Abstract 概要
Anterior cruciate ligament (ACL) injury is a common sports injury, and ACL reconstruction is an effective surgery for this trauma. Most cases gain good recovery after surgery, while some patients may experience knee stiffness, which is characterized by joint fibrosis, leading to reduced joint mobility, pain, and dysfunction. Currently, various research studies have been conducted to unveil the mechanisms underlying this condition, identifying pre-, intra-, and post-operative risk factors, and testify the efficacy of different therapeutic methods against it. In this review, we summarize the current progress regarding the advancements in knee fibrosis after ACL reconstruction. The risk factors associated with knee fibrosis are systematically delineated, accompanied by an evaluation of the efficacy of various treatment modalities for both the prevention and mitigation of fibrosis. Furthermore, recommendations for future research directions are proposed, offering a foundational basis for subsequent investigations.前交叉韧带（ACL）损伤是一种常见的运动损伤，ACL 重建术是治疗该创伤的有效手术方式。多数患者术后恢复良好，但部分患者可能出现膝关节僵硬，其特征为关节纤维化，进而导致关节活动度下降、疼痛及功能障碍。目前，多项研究已开展以揭示该病症的潜在机制，明确术前、术中及术后的危险因素，并验证不同治疗方法对其的疗效。本综述总结了 ACL 重建术后膝关节纤维化的研究进展，系统阐述了与膝关节纤维化相关的危险因素，并评估了多种治疗方式在预防和缓解纤维化方面的疗效。此外，提出了未来研究方向的建议，为后续研究提供了基础依据。
1 Introduction 1 引言
Anterior cruciate ligament (ACL) injury is a common sports-related knee injury among athletically active people (Chia et al., 2022). Arthroscopic reconstruction of the ACL is the prevalent therapy at present, with generally good recovery and a relatively low complication rate (Hanus and HudÁk, 2020). Still, knee fibrosis, intractable pain, hemarthrosis, fever, deep vein thrombosis, and infection may occur (Hanus and HudÁk, 2020). Knee fibrosis after ACL reconstruction poses a serious problem. According to the literature review, the prevalence of knee fibrosis after ACL reconstruction is 2.0%–35.0% (Eckenrode and Sennett, 2011). Knee fibrosis is characterized by an inflammatory and fibrotic response, which is manifested as a limited range of motion (ROM) and pain, affecting functional recovery (Millett et al., 2001). Knee arthrofibrosis is a joint disorder induced by an overactive inflammatory response. It is characterized by knee pain and decreased range of motion, resulting in impaired joint function. This not only causes great pain and a heavy medical burden for patients but also has a negative impact on the recovery process and long-term prognosis. To improve postoperative outcomes, it is essential to understand the mechanisms, risk factors, and treatment approaches associated with knee fibrosis following ACL reconstruction.前交叉韧带（ACL）损伤是运动活跃人群中常见的膝关节运动损伤（Chia 等，2022）。目前关节镜下 ACL 重建术是主流治疗方式，通常恢复良好且并发症发生率相对较低（Hanus 和 HudÁk，2020）。但术后仍可能发生膝关节纤维化、顽固性疼痛、关节积血、发热、深静脉血栓和感染等并发症（Hanus 和 HudÁk，2020）。ACL 重建术后膝关节纤维化已成为严峻问题。文献综述显示，ACL 重建术后膝关节纤维化发生率为 2.0%-35.0%（Eckenrode 和 Sennett，2011）。该病症以炎症和纤维化反应为特征，表现为关节活动度（ROM）受限与疼痛，影响功能恢复（Millett 等，2001）。膝关节纤维化是由过度炎症反应引发的关节病变，其临床特征为膝关节疼痛伴活动度下降，导致关节功能障碍。这不仅给患者带来巨大痛苦和沉重医疗负担，更会对康复进程及远期预后产生负面影响。 为改善术后结局，了解前交叉韧带重建术后膝关节纤维化的机制、危险因素以及治疗方法至关重要。
2 Pathophysiological mechanisms of knee fibrosis2 膝关节纤维化的病理生理机制
