Microfluidic assay in idealized microvascular network for selection and optimization of drug delivery vehicles to simulated tumors
Inventors
Prabhakarpandian, Balabhaskar • Pant, Kapil • Garson, Charles Joseph
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Assignees
MemberSynVivoSynVivoSynVivo is a pioneering provider of cell-based microfluidic organ-on-chip platforms, delivering biologically realistic microenvironments for real-time study of cellular behavior, drug delivery, and drug discovery. Their proprietary technology bridges microfluidics and bioengineering, enabling advanced research in life sciences, disease modeling, and personalized medicine. SynVivo's chips support microvascular networks that closely mimic in vivo tissue conditions, validated by scientific research to more accurately reflect human biology than conventional culture methods. The platform is especially impactful for personalized cancer therapy, allowing patient-derived cells to be used for drug efficacy testing in a simulated tumor environment. SynVivo also distributes a wide range of high-quality primary cells and cell lines from various species, supporting research in immunology, cardiovascular, and cancer biology.
SynVivo is a pioneering provider of cell-based microfluidic organ-on-chip platforms, delivering biologically realistic microenvironments for real-time study of cellular behavior, drug delivery, and drug discovery. Their proprietary technology bridges microfluidics and bioengineering, enabling advanced research in life sciences, disease modeling, and personalized medicine. SynVivo's chips support microvascular networks that closely mimic in vivo tissue conditions, validated by scientific research to more accurately reflect human biology than conventional culture methods. The platform is especially impactful for personalized cancer therapy, allowing patient-derived cells to be used for drug efficacy testing in a simulated tumor environment. SynVivo also distributes a wide range of high-quality primary cells and cell lines from various species, supporting research in immunology, cardiovascular, and cancer biology.
Publication Number
US-9453252-B2
Publication Date
2016-09-27
Expiration Date
Abstract
An apparatus for assaying a tumor drug delivery vehicle and or drug can include an idealized microvascular network (IMN) of one or more interconnected idealized flow channels in fluid communication through a porous wall with a tissue space (e.g., idealized tissue space) containing animal cells and means for quantifying drug delivery through the IMN to the animal cells.
Core Innovation
The invention provides an apparatus and methods for assaying a tumor drug delivery vehicle and/or drug using an idealized microvascular network (IMN) formed of one or more interconnected idealized flow channels in fluid communication through a porous wall with a tissue space containing animal cells, and means for quantifying drug delivery through the IMN to the animal cells. The microfluidic device comprises an optically clear microfluidic chip containing a microvascular network of interconnected flow channels having dimensions from 10-500 μm in cross-section, luminal surfaces of the flow channels coated with a confluent layer of cultured endothelial cells, and tissue spaces surrounded by the flow channels. The flow channels are separated from the tissue spaces by pores in the walls having dimensions in the range of 0.2-5 μm to represent leaky vessels that allow transport of delivery vehicles across vascular walls into the tissue spaces.
The invention addresses shortcomings of existing in-vitro tumor drug delivery models which are often poor predictors of drug delivery to tumors because simple models cannot accurately capture the complex phenomena involved in tumor drug delivery, including effects of physico-chemical properties of drugs and delivery vehicles and complex tumor microvasculature. The present invention provides methods and apparatus that account for geometric and flow properties, increased permeability, and higher interstitial pressures of tumor microvasculature to better evaluate potential drug delivery vehicles. Candidate drug delivery vehicles are introduced into and flowed through the flow channels at physiologically realistic flow conditions and the ability of candidate vehicles to reach, permeate, and/or transfect cultured tumor cells is used to select for and/or optimize performance.
The microfluidic chips may include synthetic microvascular networks (SMNs) derived from physiological images, averaged networks, or idealized networks comprising linear channels joined at acute, right, or obtuse angles, and tissue spaces that can be configured to support tumor monolayers, bilayers, or three-dimensional solid tumors. The devices are described as optically transparent and compatible with coatings and cell types on luminal surfaces and in tissue spaces, and can incorporate apertures, posts, valves, and distinct inlets/outlets to control fluid communication and simulate interstitial pressures. The devices and methods are further described as usable to quantify properties such as transport, stability, aggregation, adhesion, and interaction of delivery vehicles with cells and tissue spaces.
Claims Coverage
The patent includes one independent apparatus claim (claim 1). The main inventive features extracted from the independent claim are listed below (five inventive features).
Optically transparent microfluidic chip
An optically transparent microfluidic chip comprising one or more idealized flow channels having one or more inlets and one or more outlets and a first cross-sectional dimension.
Idealized flow channels with linear sections
One or more idealized flow channels in which each idealized flow channel has one or more linear sections and forms part of an idealized microvascular network.
Tissue spaces bordering flow channels
One or more tissue spaces bordering the one or more idealized flow channels and having a second cross-sectional dimension.
Connected linear walls defining tissue spaces
Two or more connected linear walls of two or more linear sections of a first idealized flow channel define two or more connected linear walls of a first tissue space.
Apertures fluidly coupling channels and tissue spaces
A first wall separating the first idealized flow channel from the first tissue space includes a plurality of apertures that fluidly couple the first idealized flow channel with the first tissue space, the plurality of apertures having a third cross-sectional dimension.
The independent claim defines an optically transparent microfluidic chip integrating idealized linear flow channels and bordering tissue spaces whose separating walls include apertures that fluidly couple channels and tissue spaces, with channel, tissue space, and aperture dimensions specified.
Stated Advantages
Accounts for geometric and flow properties, increased permeability, and higher interstitial pressures of tumor microvasculature to improve evaluation of drug delivery vehicles.
Mimics physiological microvascular environments by coating luminal surfaces with a confluent layer of cultured endothelial cells.
Allows quantification of drug delivery through the IMN to cultured tumor cells to select and optimize drug delivery vehicles.
Supports growth of tumor monolayers, bilayers, and three-dimensional solid tumors using configured tissue spaces and posts.
Use of PDMS (and alternative materials) offers gas permeability, optical transparency, ease of casting, and the ability to produce small volume, inexpensive, disposable chips.
Can be scaled for high-throughput screening by forming chips on standard 24 or 96 well plate formats.
Can be adapted to assay drug delivery to other tissues and to mimic other physiological barriers such as the blood-brain barrier and linings of the small intestine.
Documented Applications
Screening and selection/optimization of tumor drug delivery vehicles by introducing candidate vehicles into microfluidic flow channels and quantifying delivery to tumor cells and tissue spaces.
Assaying delivery vehicle properties including transport, adhesion to luminal surfaces, stability, aggregation, degradation, real-time circulation, and rates of adhesion and degradation.
Analyzing gene delivery by delivery vehicles using fluorescent reporter expression in tumor cells to indicate delivery vehicle success.
Analyzing drug delivery efficacy by monitoring tumor growth or impedance changes in tissue spaces as indicators of drug delivery to tumor cells.
Modeling physiological and pathological microvasculature using synthetic microvascular networks (SMNs), averaged networks, and idealized microvascular networks (IMNs) to study particle transport, particle adhesion, leukocyte adhesive cascade, and barrier diffusion (including blood-brain barrier delivery) as stated via incorporation of referenced methods.
Testing a wide variety of test substances and biologically active agents, including cells, particles, nanoparticles, microparticles, viruses, bacteria, small molecules, macromolecules, and environmental substances for their ability to reach or affect cells in flow channels or tissue spaces.
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