3D cell culture

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A 3D cell culture is an artificially created environment in which biological cells are permitted to grow or interact with their surroundings in all three dimensions. Unlike 2D environments (e.g. a Petri dish), a 3D cell culture allows cells in vitro to grow in all directions, similar to how they would in vivo. [1] These three-dimensional cultures are usually grown in bioreactors, small capsules in which the cells can grow into spheroids, or 3D cell colonies. Approximately 300 spheroids are usually cultured per bioreactor. [1]

Contents

Background

3D cell cultures have been used in research for several decades. [2] One of the first recorded approaches for their development was at the beginning of the 20th century, with the efforts of Alexis Carrel to develop methods for prolonged in vitro tissue cultures. [3] Early studies in the 80's, led by Mina Bissell from the Lawrence Berkeley National Laboratory, highlighted the importance of 3D techniques for creating accurate in vitro culturing models. This work focused on the importance of the extracellular matrix and the ability of cultures in artificial 3D matrices to produce physiologically relevant multicellular structures, such as acinar structures in healthy and cancerous breast tissue models. These techniques have been applied to in vitro disease models used to evaluate cellular responses to pharmaceutical compounds. [4]

Eric Simon, in a 1988 NIH SBIR grant report, showed that electrospinning could be used to produce nano- and submicron-scale polystyrene and polycarbonate fibrous mats (now known as scaffolds) specifically intended for use as in vitro cell substrates. This early use of electrospun fibrous lattices for cell culture and tissue engineering showed that various cell types including Human Foreskin Fibroblasts (HFF), transformed Human Carcinoma (HEp-2), and Mink Lung Epithelium (MLE) would adhere to and proliferate upon the fibers. It was noted that as opposed to the flattened morphology typically seen in 2D culture, cells grown on the electrospun fibers exhibited a more histotypic rounded 3-dimensional morphology generally observed in vivo. [5]

3D cell culture, by emulating essential aspects of the in vivo environment, including interactions between cells and the extracellular matrix, allows for the faithful recreation of structural architecture and specialized functions in normal tissues or tumors in a laboratory setting. This approach authentically models the conditions and processes of living tissues, producing responses akin to those observed in vivo. Since its inception in the 1970s, 3D cell culture has provided significant insights into the mechanisms regulating tissue homeostasis and cancer. [6] Moreover, it has expedited translational research in the realms of cancer biology and tissue engineering. [7]

Properties

In living tissue, cells exist in 3D microenvironments with intricate cell-cell and cell-matrix interactions and complex transport dynamics for nutrients and cells. [8] [9] [10] [11] [12] [13] [14] [15] [16] Standard 2D, or monolayer, cell cultures are inadequate representations of this environment, which often makes them unreliable predictors of in vivo drug efficacy and toxicity. [17] [14] 3D spheroids more closely resemble in vivo tissue in terms of cellular communication and the development of extracellular matrices. [1] These matrices help the cells to be able to move within their spheroid similar to the way cells would move in living tissue. [10] The spheroids are thus improved models for cell migration, differentiation, survival, and growth. [15] Furthermore, 3D cell cultures provide more accurate depiction of cell polarization, since in 2D, the cells can only be partially polarized. [10] Moreover, cells grown in 3D exhibit different gene expression than those grown in 2D. [10]

The third dimension of cell growth provides more contact space for mechanical inputs and for cell adhesion, which is necessary for integrin ligation, cell contraction and even intracellular signalling. [18] [19] Normal solute diffusion and binding to effector proteins (like growth factors and enzymes) is also reliant on the 3D cellular matrix, so it is critical for the establishment of tissue scale solute concentration gradients [20] [21]

For the purposes of drug toxicology screening, it is much more useful to test gene expression of in vitro cells grown in 3D than 2D, since the gene expression of the 3D spheroids will more closely resemble gene expression in vivo. Lastly, 3D cell cultures have greater stability and longer lifespans than cell cultures in 2D. [22] This means that they are more suitable for long-term studies and for demonstrating long-term effects of the drug. 3D environments also allow the cells to grow undisturbed. In 2D, the cells must undergo regular trypsinization to provide them with sufficient nutrients for normal cell growth. [23] 3D spheroids have been cultured in a lab setting for up to 302 days while still maintaining healthy, non-cancerous growth. [22]

