Nuclear deformation regulates YAP dynamics in cancer associated fibroblasts.

Cells cultured on stiff 2D substrates exert high intracellular force, resulting in mechanical deformation of their nuclei. This nuclear deformation (ND) plays a crucial role in the transport of Yes Associated Protein (YAP) from the cytoplasm to the nucleus. However, cells in vivo are in soft 3D environment with potentially much lower intracellular forces. Whether and how cells may deform their nuclei in 3D for YAP localization remains unclear. Here, by culturing human colon cancer associated fibroblasts (CAFs) on 2D, 2.5D, and 3D substrates, we differentiated the effects of stiffness, force, and ND on YAP localization. We found that nuclear translocation of YAP depends on the degree of ND irrespective of dimensionality, stiffness and total force. ND induced by the perinuclear force, not the total force, and nuclear membrane curvature correlate strongly with YAP activation. Immunostained slices of human tumors further supported the association between ND and YAP nuclear localization, suggesting ND as a potential biomarker for YAP activation in tumors. Additionally, we conducted quantitative analysis of the force dynamics of CAFs on 2D substrates to construct a stochastic model of YAP kinetics. This model revealed that the probability of YAP nuclear translocation, as well as the residence time in the nucleus follow a power law. This study provides valuable insights into the regulatory mechanisms governing YAP dynamics and highlights the significance of threshold activation in YAP localization. STATEMENT OF SIGNIFICANCE: Yes Associated Protein (YAP), a transcription cofactor, has been identified as one of the drivers of cancer progression. High tumor stiffness is attributed to driving YAP to the nucleus, wherein it activates pro-metastatic genes. Here we show, using cancer associated fibroblasts, that YAP translocation to the nucleus depends on the degree of nuclear deformation, irrespective of stiffness. We also identified that perinuclear force induced membrane curvature correlates strongly with YAP nuclear transport. A novel stochastic model of YAP kinetics unveiled a power law relationship between the activation threshold and persistence time of YAP in the nucleus. Overall, this study provides novel insights into the regulatory mechanisms governing YAP dynamics and the probability of activation that is of immense clinical significance.

Investigation of Needle Characteristics Using an Animal Model for Improved Outcomes in Anterior Chamber Paracentesis.

Background/Aims: The current standard of care to perform an anterior chamber paracentesis involves the use of a multipurpose market needle and syringe. The use of standard needles for this purpose may result in injury to the patient due to increased force with insertion and increased globe displacement during the procedure. This research investigates the current market needle characteristics and the impact of each needle characteristic on force. Methods: Several comparative trials were conducted to evaluate the needles. Needle characteristics of interest were gauge, primary bevel angle, number of bevels in the lancet, and needle hub geometry. Measurements of corneal insertion forces were made using a synthetic thermoplastic polyurethane medium, and bovine and porcine models. Needle safety was investigated with corneal abrasion experiments. Results: Reduced insertion force was observed with lower lancet primary angle. There was no difference based on the number of bevels in the lancet. Rounded hub geometry had minimal distribution to the corneal epithelium. Conclusions: Needle characteristics impact the force needed for needle insertion into the tissue. Since higher force can lead to increased risk and less efficiency during the procedure, reducing this force may improve the outcomes of the procedure. Needle entry can be reduced by designing an improved needle that includes a lower gauge and reduced primary angle of the lancet.

The Role of Soft Robotic Micromachines in the Future of Medical Devices and Personalized Medicine.

Developments in medical device design result in advances in wearable technologies, minimally invasive surgical techniques, and patient-specific approaches to medicine. In this review, we analyze the trajectory of biomedical and engineering approaches to soft robotics for healthcare applications. We review current literature across spatial scales and biocompatibility, focusing on engineering done at the biotic-abiotic interface. From traditional techniques for robot design to advances in tunable material chemistry, we look broadly at the field for opportunities to advance healthcare solutions in the future. We present an extracellular matrix-based robotic actuator and propose how biomaterials and proteins may influence the future of medical device design.