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鎂金屬因具有理想的力學模量、良好的生物相容性、體內(nèi)可降解性及促骨生成效應，有望發(fā)展成為新一代內(nèi)固定器械用于ACL重建。然而，其體內(nèi)降解速率過快和力學強度不足是限制其在臨床應用的主要障礙。對此，本文聚焦在以下三個部分進行展術：首先，介紹了鎂及其合金作為潛在的界面螺釘?shù)膬?yōu)勢；隨后，闡述了鎂離子促進腱-骨愈合的可能機制；最后，討論了鎂基界面螺釘在未來臨床應用中的難題以及針對性解決方案，包括開發(fā)鎂/鈦組合器械和具有新型結構的鎂基界面螺釘，以滿足臨床手術需求?？偠灾V基界面螺釘?shù)幕A研究和臨床轉(zhuǎn)化的努力可能為腱骨愈合和相關疾病的治療提供了新的思考策略。

01、研究內(nèi)容簡介

前交叉韌帶（ACL）損傷是最為常見的運動型損傷，會引起膝關節(jié)不穩(wěn)，進而導致關節(jié)軟骨磨損而誘發(fā)骨性關節(jié)炎（OA）的發(fā)生。臨床普遍認為ACL重建是恢復膝關節(jié)功能最有效的手段。雖然大部分患者可通過重建手術重獲其功能，但每年仍有10%以上患者重建愈合不理想。肌腱-骨界面愈合不良被認為是治療結果不理想的主要原因之一。通過與正常愈合的腱-骨界面（1A）中的結構相比較，肌腱移植物與骨隧道的骨整合失敗會導致移植物滑動（1B)，最終影響膝關節(jié)的穩(wěn)定性。據(jù)分析，這與現(xiàn)有界面螺釘材質(zhì)有關(1C)。鈦界面螺釘由于力學模量過高，易造成應力遮擋效應，引起骨隧道擴大（1D）。聚乳酸因降解產(chǎn)生酸性小分子，會誘發(fā)無菌性炎癥，導致產(chǎn)生過量纖維組織（1E），阻礙腱骨界面正常愈合。聚醚醚酮（PEEK）界面螺釘則面臨無生物活性，因此開發(fā)出新型具有生物活性材料構建的前交叉韌帶內(nèi)固定器械極為重要。鎂金屬因具有良好的力學模量和生物相容性， 成為ACL重建中非常有前景的骨科植入物材料（1F）。

Figure 1. The limitations and drawbacks of the existing orthopaedic implants in ACL reconstruction. (A) Representative histological images showing the normal tendon-bone healing with bony ingrowth towards the interface structure of the fibrous tissue or fibrocartilage after reconstruction. (B) Representative histological images showing the healing failure between the tendon graft and bone after reconstruction. (C) Representative images of Ti, PLA, PEEK, and Mg based interference screws. (D) Representative radiographic images showing the bone tunnel enlargement in patients after ACL reconstruction with currently used metallic interference screws. (E) The degradation of PLA screws producing a significant amount of oligomers, resulting in aseptic inflammation around them, eventually leading to enlarged tendon-bone interface. (F) Summary of the Young's modulus and tensile yield strength of natural bone, FDA-approved polymers and metals in orthopaedics, along with Mg or its alloys.

此外，通過有限元模型（2A）比較了鈦釘與鎂釘周圍骨組織中的應力分布。與鈦組相比，鎂組中螺釘周圍骨組織表現(xiàn)出更高的最大應力和更大的應力分布（圖2B），表明鎂界面螺釘能夠有效降低應力屏蔽效應，進而減少ACL 重建后骨隧道周圍應力相關性骨質(zhì)流失。

Fig. 2. Appropriate Young’s modulus of the Mg-based orthopaedic implants. (A) FEA model of the trabecular bone with insertion of an interference screw under 1000 N loading condition from the horizontal direction. The bone model is fixed by restricting all 6 degrees of freedom (DOF), while the interaction between the screw and bone is fixed using a binding constraint. (B) Compared to the Ti group in the FEA model, the Mg group exhibits higher von Mises stress distribution in the peri-screw bone tissue. Further, the maximum stress around the contacting bone along the force direction is 2227 MPa and 1670 MPa for the Mg and the Ti groups, respectively.

有文獻報道鎂離子可通過上調(diào)X型膠原和血管內(nèi)皮生長因子(VEGF)，顯著增強骨髓間充質(zhì)干細胞（BMSC）和成骨細胞的成骨分化能力（3A）。此外，有研究表明高純鎂界面螺釘釋放的鎂離子有利于轉(zhuǎn)化生長因子-β1（TGF-β1）和血小板衍生生長因子 BB（PDGF-BB）的分泌，募集更多的BMSC參與腱骨界面愈合，最終促進腱骨界面處的血管生成和新骨長入（圖3B）。

Fig. 3. Favorable osteopromotive functions of the Mg-based orthopaedic implants. (A) Higher extent of Mg ions can directly promote the osteogenic differentiation-related genes including BMP-2 and VEGF of BMSCs as well as osteoblasts via HIF-2α and PGC-1α-dependent mechanisms.(B) The released Mg ions from the Mg-based screws enhance the recruitment, adhesion and osteogenic differentiation of BMSCs, along with the secretion of PDGF-BB and TGF-β1, thereby, contributing to angiogenesis and osteogenesis in the tendon-bone interface, ultimately leading to the improved bone ingrowth towards the tendon graft.

