Advance in the Application and Mechanism of Citrate-Based Biomaterials in Spinal Fusion and Bone Defect Repair
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摘要: 柠檬酸是骨骼的重要组成部分和存在于三羧酸循环中的关键代谢产物。近年来因其优异的生物相容性、可降解性及多官能团化学结构，成为生物材料领域的研究热点。柠檬酸基生物材料不仅具备可调的力学性能和良好的加工性能，还能通过细胞代谢调控，免疫调节，血管-骨耦合及神经-骨整合等多种机制促进骨组织再生，目前已有部分柠檬酸基骨科固定装置获得美国食品药品监督管理局批准。本文系统综述柠檬酸基材料在骨科领域的发展历程，应用现状及促进成骨的相关机制，并对其临床转化进展与面临的挑战进行了分析与展望。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.
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Key words:
- Biocompatible materials /
- Citrates /
- Spinal fusion /
- Bone regeneration /
- Immunomodulation /
- Energy metabolism
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图 1 柠檬酸基材料的合成及其潜在作用机制示意图
Figure 1. Schematic diagram of the synthesis and potential mechanisms of action of citrate-based materials
图 2 柠檬酸基材料介导骨再生的多机制整合信号通路图
Figure 2. Schematic diagram of multi-mechanism integrated signaling pathways underlying bone regeneration mediated by citrate-based materials
表 1 柠檬酸基生物材料的应用形式及疾病模型总结
Table 1. A Summary of the application forms and disease models of citrate-based biomaterials
应用形式 材料体系 疾病模型 功能与优势 多孔支架 POC-M-click-HA POC-HA
POC-ACP（仿生矿化支架）Ci-HA
（三层复合支架）脊柱融合；大段骨缺损 模拟天然骨化学成分，促进骨
融合3D打印支架 POC-HA负载成骨干细胞/BMP9 POC-PEGDA共聚物；阴离子柠檬酸基支架 复杂骨缺损修复；颅面骨再生 负载生长因子或干细胞，控释生物制剂 固定装置/锚钉 POC-HA；复合肌腱锚钉 Citrelock/Citrefix
（FDA批准产品）；肌腱/韧带固定 前交叉韧带重建 力学强度优于传统 PLDLA-TCP，促进肌腱－骨界面的骨再生和重塑 可注射骨腻子/螺钉 柠檬酸基骨腻子；（Bone-Putty）；自膨胀聚氨酯-脲螺钉 不规则骨缺损填充；骨-肌腱愈合 可自膨胀和原位塑形，适用于微创手术及不规则缺损的填充固定 功能化水凝胶/微球 柠檬酸功能化水凝胶；BPLP-PSer/HA微球 周围神经损伤； 早期骨沉积与修复 机械性能适应神经修复，释放柠檬酸/PSer协同促进细胞能量代谢 
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表 2 柠檬酸基材料调控组织再生的关键信号通路与机制
Table 2. Key signaling pathways and mechanisms regulated by citrate-based materials in tissue regeneration
调控领域 关键信号通路/分子 机制描述与生物学效应 力学刺激与转导 YAP/TAZ； MAPK；Wnt/β-catenin 材料刚度被细胞整合素感知，激活 YAP/TAZ 核转位，将物理信号转化为生物信号 代谢组织发生 mTORC1/AMPK；
SLC13A5（转运蛋白）CaMKK2/Akt 途径同时激活 mTORC1和AMPK，提供能量底物 （ATP） 并调节乙酰辅酶A （Acetyl-CoA） 水平 免疫调节 糖酵解 vs.氧化磷酸化（代谢重编程）；三羧酸循环 抑制M1巨噬细胞的糖酵解酶，驱动巨噬细胞从促炎（M1）向抗炎（M2）表型极化 血管生成与成骨耦合 HIF-1α/VEGF； AMPK/TGF-β 激活AMPK和TGF-β通路，促进成骨分化。HIF-1α介导的VEGF分泌实现骨与血管同步再生。 神经再生与神经-骨串扰 CGRP-cAMP-CREB NGF-TrkA； CaMKK2 释放二价金属离子（Mg2+，Ca2+）和柠檬酸刺激感觉神经分泌CGRP和神经生长因子，通过cAMP-CREB通路和TrkA通路促进BMSCs成骨分化。
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表 3 FDA已批准的柠檬酸基材料及适应症
Table 3. FDA-approved citrate-based materials and their indications
核心材料平台 商业化产品名称 批准用途与适应症 临床价值 Citregen™
（基于柠檬酸的生物可吸收聚合物）Citrelock™ 肌腱固定装置 提供机械固定，还通过释放柠檬酸分子促进再生。 Citrefix™ 缝合锚系统 用于软组织与骨的连接固定，
解决传统材料生物活性不足的问题。Citrespline™ 生物可吸收组织固定 用于肌肉骨骼系统的组织固定与重建。 Citrelock ACL™ 前交叉韧带重建系统 专用于膝关节韧带重建手术中的固定。
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