Multiple cations therapy in bone tissue microenvironment can achieve bone regeneration mediated by the CNS-skeletal circuit

Guest Speaker：Prof. Yeung Waikwok Kelvin, Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

Inviter: Prof. YUAN Guangyin

Wednesday 13th December

10:00-11:30

A500, Xu Zuyao Building

Biography

Professor Kelvin Yeung currently holds the position of tenured full professor, Chief of Research Division, and Departmental Research and Postgraduate Advisor in the Department of Orthopaedics and Traumatology at the School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong. Additionally, he serves as the Director of the Research Laboratory of Orthopaedic Centre and Deputy Director of the Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma at The University of Hong Kong Shenzhen Hospital. With the h-index 77 (Scopus) with 19,744 citations and 83 (Google Scholar) with 23,333 citations and i10-index 255, he has been consistently ranked among the Top 1% of scientists worldwide (biomaterials field) by Clarivate Analytics' Essential Science Indicators (ESI) since 2014, and World’s Top 2% Scientists in standardized citation indicators (Biomedical Engineering). In 2023, he was ranked #1926 globally and #486 in China for materials science by Research.com. Yeung has published over 290 peer-reviewed SCI journal articles and filed 41 full patents across various countries. He also co-founded OrthoSmart Limited with two senior colleagues to apply their research findings clinically and has consulted for several medical device and biomaterial companies.

Throughout his career, Yeung has participated in numerous local and regional competitions, earning several awards and scholarships such as the Young Scientist Award in 2005, the Young Engineer Award in 2009, and the Faculty Research Output Award in 2019. He has also received 20 prizes and awards from local and international events and has been invited to present more than 80 plenary lectures, keynotes, or invited talks at conferences worldwide.

An active member of local and international academic organizations, Yeung has held several executive positions. He currently serves as the Associate Editor of the Bioactive Materials Journal (2022 Impact factor: 18.900, Ranking: 1/45 in materials science for Biomaterials), Secretary and founding member of the Chinese Association for Biomaterials (CAB), Chair of Orthopaedic Biomaterials for the Society for Biomaterials (SFB) USA, and has previously held positions as the Treasurer of CAB and Vice-Chair of SFB Orthopaedic Biomaterials. Moreover, he has been appointed as the Associate Dean of Student Affairs, Centre of Development and Resources for Students (CEDARS) and Warden of HKU Simon K. Y. Lee Hall, where he is responsible for overseeing student education development.

Abstract

Osteoporosis is a significant healthcare concern worldwide, and current therapeutic agents have documented side effects. In this study, we investigated the possibility of rescuing bone loss by utilizing a relatively new pathway, namely central nervous system (CNS)-skeletal axis or skeletal interoception. We accomplished this by delivering three bivalent metallic ions (i.e., magnesium, zinc, and copper) into the bone tissue microenvironment under a controlled manner. The combination of these ions was specifically designed to promote in situ intramembranous bone formation, and we also investigated the underlying mechanism.

To evaluate the effectiveness of this approach, we injected alginate hydrogels loaded with these cations into the femoral defect of knock-out mouse models, including iDTRLysM+/− and TrkAfl/fl mice. We assessed new bone formation through micro-CT, mechanical testing, as well as various histological and immunochemical analyses.

Our findings indicate that these cations stimulate skeleton interoception by promoting prostaglandin E2 secretion from macrophages, which triggers an immune response. This response is accompanied by the growth and branching of calcitonin gene-related polypeptide-α+ nerve fibers that detect the inflammatory cue with PGE2 receptor 4 and transmit the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone, promoting new bone formation. Additionally, either macrophage depletion or knockout of cyclooxygenase-2 in macrophages eliminates divalent cation-induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in sensory nerves eliminates the osteogenic effects of divalent cations.

The findings of this study could pave the way for the development of novel biomaterials that harness the therapeutic power of these divalent cations to promote bone regeneration effectively. The study also highlights the importance of the CNS-skeletal axis in bone regeneration and the potential for developing new therapies that target this pathway