Knee fibrosis is characterized by the uninhibited deposition of extracellular matrix proteins around the joint, resulting in symptomatic joint stiffness. Fibrosis is the final common pathway of many chronic inflammatory injuries and is a pathological feature of almost all organ diseases (Lee et al., 2022). This article discusses several possible pathological mechanisms, such as inflammatory response, activation and differentiation of fibroblasts, remodeling of the extracellular matrix, and abnormal proliferation of synovial cells in joints (Bayram et al., 2020). In addition, some articles have pointed out that the occurrence of connective tissue fibrosis is multifactorial, including immune cell infiltration caused by tissue damage and the involvement of a series of mediators, such as transforming growth factor-β (TGF-β), bone morphogenetic protein, connective tissue growth factor, and interleukin (Usher et al., 2019; Disser et al., 2023). TGF-β is the pivotal driver of fibrosis, resulting in the activation of fibroblasts and the migration of exogenous cells invading from outside of the tissue. It is a key factor in the regulation of fibroblast proliferation and collagen deposition (Usher et al., 2019). Many of these cells are defined as myofibroblasts, which can produce high levels of alpha-smooth muscle actin and lead to upregulation of collagen synthesis. The excessive activation of immune cells, signaling molecules, and myofibroblasts leads to unresolved post-injury inflammation, which in turn leads to the dysregulation of normal regenerative pathways and formation of fibrous scars (Bayram et al., 2020; Disser et al., 2023). A related report examines the molecular pathological features of human knee fibrosis using RNA sequencing (Jovic et al., 2022). In patients with knee fibrosis, members of the collagen family are commonly expressed as extracellular matrix-related genes, among which COL1A1, COL3A1, and COL6A1 are consistent with fibrosis characteristics (Disser et al., 2023; Morita et al., 2016; Theocharidis et al., 2016; Tao et al., 2018; Samokhin et al., 2018). In addition, integrins are another prominent family in the gene family associated with extracellular matrix organization, and the role of integrins in fibrosis has been confirmed (Disser et al., 2023; Kuivaniemi and Tromp, 2019). Moreover, LOX genes also play a potential role in fibrosis development (Disser et al., 2023; Schnittert et al., 2018). These findings provide new targets for diagnosis and drug therapy.膝关节纤维化的特征是关节周围细胞外基质蛋白不受抑制地沉积，导致有症状的关节僵硬。纤维化是许多慢性炎症性损伤的最终共同途径，也是几乎所有器官疾病的病理特征（Lee 等人，2022）。本文讨论了几种可能的病理机制，如炎症反应、成纤维细胞的激活与分化、细胞外基质的重塑以及关节滑膜细胞的异常增殖（Bayram 等人，2020）。此外，一些文章指出，结缔组织纤维化的发生是多因素的，包括组织损伤引起的免疫细胞浸润以及一系列介质的参与，如转化生长因子 - β（TGF - β）、骨形态发生蛋白、结缔组织生长因子和白细胞介素（Usher 等人，2019；Disser 等人，2023）。TGF - β是纤维化的关键驱动因素，可导致成纤维细胞激活以及来自组织外部的外源性细胞迁移入侵。 它是调节成纤维细胞增殖和胶原沉积的关键因素（Usher 等，2019）。这些细胞中有许多被定义为肌成纤维细胞，能够产生高水平的α-平滑肌肌动蛋白，并导致胶原合成上调。 免疫细胞、信号分子和肌成纤维细胞的过度激活会导致损伤后炎症无法消退，进而引起正常再生通路失调和纤维瘢痕形成（Bayram 等，2020；Disser 等，2023）。一项相关报告利用 RNA 测序研究了人类膝关节纤维化的分子病理特征（Jovic 等，2022）。在膝关节纤维化患者中，胶原家族成员常作为细胞外基质相关基因表达，其中 COL1A1、COL3A1 和 COL6A1 与纤维化特征一致（Disser 等，2023；Morita 等，2016；Theocharidis 等，2016；Tao 等，2018；Samokhin 等，2018）。此外，整合素是细胞外基质组织相关基因家族中的另一个显著家族，其在纤维化中的作用已得到证实（Disser 等，2023；Kuivaniemi 和 Tromp，2019）。而且，LOX 基因在纤维化发展中也发挥潜在作用（Disser 等，2023；Schnittert 等，2018）。这些发现为诊断和药物治疗提供了新靶点。
3 Risk factors for knee fibrosis3 膝关节纤维化的危险因素