In the interdisciplinary research of biology and aerospace, the 3D printed-scaffolds are also being used for protecting cells from the effect of gravity during the launching. [24]

Classification of 3D culture methods

There are a large number of commercially available culturing tools that claim to provide the advantages of 3D cell culture. In general, the platforms can be classified in two types of 3D culturing methods: scaffold techniques and scaffold-free techniques.

A model showing three examples of techniques used for culturing cells in a 3D environment. 3d cell culture (1).svg
A model showing three examples of techniques used for culturing cells in a 3D environment.

Scaffold techniques

Scaffold techniques include the use of solid scaffolds, hydrogels and other materials. In a recent study potentiality of human CD34+ stem cells explored by generating in vitro agarose gel 3D model to understand the bone ossification process. [25] Scaffolds can be used to generate microtissue 3D model by culturing fibroblasts outside of tumour cells, mimicking the tumor stroma interaction. [26]

The effectiveness of scaffolds in various applications, particularly in tissue engineering, is significantly impacted by factors such as pore distribution, exposed surface area, and porosity. The quantity and arrangement of these elements influence both the depth and rate at which cells penetrate the scaffold volume, the structure of the resulting extracellular matrix, and ultimately, the success of the regenerative process. [27] Scaffolds can be produced with diverse architectures depending on the manufacturing method, leading to either random or precisely designed pore distribution. [28] Recently, advanced computer-controlled rapid prototyping techniques have been employed to create scaffolds with well-organized geometries. [29]

Hydrogels

As the natural extracellular matrix (ECM) is important in the survival, proliferation, differentiation and migration of the cells, different hydrogel matrices mimicking natural ECM structure are considered as potential approaches towards in vivo –like cell culturing. [30] [31] [32] Hydrogels are composed of interconnected pores with high water retention, which enables efficient transport of e.g. nutrients and gases. Several different types of hydrogels from natural and synthetic materials are available for 3D cell culture, including e.g. animal ECM extract hydrogels, protein hydrogels, peptide hydrogels, polymer hydrogels, and wood-based nanocellulose hydrogel.

The approach to crafting the optimal ECM replica relies on the specific characteristics of the culture in question and typically involves employing diverse and independent chemical processes. [33] For example, the utilization of photolabile chemistries can lead to the erosion of specific regions within a gel, and subsequently exposing these areas allows for the application of adhesive ligands, promoting cell adhesion and migration. [34] The development of more intricate frameworks is anticipated, comprising interwoven networks of chemistries under the control of both cells and users. In essence, there is no singular network capable of faithfully emulating the intricate ECM of every tissue type. However, a thoughtful integration of bioinspired cues into synthetic gels holds the potential to yield resilient and versatile scaffolds applicable across various cell culture systems. [35]

Scaffold-free techniques

Scaffold free techniques employ another approach independent from the use scaffold. Scaffold-free methods include e.g. the use of low adhesion plates, hanging drop plates, micropatterned surfaces, and rotating bioreactors, magnetic levitation, and magnetic 3D bioprinting.

Spheroids

Electron microscopy of a mesothelioma spheroid (NCI-H226). Scale bars, 200 mm. Electron microscopy (Ho).tif
Electron microscopy of a mesothelioma spheroid (NCI-H226). Scale bars, 200 μm.

