Nanotopographic micro-nano forces finely tune the conformation of macrophage mechanosensitive membrane protein integrinβ_(2)to manipulate inflammatory responses

Finely tuning mechanosensitive membrane proteins holds great potential in precisely controlling inflammatory responses.In addition to macroscopic force,mechanosensitive membrane proteins are reported to be sensitive to micro-nano forces.Integrinβ_(2),for example,might undergo a piconewton scale stretching force in the activation state.High-aspect-ratio nanotopographic structures were found to generate nN-scale biomechanical force.Together with the advantages of uniform and precisely tunable structural parameters,it is fascinating to develop low-aspect-ratio nanotopographic structures to generate micro-nano forces for finely modulating their conformations and the subsequent mechanoimmiune responses.In this study,low-aspect-ratio nanotopographic structures were developed to finely manipulate the conformation of integrinβ_(2).The direct interaction of forces and the model molecule integrinαXβ_(2)was first performed.It was demonstrated that pressing force could successfully induce conformational compression and deactivation of integrinαXβ_(2),and approximately 270 to 720 pN may be required to inhibit its conformational extension and activation.Three low-aspect-ratio nanotopographic surfaces(nanohemispheres,nanorods,and nanoholes)with various structural parameters were specially designed to generate the micro-nano forces.It was found that the nanorods and nanohemispheres surfaces induce greater contact pressure at the contact interface between macrophages and nanotopographic structures,particularly after cell adhesion.These higher contact pressures successfully inhibited the conformational extension and activation of integrinβ_(2),suppressing focal adhesion activity and the downstream PI3K-Akt signaling pathway,reducing NF-κB signaling and macrophage inflammatory responses.Our findings suggest that nanotopographic structures can be used to finely tune mechanosensitive membrane protein conformation changes,providing an effective strategy for precisely modulating inflammatory responses.

A practical guide to promote informatics-driven efficient biotopographic material development

Micro/nano topographic structures have shown great utility in many biomedical areas including cell therapies,tissue engineering,and implantable devices.Computer-assisted informatics methods hold great promise for the design of topographic structures with targeted properties for a specific medical application.To benefit from these methods,researchers and engineers require a highly reusable“one structural parameter-one set of cell responses”database.However,existing confounding factors in topographic cell culture devices seriously impede the acquisition of this kind of data.Through carefully dissecting the confounding factors and their possible reasons for emergence,we developed corresponding guideline requirements for topographic cell culture device development to remove or control the influence of such factors.Based on these requirements,we then suggested potential strategies to meet them.In this work,we also experimentally demonstrated a topographic cell culture device with controlled confounding factors based on these guideline requirements and corresponding strategies.A“guideline for the development of topographic cell culture devices”was summarized to instruct researchers to develop topographic cell culture devices with the confounding factors removed or well controlled.This guideline aims to promote the establishment of a highly reusable“one structural parameter-one set of cell responses”database that could facilitate the application of informatics methods,such as artificial intelligence,in the rational design of future biotopographic structures with high efficacy.