Chondral and osteochondral injuries: mechanisms of injury and repair responses

Acute and repetitive impact and torsional loading of joints can damage the articular surface, causing pain, joint dysfunction and effusions, and in some instances, progressive joint degeneration. These injuries often remain undetected and their incidence, pathogenesis, natural history, and optimal treatment remain poorly understood. Advances in arthroscopy and joint imaging have improved the ability of physicians to identify articular surface injuries, and reports of new methods of promoting restoration of articular surfaces have increased interest in their treatment. Three classes of chondral and osteochondral injuries can be identified based on the type of tissue damage and the repair response: (1) damage to the joint surface that does not cause visible mechanical disruption of the articular surface but does cause chondral damage and may cause subchondral bone injury, (2) mechanical disruption of the articular surface limited to articular cartilage, and (3) mechanical disruption of articular cartilage and subchondral bone. In most instances joints can repair damage that does not disrupt the articular surface if they are protected from further injury. Mechanical disruption of articular cartilage stimulates chondrocyte synthetic activity, but it rarely results in repair of the injury. Disruption of subchondral bone stimulates chondral and bony repair, but it rarely restores an articular surface that duplicates the biological and mechanical properties of normal articular cartilage. The extent and effectiveness of the chondral and osseous repair responses vary with age: in general younger individuals, especially skeletally immature people, have more effective repair of articular surface injuries. To be of value to patients a treatment of an articular surface injury must produce better short- and long-term results than the natural repair response. Thus, before selecting a treatment for a patient with a chondral or osteochondral injury the surgeon should define the type of injury and understand its likely natural history.     

Epidemiologie, Anatomie, Biomechanik und Bildgebung von Akromioklavikulargelenkverletzungen

Current techniques of acromioclavicular (AC) joint repair primarily focus on the reconstruction of the coracoclavicular (CC) ligaments. However, it is not clear if this approach is sufficient to restore vertical as well as horizontal AC joint stability and kinematics. This review focuses on the epidemiology of AC joint injuries and the coincidence of intra-articular pathologies. Furthermore, the clinically relevant anatomy and the pathomechanism of AC joint instability are described. The biomechanical characteristics of current procedures as they have been revealed by in vitro investigations are summarized. As a basic result, neither selective repair of the CC ligaments nor selective repair of the AC ligaments could be shown to restore both vertical and horizontal joint stability. Similar to the intact ligaments CC repair primarily provides vertical joint stability while AC repair is able to restore horizontal stability. In conclusion a biomechanically effective treatment of AC joint separation should analyze the individual instability pattern in the first step. Therefore, the radiological standard according to Rockwood should be supplemented by specific stress x-rays for quantification of dynamic horizontal AC joint instability. In the second step an adequate surgical treatment considering CC and AC stabilization should be performed meeting the individual patient requirements.     

Biomechanik aktueller Rekonstruktionstechniken bei Schultereckgelenksprengungen

Current techniques for acromioclavicular (AC) joint repair primarily focus on the reconstruction of the coracoclavicular (CC) ligaments. However, it is unclear whether this approach is sufficient to restore vertical as well as horizontal AC joint stability and kinematics. Therefore, this review summarizes the biomechanical characteristics of current procedures as they have been revealed by in vitro investigations. As a basic result, neither selective repairs of the CC ligaments nor selective repairs of the AC ligaments could be shown to restore both vertical and horizontal joint stability. Similar to the intact ligaments, CC repair primarily provides vertical joint stability, while AC repair is able to restore horizontal stability. Thereby, the lack of horizontal stability of the CC repairs could not be compensated using tendon grafts, double-bundle techniques, and flip-button fixation. In conclusion, a biomechanical effective treatment of AC joint separation should analyze the individual instability pattern in the first step. In the second step, an adequate surgical treatment considering CC and AC stabilization should be performed meeting the individual demands.     

