Insights into Bioengineering Approaches for Aging Bone Regeneration: Strategies to Target Osteoimmunosenescence
Authors: Xiao Lan , Gao Wendong , Wu Jinfu , Erezuma Itsasne , Dolatshahi-Pirouz Alireza , Silva-Correia Joana , Zhou Yinghong , Sun Antonia Rujia , Prasadam Indira , Crawford Ross , Oliveira Joaquim Miguel , Orive Gorka , Wu Chengtie , Xiao Yin 
Published: January 2025

Review
Insights into Bioengineering Approaches for Aging Bone Regeneration: Strategies to Target Osteoimmunosenescence

Lan Xiao 1,2,†, Wendong Gao 1,2,†, Jinfu Wu 3, Itsasne Erezuma 4, Alireza Dolatshahi-Pirouz 5, Joana Silva-Correia 6,7, Yinghong Zhou 2,8, Antonia Rujia Sun 2,9, Indira Prasadam 2,9, Ross Crawford 2,9, Joaquim Miguel Oliveira 6,7, Gorka Orive 5,10,11,12,13, Chengtie Wu 3 and Yin Xiao 1,2,*
1 School of Medicine and Dentistry, Griffith University (GU), Gold Coast, QLD 4222, Australia
2 The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
3 State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics Chinese Academy of Sciences, Shanghai 200050, China
4 NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 01006 Vitoria-Gasteiz, Spain
5 Department of Health Technology, Technical University of Denmark (DTU), 2800 Kongens Lyngby, Denmark
6 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimarães, Portugal
7 ICVS/3B’s—PT Government Associated Laboratory, 4805-017 Guimarães, Portugal
8 School of Dentistry, University of Queensland, Brisbane, QLD 4006, Australia
9 School of Mechanical, Medical and Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
10 Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 19-01007 Vitoria-Gasteiz, Spain
11 University Institute for Regenerative Medicine and Oral Implantology (UIRMI), UPV/EHU-Fundación Eduardo Anitua, 19-01007 Vitoria-Gasteiz, Spain
12 Bioaraba, NanoBioCel Research Group, 19-01007 Vitoria-Gasteiz, Spain
13 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore
* Correspondence: yin.xiao@griffith.edu.au
† These authors contributed equally to this work.

Received: 22 October 2024; Revised: 8 January 2025; Accepted: 15 January 2025; Published: 22 January 2025

Abstract: The global accumulation of ageing population is a serious problem causing significant health and social burdens. Especially, aging results in reduced bone regeneration potential and increased risk of morbidities and mortality, which calls the urgent need for advanced therapeutic approaches to improve bone regeneration in the aged patients. The aging associated poor bone regeneration capacity can be attributed to the low-grade, sterile chronic inflammation termed “inflammaging”, which result in detrimental environment for bone healing. The pathogenesis of inflammaging is mainly due to the senescence of immune cells. The senescent immune cells, especially senescent macrophages play a major role in inflammaging via an inflammatory secretome (senescence-associated secretory phenotype/SASP) which is due to ROS accumulation associated mitochondrial dysfunction, energy metabolism change, decline in oxidized nicotinamide adenine dinucleotide (NAD+) level and insufficient autophagy. In addition, the SASP can turn the local young cells into senescent cells, a paracrine senescence effect to facilitate senescent cell accumulation and inflammation, which can also be attributed to the insufficient clearance of senescent cells due to phagocytosis deficiency in senescent immune cells. Therefore, in aging bone environment, the interplay between immune and skeletal cells, termed “osteoimmunosenescence” in this review, not only generates a long-term chronical inflammatory environment to reduce osteogenesis, but also induces senescence in young skeletal progenitor cells to dampen their osteogenic differentiation potential, suggesting osteoimmunosenescence should be considered as a key modulatory target for bone regeneration biomaterials design for the aged patients. In this review, the pathogenesis of inflammaging and the potential impact of osteoimmunosenescence on bone regeneration have been discussed. In addition, to target osteoimmunosenescence, two potential strategies are considered, one is advanced immunomodulation to correct the inflammaging environment, the other is to target immunosenescence, and the current and potential material approaches regarding these two are summarized in this review. Furthermore, it proposes potential strategies to design osteoimmunosenescence-modulating materials by targeting the molecular intersection between senescence and inflammation and by flexibly correct the local environment and environmental responsively induce osteogenesis.