Spheroids are a type of three-dimensional cell modeling that better simulate a live cell's environmental conditions compared to a two-dimensional cell model, specifically with the reactions between cells and the reactions between cells and the matrix. [37] Spheroids are useful in the study of changing physiological characteristics of cells, [38] the difference in the structure of healthy cells and tumor cells, and the changes cells undergo when forming a tumor. [39] Spheroids co-cultured with tumor and healthy cells were used to simulate how cancerous cells interact with normal cells. [40] Spheroids can also be co-cultured with fibroblasts to mimic tumor-stroma interaction. [41] Spheroids can be grown with a few different methods. One common method is to use low cell adhesion plates, typically a 96 well plate, to mass-produce spheroid cultures, where the aggregates form in the rounded bottom of the cell plates. [36] [42] Spheroids can also be cultured using the hanging drop method [43] involving forming cell aggregates in drops that hang from the surface of a cell plate. [37] Other methods under investigation include the use of rotating wall vessel bioreactors, which spins and cultures the cells when they are constantly in free fall and forms aggregates in layers [44] Recently, some protocols have been standardized to produce uniform and reliable spheroids. [45] Researchers had also explored standardized, economical and reproducible methods for 3D cell culture. [46] To improve reproducibility and transparency in spheroid experiments, an international consortium developed MISpheroID (Minimal Information in Spheroid Identity). [47]

Clusteroids

clusteroids are a type of three-dimensional cell modeling similar to spheroids but are distinguished by their creation method; grown as clusters of cells in an aqueous two-phase system of water-in-water Pickering emulsion using interfacial tension and osmotic shrinkage to pack the cells into dense clusters which are then cultured in a hydrogel into tissues or organoids. [48] [49]

In the absence of blood vessels, oxygen permeability is impaired during necrotic nucleus formation and this prevents the ex vivo use of 3D cell culture. There is an emulsion template that can overcome this problem. This approach allowed researchers to adjust the cell composition to attain the ideal conditions for promoting the synthesis of diverse angiogenic protein markers within the co-cultured clusteroids. [49] HUVEC cells exhibit a reaction to the presence of Hep-G2 cells and their derivatives by generating endothelial cell sprouts in Matrigel, all without the external introduction of vascular endothelial growth factor (VEGF) or other agents that induce angiogenesis. [50] [51] The replication of this cultivation technique is straightforward for generating various cell co-culture spheroids. [52] The w/w Pickering emulsion template greatly aids in constructing 3D co-culture models, offering significant potential for applications in drug testing and tissue engineering. [53]

Bioreactors

The bioreactors used for 3D cell cultures are small plastic cylindrical chambers that are specifically engineered for the purpose of growing cells in three dimensions. The bioreactor uses bioactive synthetic materials such as polyethylene terephthalate membranes to surround the spheroid cells in an environment that maintains high levels of nutrients. [54] [55] They are easy to open and close, so that cell spheroids can be removed for testing, yet the chamber is able to maintain 100% humidity throughout. [1] This humidity is important to achieve maximum cell growth and function. The bioreactor chamber is part of a larger device that rotates to ensure equal cell growth in each direction across three dimensions. [1]
MC2 Biotek has developed a bioreactor to incubate proto-tissue that uses gas exchange to maintain high oxygen levels within the cell chamber. [56] This is an improvement over previous bioreactors because the higher oxygen levels help the cell grow and undergo normal cell respiration. [15]

Collaborative efforts between tissue engineering (TE) firms, academic institutions, and industrial partners can enhance the transformation of research-oriented bioreactors into efficient commercial manufacturing systems. [57] Academic collaborators contribute foundational aspects, while industrial partners provide essential automation elements, ensuring compliance with regulatory standards and user-friendliness. [58] Established consortia in Europe, such as REMEDI, AUTOBONE, and STEPS, focus on developing automated systems to streamline the engineering of autologous cell-based grafts. [59] The aim is to meet regulatory criteria and ensure cost-effectiveness, making tissue-engineered products more clinically accessible and advancing the translational paradigm of TE from research to a competitive commercial field. [60]