Mechanical stimulation of mesenchymal stem cells: Implications for cartilage tissue engineering

Articular cartilage is a load‐bearing tissue playing a crucial mechanical role in diarthrodial joints, facilitating joint articulation, and minimizing wear. The significance of biomechanical stimuli in the development of cartilage and maintenance of chondrocyte phenotype in adult tissues has been well documented. Furthermore, dysregulated loading is associated with cartilage pathology highlighting the importance of mechanical cues in cartilage homeostasis. The repair of damaged articular cartilage resulting from trauma or degenerative joint disease poses a major challenge due to a low intrinsic capacity of cartilage for self‐renewal, attributable to its avascular nature. Bone marrow‐derived mesenchymal stem cells (MSCs) are considered a promising cell type for cartilage replacement strategies due to their chondrogenic differentiation potential. Chondrogenesis of MSCs is influenced not only by biological factors but also by the environment itself, and various efforts to date have focused on harnessing biomechanics to enhance chondrogenic differentiation of MSCs. Furthermore, recapitulating mechanical cues associated with cartilage development and homeostasis in vivo, may facilitate the development of a cellular phenotype resembling native articular cartilage. The goal of this review is to summarize current literature examining the effect of mechanical cues on cartilage homeostasis, disease, and MSC chondrogenesis. The role of biological factors produced by MSCs in response to mechanical loading will also be examined. An in‐depth understanding of the impact of mechanical stimulation on the chondrogenic differentiation of MSCs in terms of endogenous bioactive factor production and signaling pathways involved, may identify therapeutic targets and facilitate the development of more robust strategies for cartilage replacement using MSCs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:52–63, 2018.     

兔自体松质骨颗粒修复关节软骨损伤

目的研究兔自体松质骨颗粒在膝关节软骨损伤处移植后能够诱导软骨组织生成、促进关节软骨损伤修复的现象。方法 12只新西兰大白兔麻醉后在兔的右侧膝关节股骨远端内、外侧髁负重区用电钻分别造成直径、深度均为3 mm的骨软骨缺损创面,取同侧髂骨松质骨,制成直径约为1 mm松质骨颗粒植入股骨内侧髁软骨缺损处,作为实验组,外侧髁软骨缺损不做处理作为对照组。术后12周进行膝关节大体观察、病理切片染色,评估关节软骨损伤的修复情况。结果兔膝关节实验组软骨缺损处被新生软骨填充,软骨面光滑,组织切片染色显示有关节软骨形成。对照组缺损创面仍然凹陷,仅在缺损边缘有少量软骨生长。结论兔自体松质骨颗粒在膝关节软骨损伤处能够诱导软骨生成,促进关节软骨的修复,是一种良好的关节软骨损伤修复方法。     

Minced cartilage without cell culture serves as an effective intraoperative cell source for cartilage repair.

Traumatic articular cartilage injuries heal poorly and may predispose patients to the early onset of osteoarthritis. One current treatment relies on surgical delivery of autologous chondrocytes that are prepared, prior to implantation, through ex vivo cell expansion of cartilage biopsy cells. The requirement for cell expansion, however, is both complex and expensive and has proven to be a major hurdle in achieving a widespread adoption of the treatment. This study presents evidence that autologous chondrocyte implantation can be delivered without requiring ex vivo cell expansion. The proposed improvement relies on mechanical fragmentation of cartilage tissue sufficient to mobilize embedded chondrocytes via increased tissue surface area. Our outgrowth study, which was used to demonstrate chondrocyte migration and growth, indicated that fragmented cartilage tissue is a rich source for chondrocyte redistribution. The chondrocytes outgrown into 3-D scaffolds also formed cartilage-like tissue when implanted in SCID mice. Direct treatment of full-thickness chondral defects in goats using cartilage fragments on a resorbable scaffold produced hyaline-like repair tissue at 6 months. Thus, delivery of chondrocytes in the form of cartilage tissue fragments in conjunction with appropriate polymeric scaffolds provides a novel intraoperative approach for cell-based cartilage repair.     

