Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair

Haoxin ZHANG; Yingsong WANG

Article Contents

Article Navigation > Journal of Kunming Medical University > 2026 > Uncorrected proof

Haoxin ZHANG, Yingsong WANG. Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair[J]. Journal of Kunming Medical University.

Citation:

Haoxin ZHANG, Yingsong WANG. Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair[J]. Journal of Kunming Medical University.

Haoxin ZHANG, Yingsong WANG. Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair[J]. Journal of Kunming Medical University.

Citation:

Haoxin ZHANG, Yingsong WANG. Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair[J]. Journal of Kunming Medical University.

PDF( 1361 KB)

Advance in the Application and Mechanism of Citrate-based Biomaterials in Spinal Fusion and Bone Defect Repair

Haoxin ZHANG,
Yingsong WANG^,

Department of Orthopaedics，The Second Affiliated Hospital of Kunming Medical University，Kunming Yunnan 650101，China

Received Date: 2026-01-22
Available Online: 2026-04-27

Abstract

Abstract

Citrate is an essential component of bone and a key metabolic intermediate in the tricarboxylic acid cycle.In recent years, it has become a focal point in biomaterials research due to its excellent biocompatibility, biodegradability, and multifunctional chemical structure. Citrate-based biomaterials not only offer tunable mechanical properties and favorable processability but also actively promote bone tissue regeneration through various mechanisms, including cellular metabolic regulation, immunomodulation, vascular-bone coupling, and neuro-bone integration.To date, several citrate-based orthopedic fixation devices have been approved by the U.S. Food and Drug Administration.This article systematically reviews the development history, current application status, and osteogenic mechanisms of citrate-based materials in orthopedics, and analyzes the progress and challenges of their clinical translation.
- Biocompatible materials,
- Citrates,
- Spinal fusion,
- Bone regeneration,
- Immunomodulation,
- Energy metabolism

FullText(HTML)

References(47)

