Cartilage Restoration of Bipolar Lesions Within the Patellofemoral Joint Delays Need for Arthroplasty: A Systematic Review of Rates of Failure.

PURPOSE: The purpose of the present review is to systematically review the available literature for failure rates and complications of cartilage restoration of bipolar chondral defects in the patellofemoral (PF) joint to assess the ability to treat these lesions without arthroplasty. METHODS: PubMed and MEDLINE databases were queried between 2000 to 2020 using the keywords "osteochondral" and "knee" and "microfracture," "autologous chondrocyte implantation (ACI)," or "transplantation." Patient selection included patients with bipolar chondral lesions of the patellofemoral joint that were treated with cartilage restoration procedures. Treatment of PF joints were reviewed for surgical indications/technique, rates of failure, defect characteristics, and time to failure. For the purposes of this study, failure was defined by each individual author on their respective studies. RESULTS: After screening 1,295 articles, there were 8 publications analyzed quantitatively and 10 articles analyzed both quantitatively and qualitatively. A total of 249 knees involved bipolar lesions of the patellofemoral joint. The weighted average age was 36.5 ± 10.4 years, and weighted average follow-up was 89.0 ± 31.7 months. There were failures in 0% to 50% of cases, revision procedures in 0% to 10% of cases, conversion to arthroplasty in in 0% to 50% of cases, and unsatisfactory outcome without revision in 0% to 8.3% of cases. The range in average failure rate was 0% to 50.0% (I2 = 68.0%), whereas the range in average time to failure was 2.9 to 6.8 years (I2 = 79.0%). CONCLUSION: From the available data, established cartilage restoration procedures may provide favorable patient-reported function, avoidance of secondary surgery, and joint preservation in at least 80% of patients at short- to mid-term follow-up. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Cartilage Restoration for Tibiofemoral Bipolar Lesions Results in Promising Failure Rates: A Systematic Review.

PURPOSE: The purpose of the present study is to systematically review the available literature for management of bipolar lesions within the tibiofemoral joint and determine whether tibiofemoral cartilage restoration is an effective treatment modality. METHODS: PubMed and MEDLINE databases were queried between 2000 and 2020 using the following keywords: "osteochondral" and "knee" and "microfracture," "autologous chondrocyte implantation (ACI)," or "transplantation." Articles were reviewed for the presence of a bipolar or "kissing" tibiofemoral lesion and reported lesion size, concomitant procedures, failure rates, and time to failure. RESULTS: After screening 1,295 articles, there were 4 articles available for analysis and a total of 152 knees involving the management of bipolar tibiofemoral lesions. Age ranged from 14 to 60 years, and mean follow-up was between 12 and 240 months. There was 1 retrospective cohort study (36 knees) and 3 case series (mean, 38.7 ± 17.5 knees). There were 58 knees treated with bipolar osteochondral allograft (OCA) transplantation, 58 knees treated with bipolar ACI, 20 knees treated with femoral OCA and tibial debridement, and 16 knees treated with femoral OCA and tibial microfracture. There were 37 failures (24.3%): 16 patients (10.5%) were converted to unicompartmental or total knee arthroplasty, 4 restorative procedures (2.6%) were revised, and 8 patients (1.6%) had unsatisfactory outcomes only. The remaining 15 failures (9.9%) had an unspecified combination of objective failure. The mean rate of failure ranged between 0% and 44.1% (I 2 = 83.2%). The mean time to failure ranged between 2.7 and 4.1 years (I 2 = 79.1%). CONCLUSIONS: Cartilage restoration, through both ACI and OCA, had failure rates between 0% and 44% in patients with bipolar lesions of the tibiofemoral compartment. Although a higher level of evidence is required to prove efficacy, the current study demonstrates midterm survivorship rates between 55% and 100%, which may delay the need for secondary arthroplasty. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Role of the Hypoxia-Inducible Factor Pathway in Normal and Osteoarthritic Meniscus and in Mice after Destabilization of the Medial Meniscus.