不同应力环境对兔骨髓间充质干细胞修复关节软骨缺损的影响

目的探讨不同应力环境对骨髓间充质干细胞(MSCs)修复关节软骨缺损的影响. 方法将日本大耳白兔15只制成髌骨外侧脱位动物模型,平均分成3组,每组5只:即单纯载体脱位组(对照组)、移植物正常应力组及移植物脱位组.对兔MSCs进行分离、培养,以兔MSCs为种子细胞构建自体组织工程移植物修复关节软骨缺损.6周后处死动物,观察修复组织的成分和结构. 结果术后6周,移植物正常应力组修复组织浅层为软骨组织,甲苯胺蓝染色接近正常关节软骨;深层为软骨下骨,与正常关节软骨结构相似.移植物脱位组为骨组织所修复,缺损周围的正常关节软骨变薄,软骨下血管侵入正常关节软骨内,遗留在股骨髁滑车槽内的移植物在滑车槽正常关节软骨表面形成新生类透明软骨组织.单纯载体脱位组为纤维组织修复. 结论 MSCs修复关节软骨缺损,只有在正常应力状态下修复效果最佳;提示维持负重关节正常的应力刺激,对组织工程软骨修复组织的形成和维持必不可少.     

Biomechanical properties of mixtures of blood and synovial fluid

Synovial fluid (SF) is a viscous ultrafiltrate of plasma that lubricates articulating joint motion. During acute trauma and certain cartilage repair procedures, blood is introduced into the joint and mixes with variable amounts of SF. The hypothesis of this study was that the dilution of blood with SF alters the rheological properties of the blood and the mechanical properties of the clot formed. The objectives were to determine the composition (solid fraction, protein content), coagulation (fibrin polymerization time, torsional strength), and mechanical (stiffness, permeability) properties of mixtures of blood with 10% or 50%SF. While the initial stages of coagulation of blood were not markedly affected by the presence of the SF, dilution with SF altered the coagulation torque profile over time, decreased the final clot structure mechanical stiffness (42–90% decrease), and increased the fluid permeability of the clots (41‐ to 468‐fold). Compared to diluting blood with PBS, SF had a smaller effect on the mechanical properties of the clot, possibly due to the presence of high molecular weight hyaluronan. These properties of blood/SF mixtures may facilitate an understanding of the repair environment in the joint and of mechanisms of cartilage repair. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:240–246, 2011     

Mechanical stimulation alters tissue differentiation and molecular expression during bone healing

Further understanding of how mechanical cues modulate skeletal tissue differentiation can identify potential means of enhancing repair following injury or disease. Prior studies examined the effects of mechanical loading on osteogenesis, chondrogenesis, and fibrogenesis in an effort to enhance bony union. However, exploring how mechanical stimuli can divert the bone healing process towards formation of other mesenchymal tissues, as an endpoint, may elucidate new avenues for repair and regeneration of tissues such as cartilage and fibrous tissue. This study investigated the use of mechanical stimulation to promote cartilage rather than bone formation within an osteotomy. Our overall goal was to define skeletal tissue distribution and molecular expression patterns induced by the stimulation. Retired breeder Sprague‐Dawley rats (n = 85) underwent production of a mid‐diaphyseal, transverse femoral osteotomy followed by external fixation. Beginning on postoperative day 10 and continuing for 1, 2, or 4 weeks, a cyclic bending motion (+35°/?25° at 1 Hz) was applied in the sagittal plane for 15 min/day for 5 consecutive days/week. Control animals experienced continuous rigid fixation. Histological and molecular analyses indicated that stimulation substantially altered normal bone healing. Stimulated specimens exhibited an increase in cartilage volume over time, while control specimens demonstrated bony bridging. Stimulation induced upregulation of cartilage‐related genes (COL2A1 and COL10A1) and downregulation of bone morphogenetic proteins (BMPs) ‐4, ‐6 and ‐7. However, BMP‐3 was upregulated with stimulation. These findings illustrate that mechanical cues can selectively modulate osteogenesis and chondrogenesis in vivo, and suggest a potential basis for treatment regimens for injured or diseased cartilaginous tissues. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res     

