molecular-spring-constant-analysis-biomembrane-force-probe

Molecular Spring Constant Analysis by Biomembrane Force Probe Spectroscopy

A biomembrane force probe (BFP) has recently emerged as a native-cell-surface or in situ dynamic force spectroscopy (DFS) nanotool that can measure ...

The University of Sydney

Immune checkpoint blockade with monoclonal antibodies (mAbs) that target programmed cell death protein-1 (PD-1) has remarkably revolutionized cancer therapy. Their binding kinetics measured by surface plasmon resonance does not always correlate well with their immunotherapeutic efficacies, mainly due to the lack of two-dimensional cell plasma membrane and the capability of force sensing and manipulation. In this regard, based on a more suitable and ultra-sensitive biomechanical nanotool, biomembrane force probe (BFP), we developed a Double-edge Smart Feedback control system as an ultra-stable platform to characterize ultra-long bond lifetimes of receptor-ligand binding on living cells. We further benchmarked the dissociation kinetics for three clinically approved PD-1 blockade mAbs (Nivolumab, Pembrolizumab, and Camrelizumab), intriguingly correlating well with the objective response rates in the hepatocellular carcinoma second-line treatment. This ultra-stable BFP potentially provides a compelling kinetic platform to direct the screening, optimization, and clinical selection of therapeutic antibodies in the future.

Ultra-stable Biomembrane Force Probe for Accurately Determining Slow Dissociation Kinetics of PD-1 Blockade Antibodies on Single Living Cells.

Disturbed blood flow has been increasingly recognized for its critical role in platelet aggregation and thrombosis. Microfluidics with hump shaped contractions have been developed to mimic microvascular stenosis and recapitulate the prothrombotic effect of flow disturbance. However the physical determinants of microfluidic hemodynamics are not completely defined. Here, we report a refined computational fluid dynamics (CFD) simulation approach to map the shear rate (γ) and wall shear stress (τ) distribution in the stenotic region at high accuracy. Using ultra-fine meshing with sensitivity verification, our CFD results show that the stenosis level (S) is dominant over the bulk shear rate (γ) and contraction angle (α) in determining γ and τ distribution at stenosis. In contrast, α plays a significant role in governing the shear rate gradient (γ) distribution while it exhibits subtle effects on the peak γ. To investigate the viscosity effect, we employ a Generalized Power-Law model to simulate blood flow as a non-Newtonian fluid, showing negligible difference in the γ distribution when compared with Newtonian simulation with water medium. Together, our refined CFD method represents a comprehensive approach to examine microfluidic hemodynamics in three dimensions and guide microfabrication designs. Combining this with hematological experiments promises to advance understandings of the rheological effect in thrombosis and platelet mechanobiology.

Article	Year
Ultra-stable Biomembrane Force Probe for Accurately Determining Slow Dissociation Kinetics of PD-1 Blockade Antibodies on Single Living Cells. Nano letters\| PubMed ID: 32530632	2020
Hemodynamic analysis for stenosis microfluidic model of thrombosis with refined computational fluid dynamics simulation. Scientific reports\| PubMed ID: 33767279	2021

Yunduo Charles Zhao

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