Knee fibrosis is a multifactorial disease, and its risk factors run through the preoperative, intraoperative, and postoperative periods. Understanding these risk factors can provide guidance for clinical intervention and improve recovery. Personalized treatment and rehabilitation programs are particularly important for patients with multiple risk factors.膝关节纤维化是一种多因素疾病，其危险因素贯穿术前、术中和术后阶段。了解这些危险因素可为临床干预提供指导并促进恢复。对于具有多种危险因素的患者，个性化治疗和康复方案尤为重要。
3.1 Patient characteristics and preoperative risk factors3.1 患者特征及术前危险因素
Studies have identified that factors such as female gender and older age are associated with an increased risk of revision operation after ACL reconstruction due to joint fibrosis. Female patients have a smaller femoral notch than male patients, indicating a structural difference in the joint that may predispose them to arthrofibrosis; older patients are also more prone to chronic injury, which, when combined with degenerative changes, may result in elevated inflammation (Hopper et al., 2024; Haley et al., 2023).研究发现，女性性别和年龄较大等因素与前交叉韧带（ACL）重建术后因关节纤维化而进行翻修手术的风险增加有关。女性患者的股骨髁间窝比男性患者小，这表明关节存在结构差异，可能使她们更容易发生关节纤维化；年龄较大的患者也更易出现慢性损伤，再加上退行性改变，可能导致炎症水平升高（Hopper 等人，2024 年；Haley 等人，2023 年）。
The timing of surgery after ACL injury is suspected to be relevant to the risk of joint stiffness and fibrosis (Freshman et al., 2023) since inflammatory mediators are present in the synovial fluid during the first week after ACL injury (Aman et al., 2024; Kingery et al., 2022; Haslauer et al., 2014). This belief is supported by the evidence that ACL reconstruction performed at least 6 weeks after injury can significantly reduce the risk of surgical intervention for subsequent knee fibrosis (Agarwal et al., 2023). However, this finding was not supported by recent evidence (von Essen et al., 2020). Given these controversial reports, Vermeijden et al. (2023) conducted a systematic review and identified that early surgery is not inferior to delayed surgery regarding knee fibrosis after isolated ACL reconstruction.前交叉韧带（ACL）损伤后手术的时机被认为与关节僵硬和纤维化风险相关（Freshman 等人，2023），因为在 ACL 损伤后的第一周，滑液中会存在炎症介质（Aman 等人，2024；Kingery 等人，2022；Haslauer 等人，2014）。有证据支持这一观点，即损伤至少 6 周后进行 ACL 重建可显著降低后续因膝关节纤维化而需手术干预的风险（Agarwal 等人，2023）。然而，近期的证据并不支持这一发现（von Essen 等人，2020）。鉴于这些有争议的报道，Vermeijden 等人（2023）进行了一项系统综述，发现单纯 ACL 重建后，就膝关节纤维化而言，早期手术并不逊色于延迟手术。
The application of anticoagulants is also related to joint fibrosis. Qin et al. found that, compared with patients who did not use thromboprophylaxis, those who took this medication were significantly associated with arthrofibrosis after subsequent surgery (Qin et al., 2021). Thromboprophylaxis results in increased rate of postoperative hematoma and, consequently, inflammatory cytokines within the joint, which may lead to fibrosis. Preoperative knee restriction is a well-established risk factor for arthrofibrosis (Mayr et al., 2004). Therefore, preoperative medication and the limited range of motion should be considered when making surgical plans to reduce the risk of joint fibrosis. In addition, other studies have found that preoperative depression has a negative impact on postoperative pain and functional recovery (García et al., 2024). Patients with preoperative depression have significantly higher pain interference scores and significantly lower physical function scores before and after surgery. At present, many scholars have found that there is a certain relationship between knee joint fibrosis and genetic factors (Skutek et al., 2004; Dagneaux et al., 2020). Comorbidities, including but not limited to type 2 diabetes mellitus, ankylosing spondylitis, and rheumatoid arthritis, are also found to increase the risk of knee fibrosis (Huang et al., 2013; Owen et al., 2021).