The Ascendance of Microphysiological Systems to Solve the Drug Testing Dilemma

Dehne, Eva-Maria; Hasenberg, Tobias; Marx, Uwe

doi:10.4155/fsoa-2017-0002

Cited by 53 publications

(38 citation statements)

References 78 publications

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“…Furthermore, bioprinting technology becomes crucial in enhancing tissue models mimicking human in vivo organ interaction. Such models find increasing application in a number of sophisticated micro physiological systems used to solve the drug‐testing dilemma . Despite the usage as an in vitro organ model, bioprinted cartilage based on gelatin and hyaluronic acid could potentially find clinical application in repairing cartilage defects using patient‐specific cells incorporated in the printed constructs.…”

Section: Resultsmentioning

confidence: 99%

Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue‐engineered cartilage

Lam¹,

et al. 2019

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To create artificial cartilage in vitro, mimicking the function of native extracellular matrix (ECM) and morphological cartilage‐like shape is essential. The interplay of cell patterning and matrix concentration has high impact on the phenotype and viability of the printed cells. To advance the capabilities of cartilage bioprinting, we investigated different ECMs to create an in vitro chondrocyte niche. Therefore, we used methacrylated gelatin (GelMA) and methacrylated hyaluronic acid (HAMA) in a stereolithographic bioprinting approach. Both materials have been shown to support cartilage ECM formation and recovery of chondrocyte phenotype. We used these materials as bioinks to create cartilage models with varying chondrocyte densities. The models maintained shape, viability, and homogenous cell distribution over 14 days in culture. Chondrogenic differentiation was demonstrated by cartilage‐typical proteoglycan and type II collagen deposition and gene expression (COL2A1, ACAN) after 14 days of culture. The differentiation pattern was influenced by cell density. A high cell density print (25 × 106 cells/mL) led to enhanced cartilage‐typical zonal segmentation compared to cultures with lower cell density (5 × 106 cells/mL). Compared to HAMA, GelMA resulted in a higher expression of COL1A1, typical for a more premature chondrocyte phenotype. Both bioinks are feasible for printing in vitro cartilage with varying differentiation patterns and ECM organization depending on starting cell density and chosen bioink. The presented technique could find application in the creation of cartilage models and in the treatment of articular cartilage defects using autologous material and adjusting the bioprinted constructs size and shape to the patient. © 2019 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2649–2657, 2019.

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Section: Resultsmentioning

confidence: 99%

Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue‐engineered cartilage

Lam¹,

et al. 2019

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“…Hepatocytes are highly metabolic cells performing a multitude of enzymatic and secretory functions in the human body and are essential components of in vitro liver‐on‐chip models capturing drug metabolism. MPS models that not only enable hepatocyte culture, but also allow coculture with nonparenchymal cells is of paramount interest to the pharmaceutical industry (Bale et al, ; Bale, Moore, et al, ; Dehne, Hasenberg, & Marx, ; Ewart et al, ; Materne et al, ). To overcome the current limitations of the materials used in existing MPS platforms for PHH cultures, we have engineered a thermoplastic microfluidic MPS that meets the specific oxygen requirements for stabilization culture of primary human hepatocytes and captures their interactions in coculture with nonparenchymal cells.…”

Section: Discussionmentioning

confidence: 99%

“…The concentration effects due to the small volume of culture medium enable detection of metabolites and secreted factors that otherwise too diluted to be detectable in regular culture plates. The other attractive utility of the liver‐on‐chip models is to study the interaction of resident liver cells in a controlled in vitro system (Bale et al, ; Bale, Moore, et al, ; Dehne et al, ; Ewart et al, ; Materne et al, ). As a test case, we have introduced primary human Kupffer cells in the bottom channel of the microfluidic MPS, generating a PHH–PKC coculture model to capture their combined responses to an acute stimulus.…”

