.M.J., O’Connor K.C., Lacks D.J., Schwartz D.K., Dotson R.S. Dynamics of Spheroid Self-Assembly in Liquid-Overlay Culture of DU 145 Human Prostate Cancer Cells. Biotechnol. Bioeng. 2001;72:579-591.

    Not in our library10.1002/1097-0290(20010320)72:6<579::aid-bit1023>3.0.co;2-l

  406. 406.

    Landry J., Bernier D., Ouellet C., Goyette R., Marceau N. Spheroidal Aggregate Culture of Rat Liver Cells: Histotypic Reorganization, Biomatrix Deposition, and Maintenance of Functional Activities. J. Cell Biol. 1985;101:914-923.

    Not in our library10.1083/jcb.101.3.914

  407. 407.

    Castañeda F., Kinne R.K. Short Exposure to Millimolar Concentrations of Ethanol Induces Apoptotic Cell Death in Multicellular HepG2 Spheroids. J. Cancer Res. Clin. Oncol. 2000;126:305-310.

    Not in our library10.1007/s004320050348

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    Foty R.A., Steinberg M.S. The Differential Adhesion Hypothesis: A Direct Evaluation. Dev. Biol. 2005;278:255-263.

    Not in our library10.1016/j.ydbio.2004.11.012

  409. 409.

    Lin R.-Z., Chang H.-Y. Recent Advances in Three-Dimensional Multicellular Spheroid Culture for Biomedical Research. Biotechnol. J. 2008;3:1172-1184.

    Not in our library10.1002/biot.200700228

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    Kelm J.M., Fussenegger M. Microscale Tissue Engineering Using Gravity-Enforced Cell Assembly. Trends Biotechnol. 2004;22:195-202.

    Not in our library10.1016/j.tibtech.2004.02.002

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    Nyberg S.L., Hardin J., Amiot B., Argikar U.A., Remmel R.P., Rinaldo P. Rapid, Large-Scale Formation of Porcine Hepatocyte Spheroids in a Novel Spheroid Reservoir Bioartificial Liver. Liver Transplant. 2005;11:901-910.

    Not in our library10.1002/lt.20446

  412. 412.

    Friedrich J., Seidel C., Ebner R., Kunz-Schughart L.A. Spheroid-Based Drug Screen: Considerations and Practical Approach. Nat. Protoc. 2009;4:309-324.

    Not in our library10.1038/nprot.2008.226

  413. 413.

    Friedrich J., Ebner R., Kunz-Schughart L.A. Experimental Anti-Tumor Therapy in 3-D: Spheroids—Old Hat or New Challenge? Int. J. Radiat. Biol. 2007;83:849-871.

    Not in our library10.1080/09553000701727531

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    Direct isolation of human central nervous system stem cells · 2000
    Not checked
  415. 415.

    Ponti D., Costa A., Zaffaroni N., Pratesi G., Petrangolini G., Coradini D., Pilotti S., Pierotti M.A., Daidone M.G. Isolation and in Vitro Propagation of Tumorigenic Breast Cancer Cells with Stem/Progenitor Cell Properties. Cancer Res. 2005;65:5506-5511.

    Not in our library10.1158/0008-5472.can-05-0626

  416. 416.

    Smart C.E., Morrison B.J., Saunus J.M., Vargas A.C., Keith P., Reid L., Wockner L., Askarian-Amiri M., Sarkar D., Simpson P.T., et al. In Vitro Analysis of Breast Cancer Cell Line Tumourspheres and Primary Human Breast Epithelia Mammospheres Demonstrates Inter- and Intrasphere Heterogeneity. PLoS ONE. 2013;8:e64388.

    Not in our library10.1371/annotation/1ba8c49a-f6cb-4565-8a36-7d7c429ea670

  417. 417.

    Yu M., Bardia A., Aceto N., Bersani F., Madden M.W., Donaldson M.C., Desai R., Zhu H., Comaills V., Zheng Z., et al. Cancer Therapy. Ex Vivo Culture of Circulating Breast Tumor Cells for Individualized Testing of Drug Susceptibility. Science. 2014;345:216-220.

    Not in our library10.1126/science.1253533

  418. 418.

    Sato T., Stange D.E., Ferrante M., Vries R.G.J., Van Es J.H., Van den Brink S., Van Houdt W.J., Pronk A., Van Gorp J., Siersema P.D., et al. Long-Term Expansion of Epithelial Organoids from Human Colon, Adenoma, Adenocarcinoma, and Barrett’s Epithelium. Gastroenterology. 2011;141:1762-1772.

    Not in our library10.1053/j.gastro.2011.07.050

  419. 419.

    Kondo J., Endo H., Okuyama H., Ishikawa O., Iishi H., Tsujii M., Ohue M., Inoue M. Retaining Cell-Cell Contact Enables Preparation and Culture of Spheroids Composed of Pure Primary Cancer Cells from Colorectal Cancer. Proc. Natl. Acad. Sci. USA. 2011;108:6235-6240.

    Not in our library10.1073/pnas.1015938108

  420. 420.

    Rajcevic U., Knol J.C., Piersma S., Bougnaud S., Fack F., Sundlisaeter E., Søndenaa K., Myklebust R., Pham T.V., Niclou S.P., et al. Colorectal Cancer Derived Organotypic Spheroids Maintain Essential Tissue Characteristics but Adapt Their Metabolism in Culture. Proteome Sci. 2014;12:39.

    Not in our library10.1186/1477-5956-12-39

  421. 421.

    Young S.R., Saar M., Santos J., Nguyen H.M., Vessella R.L., Peehl D.M. Establishment and Serial Passage of Cell Cultures Derived from LuCaP Xenografts. Prostate. 2013;73:1251-1262.

    Not in our library10.1002/pros.22610

  422. 422.

    Weiswald L.-B., Richon S., Massonnet G., Guinebretière J.-M., Vacher S., Laurendeau I., Cottu P., Marangoni E., Nemati F., Validire P., et al. A Short-Term Colorectal Cancer Sphere Culture as a Relevant Tool for Human Cancer Biology Investigation. Br. J. Cancer. 2013;108:1720-1731.

    Not in our library10.1038/bjc.2013.132

  423. 423.

    Sundlisæter E., Wang J., Sakariassen P.Ø., Marie M., Mathisen J.R., Karlsen B.O., Prestegarden L., Skaftnesmo K.O., Bjerkvig R., Enger P.Ø. Primary Glioma Spheroids Maintain Tumourogenicity and Essential Phenotypic Traits after Cryopreservation. Neuropathol. Appl. Neurobiol. 2006;32:419-427.

    Not in our library10.1111/j.1365-2990.2006.00744.x

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