抗凝剂的应用也与关节纤维化有关。秦等人发现，与未使用血栓预防药物的患者相比，服用该药物的患者在后续手术后发生关节纤维化的相关性显著更高（秦等人，2021 年）。血栓预防导致术后血肿发生率增加，进而导致关节内炎症细胞因子增加，这可能会导致纤维化。术前膝关节活动受限是关节纤维化公认的危险因素（迈尔等人，2004 年）。因此，在制定手术计划时应考虑术前用药和活动范围受限情况，以降低关节纤维化的风险。此外，其他研究发现术前抑郁对术后疼痛和功能恢复有负面影响（加西亚等人，2024 年）。术前抑郁的患者在手术前后的疼痛干扰评分显著更高，身体功能评分显著更低。 目前，许多学者发现膝关节纤维化与遗传因素之间存在一定的关联（Skutek 等人，2004 年；Dagneaux 等人，2020 年）。合并症，包括但不限于 2 型糖尿病、强直性脊柱炎和类风湿性关节炎，也被发现会增加膝关节纤维化的风险（Huang 等人，2013 年；Owen 等人，2021 年）。
3.2 Intraoperative risk factors3.2 术中危险因素
At present, the autograft options for ACL reconstruction include bone–patellar tendon–bone (BTB), hamstring tendon, and quadriceps tendon. An analysis of 378 patients found that the incidence of knee joint fibrosis with BTB grafts was approximately 10.0%, compared to 1.9% with hamstring tendons and 6.3% with quadriceps tendons (Ouweleen et al., 2021). This phenomenon is suspected to be a consequence of higher collagen content in BTB grafts (Huleatt et al., 2018). Previous studies have suggested a link between graft type and knee fibrosis. Nwachukwu et al. (2011) found that using an autologous patellar tendon was a risk factor for arthrofibrosis after ACL reconstruction (Nwachukwu et al., 2011). Furthermore, Sanders et al. (2017) found that using allografts lowered the likelihood of arthrofibrosis as compared to bone-patellar tendon-bone grafts. Other studies noticed that a femoral tunnel diameter less than 9.25 mm was associated with a reduced risk of joint fibrosis compared to its counterpart in male patients (Haley et al., 2023).目前，前交叉韧带（ACL）重建的自体移植物选择包括骨-髌腱-骨（BTB）、腘绳肌腱和股四头肌腱。对 378 例患者的分析显示，使用 BTB 移植物的膝关节纤维化发生率约为 10.0%，而腘绳肌腱移植物为 1.9%，股四头肌腱移植物为 6.3%（Ouweleen 等，2021）。这种现象被认为是 BTB 移植物中胶原蛋白含量较高的结果（Huleatt 等，2018）。以往研究表明移植物类型与膝关节纤维化之间存在关联。Nwachukwu 等（2011）发现，使用自体髌腱是 ACL 重建后关节纤维化的危险因素（Nwachukwu 等，2011）。此外，Sanders 等（2017）发现，与骨-髌腱-骨移植物相比，使用同种异体移植物可降低关节纤维化的可能性。其他研究发现，在男性患者中，股骨隧道直径小于 9.25 mm 与关节纤维化风险降低相关（Haley 等，2023）。
In relation to graft tension, some believe that increasing graft tension creates excessive constraints on the joint and results in loss of movement (Elias et al., 2009). However, studies have shown that although high graft pretension may cause graft wear in the femoral tunnel, it does not lead to complete loss of knee extension (Markolf et al., 1996). Conversely, inadequate graft tension may lead to anterior–posterior laxity, resulting in instability, poor graft healing, and failure (McDermott et al., 2024; Lee et al., 2018; Magit et al., 2007). Increasing the tension of the graft reduces the postoperative loss of tension and mobility due to viscoelasticity. This means that by increasing the tension of the graft, postoperative knee laxity can be reduced. Therefore, there is a relationship between graft tension and knee stiffness, yet there is no clear answer as to whether increasing or decreasing graft tension leads to loss of motion.关于移植物张力，一些人认为增加移植物张力会对关节造成过度限制，导致活动丧失（Elias 等人，2009 年）。然而，研究表明，尽管移植物预张力过高可能会导致股骨隧道内的移植物磨损，但不会导致膝关节完全伸直受限（Markolf 等人，1996 年）。相反，移植物张力不足可能会导致前后松弛，从而造成关节不稳定、移植物愈合不良和手术失败（McDermott 等人，2024 年；Lee 等人，2018 年；Magit 等人，2007 年）。增加移植物的张力可以减少由于粘弹性导致的术后张力和活动度丧失。这意味着通过增加移植物的张力，可以减少术后膝关节的松弛。因此，移植物张力与膝关节僵硬之间存在关联，但对于增加或降低移植物张力是否会导致活动丧失，目前尚无明确答案。