Chondrocyte transplantation

The transplantation of chondrocytes as a treatment to repair defects and degeneration in hyaline articular cartilage is being tested in numerous laboratory and clinical settings. This has included transplanting chondrocytes grown in tissue culture that were procured from non-weight-bearing areas of the affected joint to transplanting allografts with living chondrocytes in their intact cartilaginous matrix. Reported success with transplanting host and donor chondrocytes has varied and widespread application of these techniques still awaits more definitive studies. The clinician needs more evidence that the transplanted chondrocytes maintain their viability and that they synthesize the appropriate extracellular matrix. This new matrix needs to reproduce the functional, mechanical, and long-term wear properties of the native articular cartilage. Chondrocyte transplantation also merits further monitoring for possible delayed immunogenicity or for any signs of neoplastic potential. This exciting technology and its potential application to damaged and degenerated articular cartilage remains a stimulus to encourage further scientific work. Duplicating the unique and complex interrelations of the chondrocytes, matrix, and various bioactive factors is still some years away from general patient care.     

Die Akromioklavikulargelenkzyste

The acromioclavicular (AC) joint cyst is a rare sequela of complete supraspinatus tendon rupture and arthritis of the AC joint. It appears as a swelling on the AC joint and must be distinguished from tumours of the shoulder and neck region. Besides physical examination, magnetic resonance imaging is the most useful tool for correct diagnosis. As reported in the literature, therapeutic procedures include observation, aspiration, excision of the cyst with or without resection of the AC joint, and repair of the underlying supraspinatus tendon rupture. All procedures should be based on consideration of the comorbidity and recurrence of the cyst. Combinations of cyst excision and rotator cuff repair or AC resection seem to be the most promising therapeutic options. We report on a 75-year-old patient with a painless swelling over the AC joint who had suffered shoulder trauma 15 years previously.     

Osteochondritis dissecans of the talus treated by the transplantation of tissue-engineered cartilage

Management of osteochondral lesions of the joint has been difficult, because articular cartilage has a poor healing capacity as a result of its lack of vessels, nerve supply, and its isolation of systemic regulation. Although a lot of basic research and surgical treatments for cartilage repair have focused on osteochondral lesions in the knee joint, orthopedic surgeons have recently diverted their attention to osteochondral lesions in the ankle joint, partly because of the widespread introduction of arthroscopy in ankle surgery. There have been many attempts to treat articular cartilage defects in the ankle joint as well as in the knee joint. However, no treatment has achieved efficient healing with hyaline cartilage. Recently, tissue engineering technique for cartilage repair has been gaining much attention in the orthopedic field. In this study, we reported on a patient with osteochondritis dissecans of the talar dome, successfully treated by transplantation of tissue-engineered cartilage made ex vivo using atelocollagen gel and low tibial osteotomy.     

Tissue engineering‐based cartilage repair with mesenchymal stem cells in a porcine model

This in vivo pilot study explored the use of mesenchymal stem cell (MSC) containing tissue engineering constructs in repair of osteochondral defects. Osteochondral defects were created in the medial condyles of both knees of 16 miniature pigs. One joint received a cell/collagen tissue engineering construct with or without pretreatment with transforming growth factor β (TGF‐β) and the other joint from the same pig received no treatment or the gel scaffold only. Six months after surgery, in knees with no treatment, all defects showed contracted craters; in those treated with the gel scaffold alone, six showed a smooth gross surface, one a hypertrophic surface, and one a contracted crater; in those with undifferentiated MSCs, five defects had smooth, fully repaired surfaces or partially repaired surfaces, and one defect poor repair; in those with TGF‐β‐induced differentiated MSCs, seven defects had smooth, fully repaired surfaces or partially repaired surfaces, and three defects showed poor repair. In Pineda score grading, the group with undifferentiated MSC, but not the group with TGF‐β‐induced differentiated MSCs, had significantly lower subchondral, cell morphology, and total scores than the groups with no or gel‐only treatment. The compressive stiffness was larger in cartilage without surgical treatment than the treated area within each group. In conclusion, this preliminary pilot study suggests that using undifferentiated MSCs might be a better approach than using TGF‐β‐induced differentiated MSCs for in vivo tissue engineered treatment of osteochondral defects. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1874–1880, 2011     