人體組織環(huán)境復雜，無機離子（如 Ca 2+、Cl -、OH -、HPO 4 2-、H 2 PO 4 -、HCO 3-和 CO 3 2-）和有機分子（如葡萄糖、氨基酸和蛋白質(zhì)）等均可參與鎂界面螺釘降解產(chǎn)物的形成（5A）。因鎂界面螺釘降解會導致其力學完整性受損，同時會伴隨氣體釋放到周圍組織并形成富集，故如何調(diào)控鎂界面螺釘?shù)慕到庑袨橐彩怯绊懫渑R床應用的主要因素（圖 5B和5C）。因此，臨床上可安全使用的鎂界面螺釘必須具有合適的降解行為，匹配組織愈合，但不會在完全愈合之前完全失去其機械完整性（圖5D）。

Figure 5. Challenges of Mg-based interference screws in clinical application. (A) The degradation behavior of the Mg-based interference screws in physiological condition involves the release of Mg ions, H2 evolution, and production of OH-, contributing to the formation of inorganic substances containing Mg(OH)2, MgCO3, Ca3 (PO4)2, and Mg3 (PO4)2 as well as organic products composed of magnesium gluconate, glycosamine, and albumin chelate. Importantly, the presence of amino acids, proteins, and lipids may alter the degradation rate of the Mg-based screws due to the deposition of the organic layers. (B) Representative histological images demonstrating the fast degradation of the Mg-based implants containing gas voids (b: bone, gb: gas voids, cp: corrosion product, square: area shown under high magnification in the below image). (C) Fast degradation of the Mg-based interference screws in vivo leading to poor fixation. (D) Illustration of desirable Mg-based interference screws with favorable degradation behavior to maintain their mechanical integrity for sufficient fixation during the graft healing process in ACL reconstruction.

除降解速率外，鎂界面螺釘?shù)目古ぞ匦阅懿蛔阋彩怯绊懪R床應用的重要原因之一。通過有限元模擬證實：與鈦界面螺釘相比，鎂界面螺釘?shù)淖畲笈ぞ亟档土私?倍（6A）。圖6B表明因接觸部位的變形，致使螺絲刀和螺釘頭之間滑絲，極易造成手術操作失敗。因此，如何解決螺釘?shù)膶嶋H扭矩與完全植入骨隧道所需克服的扭矩之間的差距問題（圖6C），極其關鍵和重要（圖6D）。

Figure 6. Challenges of Mg-based interference screws in clinical application. (A) In the model, a linear hexahedral type was used for the screwdriver with 340 elements, and the screw used the quadratic tetrahedral type to create 41002 elements. The tip of the screw (highlighted area) was clamped, whereas the screwdriver was rotated at a controlled rate of 0.2 rad/s, simulating the same boundary conditions as the experiment. The numerical torque over rotation angle curve for the pure Ti- and pure Mg-based interference screws. (B) The Mg interference screw is implanted into the bone tunnel due to insufficient torque, which causes the screw head to wear. (C) Schematic diagram of comparison between the torque required for the implantation of the Mg interference screw into the bone tunnel and the actual torque. (D) Unsatisfactory torque of the Mg-based interference screws results in surgical failure due to the damage in the screw head.

在過去的幾十年里，人們做出了巨大的努力來克服與鎂或其合金在骨科應用中的不當降解行為和機械性能不足相關的臨床問題如合金化、表面改性及復合材料等策略。在本文中著重關注于開發(fā)出新型含鎂界面螺釘?shù)男虏呗?，通過增加螺絲刀導通深度來提高螺釘頭承受的最大扭矩（7A），以及將涂層鎂棒插入在空心鈦界面螺釘?shù)慕M合系統(tǒng)調(diào)節(jié)鎂離子釋放速率以匹配骨愈合過程（7B）。為加速腱骨界面愈合，可考慮多孔界面螺釘（8B），以完成含祖細胞或生長因子的水凝膠微球的原位釋放(8A)，進而促進腱骨界面新生血管或骨的形成（8C和8D）。

Figure 7. R&D strategies for the novel Mg-containing interference screws feasible for clinical applications. (A) Optimization of the structural design of the Mg-based interference screw by altering the drill insertion depth and pitch distance for improved maximal torque. (B) Mg/Ti hybrid fixators composed of Mg rod and Ti-based interference screw with holes in the screw body to allow the release of the Mg ions in the surrounding bone tissue, exerting favorable biological effects while overcoming the concerns associated with insufficient mechanical strength.

Figure 8. R&D of the Mg-based interference screws with holes to release hydrogel microparticles with multifunctional layers for enhancing tendon-bone healing. (A) Schematic diagram of multifluidic technology for preparation of multi-layered hydrogel microparticles (W/O/W/O/W). (B)  The structure diagram of multifunctional hydrogel particles showing PDGF-BB and VEGF in the outer layer, TGF-β1 in the middle layer and stem cells and BMP-2 in the inner layer. (C) The injected hydrogels in the Mg-based interference screws further improve angiogenesis including type H vessels in the presence of PDGF-BB and VEGF released from the outer layer during the early healing stages. (D) TGF-β1, stem cells and BMP-2 released from the middle and inner layers of the hydrogel increase the number of stem cells involved in tendon-bone healing, along with promoting their osteogenic differentiation capability for bony ingrowth towards the tendon-bone interface during the later healing stage (VEGF: vascular endothelial growth factor, PDGF-BB: platelet-derived growth factor-BB, TGF-β1: transforming growth factor-β1, and BMP-2: bone morphogenetic protein-2).

綜上，新型可生物降解鎂界面螺釘有望成為新一代 ACL 重建內(nèi)固定器械。雖然扭矩性能和合適的降解行為是鎂界面螺釘走向規(guī)?；R床試驗的主要障礙，但合金化、表面改性、新型結構設計優(yōu)化、組合器械的采用可有效部分解決上述擔憂。此外，可注射含活性因子水凝膠的多孔鎂界面螺釘將可能展示出更為出色的促血管/新骨形成的潛能，從而為臨床改善腱-骨愈合提供新的治療策略。