In addition, the effect of bone tunnel position and graft placement on fibrosis during ligament reconstruction is important. Placing ACL grafts in anatomical positions can reduce the risk of joint stiffness, while placing ACL grafts in non-anatomical positions may lead to higher rates of fibrosis (Yaru et al., 1992; Tanksley et al., 2017; Romano et al., 1993; Śmigielski et al., 2016; Vignos et al., 2020; Markolf et al., 2002). Multiple studies have found that ACL reconstruction combined with meniscus repair surgery increases the risk of knee fibrosis (Hopper et al., 2024; Haley et al., 2023; Huleatt et al., 2018). Meniscal repair often requires fixation to the joint capsule, which may limit the range of motion of the knee, thus increasing the risk of fibrosis. Moreover, the increase in intra-articular blood loss is also linked to a higher rate of joint fibrosis (Karaaslan et al., 2015).此外，韧带重建过程中骨隧道位置和移植物放置对纤维化的影响也很重要。将前交叉韧带移植物置于解剖位置可降低关节僵硬的风险，而置于非解剖位置则可能导致更高的纤维化发生率（Yaru 等，1992；Tanksley 等，2017；Romano 等，1993；Śmigielski 等，2016；Vignos 等，2020；Markolf 等，2002）。多项研究发现，前交叉韧带重建联合半月板修复术会增加膝关节纤维化的风险（Hopper 等，2024；Haley 等，2023；Huleatt 等，2018）。半月板修复通常需要固定于关节囊，这可能会限制膝关节的活动范围，从而增加纤维化风险。此外，关节内出血量的增加也与更高的关节纤维化发生率相关（Karaaslan 等，2015）。
3.3 Postoperative risk factors3.3 术后危险因素
Non-standard or excessive postoperative rehabilitation training and postoperative infection may lead to further injury in the joints and increase the risk of fibrosis. Some studies have found that different postoperative weight-bearing protocols (delayed weight-bearing, progressive weight-bearing, and immediate weight-bearing) have different complication rates, among which the delayed weight-bearing protocol has the highest risk of developing stiffness (Morris et al., 2021). Furthermore, reports have pointed out that patients who undergo progressive rehabilitation training after ACL reconstruction surgery have knee function, range of motion, and muscle strength (Grindem et al., 2015; Noyes et al., 2000). The application of a brace can also contribute to the prevention of knee stiffness following ACL reconstruction (Skalsky and McDonald, 2012), while a brace in the hyperextension position for at least 3 weeks was more effective in preserving extension function (Melegati et al., 2003).不规范或过度的术后康复训练以及术后感染可能导致关节进一步损伤，增加纤维化风险。研究发现不同术后负重方案（延迟负重、渐进性负重和立即负重）的并发症发生率存在差异，其中延迟负重方案发生关节僵硬的风险最高（Morris 等，2021）。另有研究指出，前交叉韧带重建术后采用渐进式康复训练的患者在膝关节功能、活动范围和肌力恢复方面表现更佳（Grindem 等，2015；Noyes 等，2000）。支具的应用也有助于预防前交叉韧带重建术后膝关节僵硬（Skalsky 和 McDonald，2012），而保持膝关节过伸位支具固定至少 3 周对保留伸直功能效果更显著（Melegati 等，2003）。
4 Treatments 4 治疗方法
Treatments are mainly non-surgical and surgical (Figure 1). Non-surgical treatment includes physical therapy and medication. In severe cases of fibrosis, arthroscopic surgery is required to restore joint mobility. Additionally, postoperative rehabilitation after secondary surgical release is still needed to avoid recurrence.治疗方法主要分为非手术和手术两种（图 1）。非手术治疗包括物理疗法和药物治疗。对于严重的纤维化病例，需要通过关节镜手术来恢复关节活动度。此外，二次手术松解后仍需进行术后康复训练，以避免复发。FIGURE 1.
