Cancer Models (primary, metastatic, immuno-oncology)

Technologies have been developed to image and study from a mechanistic viewpoint the processes used by tumor cells to form a metastatic tumor. In addition, primary tumor organoids can also be used in in vitro experiments to screen for optimal therapeutic strategies and methods of drug delivery. Our lab has developed model systems designed to produce new understanding of these critical biological phenomena and tools for discovering new therapeutic targets and for personalized medicine.
Model for tumor cell extravasation. Two cancer cells (in red) are trapped inside a segment of a microvascular network (in green). In this time-lapse movie, one of the cancer cells escapes from the vessel through a break in the cell-cell junctions between two endothelial cells.
  1. Escribano J, Chen MB, Moeendarbary E, Cao X, Shenoy V, Garcia-Aznar JM, Kamm RD, Spill F. Balance of mechanical forces drives endothelial gap formation and may facilitate cancer and immune-cell extravasation. PLoS Computational Biology. 2019 May 2;15(5):e1006395.[PDF]

  2. Chen MB, Hajal C, Benjamin DC, Yu C, Azizgolshani H, Hynes RO, Kamm RD. Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proceedings of the National Academy of Sciences. 2018 Jul 3;115(27):7022-7.[PDF]

  3. Li R, Serrano JC, Xing H, Lee TA, Azizgolshani H, Zaman M, Kamm RD. Interstitial flow promotes macrophage polarization toward an M2 phenotype. Molecular Biology of the Cell. 2018 Aug 8;29(16):1927-40.[PDF]

  4. Aref AR, Campisi M, Ivanova E, Portell A, Larios D, Piel BP, Mathur N, Zhou C, Coakley RV, Bartels A, Bowden M. 3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Lab on a Chip. 2018;18(20):3129-43. [PDF]

  5. Boussommier-Calleja A, Atiyas Y, Haase K, Headley M, Lewis C, Kamm RD. The effects of monocytes on tumor cell extravasation in a 3D vascularized microfluidic model. Biomaterials. 2019 Apr 1;198:180-93.[PDF]

Vascular Models (lymphatic, BBB, HUVEC+FB)

One of the major obstacles to producing realistic microphysiological models of reasonable scale and with long-term viability is the need for a vascular system to delivery nutrients and oxygen to the tissues. Our group has developed microfluidic platforms for a variety of applications including models of metastatic tumors and models or transport across the blood-brain barrier or other barriers within the body.
Blood-brain barrier model. Endothelial networks (green) form by self-assembly into a complex microvascular network with permeabilities comparable to the blood-brain barrier when co-cultured with astrocytes (magenta) and pericytes (not shown).

  1. Offeddu GS, Possenti L, Loessberg‐Zahl JT, Zunino P, Roberts J, Han X, Hickman D, Knutson CG, Kamm RD. Application of Transmural Flow Across In Vitro Microvasculature Enables Direct Sampling of Interstitial Therapeutic Molecule Distribution. Small. 2019 Sep 9:1902393. [PDF]

  2. Offeddu GS, Haase K, Gillrie MR, Li R, Morozova O, Hickman D, Knutson CG, Kamm RD. An on-chip model of protein paracellular and transcellular permeability in the microcirculation. Biomaterials. 2019 Aug 1;212:115-25.[PDF]

  3. Campisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. 2018 Oct 1;180:117-29.[PDF]

  4. Osaki T, Serrano JC, Kamm RD. Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis. Regenerative Engineering and Translational Medicine. 2018 Sep 1;4(3):120-32.[PDF]

Neurological Disease Models

Neurological diseases are increasing in prevalence due to our aging population and lack of effective treatments. Microfluidic models of these systems hold considerable promise for simulating the disease process and probing new approaches to treatment. We currently have models for ALS, SMA and Alzheimer’s disease that we are using for mechanistic studies and drug screening.
To create a model of ALS, a neurosphere is generated from human neural precursor cells and seeded into a microfluidic system (left). The neurons then send out neurites (in green) that penetrate into and form neuromuscular junctions inside a muscle strip derived from induced pluripotent stem cells (red).

Human neurons genetically modified to over-express amyloid beta 40 or 42 as a model of Alzheimer’s disease. Here we co-culture the neurons with a vascular barrier to study changes in vessel permeability that occur in cerebral amyloid angiopathy, a vascular condition often associated with and possibly a cause of neuronal death.
Analysis of gene expression levels of various vascular endothelial cell junctional proteins suggests that the changes in vascular permeability may be caused by a reduction in the expression of claudin-5.
  1. Shin Y, Choi SH, Kim E, Bylykbashi E, Kim JA, Chung S, Kim DY, Kamm RD, Tanzi RE. Blood–Brain Barrier Dysfunction in a 3D In Vitro Model of Alzheimer's Disease. Advanced Science. 2019 Oct 1.[PDF]

  2. Osaki T, Uzel SG, Kamm RD. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Science advances. 2018 Oct 1;4(10):eaat5847.[PDF]

  3. Uzel SG, Platt RJ, Subramanian V, Pearl TM, Rowlands CJ, Chan V, Boyer LA, So PT, Kamm RD. Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units. Science advances. 2016 Aug 1;2(8):e1501429.[PDF]

Vascularized Organoids (cardiac, cerebral, etc...)

Organoid technology, especially using induced pluripoptent stem cells, are the focus of much development for their potential as microphysiological models and in regenerative medicine applications. Currently, however, they lack a perfusable vascular network. This project aims to connect the vascular networks developed in (2) above with networks grown internally in order to enable long-term perfusion.
A tumor (green) is shown immersed in a microvascular network (red) simulating the blood-brain barrier that can be perfused with medium containing drugs or nanoparticles to treat the tumor. This system is used to study the transport of therapeutic agents or immune cells from the vasculature into the tumor. Image by Dr. Cynthia Hajal.

Other Microphysiological Systems and Microfluidic Models

As the platform technologies developed in our lab have considerable flexibility, they can be adapted to create models of other organ systems. These include the central and peripheral nervous systems as mentioned above, but also have applications to the reproductive system, the lymphatic circulation, and for cardiac modeling.
A co-culture of a cluster of neurons (green) and vascular endothelial cells (red) show interpenetration of the neurites and the vascular network as seen in the brain.

  1. Haase K, Gillrie MR, Hajal C, Kamm RD. Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF‐Ang‐Tie2 Signaling. Advanced Science. 2019 Oct 29.[PDF]

  2. Osaki T, Sivathanu V, Kamm RD. Engineered 3D vascular and neuronal networks in a microfluidic platform. Scientific reports. 2018 Mar 26;8(1):5168.[PDF]