Microfluidics

The utilization of microfluidic technology facilitates the generation of intricate micro-scale structures and the precise manipulation of parameters, thereby emulating the in vivo cellular milieu. The integration of microfluidic technology with 3D cell culture holds considerable potential for applications that seek to replicate in vivo tissue characteristics, notably exemplified by the evolving organ-on-a-chip system. [61] The various cell structures in the human body must be vascularized to receive the nutrients and gas exchange in order to survive. Similarly, 3D cell cultures in vitro require certain levels of fluid circulation, which can be problematic for dense, 3D cultures where cells may not all have adequate exposure to nutrients. This is particularly important in hepatocyte cultures because the liver is a highly vascularized organ. One study cultured hepatocytes and vascular cells together on a collagen gel scaffold between microfluidic channels, and compared growth of cells in static and flowing environments, and showed the need for models with tissues and a microvascular network. [62] Another study showed that hanging-drop based spheroid co-culture device can be useful, generating two different cell spheroids on adjacent channels of microfluidic hanging drop device, and co-culturing spheroids with merging droplets, to monitor tumor-induced angiogenesis. [63]

Microfluidic 3D cell culture, with its potential applications in biomedical research and tissue engineering, is an area of growing interest. However, its advancement is accompanied by several formidable challenges. [64] One such challenge pertains to the difficulty in accessing cultured cells within microsystems, coupled with the intricate nature of sample extraction for subsequent assays. [65] Additionally, the development of methodologies and devices dedicated to in vivo-like cell metabolism and functions study, as well as drug discovery, represents a significant hurdle for microfluidic 3D cell culture devices. [66] Another noteworthy impediment is the limited availability of microfabrication instrumentation in conventional biology laboratories. Moreover, the commercialization of mature and user-friendly microfluidic devices poses a substantial challenge, hindering their accessibility to biologists. [67] Lastly, while biologists often seek high-throughput assay tools with optimal reproducibility, microfluidics encounters technical limitations in meeting these demands, despite the potential feasibility of parallel assays. [68]

High-throughput screening

Advanced development of 3D models for high-throughput screening in high density formats has recently been achievable due to technological achievements related to increased microplate density. These can be found in 384 and 1536-well formats that are cell repellent, cost effective, and amenable to fully automated screening platforms. [69] Two options that afford 1536-well formats are available from either Greiner Bio-One using the m3D Magnetic 3D bioprinting [70] and Corning Life Sciences which incorporates an ultra-low attachment surface coating, along with a microcavity geometry and gravity to create 3D models. [71] [72] Due to the rapid and affordable methods and technologies that have been developed for 3D screening, parallel high-throughput screening approaches to test isogenic pairs of oncogene related mutants versus wildtype have been enabled. [73] Moreover, High-throughput screening techniques play a pivotal role in connecting the realms of pharmacology and toxicology within the framework of 3D cell culture.

Pharmacology and toxicology

A primary purpose of growing cells in 3D scaffolds and as 3D cell spheroids in vitro is to test pharmacokinetic and pharmacodynamic effects of drugs and nanomaterials in preclinical trials. [15] [74] [75] [76] [77] Toxicology studies have shown 3D cell cultures to be nearly on par with in vivo studies for the purposes of testing toxicity of drug compounds. When comparing LD50 values for 6 common drugs: acetaminophen, amiodarone, diclofenac, metformin, phenformin, and valproic acid, the 3D spheroid values correlated directly with those from in vivo studies. [78] Although 2D cell cultures have previously been used to test for toxicity along with in vivo studies, the 3D spheroids are better at testing chronic exposure toxicity because of their longer life spans. [79] The matrix in 3D Spheroids causes cells to maintain actin filaments and is more relevant physiologically in cytoskeletal organization and cell polarity and shape of human cells. [80] The three-dimensional arrangement allows the cultures to provide a model that more accurately resembles human tissue in vivo without using animal test subjects. [81]

The current protocols for evaluating drug candidates and assessing toxicity heavily depend on outcomes derived from early-stage in vitro cell-based assays, with the expectation that these assays faithfully capture critical aspects of in vivo pharmacology and toxicology. [82] Various in vitro designs have been fine-tuned for high throughput to enhance screening efficiency, allowing exhaustive libraries of potential pharmacologically relevant or potentially toxic molecules to undergo scrutiny for cell signals indicative of tissue damage or aligned with therapeutic objectives. [83] Innovative approaches to multiplexed cell-based assay designs, involving the selection of specific cell types, signaling pathways, and reporters, have become standard practice. [84]