Treatments of knee fibrosis after ACL reconstruction.前交叉韧带（ACL）重建术后膝关节纤维化的治疗
4.1 Non-surgical treatment4.1 非手术治疗
Low-level laser therapy (LLLT) and continuous passive motion (CPM) are commonly used physical therapies. Studies have shown that LLLT after ACL reconstruction can reduce the formation of joint contractures by inhibiting inflammation and fibrosis (Kaneguchi et al., 2019). LLLT has anti-inflammatory and anti-fibrotic effects and causes fewer adverse reactions (Kaneguchi et al., 2019; Zhang et al., 2022; Wickenheisser et al., 2019). Moreover, it is a low-cost treatment and is widely used for a wide range of inflammatory and fibrotic diseases (Zhang et al., 2022; Khansa et al., 2016; Soleimanpour et al., 2014). Similarly, CPM treatment can reduce the incidence of knee fibrosis after various knee surgeries (Bram et al., 2019; Haller et al., 2015; Harvey et al., 2010). A recent study using an animal model of ACL rupture showed that immediate CPM therapy has a chondroprotective effect against post-traumatic osteoarthritis (Chang et al., 2017). On the contrary, in two recently published systematic reviews regarding CPM on knee ROM after ACL reconstruction, no evidence is noticed to support the application of this method in the index knee after ACL surgery (Thrush et al., 2018; D'Amore et al., 2021). Therefore, further research is required to evaluate the potential utility of CPM in the long run.低强度激光治疗（LLLT）和持续被动运动（CPM）是常用的物理治疗方法。 研究表明，前交叉韧带（ACL）重建术后采用低强度激光治疗（LLLT）可通过抑制炎症和纤维化减少关节挛缩的形成（Kaneguchi 等，2019）。LLLT 具有抗炎和抗纤维化作用，且不良反应较少（Kaneguchi 等，2019；Zhang 等，2022；Wickenheisser 等，2019）。此外，该疗法成本较低，已广泛应用于多种炎症性和纤维化疾病（Zhang 等，2022；Khansa 等，2016；Soleimanpour 等，2014）。同样，持续被动运动（CPM）治疗可降低多种膝关节术后膝纤维化的发生率（Bram 等，2019；Haller 等，2015；Harvey 等，2010）。近期一项采用 ACL 断裂动物模型的研究显示，即刻 CPM 治疗对创伤后骨关节炎具有软骨保护作用（Chang 等，2017）。相反，近期发表的两篇关于 ACL 重建术后 CPM 对膝关节活动度（ROM）影响的系统综述中，未发现支持该方法用于 ACL 术后患膝的证据（Thrush 等，2018；D'Amore 等，2021）。因此，需要进一步研究以评估持续被动运动（CPM）的长期潜在效用。
Regarding medications, the main anti-inflammatory drugs used to treat knee fibrosis can be categorized into glucocorticoids and non-steroidal anti-inflammatory drugs (Usher et al., 2019; Liu et al., 2017). The most commonly used non-steroidal drug is aspirin. Aspirin inhibits the development of fibrosis through a variety of mechanisms (Xu et al., 2022; Peng et al., 2023). Aspirin inhibits NF-κB synthesis via IKK receptors and promotes the formation of stable and powerful specialized pro-resolving lipid mediators (SPMs) (Liu et al., 2017). It is possible that aspirin lowers the incidence of fibrosis by decreasing PI3K/AKT/mTOR (phosphorylated phosphatidylinositol 3 kinase, protein kinase B, and mechanistic target of rapamycin) and increasing autophagy (Peng et al., 2023). These mechanisms make aspirin the primary drug currently prescribed for the treatment of fibrosis. Both oral and intra-articular glucocorticoids have advantages and disadvantages in the treatment of joint fibrosis (Barel et al., 2010; Melgert et al., 2001). Oral glucocorticoids can reduce joint inflammation and pain through systemic circulation, but multiple doses are required to maintain the therapeutic effectiveness, which can cause systemic side effects. On the other hand, intra-articular injection can act directly on the inflammatory and fibrotic tissue, improving treatment efficacy and reducing systemic side effects.在药物方面，用于治疗膝关节纤维化的主要抗炎药物可分为糖皮质激素和非甾体抗炎药（Usher 等人，2019 年；Liu 等人，2017 年）。最常用的非甾体药物是阿司匹林。阿司匹林通过多种机制抑制纤维化的发展（Xu 等人，2022 年；Peng 等人，2023 年）。阿司匹林通过 IKK 受体抑制 NF - κB 的合成，并促进稳定且强效的特异性促分解脂质介质（SPMs）的形成（Liu 等人，2017 年）。阿司匹林有可能通过降低 PI3K/AKT/mTOR（磷酸化磷脂酰肌醇 3 激酶、蛋白激酶 B 和雷帕霉素靶蛋白）水平和增强自噬来降低纤维化的发生率（Peng 等人，2023 年）。这些机制使阿司匹林成为目前治疗纤维化的主要处方药物。 口服和关节内糖皮质激素在治疗关节纤维化方面各有优缺点（Barel 等，2010；Melgert 等，2001）。口服糖皮质激素可通过全身循环减轻关节炎症和疼痛，但需多次给药以维持治疗效果，这会引发全身副作用。另一方面，关节内注射可直接作用于炎症和纤维化组织，提高疗效并减少全身副作用。
