Optogenetic activation of mechanical nociceptions to enhance implant osseointegration
Q. Wang, Yang Chen, Haiqi Ding, Yuanqing Cai, Xuhui Yuan, Jianhua Lv, Jiagu Huang, Jiexin Huang, Chaofan Zhang, Zihao Hong, Hongyan Li, Ying Huang, Jiamin Lin, Yuan Lin, Lan Lin, Sun‐Kyoung Yu, Canhong Zhang, Jianhua Lin, Wenbo Li, Cheng Chang, Bin Yang, Wenming Zhang, Xinyu Fang
Abstract
Orthopedic implants with high elastic modulus often suffer from poor osseointegration due to stress shielding, a phenomenon that suppresses the expression of intracellular mechanotransduction molecules (IMM) such as focal adhesion kinase (FAK). We find that reduced FAK expression under stress shielding is also mediated by decreased calcitonin gene-related peptide (CGRP) released from Piezo2+ mechanosensitive nerves surrounding the implant. To activate these nerves minimally invasively, we develop a fully implantable, wirelessly rechargeable optogenetic device. In mice engineered to express light-sensitive channels in Piezo2+ neurons, targeted stimulation of the L2-3 dorsal root ganglia (DRG) enhances localized CGRP release near the implant. This CGRP elevation activates the Protein Kinase A (PKA)/FAK signaling pathway in bone marrow mesenchymal stem cells (BMSCs), thereby enhancing osteogenesis and improving osseointegration. Here we show that bioelectronic modulation of mechanosensitive nerves offers a strategy to address implant failure, bridging neuroregulation and bone bioengineering. Stress shielding, a common cause of orthopedic implant failure, reduces the activity of intracellular mechanotransduction molecules, which are also regulated by nociceptors. Here, Wang et al. develop a small, implantable, wirelessly rechargeable device for optogenetic regulation of mechanosensitive nociceptors to investigate and improve implant osseointegration.