Despite these advancements, a considerable percentage of new chemical and biological entities (NCEs/NBEs) encounter setbacks in late-stage human drug testing. Some receive regulatory "black box" warnings, while others are withdrawn from the market due to safety concerns post-regulatory approval. [85] This recurrent pattern underscores the inadequacy of in vitro cell-based assays and subsequent preclinical in vivo studies in furnishing comprehensive pharmacological and toxicity data or reliable predictive capacity for comprehending the in vivo performance of drug candidates. [86]

The absence of a dependable translational assay toolkit for pharmacology and toxicology contributes to the high cost and inefficiency of transitioning from initial in vitro cell-based screens to in vivo testing and subsequent clinical approvals. [87] Particular emphasis is placed on their capacity to retain essential cell and molecular interactions, as well as physiological parameters influencing cell phenotypes and responses to bioactive agents. The distinctive advantages and challenges associated with these models are scrutinized, with a specific focus on their suitability for cell-based assays and their predictive capabilities, crucial for establishing accurate correlations with in vivo mechanisms of drug toxicity. [88]

While assessing safety and efficacy, these models are well equipped to model a wide range of disease states. Each of these models has advantages and limitations that require model development and data interpretation. Public-private partnerships are critical to advance and stimulate research in this area. [89]

Criticisms

Existing 3D methods are not without limitations, including scalability, reproducibility, sensitivity, and compatibility with high-throughput screening (HTS) instruments. Cell-based HTS relies on rapid determination of cellular response to drug interaction, such as dose dependent cell viability, cell-cell/cell-matrix interaction, and/or cell migration, but the available assays are not optimized for 3D cell culturing. Another challenge faced by 3D cell culturing is the limited amount of data and publications that address mechanisms and correlations of drug interaction, cell differentiation, and cell-signalling in these 3D environments. None of the 3D methods have yet replaced 2D culturing on a large scale, including in the drug development process; although the number of 3D cell culturing publications is increasing rapidly, the current limited biochemical characterization of 3D tissue diminishes the adoption of new methods.

Drug-induced liver injury (DILI) stands as a primary cause of compound attrition in the pharmaceutical realm during the course of drug development. [90] To preemptively assess the toxicity of compounds before embarking on laboratory animal testing, a range of in-vitro cell culture toxicity assays has been employed over the years. [91] While two-dimensional (2D) in-vitro cell culture models are commonly utilized and have contributed significantly to our understanding, they frequently exhibit limitations in faithfully replicating the natural structures of in-vivo tissues. [92] Although the most logical testing method involves humans, ethical constraints associated with human trials pose significant challenges. [93] Consequently, there is a pressing need for enhanced human-relevant and predictive models to overcome these limitations. [94]

The past decade has witnessed substantial endeavors aimed at advancing three-dimensional (3D) in-vitro cell culture models to better emulate in-vivo physiological conditions. The intrinsic advantages of 3D cell culture lie in its ability to represent cellular interactions akin to those in-vivo. When appropriately validated, 3D cell culture models can serve as a pivotal intermediary, bridging the gap between conventional 2D cell culture models and in-vivo animal models. This review endeavors to offer a comprehensive overview of the challenges associated with the sensitivity of biomarkers employed in detecting DILI during drug development. [95] Additionally, it explores the potential of 3D cell culture models to address the existing gaps in the current paradigm, offering a promising avenue for more accurate toxicity assessments. [96]

There are also problems using spheroids as a model for cancerous tissue. Although beneficial for 3D tissue culture, tumor spheroids have been criticized for being challenging or impossible to "manipulate gradients of soluble molecules in [3D spheroid] constructs, and to characterize cells in these complex gradients", unlike the paper-supported 3D cell culture for tissue-based bioassays explored by Ratmir et al. [55] Further challenges associated with complex 3D cell culture techniques include: imaging due to large scaffold sizes and incompatibility with many fluorescence microscopes, flow cytometry because it requires the dissociation of spheroids into a single-cell suspension, and the automation of liquid handling. [97]

