NSF DARE-transforming modeling in neurorehabilitation: perspectives and opportunities from US funding agencies.

In recognition of the importance and timeliness of computational models for accelerating progress in neurorehabilitation, the U.S. National Science Foundation (NSF) and the National Institutes of Health (NIH) sponsored a conference in March 2023 at the University of Southern California that drew global participation from engineers, scientists, clinicians, and trainees. This commentary highlights promising applications of computational models to understand neurorehabilitation ("Using computational models to understand complex mechanisms in neurorehabilitation" section), improve rehabilitation care in the context of digital twin frameworks ("Using computational models to improve delivery and implementation of rehabilitation care" section), and empower future interdisciplinary workforces to deliver higher-quality clinical care using computational models ("Using computational models in neurorehabilitation requires an interdisciplinary workforce" section). The authors describe near-term gaps and opportunities, all of which encourage interdisciplinary team science. Four major opportunities were identified including (1) deciphering the relationship between engineering figures of merit-a term commonly used by engineers to objectively quantify the performance of a device, system, method, or material relative to existing state of the art-and clinical outcome measures, (2) validating computational models from engineering and patient perspectives, (3) creating and curating datasets that are made publicly accessible, and (4) developing new transdisciplinary frameworks, theories, and models that incorporate the complexities of the nervous and musculoskeletal systems. This commentary summarizes U.S. funding opportunities by two Federal agencies that support computational research in neurorehabilitation. The NSF has funding programs that support high-risk/high-reward research proposals on computational methods in neurorehabilitation informed by theory- and data-driven approaches. The NIH supports the development of new interventions and therapies for a wide range of nervous system injuries and impairments informed by the field of computational modeling. The conference materials can be found at https://dare2023.usc.edu/ .

Publisher's Note: Multicellular density fluctuations in epithelial monolayers [Phys. Rev. E 92, 032729 (2015)].

This corrects the article DOI: 10.1103/PhysRevE.92.032729.

A Langevin model of physical forces in cell volume fluctuations.

Cells interact mechanically with their physical surroundings by attaching to the extracellular matrix or other cells and contracting the cytoskeleton. Cells do so dynamically, exhibiting fluctuating contractile motion in time. In monolayers, these dynamic contractions manifest as volume fluctuations, which involve the transport of fluid in and out of the cell. An integrated understanding of cell elasticity, actively generated stresses, and fluid transport has not yet been developed. Here we apply a minimal model of these forces to cell volume fluctuation data, elucidating the dynamic behavior of cells within monolayers.

Writing in the granular gel medium.

Gels made from soft microscale particles smoothly transition between the fluid and solid states, making them an ideal medium in which to create macroscopic structures with microscopic precision. While tracing out spatial paths with an injection tip, the granular gel fluidizes at the point of injection and then rapidly solidifies, trapping injected material in place. This physical approach to creating three-dimensional (3D) structures negates the effects of surface tension, gravity, and particle diffusion, allowing a limitless breadth of materials to be written. With this method, we used silicones, hydrogels, colloids, and living cells to create complex large aspect ratio 3D objects, thin closed shells, and hierarchically branched tubular networks. We crosslinked polymeric materials and removed them from the granular gel, whereas uncrosslinked particulate systems were left supported within the medium for long times. This approach can be immediately used in diverse areas, contributing to tissue engineering, flexible electronics, particle engineering, smart materials, and encapsulation technologies.

Multicellular density fluctuations in epithelial monolayers.

Changes in cell size often accompany multicellular motion in tissue, and cell number density is known to strongly influence collective migration in monolayers. Density fluctuations in other forms of active matter have been explored extensively, but not the potential role of density fluctuations in collective cell migration. Here we investigate collective motion in cell monolayers, focusing on the divergent component of the migration velocity field to probe density fluctuations. We find spatial patterns of diverging and converging cell groups throughout the monolayers, which oscillate in time with a period of approximately 3-4 h. Simultaneous fluorescence measurements of a cytosol dye within the cells show that fluid passes between groups of cells, facilitating these oscillations in cell density. Our findings reveal that cell-cell interactions in monolayers may be mediated by intercellular fluid flow.

Multi-scale undulations in human aortic endothelial cell fibers.

Blood vessels often have an undulatory morphology, with excessive bending, kinking, and coiling occuring in diseased vasculature. The underlying physical causes of these morphologies are generally attributed, in combination, to changes in blood pressure, blood flow rate, and cell proliferation or apoptosis. However, pathological vascular morphologies often start during developmental vasculogenesis. At early stages of vasculogenesis, angioblasts (vascular endothelial cells that have not formed a lumen) assemble into primitive vessel-like fibers before blood flow occurs. If loose, fibrous aggregates of endothelial cells can generate multi-cellular undulations through mechanical instabilities, driven by the cytoskeleton, new insight into vasculature morphology may be achieved with simple in vitro models of endothelial cell fibers. Here we study mechanical instabilities in vessel-like structures made from endothelial cells embedded in a collagen matrix. We find that endothelial cell fibers contract radially over time, and undulate at two dominant wavelengths: approximately 1cm and 1mm. Simple mechanical models suggest that the long-wavelength undulation is Euler buckling in rigid confinement, while the short-wavelength buckle may arise from a mismatch between fiber bending energy and matrix deformation. These results suggest a combination of fiber-like geometry, cystoskeletal contractions, and extracellular matrix elasticity may contribute to undulatory blood vessel morphology in the absence of a lumen or blood pressure.

Cell Volume Fluctuations in MDCK Monolayers.

Cells moving collectively in tissues constitute a form of active matter, in which collective motion depends strongly on driven fluctuations at the single-cell scale. Fluctuations in cell area and number density are often seen in monolayers, yet their role in collective migration is not known. Here we study density fluctuations at the single- and multicell level, finding that single-cell volumes oscillate with a timescale of 4 h and an amplitude of 20%; the timescale and amplitude are found to depend on cytoskeletal activity. At the multicellular scale, density fluctuations violate the central limit theorem, highlighting the role of nonequilibrium driving forces in multicellular density fluctuations.