Organ-level physiology is recapitulated in vitro by culturing cells in perfused, microfluidic devices.

Microfluidic organs-on-chips

The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies — such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs — and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.

Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.

A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice

Microscale engineering technologies provide unprecedented opportunities to create cell culture microenvironments that go beyond current three-dimensional in vitro models by recapitulating the critical tissue–tissue interfaces, spatiotemporal chemical gradients, and dynamic mechanical microenvironments of living organs Here we review recent advances in this field made over the past two years that are focused on the development of ‘Organs-on-Chips’ in which living cells are cultured within microfluidic devices that have been microengineered to reconstitute tissue arrangements observed in living organs in order to study physiology in an organ-specific context and to develop specialized in vitro disease models We discuss the potential of organs-on-chips as alternatives to conventional cell culture models and animal testing for pharmaceutical and toxicology applications We also explore challenges that lie ahead if this field is to fulfil its promise to transform the future of drug development and chemical safety testing

Microengineered physiological biomimicry: Organs-on-Chips

Multiphase monolith reactors: Chemical reaction engineering of segmented flow in microchannels

In vitro models that capture the complexity of in vivo tissue and organ behaviors in a scalable and easy-to-use format are desirable for drug discovery. To address this, we have developed a bioreactor that fosters maintenance of 3D tissue cultures under constant perfusion and we have integrated multiple bioreactors into an array in a multiwell plate format. All bioreactors are fluidically isolated from each other. Each bioreactor in the array contains a scaffold that supports formation of hundreds of 3D microscale tissue units. The tissue units are perfused with cell culture medium circulated within the bioreactor by integrated pneumatic diaphragm micropumps. Electronic controls for the pumps are kept outside the incubator and connected to the perfused multiwell by pneumatic lines. The docking design and open-well bioreactor layout make handling perfused multiwell plates similar to using standard multiwell tissue culture plates. A model of oxygen consumption and transport in the circulating culture medium was used to predict appropriate operating parameters for primary liver cultures. Oxygen concentrations at key locations in the system were then measured as a function of flow rate and time after initiation of culture to determine oxygen consumption rates. After seven days of culture, tissue formed from cells seeded in the perfused multiwell reactor remained functionally viable as assessed by immunostaining for hepatocyte and liver sinusoidal endothelial cell (LSEC) phenotypic markers.

/pdf/perfused-multiwell-plate-for-3d-liver-tissue-engineering-3flkabkw9y.pdf

Perfused multiwell plate for 3D liver tissue engineering

MRI visualisation of two-phase flow in structured supports and trickle-bed reactors

A number of phenomenologically relevant processes at hadron colliders, such as Higgs and Z boson production in association with b quarks, can be conveniently described as scattering of heavy quarks in the initial state. We present a detailed analysis of this class of processes, identifying the form of the leading initial-state collinear logarithms that allow the relation of calculations performed in different flavour schemes in a simple and reliable way. This procedure makes it possible to assess the size of the logarithmically enhanced terms and the effects of their resummation via heavy-quark parton distribution functions. As an application, we compare the production of (SM-like and heavy) scalar and vector bosons in association with b quarks at the LHC in the four- and five-flavour schemes as well as the production of a heavy Z
 ′ in association with top quarks at a future 100 TeV hadron collider in the five- and six-flavour schemes. We find that, in agreement with a previous analysis of single heavy-quark initiated processes, the size of the initial-state logarithms is mitigated by a kinematical suppression. The most important effects of the resummation are a shift of the central predictions typically of about 20% at a justified value of the scale of each considered process and a significant reduction of scale variation uncertainties.

/pdf/anatomy-of-double-heavy-quark-initiated-processes-ad4cbw2qzs.pdf

Anatomy of double heavy-quark initiated processes

Magnetic resonance imaging (MRI) has recently been used to image local pulsing events, which are associated with the transition from trickle to pulsing flow in fixed-bed reactors. This paper report...

Matthew H. M. Lim

Papers

Perfused multiwell plate for 3D liver tissue engineering

Perfused multiwell plate for 3D liver tissue engineering

MRI visualisation of two-phase flow in structured supports and trickle-bed reactors

Anatomy of double heavy-quark initiated processes

Insights into the Mechanism of the Trickle-to-Pulse Transition in Trickle-Bed Reactors