2D models cannot study cell-cell and cell-matrix interactions. As a result of the scarcity of preclinical models relevant to 2D cultures, [98] [12] [99] 3D culture provides a pathophysiological microenvironment and has the potential to play a role in cancer drug discovery. [100] [101] [102] [103] [104]

Tissue engineering requires 3D cellular scaffolds. As biomaterials, various natural and synthetic polymer hydrogels have been used by scientists to design 3D scaffolds. Since this barrier is a structure that mimics the natural ECM microenvironment, synthetic scaffolds may be more useful for studying specific tumorigenic steps. [35] Finally, it is suggested that the most suitable three-dimensional models should be carefully selected according to specific targets. [104]

See also

Related Research Articles

<i>In vitro</i> Latin term meaning outside a natural biological environment

In vitro studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and its subdisciplines are traditionally done in labware such as test tubes, flasks, Petri dishes, and microtiter plates. Studies conducted using components of an organism that have been isolated from their usual biological surroundings permit a more detailed or more convenient analysis than can be done with whole organisms; however, results obtained from in vitro experiments may not fully or accurately predict the effects on a whole organism. In contrast to in vitro experiments, in vivo studies are those conducted in living organisms, including humans, known as clinical trials, and whole plants.

<span class="mw-page-title-main">Tissue engineering</span> Biomedical engineering discipline

Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues. Tissue engineering often involves the use of cells placed on tissue scaffolds in the formation of new viable tissue for a medical purpose, but is not limited to applications involving cells and tissue scaffolds. While it was once categorized as a sub-field of biomaterials, having grown in scope and importance, it can is considered as a field of its own.

In vitro toxicity testing is the scientific analysis of the toxic effects of chemical substances on cultured bacteria or mammalian cells. In vitro testing methods are employed primarily to identify potentially hazardous chemicals and/or to confirm the lack of certain toxic properties in the early stages of the development of potentially useful new substances such as therapeutic drugs, agricultural chemicals and food additives.

<span class="mw-page-title-main">Cell culture</span> Process by which cells are grown under controlled conditions

Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been isolated from living tissue, they can subsequently be maintained under carefully controlled conditions. They need to be kept at body temperature (37 °C) in an incubator. These conditions vary for each cell type, but generally consist of a suitable vessel with a substrate or rich medium that supplies the essential nutrients (amino acids, carbohydrates, vitamins, minerals), growth factors, hormones, and gases (CO2, O2), and regulates the physio-chemical environment (pH buffer, osmotic pressure, temperature). Most cells require a surface or an artificial substrate to form an adherent culture as a monolayer (one single-cell thick), whereas others can be grown free floating in a medium as a suspension culture. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, such as broth or agar. Tissue culture commonly refers to the culture of animal cells and tissues, with the more specific term plant tissue culture being used for plants. The lifespan of most cells is genetically determined, but some cell-culturing cells have been 'transformed' into immortal cells which will reproduce indefinitely if the optimal conditions are provided.

<span class="mw-page-title-main">Organ printing</span> Method of creating artificial organs

Organ printing utilizes techniques similar to conventional 3D printing where a computer model is fed into a printer that lays down successive layers of plastics or wax until a 3D object is produced. In the case of organ printing, the material being used by the printer is a biocompatible plastic. The biocompatible plastic forms a scaffold that acts as the skeleton for the organ that is being printed. As the plastic is being laid down, it is also seeded with human cells from the patient's organ that is being printed for. After printing, the organ is transferred to an incubation chamber to give the cells time to grow. After a sufficient amount of time, the organ is implanted into the patient.

