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Animal cells in tissues are supported by biopolymer matrices, which typically exhibit highly nonlinear mechanical properties. While the linear elasticity of the matrix can significantly impact cell mechanics and functionality, it remains largely unknown how cells, in turn, affect the nonlinear mechanics of their surrounding matrix. Here, we show that living contractile cells are able to generate a massive stiffness gradient in three distinct 3D extracellular matrix model systems: collagen, fibrin, and Matrigel. We decipher this remarkable behavior by introducing nonlinear stress inference microscopy (NSIM), a technique to infer stress fields in a 3D matrix from nonlinear microrheology measurements with optical tweezers. Using NSIM and simulations, we reveal large long-ranged cell-generated stresses capable of buckling filaments in the matrix. These stresses give rise to the large spatial extent of the observed cell-induced matrix stiffness gradient, which can provide a mechanism for mechanical communication between cells.

Lateral flow assays (LFAs) as rapid analytical techniques promise to be widely used in point-of-care (POC) diagnostics because of their affordability and simplicity. However, LFAs still suffer from low sensitivity in detection of various biomarkers, e.g., nucleic acids. In this study, we developed a simple and general one-step signal amplification strategy, which employed oligonucleotide-linked gold nanoparticle (AuNP) aggregates to enhance the sensitivity in nucleic acid lateral flow (NALF) assays. Using a nucleic acid sequence of human immunodeficiency virus type 1 (HIV-1) as a model analyte, we observed that the detection limit of the developed NALF assay was 0.1 nM, which was improved by 2.5-fold compared with that of a non-signal amplification approach. The methodology described here could be used to detect a broad range of nucleic acids, and the general signal amplification approach could be potentially adopted in other types of LFAs.

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The unique benefit of electrostatic self-assembly of microscale components in solution is demonstrated for the first time. In particular, positive and negative treatment of poly(ethylene glycol) (PEG) facilitates a novel bottom-up assembly approach using electrostatic interaction from microgels with opposite charges. Fundamental investigations of electrostatic interaction of microgels reveal that the contact area of microgels determines the total energy of construct and thus the final patterns. The electrostatic self-assembly approach enables the fabrication of large and complex biological related structures (e.g., multi-layer spheroid) with accurate control. By the design of the microgels, the thickness and number of microgels in each layer can be controlled. Biological investigations of positive and negative treatments of PEG further prove the possibility of using this approach in tissue engineering, regenerative medicine and drug delivery.

Summary It is well established that the early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells, surrounding ECM, and their interactions. Recent studies have established the capacity of the invading tumor spheroids to evolve into coexistent solid-like, fluid-like, and gas-like phases. Using breast cancer cell lines invading into engineered ECM, here we show that the spheroid interior develops spatial and temporal heterogeneities in material phase which, depending upon cell type and matrix density, ultimately result in a variety of phase separation patterns at the invasive front. Using a computational approach, we further show that these patterns are captured by a novel jamming phase diagram. We suggest that non-equilibrium phase separation based upon jamming and unjamming transitions may provide a unifying physical picture to describe cellular migratory dynamics within, and invasion from, a tumor.

Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.