By managing the pro-inflammatory and pro-fibrogenic pathways, bio-agents against fibrotic disorders have attracted increasing attention in recent years. Montelukast and Pranlukast are two cytoplasmic leukotriene receptor antagonists mainly used to treat respiratory diseases such as asthma and allergic rhinitis (Wenzel, 1998; Huang and Handel, 2010; Menkü Özdemir et al., 2022; Lynch et al., 1999). In the treatment of arthrofibrosis, these two drugs show therapeutic potential in reducing the postoperative inflammatory response after joint surgery (Chen et al., 2024). Relaxin-2 (RLX-2) is an endogenous anti-fibrotic peptide that is capable of alleviating TGF-β-induced myofibroblast differentiation (Wang et al., 2016; Samuel et al., 2016; Shabanpoor et al., 2012; Sassoli et al., 2013), and thus is used as an anti-fibrotic agent in knee contracture after ACL reconstruction. However, a major obstacle to the clinical translation of RLX is its short half-life (Metra et al., 2019; Khanna et al., 2009; Weiss et al., 2016), which requires further investigations regarding effective delivery modalities. Botulinum toxin type A is currently used as an anti-fibrotic agent for adhesive capsulitis (Blessing et al., 2021; Khenioui et al., 2016; Chen et al., 2011) and is observed to reduce scar formation in animal models of knee fibrosis (Namazi and Torabi, 2007; Gao et al., 2017). Platelet-rich plasma also has potential against joint fibrosis (Araya et al., 2020; Lin et al., 2023). Intra-articular delivery of hyaluronic acid is also a good method for treating knee fibrosis in animal models, while there are few clinical trials testing the efficacy of knee stiffness after ACL reconstruction (Kanazawa et al., 2015; Qu et al., 2023). In addition, vitamin D and angiotensin II receptor antagonists have also been successfully used under different fibrosis conditions and are becoming ideal candidates for joint fibrosis (Jagodzinski and Traut, 2022).通过调控促炎和促纤维化通路，抗纤维化生物制剂近年来备受关注。孟鲁司特和普仑司特是两种胞质白三烯受体拮抗剂，主要用于治疗哮喘和过敏性鼻炎等呼吸系统疾病（Wenzel, 1998; Huang and Handel, 2010; Menkü Özdemir 等, 2022; Lynch 等, 1999）。在关节纤维化治疗中，这两种药物显示出减轻关节术后炎症反应的治疗潜力（Chen 等, 2024）。松弛素-2（RLX-2）是一种内源性抗纤维化多肽，能够缓解 TGF-β诱导的肌成纤维细胞分化（Wang 等, 2016; Samuel 等, 2016; Shabanpoor 等, 2012; Sassoli 等, 2013），因此被用作前交叉韧带重建术后膝关节挛缩的抗纤维化制剂。然而，RLX 临床转化的主要障碍是其半衰期较短（Metra 等, 2019; Khanna 等, 2009; Weiss 等, 2016），这需要进一步研究有效的递送方式。 A 型肉毒毒素目前被用作粘连性关节囊炎的抗纤维化剂（Blessing 等，2021；Khenioui 等，2016；Chen 等，2011），且在膝关节纤维化动物模型中观察到其可减少瘢痕形成（Namazi 和 Torabi，2007；Gao 等，2017）。富血小板血浆也具有抗关节纤维化的潜力（Araya 等，2020；Lin 等，2023）。透明质酸的关节内注射在动物模型中也是治疗膝关节纤维化的有效方法，但针对前交叉韧带重建后膝关节僵硬疗效的临床试验较少（Kanazawa 等，2015；Qu 等，2023）。此外，维生素 D 和血管紧张素 II 受体拮抗剂也已在不同纤维化条件下成功应用，正成为关节纤维化的理想候选药物（Jagodzinski 和 Traut，2022）。
4.2 Surgical treatment 4.2 手术治疗
