Regenerative Medicine and Dentistry

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

2025-01-22T17:26:28+08:00

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.

A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia

2025-03-11T12:07:16+08:00

Article

A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia

Wan Yang ^1,^†, Siyu Jin ^1,^†, Jie Jiang ¹, Wei Ji ^1,2,*^,‡ and Qing He ^1,*^,‡

¹State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China

²Department of Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China

* Correspondence: wei.ji@whu.edu.cn (W.J.); qing.he@whu.edu.cn (Q.H.);
Tel.: +86-131-0061-5376 (W.J.); +86-183-2719-2492 (Q.H.)

† These authors contributed equally as first authors.

‡ These authors share equal senior authorships.

Received: 3 January 2025; Revised: 11 February 2025; Accepted: 25 February 2025; Published: 11 March 2025

Abstract: Hypohidrotic Ectodermal Dysplasia (HED) is a rare genetic disorder characterized by hypodontia, hypohidrosis, and hypotrichosis. The study aims to identify a novel mutation in the EDA2R gene in a 20-year-old female with HED and investigate its impact on the NF-κB signaling pathway. Whole genome sequencing confirmed the mutation, and bioinformatic tools predicted it to be pathogenic by destabilizing the EDA2R structure and weakening its interaction with EDA-A2. Molecular dynamics simulation and binding free energy calculations further revealed reduced hydrogen bond formation in the mutant EDA2R/EDA-A2 complex, while molecular docking and AlphaFold analyses indicated decreased binding to TRAF3 and TRAF6. In vitro experiments demonstrated that cells expressing the mutant EDA2R had significantly reduced proliferation and NF-κB activity, along with impaired nuclear translocation of NF-κB p65. However, Western blot analysis showed that the JNK signaling pathway remained unaffected. This study identifies a novel missense mutation in EDA2R and introduces a new pathogenic mechanism of HED, emphasizing the crucial role of EDA2R in regulating NF-κB signaling.

Underestimated Roles of Osteocytes in Medication-Related Osteonecrosis of the Jaw

2025-03-14T17:06:06+08:00

Perspective

Underestimated Roles of Osteocytes in Medication-Related Osteonecrosis of the Jaw

Chunfeng Xu and Yiqun Wu *

Department of Second Dental Center, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Centre for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 201900, China

* Correspondence: yiqunwu@hotmail.com

Received: 18 February 2025; Revised: 10 March 2025; Accepted: 11 March 2025; Published: 14 March 2025

Abstract: Medication-related osteonecrosis of the jaw (MRONJ) is a grievous complication after the long-duration administration of some bone-modifying agents, mainly containing bisphosphonates (BPs), denosumab, angiogenesis inhibitors, immunosuppressors, glucocorticoids, and chemotherapeutics. Its prevalence is rare but mounting due to the widespread application of MRONJ-associated drugs in the aging population and cancer patients. Although MRONJ is excruciating, there has been no specific and efficient remedy for it. To date, the understanding of MRONJ is not thorough, and various theories on MRONJ have been proposed, among which impaired bone remodeling as a result of inhibited osteoclast generation and activity is the predominant one. However, the role of osteocytes in MRONJ has been omitted, given their crucial roles in governing bone metabolism: they not only communicate with osteoblasts for bone formation but also promote osteoclastogenesis.

Global Research Trends and Hotspots in Meibomian Gland Dysfunction (2014–2023): A Comprehensive Bibliometric and Visualization Analysis

2025-03-17T15:57:47+08:00

Review

Global Research Trends and Hotspots in Meibomian Gland Dysfunction (2014–2023): A Comprehensive Bibliometric and Visualization Analysis

Qian Liu ¹, Fangkun Zhao ², Jun Liu ¹, Minmei Guo ¹, Chengyu Jiang ¹, Tao Yu ¹, Ting Wang ¹, Tzu-Cheng Sung ¹, Jun Kong ² and Akon Higuchi ^1,3,*

¹State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China

²Department of Ophthalmology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110005, China

³Department of Chemical and Materials Engineering, National Central University, Taoyuan 32001, Taiwan

* Correspondence: higuchi@ncu.edu.tw or higuchi@wmu.edu.cn; Tel.: +86-577-88068822; Fax: +86-086-577-88832083

Received: 21 January 2025; Revised: 11 March 2025; Accepted: 12 March 2025; Published: 17 March 2025