Comparison of osmotic swelling influences on meniscal fibrocartilage and articular cartilage tissue mechanics in compression and shear

Although the contribution of the circumferential collagen bundles to the anisotropic tensile stiffness of meniscal tissue has been well described, the implications of interactions between tissue components for other mechanical properties have not been as widely examined. This study compared the effects of the proteoglycan‐associated osmotic swelling stress on meniscal fibrocartilage and articular cartilage (AC) mechanics by manipulating the osmotic environment and tissue compressive offset. Cylindrical samples were obtained from the menisci and AC of bovine stifles, equilibrated in phosphate‐buffered saline solutions ranging from 0.1× to 10×, and tested in oscillatory torsional shear and unconfined compression. Biochemical analysis indicated that treatments and testing did not substantially alter tissue composition. Mechanical testing revealed tissue‐specific responses to both increasing compressive offset and decreasing bath salinity. Most notably, reduced salinity dramatically increased the shear modulus of both axially and circumferentially oriented meniscal tissue explants to a much greater extent than for cartilage samples. Combined with previous studies, these findings suggest that meniscal proteoglycans have a distinct structural role, stabilizing, and stiffening the matrix surrounding the primary circumferential collagen bundles. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:95–102, 2012     

非诱导脂肪源性干细胞对修复全层透明软骨创伤的可行性研究

目的探讨源自分布广泛的脂肪组织的干细胞的体内分化潜能及非诱导修复全层透明软骨缺损的效果。方法体外切取脂肪组织并分离培养脂肪源性干细胞（ADSCs）。随机将36只新西兰大白兔分为三组,混合有藻酸钙凝胶的ADSCs用来填充髌股关节的全层透明软骨损伤,凝胶修复或未做治疗组作为对照组。4周和12周后对重建组织进行大体和光镜、电镜下观察,组织学分析和定量计分也用于检测结果。结果ADSCs重建的组织白色质韧,完全充填缺损处,表面光整与周围软骨连接,修复组织的微观结构与软骨相似,含有更多的细胞和规则的基质纤维,基质有甲苯胺蓝异染性,优于其他各组。透射电镜可见大量胶原纤维环绕细胞周围。凝胶组和对照组修复组织为薄层纤维组织。修复效果评分的统计分析显示实验组在各时问点上与其他组相比有统计学差异（P〈0.01。结论这些结果表明源自成熟脂肪而未经诱导的干细胞拥有修复软骨创伤的能力,组织显示为透明样,产生生物学可行性结果。     

Inhibition of integrative repair of the meniscus following acute exposure to interleukin‐1 in vitro

Damage or loss of the meniscus is associated with progressive osteoarthritic degeneration of the knee joint. Injured and degenerative joints are characterized by elevated levels of the pro‐inflammatory cytokine interleukin‐1 (IL‐1), which with prolonged exposure can induce catabolic and anti‐anabolic activities that inhibit tissue repair. We used an in vitro model system to examine the hypotheses that acute exposure to IL‐1 inhibits meniscal repair, and that an IL‐1–mediated increase in matrix metalloproteinase (MMP) activity is associated with the inhibition of repair. Integrative tissue repair was studied between concentric explants of porcine medial menisci that were treated with IL‐1α acutely (100 pg/mL for 1 or 3 days) or chronically (100 pg/mL for entire culture duration). After 14 and 28 days in culture, biomechanical testing, cell viability, and histology were performed to assess meniscal repair. Total specific MMP activity in the culture media was measured using a quenched fluorescent substrate. As little as 1 day of IL‐1 exposure significantly reduced shear strength, cell accumulation, and tissue repair compared to controls. IL‐1 exposure for 1 or 3 days significantly increased MMP activity that subsided by day 9. With chronic IL‐1 exposure, MMP activity remained elevated for the duration of culture and was negatively correlated with repair strength. Our study shows that short‐term exposure to physiologically relevant concentrations of IL‐1 significantly reduces meniscal repair in vitro, and thus may potentially inhibit the intrinsic repair response in vivo. The suppression of IL‐1 or MMP expression and/or activity warrant investigation as potential strategies for promoting meniscal repair. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:504–512, 2008     

