The third dimension bridges the gap between cell culture and live tissue
01 Oct 2007-Nature Reviews Molecular Cell Biology (Nature Publishing Group)-Vol. 8, Iss: 10, pp 839-845
TL;DR: It is believed that 3D cultures will have a strong impact on drug screening and will also decrease the use of laboratory animals, for example, in the context of toxicity assays.
Abstract: Cell monolayers have serious limitations for cell biological investigations and for cell-based assays in drug screening and toxicity studies. However, the establishment of three-dimensional cultures as a mainstream approach requires the development of reliable protocols, new cell lines and suitable imaging techniques.
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TL;DR: Mechanically active “organ-on-a-chip” microdevices that reconstitute tissue-tissue interfaces critical to organ function may expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.
Abstract: Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active "organ-on-a-chip" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.
3,081 citations
TL;DR: New advances in 3D culture that leverage microfabrication technologies from the microchip industry and microfluidics approaches to create cell-culture microen environments that both support tissue differentiation and recapitulate the tissue-tissue interfaces, spatiotemporal chemical gradients, and mechanical microenvironments of living organs are reviewed.
1,501 citations
TL;DR: Current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression are discussed, and how improving understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies.
Abstract: Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.
1,280 citations
Cites background from "The third dimension bridges the gap..."
...Consequently, even sophisticated 3D in vitro models might not represent the physiological conditions found in vivo (Schmeichel and Bissell, 2003; Pampaloni et al., 2007; Yamada and Cukierman, 2007)....
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TL;DR: A multimaterial 3D bioprinting method is reported that enables the creation of thick human tissues (>1 cm) replete with an engineered extracellular matrix, embedded vasculature, and multiple cell types that can be actively perfused for long durations.
Abstract: The advancement of tissue and, ultimately, organ engineering requires the ability to pattern human tissues composed of cells, extracellular matrix, and vasculature with controlled microenvironments that can be sustained over prolonged time periods. To date, bioprinting methods have yielded thin tissues that only survive for short durations. To improve their physiological relevance, we report a method for bioprinting 3D cell-laden, vascularized tissues that exceed 1 cm in thickness and can be perfused on chip for long time periods (>6 wk). Specifically, we integrate parenchyma, stroma, and endothelium into a single thick tissue by coprinting multiple inks composed of human mesenchymal stem cells (hMSCs) and human neonatal dermal fibroblasts (hNDFs) within a customized extracellular matrix alongside embedded vasculature, which is subsequently lined with human umbilical vein endothelial cells (HUVECs). These thick vascularized tissues are actively perfused with growth factors to differentiate hMSCs toward an osteogenic lineage in situ. This longitudinal study of emergent biological phenomena in complex microenvironments represents a foundational step in human tissue generation.
1,127 citations
TL;DR: The current understanding of multicellular spheroid formation mechanisms, their biomedical applications, and recent advances in sp heroid culture, manipulation, and analysis techniques are reviewed.
Abstract: Many types of mammalian cells can aggregate and differentiate into 3-D multicellular spheroids when cultured in suspension or a nonadhesive environment. Compared to conventional monolayer cultures, multicellular spheroids resemble real tissues better in terms of structural and functional properties. Multicellular spheroids formed by transformed cells are widely used as avascular tumor models for metastasis and invasion research and for therapeutic screening. Many primary or progenitor cells on the other hand, show significantly enhanced viability and functional performance when grown as spheroids. Multicellular spheroids in this aspect are ideal building units for tissue reconstruction. Here we review the current understanding of multicellular spheroid formation mechanisms, their biomedical applications, and recent advances in spheroid culture, manipulation, and analysis techniques.
1,107 citations
Cites background from "The third dimension bridges the gap..."
...As a result, loss of tissue-specific properties is common for cells grown in 2-D monolayer cultures [1–3]....
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References
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TL;DR: OCT as discussed by the authors uses low-coherence interferometry to produce a two-dimensional image of optical scattering from internal tissue microstructures in a way analogous to ultrasonic pulse-echo imaging.