References

[1]	Xu H, Yan S, Gerhard E, et al. Citric acid: A nexus between cellular mechanisms and biomaterial innovations[J]. Adv Mater, 2024, 36(32): 2402871. doi: 10.1002/adma.202402871
[2]	Tran R T, Yang J, Ameer G A. Citrate-based biomaterials and their applications in regenerative engineering[J]. Annu Rev Mater Res, 2015, 45: 277-310. doi: 10.1146/annurev-matsci-070214-020815
[3]	Yang J, Webb A R, Pickerill S J, et al. Synthesis and evaluation of poly(diol citrate) biodegradable elastomers[J]. Biomaterials, 2006, 27(9): 1889-1898.
[4]	曹冉, 于亚东, 于晓飞, 等. 3D打印部分手舟骨置换术的初步临床应用[J]. 河北医科大学学报, 2024, 45(1): 9-12.
[5]	Tang J, Guo J, Li Z, et al. A fast degradable citrate-based bone scaffold promotes spinal fusion[J]. J Mater Chem B, 2015, 3(27): 5569-5576. doi: 10.1039/C5TB00607D
[6]	Guo J, Tian X, Xie D, et al. Citrate-based tannin-bridged bone composites for lumbar fusion[J]. Adv Funct Mater, 2020, 30(27): 2002438.
[7]	Zhao P, Zhu Y, Kim M, et al. Effective bone tissue fabrication using 3D-printed citrate-based nanocomposite scaffolds laden with BMP9-stimulated human urine stem cells[J]. ACS Appl Mater Interfaces, 2025, 17(1): 197-210. doi: 10.1021/acsami.4c13246
[8]	Lee S H, Lu R, House A, et al. Anionic citrate-based 3D-printed scaffolds for tunable and sustained orthobiologic delivery to enhance tissue regeneration[J]. Adv Funct Mater, 2025, 35(47): 2506063. doi: 10.1002/adfm.202506063
[9]	Tan X, Gerhard E, Wang Y, et al. Development of biodegradable osteopromotive citrate-based bone putty[J]. Small, 2022, 18(36): 2203003. doi: 10.1002/smll.202203003
[10]	Thirumaran A, Doulgkeroglou M N, Sankar M, et al. A functional analysis of a resorbable citrate-based composite tendon anchor[J]. Bioact Mater, 2024, 41: 207-220. doi: 10.1101/2024.01.08.571095
[11]	Wales D J, Keshavarz M, Howe C, et al. 3D Printability assessment of poly (octamethylene maleate (anhydride) citrate) and poly (ethylene glycol) diacrylate copolymers for biomedical applications[J]. ACS Appl Polym Mater, 2022, 4(8): 5457-5470.
[12]	Wan L, Lu L, Liang X, et al. Citrate-based polyester elastomer with artificially regulatable degradation rate on demand[J]. Biomacromolecules, 2023, 24(9): 4123-4137. doi: 10.1021/acs.biomac.3c00479
[13]	Wang M, Xu P, Lei B. Engineering multifunctional bioactive citrate-based biomaterials for tissue engineering[J]. Bioact Mater, 2023, 19: 511-537. doi: 10.1016/j.bioactmat.2022.04.027
[14]	Wan L, Lu L, Zhu T, et al. Bulk erosion degradation mechanism for poly(1, 8-octanediol-co-citrate) elastomer: An in vivo and in vitro investigation[J]. Biomacromolecules, 2022, 23(10): 4268-4281. doi: 10.1021/acs.biomac.2c00737
[15]	Shi H, Zhou K, Wang M, et al. Integrating physicomechanical and biological strategies for BTE: Biomaterials-induced osteogenic differentiation of MSCs[J]. Theranostics, 2023, 13(10): 3245-3275.
[16]	Naqvi S M, McNamara L M. Stem cell mechanobiology and the role of biomaterials in governing mechanotransduction and matrix production for tissue regeneration[J]. Front Bioeng Biotechnol, 2020, 8: 597661. doi: 10.3389/fbioe.2020.597661
[17]	El-Rashidy A A, El Moshy S, Radwan I A, et al. Effect of polymeric matrix stiffness on osteogenic differentiation of mesenchymal stem/progenitor cells: Concise review[J]. Polymers, 2021, 13(17): 2950. doi: 10.3390/polym13172950
[18]	Liu Y, Li J, Yao B, et al. The stiffness of hydrogel-based bioink impacts mesenchymal stem cells differentiation toward sweat glands in 3D-bioprinted matrix[J]. Mater Sci Eng C, 2021, 118: 111387. doi: 10.1016/j.msec.2020.111387
[19]	黄康斌, 陈曾凤, 陈从山, 等. 体外冲击波治疗通过激活Wnt5a/Ca²⁺信号通路改善大鼠股骨牵张成骨的分子机制[J]. 河北医科大学学报, 2024, 45(1): 40-46. doi: 10.3969/j.issn.1007-3205.2024.01.009
[20]	Dirckx N, Zhang Q, Chu E Y, et al. A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth[J]. Proc Natl Acad Sci U S A, 2022, 119(45): e2212178119. doi: 10.1073/pnas.2212178119
[21]	Chu E Y, Wu J, Clemens T L, et al. The osteoblast sodium-citrate co-transporter (SLC13A5): A gatekeeper between global citrate homeostasis and tissue mineralization[J]. Curr Opin Endocr Metab Res, 2023, 32: 100474. doi: 10.1016/j.coemr.2023.100474
[22]	Han C, Zhang L, Bao R, et al. Biodegradable metabotissugenic citrate-based polymer derived self-sealing pro-regenerative membrane for tendon anti-biofouling and repair[J]. Bioact Mater, 2025, 51: 598-612. doi: 10.1016/j.bioactmat.2025.05.020
[23]	Morganti C, Bonora M, Marchi S, et al. Citrate mediates crosstalk between mitochondria and the nucleus to promote human mesenchymal stem cell in vitro osteogenesis[J]. Cells, 2020, 9(4): 1034. doi: 10.3390/cells9041034
[24]	Pouikli A, Parekh S, Maleszewska M, et al. Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells[J]. Nat Aging, 2021, 1(9): 810-825. doi: 10.1038/s43587-021-00105-8
[25]	Pouikli A, Maleszewska M, Parekh S, et al. Hypoxia promotes osteogenesis by facilitating acetyl‐CoA‐mediated mitochondrial–nuclear communication[J]. EMBO J, 2022, 41(23): EMBJ2022111239. doi: 10.15252/embj.2022111239
