This is the third article in a review series of “Nanomedicine: A Vast Horizon on a Molecular Landscape”. In Part I we discussed the major research and development areas in the field.  Then, we briefly introduced some representative research groups and companies and their patents in nanomedicine (Part II). Here, we will start the discussion about the diagnostic applications of nanomedicine.

Diagnostics

The applications of micro/nanotechnology in biomedical diagnostics have significantly increased the accuracy and cost of analyzing patient samples and stratifying personalized therapeutics. The advanced diagnostic technologies include in-vivo imaging using contrast agents, in-vivo non-imaging diagnostics, and in-vitro miniaturized diagnostics. In this article, I will focus on the in-vitro miniaturized diagnostics, especially the so-called “organs-on-a-chip” for medical diagnostics.

Organs-on-a-chip

Organs-on-a-chip is a 3D microfluidic based multi-cell co-culture system that simulates the physiological, mechanical, and molecular environment of the human body and mimics the physiological activities of human organs and organ systems. These miniaturized systems enable the investigation of human physiology in an organ-specific environment and permit the development of in vitro disease models.  The technology offers novel platforms for new drug screening and toxicology testing as a replacement for animal models.

History

Organs-on-a-chip integrates 3D cell culture models with microfabricated devices to mimic the human physiology of organ systems. Compared to 2D cell culture systems, 3D cell-culture models having cells within extracellular matrix gels more successfully reconstitute the in vivo cellular microenvironment and maintain the differentiated functions of cells. However, 3D culture models fail to mimic the tissue-tissue interfaces, spatiotemporal gradients of chemicals and oxygen, and the mechanically active microenvironment that have an impact on the functionality of cells under natural physiological conditions. Microengineering introduces microfluidics which can precisely tune the dynamic fluid flow to generate spatiotemporal gradients of biochemicals and nutrients. Performing 3D cell cultures in microfluidics enables the possibility to reconstitute more complex 3D organ-level structures with controlled crucial dynamic mechanical cues, as well as biochemical signals that capture the response and functionality of human organ systems in vitro.

Patent Review

The first biology-on-a-chip project was lead by Dr. Michael Shuler at Cornell University (US patent 8,748,180) in the late 1990s. Later on, variant organs-on-a-chip systems were created, such as models for liver, lung, intestine, heart, kidney, cornea, and even cancers. Dr. Luke Lee at the University of California, Berkeley developed a 3D multiple liver cell co-culture system to maintain the viability of hepatic cells in vitro (US patent 9,260,688). Dr. Mehmet Toner, Dr. Sangeeta Bhatia and Dr. Linda Griffith at MIT have created different liver-on-chip systems for disease model and drug screening (US patent 8,318,479 and US patent 6,562,616). Dr. Donald Ingber at Harvard University has used multilayered microfluidics to create an air-liquid interface for mimicking human lung system (US patent 8,647,861). Dr. Shuichi Takayama introduced mechanical stimulation into a lung chip to investigate the mechanisms of traumatic damage to human lung tissue (US patent 7,704,728). A similar strategy was used to model intestine systems. At Harvard’s Wyss Institute, Dr. Kevin Kit Parker and Dr. William Pu collaborated to create a heart disease model on a microchip. Dr. Kahp-Yang Suh at Seoul National University and Dr. Xingyu Jiang at National Center for NanoScience and Technology in China have created on-chip nephron constructs to mimic kidney function. Dr. Jennifer Elisseeff and Dr. Tza-Huei Wang at Johns Hopkins University integrated hydrogels into multilayered microfluidics to generate corneal microtissues. Dr. Roger Kamm at MIT applied lab-on-a-chip techniques to investigate angiogenesis and metastasis in cancers (US patent 9,261,496).

Patent Number Title Assignee Inventor
8,748,180 Microfluidic Device for Pharmacokinetic-Pharmacodynamic Study of Drugs and Uses Thereof Cornell University Michael L. Shuler & Jong Hwan Sung
9,260,688 Method and Apparatus for Cell Culture Array The Regents of the University of California Paul J. Hung, Phillip J. Lee & Luke P. Lee
8,318,479 Perfused Three-Dimensional Cell/Tissue Disease Models Massachusetts Institute of Technology & University of Pittsburgh Karl Domansky, Linda G. Griffith, Steven R. Tannenbaum, Alan Wells & Samuel Walker Inman
6,562,616 Methods and Devices for Cell Culturing and Organ Assist Systems The General Hospital Corporation Mehment Toner, Martin L. Yarmush, Ulysses J. Balis & Arno W. Tilles
8,647,861 Organ Mimic Device with Microchannels and Methods of Use and Manufacturing Thereof Children’s Medical Center Corporation Donald E. Ingber & Donegeun Huh
7,704,728 Microfluidic Gravity Pump with Constant Flow Rate The University of Michigan Shuichi Takayama, Joseph Chang, Dongeun Huh, Xiaoyue Zhu, Brenda Cho & Gary D. Smith
9,261,496 Device for High Thoroughput Investigation of Multi-Cellular Interactions Massachusetts Institute of Technology, The General Hospital Corporation, The Brigham and Women’s Hospital, Inc., & Children’s Medical Center, Corp.

 

 Roger Dale Kamm, Haruhiko Harry Asada, Waleed Ahmed Farahat, Ioannis K. Zervantonakis, Levi B. Wood, Chandrasekhar Kothapalli, Seok Chung, Jeffrey D. Macklis, Suzanne Tharin, Johanna Varner, Young Kum Park, Kwang Ho Lee, Le Thanh Tu Nguyen & Choong Kim

 

To catch up with the rapid progress in this field, the US FDA is preparing to issue guidelines on how to replace animal tests with chips or related technologies, including computational and cell-based screening. With the development in the research of organs-on-a-chip, new startups have been spun off to commercialize the technology. Examples of such companies are: Emulate, Hepregen, Hesperos, HuREL, and CellASIC. Recently established pharma companies have started to recognize the potential of organ-on-a-chip systems and have collaborated with these start-ups for further development in drug screening. For example, Merck ($MRK) announced it was expanding its collaboration with Cambridge, MA’s Emulate on predictive modeling of inflammatory processes in the human lung and the gastrointestinal system using the Small Airway Lung-Chip and Intestine-Chip.

As you can see, organ-on-a-chip technology has the potential to predict responses in animals and humans and might have tremendous impact on the drug development and toxicology testing. It is a great example of transforming laboratory research into pharmaceutical and biotechnology industries, although development of system validation and scale-up manufacturing are needed to further push this technique toward commercialization stage. We will expect more patents related to the improvement of current technology coming soon.

– Jing Zhou, PhD and Anthony D. Sabatelli, PhD, JD

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