Surgical intervention for fibrosis mainly includes manual release under anesthesia (MUA) and arthroscopic lysis of adhesions (LOA). Patients who did not reach a full extension by 3 months postoperatively, defined as lacking 10°, and had a symptomatic difference in the range of motion relative to the unaffected knee were eligible for MUA or LOA. If MUA did not provide a sufficient range of motion, arthroscopy with LOA was recommended instead (Crabtree et al., 2023). MUA is also commonly used to treat knee fibrosis, either alone or in combination with arthroscopy (Crabtree et al., 2023; Baghdadi et al., 2022). For severe fibrosis, soft tissue release via LOA is still the recommended option. By removing the excessive extracellular matrix, LOA can not only relieve the joint movement restriction but also dilute the concentration of intra-articular pro-fibrotic mediators, thus blocking the vicious cycle formed by the ECM (Sanders et al., 2017; Lamba et al., 2023).纤维化的手术干预主要包括麻醉下手法松解（MUA）和关节镜下粘连松解（LOA）。术后 3 个月未能达到完全伸直（定义为伸直差 10°）且与未受影响膝关节相比活动范围存在症状性差异的患者适合进行 MUA 或 LOA。如果 MUA 不能提供足够的活动范围，则建议改为进行带 LOA 的关节镜检查（Crabtree 等人，2023 年）。MUA 也常用于治疗膝关节纤维化，可单独使用或与关节镜检查联合使用（Crabtree 等人，2023 年；Baghdadi 等人，2022 年）。对于严重纤维化，通过 LOA 进行软组织松解仍是推荐的选择。通过去除过多的细胞外基质，LOA 不仅可以缓解关节活动受限，还可以稀释关节内促纤维化介质的浓度，从而阻断由细胞外基质形成的恶性循环（Sanders 等人，2017 年；Lamba 等人，2023 年）。
Arthroscopic LOA and MUA are safe and effective treatments for the postoperative fibrosis of the knee (Fackler et al., 2022). However, both techniques have complications. These surgical procedures may lead to neurological and vascular disorders, fractures, ligament relaxation, etc (Pivec et al., 2013; Egol et al., 2005; Laskin and Beksac, 2004; Fisher and Shelbourne, 1993). Therefore, careful pre-operative planning is necessary in facilitating knee function after the operation.关节镜下关节松解术（LOA）和手法松解术（MUA）是治疗膝关节术后纤维化的安全有效方法（法克勒等人，2022 年）。然而，这两种技术都有并发症。这些外科手术可能会导致神经和血管紊乱、骨折、韧带松弛等（皮韦克等人，2013 年；埃戈尔等人，2005 年；拉斯金和贝克萨克，2004 年；费舍尔和谢尔伯恩，1993 年）。因此，术前进行仔细规划对于促进术后膝关节功能很有必要。
In current clinical practice, the prevention of fibrosis development is still challenging. If a physician or surgeon identifies a trend toward knee stiffness, interventions such as physiotherapy regimens and antifibrotic or anti-inflammatory medication can be considered. However, given the lack of evidence-based decision-making, the establishment of a sequential prevention method is still in progress.在当前临床实践中，预防纤维化的发生仍然具有挑战性。如果医生或外科医生发现膝关节僵硬的趋势，可以考虑采取物理治疗方案、抗纤维化或抗炎药物等干预措施。然而，由于缺乏循证决策依据，序贯预防方法的建立仍在进行中。
Currently, there are studies on the treatment of arthrofibrosis, but reports are still in the basic research stage. In the future, one can consider exploring the mechanism of occurrence and development from the perspectives of molecular biology and genetics, while also searching for new biomarkers and therapeutic targets to facilitate early diagnosis and intervention. In addition, personalized rehabilitation programs and prevention strategies based on specific patient characteristics can be developed to improve efficacy.目前已有关于关节纤维化治疗的研究，但相关报道仍处于基础研究阶段。未来可考虑从分子生物学和遗传学角度探索其发生发展机制，同时寻找新的生物标志物和治疗靶点，以促进早期诊断和干预。此外，可根据患者的具体特征制定个性化康复方案和预防策略，以提高疗效。
5 Conclusion 5 结论
Knee fibrosis after anterior cruciate ligament reconstruction is a complex complication involving multiple risk factors. Early identification and intervention are essential in preventing or treating this condition. Conservative treatment may be useful in the early stages of joint fibrosis, while secondary surgery should be considered in the advanced stage. Determining the appropriate treatment plan requires assessment and decision-making by the physician based on the patient’s specific situation. Future research is still required to explore the biological mechanisms and establish risk models to predict the occurrence of this condition, thereby improving the prognosis of patients after ACL reconstruction.前交叉韧带重建术后膝关节纤维化是一种涉及多种危险因素的复杂并发症。早期识别和干预对于预防或治疗这种情况至关重要。保守治疗在关节纤维化早期可能有用，而晚期则应考虑二次手术。确定合适的治疗方案需要医生根据患者的具体情况进行评估和决策。未来仍需开展研究，以探索其生物学机制并建立风险模型来预测这种情况的发生，从而改善前交叉韧带重建术后患者的预后。