<span class="mw-page-title-main">Organoid</span> Miniaturized and simplified version of an organ

An organoid is a miniaturised and simplified version of an organ produced in vitro in three dimensions that mimics the key functional, structural, and biological complexity of that organ. It is derived from one or a few cells from a tissue, embryonic stem cells, or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities. The technique for growing organoids has rapidly improved since the early 2010s, and The Scientist named it one of the biggest scientific advancements of 2013. Scientists and engineers use organoids to study development and disease in the laboratory, for drug discovery and development in industry, personalized diagnostics and medicine, gene and cell therapies, tissue engineering, and regenerative medicine.

An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture, integrated circuit (chip) that simulates the activities, mechanics and physiological response of an entire organ or an organ system. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context. By acting as a more sophisticated in vitro approximation of complex tissues than standard cell culture, they provide the potential as an alternative to animal models for drug development and toxin testing.

<span class="mw-page-title-main">3D bioprinting</span> Utilization of 3D printing to fabricate biomedical parts

Three dimensional (3D) bioprinting is the utilization of 3D printing–like techniques to combine cells, growth factors, bio-inks, and biomaterials to fabricate functional structures that were traditionally used for tissue engineering applications but in recent times have seen increased interest in other applications such as biosensing, and environmental remediation. Generally, 3D bioprinting utilizes a layer-by-layer method to deposit materials known as bio-inks to create tissue-like structures that are later used in various medical and tissue engineering fields. 3D bioprinting covers a broad range of bioprinting techniques and biomaterials. Currently, bioprinting can be used to print tissue and organ models to help research drugs and potential treatments. Nonetheless, translation of bioprinted living cellular constructs into clinical application is met with several issues due to the complexity and cell number necessary to create functional organs. However, innovations span from bioprinting of extracellular matrix to mixing cells with hydrogels deposited layer by layer to produce the desired tissue. In addition, 3D bioprinting has begun to incorporate the printing of scaffolds which can be used to regenerate joints and ligaments. Apart from these, 3D bioprinting has recently been used in environmental remediation applications, including the fabrication of functional biofilms that host functional microorganisms that can facilitate pollutant removal.

<span class="mw-page-title-main">3D cell culturing by magnetic levitation</span> Application of growing 3D tissue

3D cell culturing by Magnetic LevitationMethod (MLM) is the application of growing 3D tissue by inducing cells treated with magnetic nanoparticle assemblies in spatially varying magnetic fields, using neodymium magnetic drivers and promoting cell-to-cell interactions by levitating the cells up to the air/liquid interface of a standard petri dish. The magnetic nanoparticle assemblies consist of magnetic iron oxide nanoparticles, gold nanoparticles, and the polymer polylysine. 3D cell culturing is scalable, with the capability of culturing as few as 500 cells up to millions of cells, or from a single dish to high-throughput low volume systems. Once magnetized cultures are generated, they can also be used as the building block material, or the "ink" for the magnetic 3D bioprinting process.

MC2 Biotek is a biotechnology company established in 2006, with offices in Denmark and external labs in the United Kingdom. MC2 is a holding company, comprising three smaller Biotechnology companies with their own biotechnology solutions, they are: DrugMode (DK), Zadec (DK), and Drug Delivery Solutions (UK). DrugMode specializes in 3D cell culture, and is based out of the University of Southern Denmark at Odense. Zadec focuses on Diabetes and nutrition, and has developed an oral anti-diabetes drug, RX-1, which is currently in clinical trials. Drug Delivery Solutions works in the field of dermatology and ophthalmology, developing topical drugs such as a cream to treat psoriasis.

Magnetic 3D bioprinting is a methodology that employs biocompatible magnetic nanoparticles to print cells into 3D structures or 3D cell cultures. In this process, cells are tagged with magnetic nanoparticles that are used to render them magnetic. Once magnetic, these cells can be rapidly printed into specific 3D patterns using external magnetic forces that mimic tissue structure and function.

The in vivo bioreactor is a tissue engineering paradigm that uses bioreactor methodology to grow neotissue in vivo that augments or replaces malfunctioning native tissue. Tissue engineering principles are used to construct a confined, artificial bioreactor space in vivo that hosts a tissue scaffold and key biomolecules necessary for neotissue growth. Said space often requires inoculation with pluripotent or specific stem cells to encourage initial growth, and access to a blood source. A blood source allows for recruitment of stem cells from the body alongside nutrient delivery for continual growth. This delivery of cells and nutrients to the bioreactor eventually results in the formation of a neotissue product. 