OBJECTIVE: Meniscus injury and the hypoxia-inducible factor (HIF) pathway are independently linked to osteoarthritis pathogenesis, but the role of the meniscus HIF pathway remains unclear. We sought to identify and evaluate HIF pathway response in normal and osteoarthritic meniscus and to examine the effects of Epas1 (HIF-2α) insufficiency in mice on early osteoarthritis development. METHODS: Normal and osteoarthritic human meniscus specimens were obtained and used for immunohistochemical evaluation and cell culture studies for the HIF pathway. Meniscus cells were treated with pro-inflammatory stimuli, including interleukins (IL)-1ß, IL-6, transforming growth factor (TGF)-α, and fibronectin fragments (FnF). Target genes were also evaluated with HIF-1α and HIF-2α (Epas1) overexpression and knockdown. Wild-type (n = 36) and Epas1+/- (n = 30) heterozygous mice underwent destabilization of the medial meniscus (DMM) surgery and were evaluated at 2 and 4 weeks postoperatively for osteoarthritis development using histology. RESULTS: HIF-1α and HIF-2α immunostaining and gene expression did not differ between normal and osteoarthritic meniscus. While pro-inflammatory stimulation significantly increased both catabolic and anabolic gene expression in the meniscus, HIF-1α and Epas1 expression levels were not significantly altered. Epas1 overexpression significantly increased Col2a1 expression. Both wild-type and Epas1+/- mice developed osteoarthritis following DMM surgery. There were no significant differences between genotypes at either time point. CONCLUSION: The HIF pathway is likely not responsible for osteoarthritic changes in the human meniscus. Additionally, Epas1 insufficiency does not protect against osteoarthritis development in the mouse at early time points after DMM surgery. The HIF pathway may be more important for protection against catabolic stress.

Impact of Clinical Presentation on Imaging Evaluation to Direct Effective Treatment Strategies.

A multitude of musculoskeletal disorders of the knee are commonly encountered in clinical practice. Ensuring an accurate diagnosis can be challenging. It is critical to establish a thoughtful and systematic approach to assessing the patient using history and physical exam followed by appropriate imaging studies. The physical exam may be complicated due to various test maneuvers designed to help make the diagnosis. It is also important to understand the limitations of each physical exam maneuver. When appropriate, imaging is obtained to help make the diagnosis and guide treatment. There are various imaging examinations to choose from when evaluating the knee, including X-rays, computed tomography, magnetic resonance imaging, and ultrasound. An algorithmic approach to choosing the best imaging study is often helpful to avoid unnecessary costs and burden to the patients. The combination of a thorough clinical assessment and appropriate imaging examinations will result in accurate diagnosis, which directs proper treatment.

Variability in Patellofemoral Alignment Measurements on MRI: Influence of Knee Position.