Abstract: This study aimed to explore the global research landscape, emerging hotspots, and advancements in Meibomian Gland Dysfunction (MGD) over the last decade through a bibliometric and visualization analysis for regenerative medicine strategy to treat MGD patients. Data were collected from the Web of Science Core Collection, covering the period from 2014 to 2023. VOSviewer and CiteSpace were used to analyze and visualize publication trends, contributions by countries and institutions, co-authorship analysis, journal impact, and keyword co-occurrence. Emerging topics were identified using keyword citation burst analysis. A total of 1271 publications were included. Four major research hotspots were identified: (1) etiology and pathogenesis, (2) advancements in diagnostic technologies, (3) therapeutic innovations, and (4) epidemiological trends. The United States and Yonsei University were the leading contributors in terms of publication and citation counts. Ocular Surface, Cornea, and Investigative Ophthalmology & Visual Science were the top journals by productivity and impact. The study revealed significant progress in MGD research and highlighted key areas requiring further investigation, including the establishment of global diagnostic standards and targeted therapies in regenerative medicine. These findings provide a roadmap for future collaborative efforts and strategic research directions in regenerative medicine of the field.

hiPSC-Driven Organoid Construction and Application Prospects

2025-03-21T17:09:42+08:00

Perspective

hiPSC-Driven Organoid Construction and Application Prospects

Bangheng Liu ^1,2, Yulei Mu ^2,3 and Dong-An Wang ^1,2,*

¹Department of Biomedical Engineering, Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong SAR 999077, China

²Center for Neuromusculoskeletal Restorative Medicine, InnoHK, HKSTP, Sha Tin, New Territories, Hong Kong SAR 999077, China

³Department of Biomedical Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong SAR 999077, China

* Correspondence: donganwang@cuhk.edu.hk

Received: 5 March 2025; Revised: 19 March 2025; Accepted: 20 March 2025; Published: 21 March 2025

Abstract: Induced pluripotent stem cell (iPSC)-derived organoid platforms can simulate various target tissues and hold broad application prospects in personalized medicine, disease modeling, drug screening, organ transplantation, and understanding organ development mechanisms. Currently, the development of human iPSC (hiPSC) organoids is gradually shifting towards Matrigel-free and scaffold-free systems, promoting precise control over the composition and structure of these systems and establishing induction protocols for specialized organoids. Researchers are also exploring the construction of multifunctional systems with complex structures and material exchange channels through vascularization, segmented induction, and assembly technologies, though further breakthroughs are needed. In the future, hiPSC organoids are expected to advance towards personalized precision treatment, high-throughput module detection systems, multi-organ integration, and automation. Additionally, when combined with large artificial intelligence models, there is potential to establish hiPSC data and medical platforms, providing support for drug development and clinical decision-making. Moreover, the development of medical AI is anticipated to foster collaboration rather than competition, promoting coordinated growth in the field. For hiPSC-derived platforms, it is crucial to further enhance the ethical review framework to balance radical scientific exploration with conservative public attitudes. Researchers must also optimize or develop new induction protocols to reduce genomic instability and tumorigenic risks, while avoiding the emergence of non-target cells and insufficient functional maturity.

The Current State and Future of Oral Health: A Position Paper Exploring the Role of Regenerative Dentistry

2025-03-25T14:26:57+08:00

Review

The Current State and Future of Oral Health: A Position Paper Exploring the Role of Regenerative Dentistry

John A. Jansen

Department of Dentistry-Regenerative Biomaterials, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; john.jansen@radboudumc.nl

Received: 12 February 2025; Revised: 17 March 2025; Accepted: 20 March 2025; Published: 25 March 2025

Abstract: Regenerative dentistry combines dental science, biology, and technology to develop new therapeutic approaches for treating oral and orofacial problems. It focuses on restoring or regeneration lost or damaged tissues using tissue engineering technology. Current methodologies and methods used in regenerative dentistry are: stem cells, growth factors/biomolecules, tissue engineering and bioactive materials, platelet-rich plasma (PRP), tooth regeneration, and tooth-on-a-chip and organoids. Despite its potential, regenerative dentistry has not met the initial expectations due to unrealistic goals, regulatory challenges, and ethical concerns. Therefore, the field needs a breakthrough discovery with significant clinical impact. It is recommended that future efforts should focus on products with clear clinical need and improving existing materials. In conclusion, regenerative dentistry has great potential, but the research lacks a clear vision and focus. Integration of artificial intelligence (AI) can help guide the field into a new era.