Muscle tissue engineering is a subset of the general field of tissue engineering, which studies the combined use of cells and scaffolds to design therapeutic tissue implants. Within the clinical setting, muscle tissue engineering involves the culturing of cells from the patient's own body or from a donor, development of muscle tissue with or without the use of scaffolds, then the insertion of functional muscle tissue into the patient's body. Ideally, this implantation results in full regeneration of function and aesthetic within the patient's body. Outside the clinical setting, muscle tissue engineering is involved in drug screening, hybrid mechanical muscle actuators, robotic devices, and the development of engineered meat as a new food source.

<span class="mw-page-title-main">3D cell culture in wood-based nanocellulose hydrogel</span>

Hydrogel from wood-based nanofibrillated cellulose (NFC) is used as a matrix for 3D cell culture, providing a three-dimensional environment that more closely resembles the conditions found in living tissue. As plant based material, it does not contain any human- or animal-derived components. Nanocellulose is instead derived from wood pulp that has been processed to create extremely small, nanoscale fibers. These fibers can be used to create a hydrogel, which is a type of material that is made up of a network of cross-linked polymer chains and is able to hold large amounts of water.

Microfluidic cell culture integrates knowledge from biology, biochemistry, engineering, and physics to develop devices and techniques for culturing, maintaining, analyzing, and experimenting with cells at the microscale. It merges microfluidics, a set of technologies used for the manipulation of small fluid volumes within artificially fabricated microsystems, and cell culture, which involves the maintenance and growth of cells in a controlled laboratory environment. Microfluidics has been used for cell biology studies as the dimensions of the microfluidic channels are well suited for the physical scale of cells. For example, eukaryotic cells have linear dimensions between 10 and 100 μm which falls within the range of microfluidic dimensions. A key component of microfluidic cell culture is being able to mimic the cell microenvironment which includes soluble factors that regulate cell structure, function, behavior, and growth. Another important component for the devices is the ability to produce stable gradients that are present in vivo as these gradients play a significant role in understanding chemotactic, durotactic, and haptotactic effects on cells.

<span class="mw-page-title-main">Antonios Mikos</span> Greek-American biomedical engineer

Antonios Georgios Mikos is a Greek-American biomedical engineer who is the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering at Rice University. He specialises in biomaterials, drug delivery, and tissue engineering.

Microfluidics refers to the flow of fluid in channels or networks with at least one dimension on the micron scale. In open microfluidics, also referred to as open surface microfluidics or open-space microfluidics, at least one boundary confining the fluid flow of a system is removed, exposing the fluid to air or another interface such as a second fluid.

Multicellular tumor spheroids are scaffold-free spherical self-assembled aggregates of cancer cells. It is a 3 dimensional culture model which closely models oxygen gradients in small avascular tumors. They are cellular model used in cancer research to assess drug response.

Cultrex Basement Membrane Extract (BME) is the trade name for a extracellular protein mixture secreted by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells and manufactured into a hydrogel by R&D Systems, a brand of Bio-Techne. Similar to Matrigel, this hydrogel is a natural extracellular matrix that mimics the complex extracellular environment within complex tissues. It is used as a general cell culture substrate across a wide variety of research applications.

Intestines-on-a-chip are microfluidic bioengineered 3D-models of the real organ, which better mimic physiological features than conventional 3D intestinal organoid culture. A variety of different intestine-on-a-chip models systems have been developed and refined, all holding their individual strengths and weaknesses and collectively holding great promise to the ultimate goal of establishing these systems as reliable high-throughput platforms for drug testing and personalised medicine. The intestine is a highly complex organ system performing a diverse set of vital tasks, from nutrient digestion and absorption, hormone secretion, and immunological processes to neuronal activity, which makes it particularly challenging to model in vitro.

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