µSiM

The µSiM (microphysiological system featuring a Silicon Membrane) tissue chip platform¹ is ideally suited for the design and construction of MPS systems focused on the role of barrier functions in physiology and disease. The enabling feature of the µSiM isan ultrathin membrane (< 100 nm thick) with abundant pores that can be tuned in size from 40 nm to tens-of-microns^2-5. We have also engineered versions with mixed micropores and nanopores to enable cell trafficking and cell-cell contact across the membranes^1,6,7. Because of their ultrathin nature andhigh porosity (10¹⁰ nanopores / cm²), ‘nanomembranes’ offer no measurable resistance to the diffusion of molecules smaller than pores^1,8,9. In this way paracrine factors and other small molecules move freely between tissue compartments with rates controlled by cellular processes and cell/matrix barriers¹. More than 3 times thinner than the wavelength of visible light, the membranes enable glass-like imaging by phase contrast microscopy^10,11 and are undetectable in basement membranes formed by co-cultures on either side of the membrane¹². The membranes are made of silicon nitride, an inert material that adsorbs proteincoatings to promote cell adhesion, but is incapable of absorbing biomolecules or organic compounds as seen with PDMS. While silicon nitride has a high modulus, the nanomembranes are so thin that they are flexible: they deflect under pressure¹³ and spontaneously wrinkle when free of their silicon support^4,14.The current µSiM is the product of a nearly decade long effort to meet growing demand from investigators who found commercial devices containing track-etched and/or PDMS membranes unsuitable for studying tissue barrier phenomena. To meet demand for more than 5,000 devices per year in customized formats, McGrath and colleagues have engineered a modular version of the µSiM^1,15,16 that uses pressure sensitive adhesives (PSA) to enable rapid assembly (minutes) from mass-produced components. Modularity enables rapid redesign and mass production of closed (microfluidic) and open (well-based) nanomembrane devices to address a diverse range of tissue models. Published examples include tendon fibrosis¹⁵, immune cell trafficking at the blood-brain barrier^12,17-19, and S. aureus infection of bone^2,20-22. Modularity also allows reconfigurations with functional accessories for flow, TEER, and integrated sensing^16,23-25.

