Biomimetic Device for Drug Evaluation

IDF No.: LU-061114-01

 

Lead Inventor: Yaling Liu

 

Department: Bioengineering, Mechanical Engineering & Mechanics

 

Patent Status: Issued US Patent 10,870,823 and Pending US Patent App. No.: 17/130,142

 

Summary:

The invention is a biomimetic microfluidic platform that can prototype an in-vivo blood vessel outside the human body. The platform integrates an endothelial cell layer in a microfluidic channel, which can be subjected to specific flow and chemokine stimulations. It consists of a top and bottom channel separated by a semi-permeable, porous, cell culture friendly membrane. Endothelial cells that form the inner lining of blood vessels are coated on the semi-permeable membrane in the top channel. The microfluidic channel platform is designed such that it allows specific sections to access the top channel from the bottom channel, which allows spatially controlled stimulation of these endothelial cells from the basal side. This in-vitro blood vessel model can serve as a generic platform to study targeted drug delivery (ligand-receptor specificity, drug carrier features, hemorheology factors), cardiovascular conditions (atherosclerosis, drug-eluting stents), immunology (inflammation, leukocyte adhesion, and migration). In addition, perform explicit studies on patient-specific blood vessels (design channel geometries specific to a patient's blood vessel; integrate endothelial cells from the patient) to understand the best treatment strategy for a disease condition or study various factors that culminated in the onset of a disease condition, etc. This technology addresses the needs of a blood vessel model that can cater to the demands for patient-specific therapeutics, as well as provide a more realistic platform to enhance current conventional drug development studies.

 

The developed microfluidic blood vessel model has advantages over in-vivo and animal blood vessel models, as well as bettering current gold standard in-vitro works on a petri dish and flow chamber platforms.

 

Advantages:

 

The novel features and advantages of this novel device are:

  • The device has a novel bi-layer design where the top and bottom channels are separated by a semi-permeable membrane. Endothelial cells are grown on the cell culture friendly, semi-permeable membrane rather than glass or other substrates as in other platforms.
  • The endothelial cells growing in the top channel of the bi-layer device can be subjected to physiological (flow, stretching, etc.) and biochemical (chemokine, enzyme stimulation) conditions to mimic an in-vivo environment for the cells.
  • The bi-layer nature of the device facilitates localized access to the top channel from the bottom channel. This enables site-specific chemokine treatment of the endothelial cells growing on the top channel. The study of localized endothelial cell receptor expression levels and cell cycle pathways leading to their upregulation via cytokine treatment is capable. Tumor necrosis factor-α is a cytokine and leads to upregulation of ICAM-1, E-Selectin, and VCAM-1 on endothelial cells. (Current research in Dr. Liu’s lab using this device looks into the upregulation of ICAM-1.)
  • This platform enables the in-situ study of targeted drug-loaded particle delivery onto endothelial cells subjected to inflammatory conditions. In the lab’s current work, anti-ICAM-1 coated particles that model drug carriers flow in channels having endothelial cells expressing upregulated ICAM-1.
  • The device design can be tuned to patient-specific dimensions and geometry by obtaining a scan of the patient blood vessel under study.
  • The device also has the capability to model organ-level functions by culturing different cell lines on the two sides of the membrane and studying their cell-cell interaction. Different models that are possible are Lungs, Intestine (endothelial and epithelial cells); Blood-brain barrier (endothelial cells and nerve cells); Liver (endothelial cells and hepatocytes), etc.

Advantages and improvements over existing methods, devices, or materials.

The current gold standard platforms where blood vessels are modeled are typically done on petri dishes and/or flow chambers. The main benefits of this technology, not currently offered in the market, is the ability to closely mimicking in-vivo healthy and diseased blood vessel conditions, such as inflammation, thrombosis, and atherosclerosis. The introduction of a bilayer system allows the growth of two types of cells in the same system, locally trigger receptor expression on cells that mimic vascular disease, and test targeted drug particle delivery and uptake.  This technology allows control and target cells to be grown on the same device, integrated in-situ imaging and testing, patient-specific vascular geometry and flow conditions, and fast parametric evaluation with minimal sample volume.

 

 

The unique feature introduced into this microfluidic platform is a versatile combination of two layers of independently controllable channels, as well as the introduction of a semi-permeable membrane to allow coupling between the two layers.  Currently, the membrane incorporated into the device is composed of polycarbonate, which functions well for cell seeding and growth.  The introduction of this bi-layer and semi-permeable membrane provides this platform the advantage of a more realistic model of the boundary regions in the body where two types of tissue interact. The ability to more closely mimic conditions found in-vivo, allow for studies where exchange occurs within the human body.  Such phenomena as nutrient exchange from digestive to circulatory tracts and gaseous exchange from the respiratory tract to tissues can also be studied.  Another key capability of the semi-permeable membrane is that it allows localized expression of biomarkers by injecting triggering chemicals from one channel, allows its diffusion across the membrane, and triggers the expression of certain biomarkers. The introduction of this key semi-permeable membrane allows for an advantage in studies related to exchange, uptake, and delivery, above and beyond what the competitors currently offer, making the Lehigh platform well suited for studying nanomedicine delivery and other phenomena.

 

Additional Capabilities

The bi-layer microfluidic system that has been developed is capable of facilitating active convective nutrient supply to populations of cancer cells. The microfluidic 3D culturing system has several advantages over current cancer growth techniques that are capable of producing physiologically relevant tumors in an expedited fashion while only requiring a small number of initial cancer cells. This 3D culturing system is believed to be the first attempt to grow cancers in an expedited fashion utilizing only a convective nutrient supply, which has the potential to offer improved drug screening for patients in clinical settings. A mathematical model has been developed which allows for adjustments to be made to the dynamic delivery of nutrients in order to efficiently use culture media without excessive waste.

 

Category(s):
Biology
Life Sciences
For Information, Contact:
Rick Smith
Director
Lehigh University
res419@lehigh.edu
Inventors:
Yaling Liu
Anthony Thomas
Keywords: