髌骨骨折和创伤性关节炎的基础与临床研究
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摘要
目的：髌骨骨折是临床上常见的肢体创伤，各类文献中也有大量报道。在各种类型的骨折中，横行骨折是最为常见的的。曾有报道指出膝关节交叉韧带损伤多见于运动创伤。在临床治疗中，横行骨折最常用的治疗方法是张力带钢丝固定技术。手术目的是将骨折块进行解剖复位，重建关节面和伸膝装置，全面恢复膝关节功能。虽然髌骨骨折和交叉韧带损伤机制相似，但是闭合性髌骨骨折合并交叉韧带损伤的病例鲜有报道。然而，发生高能量或粉碎性骨折可能会出现交叉韧带损伤或断裂。骨科医师经常会忽略合并伤的问题，造成临床误诊以及不恰当的治疗。
髌骨骨折约占全身骨折的1%。纵观历史，各种固定方法均存有争议。近年来，髌骨在伸膝过程中发挥的作用逐渐被人们所知，主张最大限度的保留髌骨以利于日后的功能恢复。然而，由于髌骨的特殊位置以及患者的主观愿望，治疗过程仍具有挑战性。
随着时代的发展，手术治疗髌骨骨折已得到较为广泛的认可，临床疗效不断提高，但其存在的中远期并发症也备受关注，如膝关节僵直、创伤性关节炎等。因此，我们应对髌骨骨折术后患者进行更为客观的疗效评估，以便通过适当的保守治疗或手术干预来阻止病理学变化的恶性循环，维持膝关节正常的生物力学机制。目前，步态分析系统在国外已广泛应用于各种下肢疾病的预防和术式评估等方面。2012年3月至2012年11月期间我院行切开复位内固定术治疗27例单侧髌骨骨折患者，本文于术后3个月对患者进行步态分析，测量其足底各区域的压力峰值，探讨动态步态分析技术在髌骨骨折术后疗效评估中的应用价值。
创伤性关节炎（TOA）作为髌骨骨折的主要并发症，其病例特征为关节软骨的退行性改变以及软骨下骨重塑。关节软骨的结构性改变包括蛋白多糖耗竭、关节表面裂隙以及潮线的破坏。正常的关节软骨中不存在血管，但在创伤性关节炎的病理变化中，软骨下骨内血管逐渐侵入钙化软骨层并突破潮线。同时，血管侵入也被认为是骨赘形成的重要因素。然而，关节软骨退变及血管侵入的病理机制尚不完全清楚。
软骨基质的降解对于关节软骨血管化是至关重要的。多种蛋白酶将胶原蛋白降解，这些蛋白酶属于基质金属蛋白酶家族（MMP），其作用为切割胶原和蛋白聚糖。软骨退变所形成的各种生化指标可以作为诊断创伤性关节炎的特征性依据。近来有研究表明，创伤性关节炎软骨细胞中的若干种基质金属蛋白酶出现上调或下降。有学者曾经在大鼠体内利用MMP抑制剂延缓软骨破坏及血管化。Kruppel样因子5（KLF5）通过诱导MMP-9的转录间接导致软骨基质退变。然而，KLF5与MMP-9的表达以及关节软骨病理改变的机制尚不完全了解。
我们推测KLF5和MMP-9的表达与关节软骨血管化有密切联系。本研究首先评估的是KLF5和MMP-9的表达与TOA严重程度之间的关系。实验结果显示在TOA患者中MMP-9和KLF5的高表达与关节软骨的退变存在必然联系，这两者成为介入治疗TOA的新型分子靶点。
方法：首先，自2012年3月1日至2012年6月30日，在我院对60例单膝髌骨骨折患者进行膝关节核磁共振（MRI）检查。患者的平均年龄为40.2岁（13-64岁），其中48例为男性。将患者按照致伤原因进行分组，其中28例为坠落伤或车祸伤，属于高能量创伤；32例为行走时摔伤，属于低能量创伤。继而将患者按照骨折类型进行分类，其中31例属于横行骨折，29人属于粉碎性骨折。
其次，采用Bostman髌骨损伤疗效评分标准对术后3个月的27例单侧髌骨骨折患者的膝关节功能进行评价。该标准包括：关节运动范围、疼痛、股四头肌萎缩、爬楼梯及工作影响等方面，满分为30分，其中满意：28～30分，不满意：＜28分，根据评分结果将所有患者分为评分满意组和评分不满意组。动态足底压力测量过程：术后3个月要求每一受试者挺胸抬头在测力平板上常速自然行走，左、右脚各有3次落在平板内。在距离平板2m的位置开始行走，通过测力平板后再走出1m左右。在正式测试之前每位受试者应进行练习，以确保试验过程的顺利进行及数据的准确。利用分析软件中的时间分析模块计算出足底各解剖部位的平均峰值压力，其中M1～M5分别代表第1～5跖骨区，HM为足跟内侧区，HL为足跟外侧区。每位受试者分别进行3次动态足底压力数据采集，取其平均值。分别计算两组患者健足与患足的足底峰值压力分布差异。
最后，随机挑选20例全膝置换术患者的31个关节标本，其中男性3例、女性17例，平均年龄67.2岁（55-74岁）。排除患有包括风湿及类风湿关节炎在内的其他炎症性关节疾病。将每个标本分别截取2-3个边长为0.5cm的骨块，将磨损程度最重的胫骨平台内侧面的截骨骨块作为磨损组（SC, n=29）；以软骨表面无磨损的骨块为对照组（NC，n=17），所有标本放入10%的中性福尔马林溶液中固定。排除其他炎症性关节炎的患者。
将骨块整体放入福尔马林-硝酸液中浸泡进行脱钙处理，每隔12小时换液1次，脱钙7天。完全脱钙的标准：取5ml脱钙液用2M的NaOH调整至中性，再倒入5%的草酸钠或草酸铵溶液1ml，如5分钟后脱钙液不浑浊，则认为脱钙完全；否则，仍需继续脱钙。将脱钙后的标本进行脱蜡包埋，5μm连续切片，随后进行苏木精伊红染色和番红O染色，确定关节软骨受损程度。所有样本均由两名资深病理科医师在双盲状态下查证。利用改良Janusz评分判定软骨损伤程度。评分范围为0-5分，0分代表软骨正常无损伤染色均匀，作为对照组（NC）；≥3代表软骨重度损伤，表面或中间区域出现染色缺失（SC）。
结果：
1高能量创伤和粉碎性髌骨骨折容易导致膝关节交叉韧带损伤
1.17例合并交叉韧带损伤患者的详细情况
MRI扫描结果显示了这7例髌骨骨折合并交叉韧带损伤患者的具体情况。平均年龄45.7岁（13-64岁），其中6例为男性。在所有7例患者中，1例为摔伤，4例为车祸伤，以及2例坠落伤。其中3例为左膝髌骨骨折，6例为粉碎性骨折。7例韧带损伤分别为2例为后交叉韧带完全断裂，2例为后交叉韧带部分断裂，3例为前交叉韧带部分断裂。髌骨骨折合并交叉韧带损伤率为11.6%。由于膝关节的肌肉拮抗，物理诊断的结果与MRI的扫描结果并非完全一致。在这7例患者中，只有5例抽屉试验阳性，4例Lachman试验阳性。
1.2不同组别之间损伤率的比较
在这7例髌骨骨折合并交叉韧带损伤的患者中，只有1例为低能量创伤（3.1%,1/32）,而有6例为高能量创伤（21.4%，6/28）。高能量创伤组的韧带损伤率明显高于低能量创伤组（P＜0.05）。
在这7例髌骨骨折合并交叉韧带损伤的患者中，只有1例为横行骨折（3.2%，1/31），而有6例为粉碎性骨折（20.7%，6/29）。粉碎性骨折组的韧带损伤率明显高于横行骨折组（P＜0.05）。
2Footscan步态分析技术所提供的足底压力峰值有助于髌骨骨折术后生物力学早期变化的诊断
2.1Bostman评分满意组
本组20例，临床上无明显不适症状，关节屈伸度≥120°，股四头肌萎缩不明显。目测步态正常，且经规范的训练后能达到水平匀速直线行走的标准步态，步速范围为97～113步/min，平均104步/min。足底压力测量结果显示：本组患者健侧在1个步态周期中的足底各区域平均压力峰值总和与患侧相似，差异无统计学意义（P＞0.05）。健侧第5跖骨头区域压力平均峰值较患侧高，差异有统计学意义（P＜0.05）；但双足足底其他区域压力平均峰值数值相近，差异均无统计学意义（P＞0.05）。本组患者双下肢足底压力的最大峰值均出现在足跟外侧区，健侧平均为（218.3±19.7） N，患侧平均为（208.4±25.0） N。2.2Bostman评分不满意组
本组7例，临床上存在不适症状，关节屈伸度≤90°，股四头肌周径萎缩≥1cm。目测步态具有不同程度的异常，经规范的行走训练后基本能够达到水平匀速直线行走的标准步态，步速范围为87～98步/min,平均92步/min。足底压力测量结果显示：本组患者健侧在1个步态周期中的足底各区域平均峰值压力总和与患侧相似，差异无统计学意义（P＞0.05）。双足第3跖骨区和足跟外侧区的足底压力峰值比较差异无统计学意义（P＞0.05）；但是，在第1、2、4、5跖骨区及足跟内侧区这5个区域内双足的足底压力峰值比较差异有统计学意义（P＜0.05）。
3增加的KLF5与MMP-9表达通过促进软骨降解而诱导关节软骨血管化
3.1关节软骨损伤的形态学观察
将检测的标本通过HE、番红O染色，确定关节软骨磨损与否。显微镜观察染色切片，无磨损的软骨切片表现为，关节软骨表层光滑、平整,软骨细胞分布均匀,无簇聚软骨细胞,潮线完整;番红O染色均匀,无失染现象。损伤处的关节软骨表面不平整、高低起伏、纹理紊乱，表层变薄；有大小不等的裂隙。根据形态学鉴定结果，将标本分为磨损组和无磨损组，进行下列指标的检测。
3.2关节软骨损伤与血管和神经侵入的关系
HE染色和CD34标志物免疫组化均显示，软骨磨损部位的切片，有血管突破潮线侵入软骨。在所检测的29例软骨磨损的标本切片中，有16例（55.2%）可观察到侵入软骨的血管；同一标本用扫描电镜也观察到在损伤软骨的近潮线处分布的血管，血管腔面的内皮结构和腔内双凹圆盘状的红细胞清晰可见，这更近一步印证了此管腔的性质。而在相应的无磨损的软骨区，仅有2例（2/17）发现有血管存在，占11.7%，出现新生血管的频率明显低于磨损组，两组之间具有显著性差异(P＜0.05)。表明血管侵入数量与软骨磨损程度成正相关。
为了确定磨损软骨中是否有神经侵入，本实验采用感觉神经特异性标志物PGP9.5抗体进行免疫组化染色。在磨损组有新生血管形成的软骨标本中检出数量稀少的神经纤维，且靠近增生的血管，而磨损组无血管侵袭的标本以及无磨损组中均未发现神经纤维，PGP9.5染色为阴性。提示神经侵入可能滞后于血管生成。
3.3软骨退行性变与KLF5和MMP-9表达的关系
免疫组化染色显示，在无磨损处的软骨细胞内，可观察到极少量的KLF5和MMP-9阳性染色颗粒；而在关节软骨磨损部位簇集的软骨细胞中， KLF5、MMP-9的表达活性均明显升高，镜下可见密集分布的阳性染色棕色颗粒；在KLF5表达活性高的细胞中，其MMP-9的表达水平也相应升高，二者的变化趋势具有一致性。利用形态学Fig.像分析软件通过测定颗粒平均光密度值(IOD)，也证实磨损组的KLF5和MMP-9表达活性显著高于无磨损组，二者比较具有显著性差异（P＜0.05）。两种蛋白表达活性与血管侵袭数量具有正相关性。
3.4关节软骨胶原纤维结构变化
分别取磨损组和无磨损组的软骨标本（每组n=5），经处理后进行扫描电镜观察。无磨损的软骨表面较为光滑，切面可见排列整齐、均匀而密集的胶原纤维，方向与表面呈切线；磨损组软骨表面粗糙不平，浅坑和隆起相间；切面可见胶原纤维增粗、断裂、排列混乱，空隙增大，有软骨细胞分布其中。
结论：
1高能量创伤和粉碎性髌骨骨折容易导致膝关节交叉韧带损伤。
2Footscan步态分析技术所提供的足底压力峰值有助于髌骨骨折术后生物力学早期变化的诊断。
3增加的KLF5与MMP-9表达通过促进软骨降解而诱导关节软骨血管化。
Objectives: Firstly, the patellar is a component of the patellofemoral joint.Patellar fractures are commonly encountered in orthopedic practice and arewell reported in the literature. Approximately1%of all skeletal injuries arerelated to the patella, wheres transverse fractures are the most commonpatellar injury. Previous studies have shown that injuries to the cruciateligament in the knee are common in sports, as well as other activities. Inclinical treatment, the most common method of transverse patella fracturefixation is the tension band wiring technique. The aim of operative treatmentof transverse patella fractures is the anatomic reduction of the fracture parts toreconstruct the articular surface and extensor mechanism to regain full kneejoint function. Closed patellar fractures with a cruciate ligament injury arerarely reported, although the mechanisms of patellar fracture and cruciateliament injury are similar. However, high-energy or comminuted patellarfractures might occur in which the cruciate ligament may be injured ordisrupted. Surgeons often neglect whether the closed patellar fracture iscombined with a cruciate ligament injury, resulting in misdiagnosis andinappropriate treatment.
Patellar fracture account for1%of body fractures. Throughout history,various fixation methods are controversial. In recent years, the role of play inthe patella extensor process of gradually been kown advocate maximize theretention of the patella in order to facilitate future fuctional recovery. However,due to the special position of the patella and the patient's subjective desire, thecourse of treatment remains challenging.
With the development of surgical treatment of patellar fracture has beenmore widely recognized, the clinical efficacy of continuous improvement, butits existence is also of concern in the long-term complications, such as knee stiffness, traumatic arthritis. Therefore, wu should patellar fracture surgery inpatients with a more objective assessment of the efficacy, in order to adopt anappropriate conservative treatment or surgical intervention to stop the viciouscycle of pathological changes, maintenance of normal biomechanicalmechanism of the knee. Currently, the gait analysis system has been widelyused in foreign countries to prevent and surgical evaluation of various aspectsof lower limb disorders. Period from March2012to November2012in ourhospital open reduction and internal fixation treatment of27cases of unilateralpatellar fracture patients, the paper after3months in patients with gait analysis,measuring the plantar pressure in the regions peak, evaluate the value ofdynamic gait analysis techniques patellar fracture surgery in the efficacyevaluation.
Traumatic osteoarthritis(TOA) is characterized by progressive loss ofjoint articular cartilage and subchondral bone remodeling. Structural changesin the osteoarthritic articular cartilage include proteoglycan depletion,fissuring, and tidemark duplication. Blood vessels are absent in normal adultarticular cartilage, and invade from the subchondral bone into the calcifiedcartilage and breach the tidemark in TOA. Vascular invasion is also thought tobe important in osteophyte formation. However, the mechanism of articularcartilage degeneration and vascular invasion is incompletely understood.
The degradation of cartilage matrix is particular crucial for vascularinvasion. This step requires proteolytic breakdown by a variety of proteinases,among which members of the matrix metalloproteinase(MMP) family are ofspecial interest due to their ability to cleave collagens and aggrecan, the twoprincipal matrix components of cartilage. The products of catilage degradation,as biochemical markers, have diagnostic applicability in TOA. Recent studieshave shown that several MMPs are up-or down-regulated in osteoarthriticchondrocytes as compared with normal chondrocytes. Treatment with a MMPinhibitor inhibits joint damage and osteochondral angiogenesis in rats.Kruppel-like factor(KLF)5causes cartilage matrix degradation throughtranscriptional induction of MMP-9in mice. However, the expression of KLF5and MMP-9as well as the clinicopathololgical significance for thesealterations in the carilage degeneration of human knee TOA has not yet beenclarified.
We hypothesized that, in TOA, the expression of KLF5and MMP-9isassociated with cartilage degeneration, and is linked to vascular invasion. Thepresent study is the first to evaluate the association of the expression of KLF5and MMP-9with the severity of TOA cartilage change. Our results indicatethat high expression of KLF5and MMP-9may be involved in the articularcartilage degeneration in TOA patients, and that KLF5and MMP-9may benovel molecular targets for therapeutic intervention in TOA.
Methods: Firstly, full approval from the Research Ethics Committee andthe Research Governance Committee was received for the study. All thesubjects who participated in the study provided informed consent. Patientswere identified by Picture Archiving and Communication System for theperiod from March1to June30,2012. A total of sixty patients with patellarfracture who underwent open reduction and internal fixation were enrolled tothe study. Patients that were13to64years of age were included. The meanage of the patients was40.2years and48patients were men. Sixty patientshad unilateral patellar fracture and24patients had a left patellar fracture. Allpatients had their histories taken and were examined by the orthopedist withfellowship teraining in sports medicine, including Drawer test and Lachmantest. According to the cause of injury,31patients had low-energytrauma(tumbling injury) and29patients had had high-energy trauma(fallinginjury or motor vehicle). According to the fracture pattern, there were32cases of transverse fracture and28cases of comminuted fracture. In our seriesof patellar injuries, all60patients had an isolated and closed injury.
All images were read and interpreted by two fellowship-trainedmusculoskeletal radiologists who was blinded to the results of the clinicalassessment for each subject. Each scan diagnosed on the condition of thecrucaite ligament pathology. The cruciate ligament was assessed and classifiedas normal, partially torn, or completely ruptured. Patients with multiple fractures, or those who had total and partial patellectomy were excluded fromthe study.
Secondly, twenty-seven patients with unilateral patellar fracture treatedwith open reduction internal fixation (ORIF) were following up for evaluatingknee function based on patella injury efficacy score (Bostman). The dynamicgait analysis (Footscan, RsScan International, Belgium) was used to calculateand analyze mean peak pressure of seven anatomical areas including the firstto fifth metatarsal head, medial heel and lateral heel. The distributiondifference of peak pressures was compared between the healthy feet andinjured feet according to index.
Thirdly, approval was obtained from the Hebei Medical UniversityClinical Research Ethics Committee. After informed consent had been given,31tibiofemoral joints, including articular surfaces, joint capsule, andintra-articular structures, were collected from20patients that met clinicalsymptomatic criteria(American College of Rheumatology revised criteria forTOA) at the time of total knee joint replacement(TKR) surgery. In the presentstudy, we used joint samples from20patients(31knee joints,3male) with amedian age of68.4(range55-74) years. Each sample was sawn into2-3blocks(5mm×5mm×5mm), and categorized according to its grossmorphology, as either belonging to the severe change group(SC, n=29) ofcartilage, which was taken from the main defective area of maximal load, or tothe group with no observed change(NC, n=17), taken from areas with noobvious surface defects. All of the specimens were then verified by safranin Ostaining by two independent observers in a double-blind manner. Cartilagedamages were evaluated using the modified Janusz's system. Using thismethod, cartilage damage was scored on a scale of0-5. Score0representscartilage of normal appearance that shows uniform staining throughoutarticular cartilage, serving as a control(NC); and≥3, severe, differentdegrees of loss of staining in the superficial and middle zones(SC) assessed inthis study. Patients with other forms of arthritis or other clinical inflammatoryjoint disease were excluded.
All samples were fixed and preserved in10%neutral buffered formalinfor48-72h and subsequently decalcified for24-36h in10%EDTA-PBS. Theserial sections(6μm) were prepared, and were then routinely stained withhematoxylin and eosin(HE) and safranin O as described.
Results:
1. High-energy trauma often results in a comminuted patellar fracture, whichis often combined with cruciate ligament injury.
1.1Details of the seven patients with combined cruciate ligament injuries
MRI findings showede that there were seven cases of patellar fracturecombined with cruciate ligament injury. The mean age was45.7years(range,13-64years) and six patients were men. There were one case of a trumbleinjury, four cases of a motor vehicle accident and two cases of a fall injury.Three patients had a left patellar fracture. And six cases had a comminutedfracture. There were two cases of a completely ruptured posterior cruciateligament, two cases of a partially torn posterior cruciate ligament, and threecases of a partially torn anterior cruciate ligament. The percentage of patientswith these combined injuries was11.6%(7/60). Because of antagonistic andpainful knees, the diagnostic results of the two tests are not the same as MRI.In our seven patients with cruciate ligament injury, only five patients werepositive for the Drawer test and four were positive for the Lachman test.
1.2Comparision of different groups and combined injuries
Among seven patients with combined cruciate ligament injuries, therewas one case of low-energy trauma(3.1%,1/32) and six cases of high-energytrauma(21.4%,6/28). The incidence of a combined injury of the crucatieligament with high-energy trauma was significantly higher than that withlow-energy trauma(P＜0.05).Among the seven patients with combined injuries, one had a transversefracture(3.2%,1/31) and six had a comminuted fracture(20.7%,6/29). Theincidence of combined injuries in those with a comminuted fracture washigher than that in those with a transverse fracture(P＜0.05).
2. Footscan gait analysis may therefore be a useful tool for detecting the early change of biomechanics and can evaluate the recovery of the patellar fracture.
Follow-up lasted for6-15months (mean12months). In the group withsatisfaction(20cases), there showed no significant difference of sum of peakpressure between the healthy feet and injured feet (P＞0.05). And nosignificant difference was shown of plantar peak pressure distribution, expectthe fifth metatarsal head(P＜0.05). In the group with dissatisfaction(7cases),there also showed no significant difference of sum of peak pressure betweenthe healthy feet and injured feet (P＞0.05). But the obvious difference wasshown in the first, second, fourth, fifth metatarsal head and medial heel(P＜0.05).
3. The expression of KLF5and MMP-9may be involved in cartilagedegeneration, contribution to human TOA.
3.1The morphology of articular cartilage injury
All of the samples were divided into two groups, SC and NC by safraninO and HE staining, according to the damages of articular cartilages. Thecartilage surfaces in the SC group revealed more severe changes in structurecompared to samples of the NC group, which had smooth surfaces.
3.2Neurovascular invasion is associated with severity of cartilage damages inTOA
Blood vessels verfied by CD-34positve endothelium crossed multipletidemarks and entered the non-calcified cartilage, which were observed inboth SC and NC samples. However, the frequency of vascular invasion in theSC group(16/29,55.2%) was higher than that in NC samples(2/17,11.7%)(P＜0.05). Moreover, endothelial cells, fibrovascular tissue, perivascular cells,and red blood cells were also observed in vascular structures by scanningelectron microscopy. In the SC group, the articular surfaces with vascularinvasion in the cartilage revealed severe damages, as compared with thosewhere wessels were not detected.
PGP9.5-positive nerves were observed only in30%of samples of the SCgroup, and were always associated with blood vessels. Nerves were notobserved in the NC group.
3.3Cartilage degenberation is associated with expression of KLF5andMMP-9in TOA
The results of dual-immunofluorescent staining showed that theexpression of KLF5and MMP-9was significantly increased in chondrocytesseen in the severe change area of articular cartilage, and was co-localized inthe same cells. The chondrocytes expressing KLF5and MMP-9were mainlydistributed in the areas of the damaged articular surface. However, theexpression of the two proteins was hardly detected in articular cartilage fromthe NC group. The expression of KLF5and MMP-9was significantlydifferently between SC and NC samples(P＜0.05).
3.4Structure changes in articular cartilage collagen fibers
The fine structure of the articular cartilage and collagen fibers wasassessed by SEM. Collagen fibers in some areas of the articular surface of theNC group formed smooth and parallel waves. However, in damaged cartilage,the collagen fibers appear to have a smaller diameter and to be less tightlypacked and less highly organized than those seen in the superficial zone ofnormal articular cartilage in the NC group. Collagen fibers of the normalcartilage are scattered homogeneously and deeply in the matrix, while thefibers on the damaged articular cartilage are interrupted and disordered.
Conclusion:
1High-energy trauma often results in a comminuted patellar fracture,which is often combined with cruciate ligament injury.
2Footscan gait analysis may therefore be a useful tool for detecting theearly change of biomechanics and can evaluate the recovery of the patellarfracture.
3The expression of KLF5and MMP-9may be involved in cartilagedegeneration, contribution to human TOA.
髌骨骨折约占全身骨折的1%。纵观历史，各种固定方法均存有争议。近年来，髌骨在伸膝过程中发挥的作用逐渐被人们所知，主张最大限度的保留髌骨以利于日后的功能恢复。然而，由于髌骨的特殊位置以及患者的主观愿望，治疗过程仍具有挑战性。
随着时代的发展，手术治疗髌骨骨折已得到较为广泛的认可，临床疗效不断提高，但其存在的中远期并发症也备受关注，如膝关节僵直、创伤性关节炎等。因此，我们应对髌骨骨折术后患者进行更为客观的疗效评估，以便通过适当的保守治疗或手术干预来阻止病理学变化的恶性循环，维持膝关节正常的生物力学机制。目前，步态分析系统在国外已广泛应用于各种下肢疾病的预防和术式评估等方面。2012年3月至2012年11月期间我院行切开复位内固定术治疗27例单侧髌骨骨折患者，本文于术后3个月对患者进行步态分析，测量其足底各区域的压力峰值，探讨动态步态分析技术在髌骨骨折术后疗效评估中的应用价值。
创伤性关节炎（TOA）作为髌骨骨折的主要并发症，其病例特征为关节软骨的退行性改变以及软骨下骨重塑。关节软骨的结构性改变包括蛋白多糖耗竭、关节表面裂隙以及潮线的破坏。正常的关节软骨中不存在血管，但在创伤性关节炎的病理变化中，软骨下骨内血管逐渐侵入钙化软骨层并突破潮线。同时，血管侵入也被认为是骨赘形成的重要因素。然而，关节软骨退变及血管侵入的病理机制尚不完全清楚。
软骨基质的降解对于关节软骨血管化是至关重要的。多种蛋白酶将胶原蛋白降解，这些蛋白酶属于基质金属蛋白酶家族（MMP），其作用为切割胶原和蛋白聚糖。软骨退变所形成的各种生化指标可以作为诊断创伤性关节炎的特征性依据。近来有研究表明，创伤性关节炎软骨细胞中的若干种基质金属蛋白酶出现上调或下降。有学者曾经在大鼠体内利用MMP抑制剂延缓软骨破坏及血管化。Kruppel样因子5（KLF5）通过诱导MMP-9的转录间接导致软骨基质退变。然而，KLF5与MMP-9的表达以及关节软骨病理改变的机制尚不完全了解。
我们推测KLF5和MMP-9的表达与关节软骨血管化有密切联系。本研究首先评估的是KLF5和MMP-9的表达与TOA严重程度之间的关系。实验结果显示在TOA患者中MMP-9和KLF5的高表达与关节软骨的退变存在必然联系，这两者成为介入治疗TOA的新型分子靶点。
方法：首先，自2012年3月1日至2012年6月30日，在我院对60例单膝髌骨骨折患者进行膝关节核磁共振（MRI）检查。患者的平均年龄为40.2岁（13-64岁），其中48例为男性。将患者按照致伤原因进行分组，其中28例为坠落伤或车祸伤，属于高能量创伤；32例为行走时摔伤，属于低能量创伤。继而将患者按照骨折类型进行分类，其中31例属于横行骨折，29人属于粉碎性骨折。
其次，采用Bostman髌骨损伤疗效评分标准对术后3个月的27例单侧髌骨骨折患者的膝关节功能进行评价。该标准包括：关节运动范围、疼痛、股四头肌萎缩、爬楼梯及工作影响等方面，满分为30分，其中满意：28～30分，不满意：＜28分，根据评分结果将所有患者分为评分满意组和评分不满意组。动态足底压力测量过程：术后3个月要求每一受试者挺胸抬头在测力平板上常速自然行走，左、右脚各有3次落在平板内。在距离平板2m的位置开始行走，通过测力平板后再走出1m左右。在正式测试之前每位受试者应进行练习，以确保试验过程的顺利进行及数据的准确。利用分析软件中的时间分析模块计算出足底各解剖部位的平均峰值压力，其中M1～M5分别代表第1～5跖骨区，HM为足跟内侧区，HL为足跟外侧区。每位受试者分别进行3次动态足底压力数据采集，取其平均值。分别计算两组患者健足与患足的足底峰值压力分布差异。
最后，随机挑选20例全膝置换术患者的31个关节标本，其中男性3例、女性17例，平均年龄67.2岁（55-74岁）。排除患有包括风湿及类风湿关节炎在内的其他炎症性关节疾病。将每个标本分别截取2-3个边长为0.5cm的骨块，将磨损程度最重的胫骨平台内侧面的截骨骨块作为磨损组（SC, n=29）；以软骨表面无磨损的骨块为对照组（NC，n=17），所有标本放入10%的中性福尔马林溶液中固定。排除其他炎症性关节炎的患者。
将骨块整体放入福尔马林-硝酸液中浸泡进行脱钙处理，每隔12小时换液1次，脱钙7天。完全脱钙的标准：取5ml脱钙液用2M的NaOH调整至中性，再倒入5%的草酸钠或草酸铵溶液1ml，如5分钟后脱钙液不浑浊，则认为脱钙完全；否则，仍需继续脱钙。将脱钙后的标本进行脱蜡包埋，5μm连续切片，随后进行苏木精伊红染色和番红O染色，确定关节软骨受损程度。所有样本均由两名资深病理科医师在双盲状态下查证。利用改良Janusz评分判定软骨损伤程度。评分范围为0-5分，0分代表软骨正常无损伤染色均匀，作为对照组（NC）；≥3代表软骨重度损伤，表面或中间区域出现染色缺失（SC）。
结果：
1高能量创伤和粉碎性髌骨骨折容易导致膝关节交叉韧带损伤
1.17例合并交叉韧带损伤患者的详细情况
MRI扫描结果显示了这7例髌骨骨折合并交叉韧带损伤患者的具体情况。平均年龄45.7岁（13-64岁），其中6例为男性。在所有7例患者中，1例为摔伤，4例为车祸伤，以及2例坠落伤。其中3例为左膝髌骨骨折，6例为粉碎性骨折。7例韧带损伤分别为2例为后交叉韧带完全断裂，2例为后交叉韧带部分断裂，3例为前交叉韧带部分断裂。髌骨骨折合并交叉韧带损伤率为11.6%。由于膝关节的肌肉拮抗，物理诊断的结果与MRI的扫描结果并非完全一致。在这7例患者中，只有5例抽屉试验阳性，4例Lachman试验阳性。
1.2不同组别之间损伤率的比较
在这7例髌骨骨折合并交叉韧带损伤的患者中，只有1例为低能量创伤（3.1%,1/32）,而有6例为高能量创伤（21.4%，6/28）。高能量创伤组的韧带损伤率明显高于低能量创伤组（P＜0.05）。
在这7例髌骨骨折合并交叉韧带损伤的患者中，只有1例为横行骨折（3.2%，1/31），而有6例为粉碎性骨折（20.7%，6/29）。粉碎性骨折组的韧带损伤率明显高于横行骨折组（P＜0.05）。
2Footscan步态分析技术所提供的足底压力峰值有助于髌骨骨折术后生物力学早期变化的诊断
2.1Bostman评分满意组
本组20例，临床上无明显不适症状，关节屈伸度≥120°，股四头肌萎缩不明显。目测步态正常，且经规范的训练后能达到水平匀速直线行走的标准步态，步速范围为97～113步/min，平均104步/min。足底压力测量结果显示：本组患者健侧在1个步态周期中的足底各区域平均压力峰值总和与患侧相似，差异无统计学意义（P＞0.05）。健侧第5跖骨头区域压力平均峰值较患侧高，差异有统计学意义（P＜0.05）；但双足足底其他区域压力平均峰值数值相近，差异均无统计学意义（P＞0.05）。本组患者双下肢足底压力的最大峰值均出现在足跟外侧区，健侧平均为（218.3±19.7） N，患侧平均为（208.4±25.0） N。2.2Bostman评分不满意组
本组7例，临床上存在不适症状，关节屈伸度≤90°，股四头肌周径萎缩≥1cm。目测步态具有不同程度的异常，经规范的行走训练后基本能够达到水平匀速直线行走的标准步态，步速范围为87～98步/min,平均92步/min。足底压力测量结果显示：本组患者健侧在1个步态周期中的足底各区域平均峰值压力总和与患侧相似，差异无统计学意义（P＞0.05）。双足第3跖骨区和足跟外侧区的足底压力峰值比较差异无统计学意义（P＞0.05）；但是，在第1、2、4、5跖骨区及足跟内侧区这5个区域内双足的足底压力峰值比较差异有统计学意义（P＜0.05）。
3增加的KLF5与MMP-9表达通过促进软骨降解而诱导关节软骨血管化
3.1关节软骨损伤的形态学观察
将检测的标本通过HE、番红O染色，确定关节软骨磨损与否。显微镜观察染色切片，无磨损的软骨切片表现为，关节软骨表层光滑、平整,软骨细胞分布均匀,无簇聚软骨细胞,潮线完整;番红O染色均匀,无失染现象。损伤处的关节软骨表面不平整、高低起伏、纹理紊乱，表层变薄；有大小不等的裂隙。根据形态学鉴定结果，将标本分为磨损组和无磨损组，进行下列指标的检测。
3.2关节软骨损伤与血管和神经侵入的关系
HE染色和CD34标志物免疫组化均显示，软骨磨损部位的切片，有血管突破潮线侵入软骨。在所检测的29例软骨磨损的标本切片中，有16例（55.2%）可观察到侵入软骨的血管；同一标本用扫描电镜也观察到在损伤软骨的近潮线处分布的血管，血管腔面的内皮结构和腔内双凹圆盘状的红细胞清晰可见，这更近一步印证了此管腔的性质。而在相应的无磨损的软骨区，仅有2例（2/17）发现有血管存在，占11.7%，出现新生血管的频率明显低于磨损组，两组之间具有显著性差异(P＜0.05)。表明血管侵入数量与软骨磨损程度成正相关。
为了确定磨损软骨中是否有神经侵入，本实验采用感觉神经特异性标志物PGP9.5抗体进行免疫组化染色。在磨损组有新生血管形成的软骨标本中检出数量稀少的神经纤维，且靠近增生的血管，而磨损组无血管侵袭的标本以及无磨损组中均未发现神经纤维，PGP9.5染色为阴性。提示神经侵入可能滞后于血管生成。
3.3软骨退行性变与KLF5和MMP-9表达的关系
免疫组化染色显示，在无磨损处的软骨细胞内，可观察到极少量的KLF5和MMP-9阳性染色颗粒；而在关节软骨磨损部位簇集的软骨细胞中， KLF5、MMP-9的表达活性均明显升高，镜下可见密集分布的阳性染色棕色颗粒；在KLF5表达活性高的细胞中，其MMP-9的表达水平也相应升高，二者的变化趋势具有一致性。利用形态学Fig.像分析软件通过测定颗粒平均光密度值(IOD)，也证实磨损组的KLF5和MMP-9表达活性显著高于无磨损组，二者比较具有显著性差异（P＜0.05）。两种蛋白表达活性与血管侵袭数量具有正相关性。
3.4关节软骨胶原纤维结构变化
分别取磨损组和无磨损组的软骨标本（每组n=5），经处理后进行扫描电镜观察。无磨损的软骨表面较为光滑，切面可见排列整齐、均匀而密集的胶原纤维，方向与表面呈切线；磨损组软骨表面粗糙不平，浅坑和隆起相间；切面可见胶原纤维增粗、断裂、排列混乱，空隙增大，有软骨细胞分布其中。
结论：
1高能量创伤和粉碎性髌骨骨折容易导致膝关节交叉韧带损伤。
2Footscan步态分析技术所提供的足底压力峰值有助于髌骨骨折术后生物力学早期变化的诊断。
3增加的KLF5与MMP-9表达通过促进软骨降解而诱导关节软骨血管化。
Objectives: Firstly, the patellar is a component of the patellofemoral joint.Patellar fractures are commonly encountered in orthopedic practice and arewell reported in the literature. Approximately1%of all skeletal injuries arerelated to the patella, wheres transverse fractures are the most commonpatellar injury. Previous studies have shown that injuries to the cruciateligament in the knee are common in sports, as well as other activities. Inclinical treatment, the most common method of transverse patella fracturefixation is the tension band wiring technique. The aim of operative treatmentof transverse patella fractures is the anatomic reduction of the fracture parts toreconstruct the articular surface and extensor mechanism to regain full kneejoint function. Closed patellar fractures with a cruciate ligament injury arerarely reported, although the mechanisms of patellar fracture and cruciateliament injury are similar. However, high-energy or comminuted patellarfractures might occur in which the cruciate ligament may be injured ordisrupted. Surgeons often neglect whether the closed patellar fracture iscombined with a cruciate ligament injury, resulting in misdiagnosis andinappropriate treatment.
Patellar fracture account for1%of body fractures. Throughout history,various fixation methods are controversial. In recent years, the role of play inthe patella extensor process of gradually been kown advocate maximize theretention of the patella in order to facilitate future fuctional recovery. However,due to the special position of the patella and the patient's subjective desire, thecourse of treatment remains challenging.
With the development of surgical treatment of patellar fracture has beenmore widely recognized, the clinical efficacy of continuous improvement, butits existence is also of concern in the long-term complications, such as knee stiffness, traumatic arthritis. Therefore, wu should patellar fracture surgery inpatients with a more objective assessment of the efficacy, in order to adopt anappropriate conservative treatment or surgical intervention to stop the viciouscycle of pathological changes, maintenance of normal biomechanicalmechanism of the knee. Currently, the gait analysis system has been widelyused in foreign countries to prevent and surgical evaluation of various aspectsof lower limb disorders. Period from March2012to November2012in ourhospital open reduction and internal fixation treatment of27cases of unilateralpatellar fracture patients, the paper after3months in patients with gait analysis,measuring the plantar pressure in the regions peak, evaluate the value ofdynamic gait analysis techniques patellar fracture surgery in the efficacyevaluation.
Traumatic osteoarthritis(TOA) is characterized by progressive loss ofjoint articular cartilage and subchondral bone remodeling. Structural changesin the osteoarthritic articular cartilage include proteoglycan depletion,fissuring, and tidemark duplication. Blood vessels are absent in normal adultarticular cartilage, and invade from the subchondral bone into the calcifiedcartilage and breach the tidemark in TOA. Vascular invasion is also thought tobe important in osteophyte formation. However, the mechanism of articularcartilage degeneration and vascular invasion is incompletely understood.
The degradation of cartilage matrix is particular crucial for vascularinvasion. This step requires proteolytic breakdown by a variety of proteinases,among which members of the matrix metalloproteinase(MMP) family are ofspecial interest due to their ability to cleave collagens and aggrecan, the twoprincipal matrix components of cartilage. The products of catilage degradation,as biochemical markers, have diagnostic applicability in TOA. Recent studieshave shown that several MMPs are up-or down-regulated in osteoarthriticchondrocytes as compared with normal chondrocytes. Treatment with a MMPinhibitor inhibits joint damage and osteochondral angiogenesis in rats.Kruppel-like factor(KLF)5causes cartilage matrix degradation throughtranscriptional induction of MMP-9in mice. However, the expression of KLF5and MMP-9as well as the clinicopathololgical significance for thesealterations in the carilage degeneration of human knee TOA has not yet beenclarified.
We hypothesized that, in TOA, the expression of KLF5and MMP-9isassociated with cartilage degeneration, and is linked to vascular invasion. Thepresent study is the first to evaluate the association of the expression of KLF5and MMP-9with the severity of TOA cartilage change. Our results indicatethat high expression of KLF5and MMP-9may be involved in the articularcartilage degeneration in TOA patients, and that KLF5and MMP-9may benovel molecular targets for therapeutic intervention in TOA.
Methods: Firstly, full approval from the Research Ethics Committee andthe Research Governance Committee was received for the study. All thesubjects who participated in the study provided informed consent. Patientswere identified by Picture Archiving and Communication System for theperiod from March1to June30,2012. A total of sixty patients with patellarfracture who underwent open reduction and internal fixation were enrolled tothe study. Patients that were13to64years of age were included. The meanage of the patients was40.2years and48patients were men. Sixty patientshad unilateral patellar fracture and24patients had a left patellar fracture. Allpatients had their histories taken and were examined by the orthopedist withfellowship teraining in sports medicine, including Drawer test and Lachmantest. According to the cause of injury,31patients had low-energytrauma(tumbling injury) and29patients had had high-energy trauma(fallinginjury or motor vehicle). According to the fracture pattern, there were32cases of transverse fracture and28cases of comminuted fracture. In our seriesof patellar injuries, all60patients had an isolated and closed injury.
All images were read and interpreted by two fellowship-trainedmusculoskeletal radiologists who was blinded to the results of the clinicalassessment for each subject. Each scan diagnosed on the condition of thecrucaite ligament pathology. The cruciate ligament was assessed and classifiedas normal, partially torn, or completely ruptured. Patients with multiple fractures, or those who had total and partial patellectomy were excluded fromthe study.
Secondly, twenty-seven patients with unilateral patellar fracture treatedwith open reduction internal fixation (ORIF) were following up for evaluatingknee function based on patella injury efficacy score (Bostman). The dynamicgait analysis (Footscan, RsScan International, Belgium) was used to calculateand analyze mean peak pressure of seven anatomical areas including the firstto fifth metatarsal head, medial heel and lateral heel. The distributiondifference of peak pressures was compared between the healthy feet andinjured feet according to index.