[26]	Bispo D S C, Graça I C R, Jesus C S H, et al. Metabolic markers detect early ostedifferentiation of mesenchymal stem cells from multiple donors[J]. Stem Cell Res Ther, 2025, 16(1): 294. doi: 10.1186/s13287-025-04419-x
[27]	Xu H, Tan X, Gerhard E, et al. Metabotissugenic citrate biomaterials orchestrate bone regeneration via citrate-mediated signaling pathways[J]. Sci Adv, 2025, 11(30): eady2862. doi: 10.1126/sciadv.ady2862
[28]	Li J, Qu Y, Chu B, et al. Research progress on biomaterials with immunomodulatory effects in bone regeneration[J]. Adv Sci, 2025, 12(33): e01209. doi: 10.1002/advs.202501209
[29]	Pérez S, Rius-Pérez S. Macrophage polarization and reprogramming in acute inflammation: A redox perspective[J]. Antioxidants, 2022, 11(7): 1394. doi: 10.3390/antiox11071394
[30]	Qiao W, Xie H, Fang J, et al. Sequential activation of heterogeneous macrophage phenotypes is essential for biomaterials-induced bone regeneration[J]. Biomaterials, 2021, 276: 121038. doi: 10.1016/j.biomaterials.2021.121038
[31]	Yang T, Fang Z, Zhang J, et al. Physical cues in biomaterials modulate macrophage polarization for bone regeneration: A review[J]. Front Bioeng Biotechnol, 2025, 13: 1640560. doi: 10.3389/fbioe.2025.1640560
[32]	Wu X, Xia Y, Dai H, et al. Metabolic control during macrophage polarization by a citrate-functionalized scaffold for maintaining bone homeostasis[J]. Adv Healthc Mater, 2024, 13(22): e2400770. doi: 10.1002/adhm.202400770
[33]	Pan S, Li Y, Wang L, et al. Microenvironment-optimized gastrodin-functionalized scaffolds orchestrate asymmetric division of recruited stem cells in endogenous bone regeneration[J]. Journal of Nanobiotechnology, 2024, 22(1): 722. doi: 10.1186/s12951-024-02886-7
[34]	Hristov K, Ishkitiev N, Miteva M, et al. The effect of citric acid on mineralisation and vascular endothelial growth factor secretion from apical papilla stem cells[J]. Acta Odontologica Scandinavica, 2024, 83: 42026. doi: 10.2340/aos.v83.42026
[35]	Miao Q, Yang X, Diao J, et al. 3D printed strontium-doped calcium phosphate ceramic scaffold enhances early angiogenesis and promotes bone repair through the regulation of macrophage polarization[J]. Materials Today Bio, 2023, 23: 100871. doi: 10.1016/j.mtbio.2023.100871
[36]	Qin H, Guan Z, Wang Y, et al. An injectable phosphocreatine-grafted hydrogel incorporating hierarchically structured teriparatide/SrZnP-functionalized Zn–Cu particles for osteogenesis–angiogenesis coupling and osteoporotic bone regeneration[J]. Mater Today Bio, 2025, 35: 102272. doi: 10.1016/j.mtbio.2025.102272
[37]	Qiu W, Zhang K, Wu M, et al. Tri-layer citrate-based hydroxyapatite composite scaffold promoting osteogenesis and gingival tissue regeneration for periodontal bone defect repair[J]. Adv Healthc Mater, 2025, 14(13): 2501002. doi: 10.1002/adhm.202501002
[38]	Chen J, Xian G, Xiao Z, et al. Biomineralization-inspired scaffolds using citrate-based polymers to stabilize amorphous calcium phosphate promote osteogenesis and angiogenesis for bone defect repair[J]. Bioact Mater, 2026, 56: 260-276. doi: 10.1016/j.bioactmat.2025.10.016
[39]	Wang Y, Pan Z, Wang Q, et al. Sequential SDF-1/CGRP-releasing smart composite hydrogel promotes osteoporotic fracture healing by targeting sensory nerve-regulated bone remodeling[J]. Mater Today Bio, 2025, 32: 101750. doi: 10.1016/j.mtbio.2025.101750
[40]	Zhang Z, Wang F, Huang X, et al. Engineered sensory nerve guides self-adaptive bone healing via NGF-TrkA signaling pathway[J]. Adv Sci, 2023, 10(10): 2206155. doi: 10.1002/advs.202206155
[41]	王锋, 毛宇翔, 李靖龙, 等. 外泌体在促进腱-骨损伤愈合中应用的研究进展[J]. 河北医科大学学报, 2025, 46(2): 154-158. doi: 10.3969/j.issn.1007-3205.2025.02.005
[42]	Tao M, Fang Z, Zhu Y, et al. Injectable citrate-based polyurethane-urea as a tug-of-war-inspired bioactive self-expansive and planar-fixing screw augmented bone-tendon healing[J]. Bioact Mater, 2024, 41: 108-126. doi: 10.1016/j.bioactmat.2024.07.004
[43]	Tan X, Gerhard E, Wang Y, et al. Development of biodegradable osteopromotive citrate-based bone putty[J]. Small, 2022, 18(36): 2203003. doi: 10.1002/smll.202203003
[44]	Wang H, Huddleston S, Yang J, et al. Enabling proregenerative medical devices via citrate-based biomaterials: Transitioning from inert to regenerative biomaterials (adv. mater. 6/2024)[J]. Adv Mater, 2024, 36(6): 2470043. doi: 10.1002/adma.202470043
[45]	Zhu Y, Liu Q, Yu C, et al. An intervertebral disc (IVD) regeneration model using human nucleus pulposus cells (iHNPCs) and annulus fibrosus cells (iHAFCs)[J]. Adv Healthc Mater, 2025, 14(10): 2403742. doi: 10.1002/adhm.202403742
[46]	Kim M, Wang X, Li Y, et al. Personalized composite scaffolds for accelerated cell- and growth factor-free craniofacial bone regeneration[J]. Bioact Mater, 2024, 41: 427-439. doi: 10.1101/2024.02.18.580898
[47]	Mao L, Yin Y, Zhang L, et al. Regulation of inflammatory response and osteogenesis to citrate-based biomaterials through incorporation of alkaline fragments[J]. Adv Healthc Mater, 2022, 11(4): e2101590. doi: 10.1002/adhm.202101590