Section: Discussionmentioning

confidence: 99%

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions

Bale

Manoppo

Thompson

et al. 2019

Biotech & Bioengineering

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Hepatic in vitro platforms ranging from multi-well cultures to bioreactors and microscale systems have been developed as tools to recapitulate cellular function and responses to aid in drug screening and disease model development. Recent developments in microfabrication techniques and cellular materials enabled fabrication of next-generation, advanced microphysiological systems (MPSs) that aim to capture the cellular complexity and dynamic nature of the organ presenting highly controlled extracellular cues to cells in a physiologically relevant context. Historically, MPSs have heavily relied on elastomeric materials in their manufacture, with unfavorable material characteristics (such as lack of structural rigidity) limiting their use in high-throughput systems. Herein, we aim to create a microfluidic bilayer model (microfluidic MPS) using thermoplastic materials to allow hepatic cell stabilization and culture, retaining hepatic functional phenotype and capturing cellular interactions. The microfluidic MPS consists of two overlapping microfluidic channels separated by a porous tissue-culture membrane that acts as a surface for cellular attachment and nutrient exchange; and an oxygen permeable material to stabilize and sustain primary human hepatocyte (PHH) culture. Within the microfluidic MPS, PHHs are cultured in the top channel in a collagen sandwich gel format with media exchange accomplished through the bottom channel. We demonstrate PHH culture for 7 days, exhibiting measures of hepatocyte stabilization, secretory and metabolic functions. In addition, the microfluidic MPS dimensions provide a reduced media-to-cell ratio in comparison with multi-well tissue culture systems, minimizing dilution and enabling capture of cellular interactions and responses in a hepatocyte-Kupffer coculture modelunder an inflammatory stimulus. Utilization of thermoplastic materials in the model and ability to incorporate multiple hepatic cells within the system is our initial step towards the development of a thermoplastic-based high-throughput microfluidic MPS platform for hepatic culture. We envision the platform to find utility in development and interrogation of disease models of the liver, multi-cellular interactions and therapeutic responses.

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“…Moreover, the combination of TE with microfabrication techniques and microfluidics have enabled the development of microphysiological systems, also termed organs-on-chips, which can serve as systemic models of human physiology and disease [32,33]. Organs-on-chips platforms offer the unique ability to host bioengineered 3D constructs in a controlled microenvironment, while allowing the delivery of mechanical and electrophysiological stimuli [34]. This is particularly important, since cardiovascular tissues are comprised of a multitude of cell types (e.g., cardiomyocytes (CMs), cardiac fibroblasts, endothelial cells, Purkinje cells, etc.)…”

Section: Introductionmentioning

confidence: 99%

Biomimetic cardiovascular platforms for in vitro disease modeling and therapeutic validation

et al. 2019

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Bioengineered tissues have become increasingly more sophisticated owing to recent advancements in the fields of biomaterials, microfabrication, microfluidics, genetic engineering, and stem cell and developmental biology. In the coming years, the ability to engineer artificial constructs that accurately mimic the compositional, architectural, and functional properties of human tissues, will profoundly impact the therapeutic and diagnostic aspects of the healthcare industry. In this regard, bioengineered cardiac tissues are of particular importance due to the extremely limited ability of the myocardium to self-regenerate, as well as the remarkably high mortality associated with cardiovascular diseases worldwide. As novel microphysiological systems make the transition from bench to bedside, their implementation in high throughput drug screening, personalized diagnostics, disease modeling, and targeted therapy validation will bring forth a paradigm shift in the clinical management of cardiovascular diseases. Here, we will review the current state of the art in experimental in vitro platforms for next generation diagnostics and therapy validation. We will describe recent advancements in the development of smart biomaterials, biofabrication techniques, and stem cell engineering, aimed at recapitulating cardiovascular function at the tissue- and organ levels. In addition, integrative and multidisciplinary approaches to engineer biomimetic cardiovascular constructs with unprecedented human and clinical relevance will be discussed. We will comment on the implementation of these platforms in high throughput drug screening, in vitro disease modeling and therapy validation. Lastly, future perspectives will be provided on how these biomimetic platforms will aid in the transition towards patient centered diagnostics, and the development of personalized targeted therapeutics.

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The Ascendance of Microphysiological Systems to Solve the Drug Testing Dilemma

Cited by 53 publications

References 78 publications

Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue‐engineered cartilage

Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue‐engineered cartilage

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions

Biomimetic cardiovascular platforms for in vitro disease modeling and therapeutic validation

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