Abstract: A technique called optical coherence tomography (OCT) has been developed for noninvasive cross-sectional imaging in biological systems. OCT uses low-coherence interferometry to produce a two-dimensional image of optical scattering from internal tissue microstructures in a way that is analogous to ultrasonic pulse-echo imaging. OCT has longitudinal and lateral spatial resolutions of a few micrometers and can detect reflected signals as small as approximately 10(-10) of the incident optical power. Tomographic imaging is demonstrated in vitro in the peripapillary area of the retina and in the coronary artery, two clinically relevant examples that are representative of transparent and turbid media, respectively.
11,568 citations
16 Nov 1992
TL;DR: Optical coherence tomography (OCT) has developed rapidly since its first realisation in medicine and is currently an emerging technology in the diagnosis of skin disease as mentioned in this paper, where OCT is an interferometric technique that detects reflected and backscattered light from tissue.
Abstract: Optical coherence tomography (OCT) has developed rapidly since its first realisation in medicine and is currently an emerging technology in the diagnosis of skin disease. OCT is an interferometric technique that detects reflected and backscattered light from tissue and is often described as the optical analogue to ultrasound. The inherent safety of the technology allows for in vivo use of OCT in patients. The main strength of OCT is the depth resolution. In dermatology, most OCT research has turned on non-melanoma skin cancer (NMSC) and non-invasive monitoring of morphological changes in a number of skin diseases based on pattern recognition, and studies have found good agreement between OCT images and histopathological architecture. OCT has shown high accuracy in distinguishing lesions from normal skin, which is of great importance in identifying tumour borders or residual neoplastic tissue after therapy. The OCT images provide an advantageous combination of resolution and penetration depth, but specific studies of diagnostic sensitivity and specificity in dermatology are sparse. In order to improve OCT image quality and expand the potential of OCT, technical developments are necessary. It is suggested that the technology will be of particular interest to the routine follow-up of patients undergoing non-invasive therapy of malignant or premalignant keratinocyte tumours. It is speculated that the continued technological development can propel the method to a greater level of dermatological use.
6,095 citations
TL;DR: Multiphoton microscopy has found a niche in the world of biological imaging as the best noninvasive means of fluorescence microscopy in tissue explants and living animals and its use is now increasing exponentially.
Abstract: Multiphoton microscopy (MPM) has found a niche in the world of biological imaging as the best noninvasive means of fluorescence microscopy in tissue explants and living animals. Coupled with transgenic mouse models of disease and 'smart' genetically encoded fluorescent indicators, its use is now increasing exponentially. Properly applied, it is capable of measuring calcium transients 500 microm deep in a mouse brain, or quantifying blood flow by imaging shadows of blood cells as they race through capillaries. With the multitude of possibilities afforded by variations of nonlinear optics and localized photochemistry, it is possible to image collagen fibrils directly within tissue through nonlinear scattering, or release caged compounds in sub-femtoliter volumes.
3,738 citations
"The third dimension bridges the gap..." refers methods in this paper
...Multiphoton microscopy is often regarded as the technique of choice for imaging 3D sample...
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TL;DR: It is found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation.
3,553 citations
"The third dimension bridges the gap..." refers background in this paper
...Recent studies provide evidence that changes in the mechanical properties of the ECM (for example, an increase in stiffness) can promote neoplastic transformation by perturbing the extracellular signal-regulated kinase (ERK)/Rho mechanoregulatory circuit of breast epithelial cell...
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TL;DR: Cancer cells possess a broad spectrum of migration and invasion mechanisms and learning more about the cellular and molecular basis of these different migration/invasion programmes will help to understand how cancer cells disseminate and lead to new treatment strategies.
Abstract: Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumour progression in clinical trials — this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programmes will help us to understand how cancer cells disseminate and lead to new treatment strategies.
3,064 citations
"The third dimension bridges the gap..." refers background in this paper
...Such a process is triggered by the inhibition of integrins or of the proteolytic activity of matrix-metalloproteinase...
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