References

1. McCloskey MC, Kasap P, Ahmad SD, Su SH, Chen K, Mansouri M, Ramesh N, Nishihara H, Belyaev Y, Abhyankar VV, Begolo S, Singer BH, Webb KF, Kurabayashi K, Flax J, Waugh RE, Engelhardt B, McGrath JL. The Modular muSiM: a Mass Produced, Rapidly Assembled, and Reconfigurable Platform for the Study of Barrier Tissue Models In Vitro. Adv Healthc Mater. 2022:e2200804.
2. de Mesy Bentley KL, Trombetta R, Nishitani K, Bello-Irizarry SN, Ninomiya M, Zhang L, Chung HL, McGrath JL, Daiss JL, Awad HA, Kates SL, Schwarz EM. Evidence of Staphylococcus Aureus Deformation, Proliferation, and Migration in Canaliculi of Live Cortical Bone in Murine Models of Osteomyelitis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;32(5):985-90.
3. DesOrmeaux JPS, Winans JD, Wayson SE, Gaborski TR, Khire TS, Striemer CC, McGrath JL. Nanoporous silicon nitride membranes fabricated from porous nanocrystalline silicon templates. Nanoscale. 2014;6(18):10798-805.
4. Striemer CC, Fauchet PM, Gaborski TR, McGrath JL, inventors; University of Rochester, assignee. Ultrathin Porous Nanoscale Membranes, Methods of Making, and Uses Thereof patent 8,518,276.
5. Wright E, Miller JJ, Csordas M, Gosselin AR, Carter JA, McGrath JL, Latulippe DR, Roussie JA. Development of isoporous microslit silicon nitride membranes for sterile filtration applications. Biotechnol Bioeng. 2019;117:879-85.
6. Salminen AT, McCloskey MC, Ahmad SD, Romanick SS, Chen K, Houlihan W, Klaczko ME, Flax J, Waugh RE, McGrath JL. Molecular mechanisms underlying the heterogeneous barrier responses of two primary endothelial cell types to sphingosine-1-phosphate. Eur J Cell Biol. 2022;101(3):151233.
7. Ahmad D, Linares I, Pietropaoli A, Waugh RE, McGrath JL. Sided Stimulation of Endothelial Cells Modulates Neutrophil Trafficking in an In Vitro Sepsis Model. Adv Healthc Mater. 2024:e2304338.
8. Snyder JL, Getpreecharsawas J, Fang DZ, Gaborski TR, Striemer CC, Fauchet PM, Borkholder DA, McGrath JL. High-performance, low-voltage electroosmotic pumps with molecularly thin silicon nanomembranes. P Natl Acad Sci USA. 2013;110(46):18425-30.
9. Kim E, Xiong H, Striemer CC, Fang DZ, Fauchet PM, McGrath JL, Amemiya S. A structure-permeability relationship of ultrathin nanoporous silicon membrane: a comparison with the nuclear envelope. Journal of the American Chemical Society. 2008;130(13):4230-1.
10. McCloskey MC, Zhang VZ, Ahmad SD, Walker S, Romanick SS, Awad HA, McGrath JL. Sourcing cells for in vitro models of human vascular barriers of inflammation. Frontiers in Medical Technology. 2022;4.
11. Salminen AT, Zhang J, Madejski GR, Khire TS, Waugh RE, McGrath JL, Gaborski TR. Ultrathin Dual-Scale Nano- and Microporous Membranes for Vascular Transmigration Models. Small. 2019:15:e1804111.
12. McCloskey MC, Ahmad SD, Widom LP, Kasap P, Gastfriend BD, Shusta EV, Palecek SP, Engelhardt B, Gaborski TR, Flax J, Waugh RE, McGrath J. Pericytes enrich the basement membrane and reduce neutrophil transmigration in an in vitro model of peripheral inflammation at the blood brain barrier. Biomaterials Research. 2024.
13. Walker SN, Lucas K, Dewey MJ, Badylak SF, Hussey GS, Flax J, McGrath JL. Rapid Assessment of Biomarkers on Single Extracellular Vesicles Using “Catch and Display” on Ultrathin Nanoporous Silicon Nitride Membranes. Small. 2025:21: 2405505
14. Gillmer SR, Fang DZ, Wayson SE, Winans JD, Abdolrahim N, DesOrmeaux JPS, Getpreecharsawas J, Ellis JD, Fauchet PM, McGrath JL. Predicting the failure of ultrathin porous membranes in bulge tests. Thin Solid Films. 2017;631:152-60.
15. Ajalik RE, Linares I, Alenchery RG, Zhang VZ, Wright TW, Miller BL, McGrath JL, Awad HA. Human Tendon-on-a-Chip for Modeling the Myofibroblast Microenvironment in Peritendinous Fibrosis. Adv Healthc Mater. 2025:14:2403116
16. Mansouri M, Ahmed A, Ahmad SD, McCloskey MC, Joshi IM, Gaborski TR, Waugh RE, McGrath JL, Day SW, Abhyankar VV. The Modular microSiM Reconfigured: Integration of Microfluidic Capabilities to Study In Vitro Barrier Tissue Models under Flow. Adv Healthc Mater. 2022;11(21):e2200802.
17. Castro Dias M, Odriozola Quesada A, Soldati S, Bösch F, Gruber I, Hildbrand T, Sönmez D, Khire T, Witz G, McGrath JL, Piontek J, Kondoh M, Deutsch U, Zuber B, Engelhardt B. Brain endothelial tricellular junctions as novel sites for T-cell diapedesis across the blood-brain barrier. Journal of Cell Science. 2021.
18. Mossu A, Rosito M, Khire T, Li Chung H, Nishihara H, Gruber I, Luke E, Dehouck L, Sallusto F, Gosselet F, McGrath JL, Engelhardt B. A silicon nanomembrane platform for the visualization of immune cell trafficking across the human blood-brain barrier under flow. J Cereb Blood Flow Metab. 2019;39:395-410.
19. Soldati S, Bar A, Vladymyrov M, Glavin D, McGrath JL, Gosselet F, Nishihara H, Goelz S, Engelhardt B. High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro. J Neuroinflammation. 2023;20(1):123.
20. Masters EA, de Mesy Bentley KL, Gill AL, Hao SP, Galloway CA, Salminen AT, Guy DR, McGrath JL, Awad HA, Gill SR, Schwarz EM. Identification of Penicillin Binding Protein 4 (PBP4) as a critical factor for Staphylococcus aureus bone invasion during osteomyelitis in mice. PLoS Pathog. 2020;16(10):e1008988.
21. Young M, Walsh DJ, Masters E, Gondil VS, Laskey E, Klaczko M, Awad H, McGrath J, Schwarz EM, Melander C, Dunman PM. Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors. Antibiotics 2022;11:1351.
22. Masters EA, Salminen AT, Begolo S, Luke EN, Barrett SC, Overby CT, Gill AL, de Mesy Bentley KL, Awad HA, Gill SR, Schwarz EM, McGrath JL. An in vitro platform for elucidating the molecular genetics of S. aureus invasion of the osteocyte lacuno-canalicular network during chronic osteomyelitis. Nanomedicine. 2019;21:102039.
23. Linares I, Chen K, Saffren A, Mansouri M, Abhyankar VV, Miller BL, Begolo S, Awad HA, McGrath JL. Fluid Flow Impacts Endothelial-Monocyte Interactions in a Model of Vascular Inflammatory Fibrosis. bioRxiv. 2024.
24. Khire TS, Nehilla BJ, Getpreecharsawas J, Gracheva ME, Waugh RE, McGrath JL. Finite element modeling to analyze TEER values across silicon nanomembranes. Biomed Microdevices. 2018;20(1):11.
25. Cognetti JS, Moen MT, Brewer MG, Bryan MR, Tice JD, McGrath JL, Miller BL. A photonic biosensor-integrated tissue chip platform for real-time sensing of lung epithelial inflammatory markers. Lab on a chip. 2023.