Artificial articular cartilage: mechanoelectrical transduction under dynamic compressive loading

The search for biomaterials to be used as an artificial articular cartilage in joint restoration is a challenging research area. Because the articular cartilage plays a fundamental role in joint function, the biomaterial has to be able to mimic the behavior of the natural healthy surface. Articular cartilage is a biphasic material composed by a solid extracellular matrix and a fluid phase, the synovial fluid. When the tissue is pressed, there is a mechanoelectrical transduction that is believed to modulate the cellular activity of chondrocytes, being fundamental for tissue repair. This work aimed at the development of hydrogels for use as an artificial articular cartilage. Hydrogels with negative groups fixed in the macromolecular network were obtained by copolymerizing 2-hydroxyethyl methacrylate with acrylic acid. The obtained hydrogels showed a mechanoelectrical transduction under dynamic compressive loading with potential amplitude increasing with fixed charge density values.     

Cartilage repair: A review of Stanmore experience in the treatment of osteochondral defects in the knee with various surgical techniques

Articular cartilage damage in the young adult knee, if left untreated, it may proceed to degenerative osteoarthritis and is a serious cause of disability and loss of function. Surgical cartilage repair of an osteochondral defect can give the patient significant relief from symptoms and preserve the functional life of the joint. Several techniques including bone marrow stimulation, cartilage tissue based therapy, cartilage cell seeded therapies and osteotomies have been described in the literature with varying results. Established techniques rely mainly on the formation of fibro-cartilage, which has been shown to degenerate over time due to shear forces. The implantation of autologous cultured chondrocytes into an osteochondral defect, may replace damaged cartilage with hyaline or hyaline-like cartilage. This clinical review assesses current surgical techniques and makes recommendations on the most appropriate method of cartilage repair when managing symptomatic osteochondral defects of the knee. We also discuss the experience with the technique of autologous chondrocyte implantation at our institution over the past 11 years.     

不同手术方式对关节软骨影响的实验研究

[目的]了解3种不同手术方式对活体关节软骨的影响。[方法]用光镜、扫描电镜及生物化学方法观察3种手术后不同时点兔膝关节软骨的结构及基质蛋白多糖的变化。[结果]3种手术对关节软骨都会造成损伤，使蛋白多糖的含量降低，暴露组造成不可逆性损伤，保护组和灌注组造成可逆性损伤，灌注组软骨损伤最轻、恢复最快。[结论]3种关节手术均会造成关节软骨损伤，关节灌注组的影响最小。     

生物力学在关节软骨修复中的作用

活动关节软骨是无血管的透明软骨,损伤后修复困难。传统的修复方式以手术为主,但修复的软骨组织常常无法满足透明软骨的结构条件。软骨组织工程是修复关节软骨的又一途径,在过去几十年,研究者们除了关注"细胞、支架、生长因子"3要素,也开始关注力学条件对构建组织工程软骨的作用。活动关节有复杂的力学性能,关节软骨、软骨基质和其中的细胞都受到不同强度、频率和不同方向的力学刺激,从而影响其功能和结构。在构建组织工程软骨的过程中,添加了力学刺激对软骨细胞的功能、间充质细胞的分化都有重要作用。何种力学条件最有利于构建具有类似天然透明软骨结构和功能的组织工程软骨是该研究领域的热点。