Relative Articles(20)

Relative Articles

[1]	Haiwei WANG, Xiaohui ZHANG, Yunxiao TIAN, Shiqian WU. Mechanism of TPI-1 in Promoting the Proliferation and Invasion of Gastric Cancer Cells through Glycolytic Reprogramming. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20260204
[2]	Yunrong XU, Fei HE. Effect of Material Structure on Angiogenesis in Bone Regeneration. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20250919
[3]	Guozhu LIANG, Shimei RUAN, Yanmei HE, Hailong YANG. Prospects of Antimicrobial Peptides as Immunomodulators in the Treatment of Bacterial Infections. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20231013
[4]	Yunrong XU, Ziwen TANG, Fei HE. Molecular Mechanisms of Osteogenesis Promoted by Bone Repair Materials. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20231007
[5]	Zhang Ying , Wang Ying Song , Jie Jing Ming , Zhao Zhi , Li Tao , Bi Ni . . Journal of Kunming Medical University,
[6]	Li Li , Li Jin Tao , Guo Yu Qing , Wu Chao , Lu Jiang Li , Zeng Yue Qin , Jiao Jian Lin . . Journal of Kunming Medical University,
[7]	Wang Zeng Tao , Zhang Jie , Guo Tao . . Journal of Kunming Medical University,
[8]	Zhang Guo Zhi , Deng Yong Cheng , Lu Xiao Tao . . Journal of Kunming Medical University,
[9]	Chen Mo , Zhou Ze Ping . The Progress of IL-10 and Autoimmune Diseases. Journal of Kunming Medical University,
[10]	Lu Qiu An , Du Kai Li , Zhang Chun Qiang , Guo Pei Yu , Sun Yu Peng , He Shao Bo . . Journal of Kunming Medical University,
[11]	Li Qiang , Tao Qi Chang , Dai Jian Hao , Chang Bin . Clinical Efficacy of Interbody Fusion with Autogeneous Bone in the Treatment of Lumbar Spondylolisthesis. Journal of Kunming Medical University,
[12]	He Li Ming , He Yong Wen . . Journal of Kunming Medical University,
[13]	Ren Chao Feng . Cuture of Regulatory T Cells and the Changes of Immune Factors in COPD Rats after Venous injection of Regulatory T Cells. Journal of Kunming Medical University,
[14]	Lv Tao . . Journal of Kunming Medical University,
[15]	Kong Wei Yun . . Journal of Kunming Medical University,
[16]	Kong Wei Yun . . Journal of Kunming Medical University,
[17]	Yang Li Li . . Journal of Kunming Medical University,
[18]	Wang Feng . . Journal of Kunming Medical University,
[19]	Wang Fu Ke . . Journal of Kunming Medical University,
[20]	Zhang Cai Jun . . Journal of Kunming Medical University,