Thirdly, approval was obtained from the Hebei Medical UniversityClinical Research Ethics Committee. After informed consent had been given,31tibiofemoral joints, including articular surfaces, joint capsule, andintra-articular structures, were collected from20patients that met clinicalsymptomatic criteria(American College of Rheumatology revised criteria forTOA) at the time of total knee joint replacement(TKR) surgery. In the presentstudy, we used joint samples from20patients(31knee joints,3male) with amedian age of68.4(range55-74) years. Each sample was sawn into2-3blocks(5mm×5mm×5mm), and categorized according to its grossmorphology, as either belonging to the severe change group(SC, n=29) ofcartilage, which was taken from the main defective area of maximal load, or tothe group with no observed change(NC, n=17), taken from areas with noobvious surface defects. All of the specimens were then verified by safranin Ostaining by two independent observers in a double-blind manner. Cartilagedamages were evaluated using the modified Janusz's system. Using thismethod, cartilage damage was scored on a scale of0-5. Score0representscartilage of normal appearance that shows uniform staining throughoutarticular cartilage, serving as a control(NC); and≥3, severe, differentdegrees of loss of staining in the superficial and middle zones(SC) assessed inthis study. Patients with other forms of arthritis or other clinical inflammatoryjoint disease were excluded.
All samples were fixed and preserved in10%neutral buffered formalinfor48-72h and subsequently decalcified for24-36h in10%EDTA-PBS. Theserial sections(6μm) were prepared, and were then routinely stained withhematoxylin and eosin(HE) and safranin O as described.
Results:
1. High-energy trauma often results in a comminuted patellar fracture, whichis often combined with cruciate ligament injury.
1.1Details of the seven patients with combined cruciate ligament injuries
MRI findings showede that there were seven cases of patellar fracturecombined with cruciate ligament injury. The mean age was45.7years(range,13-64years) and six patients were men. There were one case of a trumbleinjury, four cases of a motor vehicle accident and two cases of a fall injury.Three patients had a left patellar fracture. And six cases had a comminutedfracture. There were two cases of a completely ruptured posterior cruciateligament, two cases of a partially torn posterior cruciate ligament, and threecases of a partially torn anterior cruciate ligament. The percentage of patientswith these combined injuries was11.6%(7/60). Because of antagonistic andpainful knees, the diagnostic results of the two tests are not the same as MRI.In our seven patients with cruciate ligament injury, only five patients werepositive for the Drawer test and four were positive for the Lachman test.
1.2Comparision of different groups and combined injuries
Among seven patients with combined cruciate ligament injuries, therewas one case of low-energy trauma(3.1%,1/32) and six cases of high-energytrauma(21.4%,6/28). The incidence of a combined injury of the crucatieligament with high-energy trauma was significantly higher than that withlow-energy trauma(P＜0.05).Among the seven patients with combined injuries, one had a transversefracture(3.2%,1/31) and six had a comminuted fracture(20.7%,6/29). Theincidence of combined injuries in those with a comminuted fracture washigher than that in those with a transverse fracture(P＜0.05).
2. Footscan gait analysis may therefore be a useful tool for detecting the early change of biomechanics and can evaluate the recovery of the patellar fracture.
Follow-up lasted for6-15months (mean12months). In the group withsatisfaction(20cases), there showed no significant difference of sum of peakpressure between the healthy feet and injured feet (P＞0.05). And nosignificant difference was shown of plantar peak pressure distribution, expectthe fifth metatarsal head(P＜0.05). In the group with dissatisfaction(7cases),there also showed no significant difference of sum of peak pressure betweenthe healthy feet and injured feet (P＞0.05). But the obvious difference wasshown in the first, second, fourth, fifth metatarsal head and medial heel(P＜0.05).
3. The expression of KLF5and MMP-9may be involved in cartilagedegeneration, contribution to human TOA.
3.1The morphology of articular cartilage injury
All of the samples were divided into two groups, SC and NC by safraninO and HE staining, according to the damages of articular cartilages. Thecartilage surfaces in the SC group revealed more severe changes in structurecompared to samples of the NC group, which had smooth surfaces.
3.2Neurovascular invasion is associated with severity of cartilage damages inTOA
Blood vessels verfied by CD-34positve endothelium crossed multipletidemarks and entered the non-calcified cartilage, which were observed inboth SC and NC samples. However, the frequency of vascular invasion in theSC group(16/29,55.2%) was higher than that in NC samples(2/17,11.7%)(P＜0.05). Moreover, endothelial cells, fibrovascular tissue, perivascular cells,and red blood cells were also observed in vascular structures by scanningelectron microscopy. In the SC group, the articular surfaces with vascularinvasion in the cartilage revealed severe damages, as compared with thosewhere wessels were not detected.
PGP9.5-positive nerves were observed only in30%of samples of the SCgroup, and were always associated with blood vessels. Nerves were notobserved in the NC group.
3.3Cartilage degenberation is associated with expression of KLF5andMMP-9in TOA
The results of dual-immunofluorescent staining showed that theexpression of KLF5and MMP-9was significantly increased in chondrocytesseen in the severe change area of articular cartilage, and was co-localized inthe same cells. The chondrocytes expressing KLF5and MMP-9were mainlydistributed in the areas of the damaged articular surface. However, theexpression of the two proteins was hardly detected in articular cartilage fromthe NC group. The expression of KLF5and MMP-9was significantlydifferently between SC and NC samples(P＜0.05).
3.4Structure changes in articular cartilage collagen fibers
The fine structure of the articular cartilage and collagen fibers wasassessed by SEM. Collagen fibers in some areas of the articular surface of theNC group formed smooth and parallel waves. However, in damaged cartilage,the collagen fibers appear to have a smaller diameter and to be less tightlypacked and less highly organized than those seen in the superficial zone ofnormal articular cartilage in the NC group. Collagen fibers of the normalcartilage are scattered homogeneously and deeply in the matrix, while thefibers on the damaged articular cartilage are interrupted and disordered.
Conclusion:
1High-energy trauma often results in a comminuted patellar fracture,which is often combined with cruciate ligament injury.
2Footscan gait analysis may therefore be a useful tool for detecting theearly change of biomechanics and can evaluate the recovery of the patellarfracture.
3The expression of KLF5and MMP-9may be involved in cartilagedegeneration, contribution to human TOA.
引文
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