OBJECTIVE: The purpose of this study was to determine the variability of distances between four distinct anatomic landmarks used for the evaluation of patellofemoral alignment while implementing controlled changes in patient positioning during MRI. MATERIALS AND METHODS: Limited MRI was performed of 12 knees in healthy volunteers (10 men, two women; mean age, 28 years) with the knees in four different positions. The four landmarks used were TT (the most anterior point of the osseous tibial tubercle), TG (the nadir of the cartilaginous trochlear groove), PT (the center of the patellar tendon insertion on the tibia), and PCL (the medial border of the posterior cruciate ligament at its insertion along the posterior tibia). TT-TG, PT-TG, TT-PCL, and PT-PCL distances were measured on the MR images. Each distance was measured with the knee at maximum patient comfort (rest), full extension, 15° of flexion, and 30° of flexion. Linear mixed models with random intercepts were implemented to determine variability between measurements and knee position. RESULTS: In general, measurements based on anatomic landmark and knee position varied greatly. The greatest variability in different knee positions was seen in mean TT-TG and PT-TG distances ± SD (TT-TG: rest, 18.1 ± 7.9 mm; full extension, 17.3 ± 5.3 mm; 15° of flexion, 11.4 ± 5.7 mm; 30° of flexion, 11.7 ± 6.0 mm; intraclass correlation coefficient [ICC] = 0.539; PT-TG: rest, 18.1 ± 6.3 mm; full extension, 17.9 ± 4.7 mm; 15° of flexion, 13.2 ± 5.2 mm; 30° of flexion, 11.8 ± 4.3 mm; ICC = 0.633). In contrast, knee position did not significantly affect distances for TT-PCL and PT-PCL (TT-PCL: rest, 23.5 ± 6.8 mm; full extension, 20.5 ± 5.5 mm; 15° of flexion, 22.8 ± 6.2 mm; 30° of flexion, 22.8 ± 6.7 mm; ICC = 0.484; PTPCL: rest, 23.4 ± 5.3 mm; full extension, 21.5 ± 4.5 mm; 15° of flexion, 22.3 ± 4.3 mm; 30° of flexion, 23.1 ± 4.8 mm; ICC = 0.509). CONCLUSION: On MRI, TT-PCL and PT-PCL measurements have significantly less variability compared with TT-TG and PT-TG measurements, regardless of knee position. Although further studies are warranted, the use of TT-PCL and PT-PCL measurements may offer more reliable assessment of tibial tubercle lateralization and patellofemoral alignment.

Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice.

OBJECTIVE: To better understand the contribution of age to the development of osteoarthritis (OA). METHODS: Surgical destabilization of the medial meniscus (DMM) was used to model OA in 12-week-old and 12-month-old male C57BL/6 mice. OA severity was evaluated histologically. RNA used for microarray and real-time polymerase chain reaction analysis was isolated from joint tissue collected from the medial side of the joint, including cartilage, meniscus, subchondral bone, and the joint capsule with synovium. Computational analysis was used to identify patterns of gene expression, and immunohistochemistry was used to evaluate tissue distribution of selected proteins. RESULTS: OA was more severe in older mice than in young mice. Only 55 genes showed a similar expression with DMM-induced OA in the 2 age groups, while 493 genes showed differential expression, the majority having increased expression in older mice. Functional categories for similarly expressed genes included extracellular matrix- and cell adhesion-related genes; differentially expressed genes included those related to muscle structure and development and immune response genes. Comparison of expression in sham-operated control joints revealed an age-related decrease in matrix gene expression and an increase in immune and defense response gene expression. Interleukin-33 was present in multiple joint tissue cells, while CCL21 was more localized to chondrocytes and meniscal cells. Periostin was found in the extracellular matrix of cartilage and meniscus. CONCLUSION: Age affects both the basal pattern of gene expression in joint tissues and the response to surgically induced OA. Examining tissue from the joint beyond only cartilage revealed novel genes and proteins that would be important to consider in OA.

A Comprehensive Histological Assessment of Osteoarthritis Lesions in Mice.

OBJECTIVE: Accurate histological assessment of osteoarthritis (OA) is critical in studies evaluating the effects of interventions on disease severity. The purpose of the present study was to develop a histological grading scheme that comprehensively and quantitatively assesses changes in multiple tissues that are associated with OA of the stifle joint in mice. DESIGN: Two representative midcoronal sections from 158 stifle joints, including naturally occurring and surgically induced OA, were stained with H&E and Safranin-O stains. All slides were evaluated to characterize the changes present. A grading scheme that includes both measurements and semiquantitative scores was developed, and principal components analysis (PCA) was applied to the resulting data from the medial tibial plateaus. A subset of 30 tibial plateaus representing a wide range of severity was then evaluated by 4 observers. Reliability of the results was evaluated using intraclass correlation coefficients (ICCs) and area under the receiver operating characteristic (ROC) curve. RESULTS: Five factors were retained by PCA, accounting for 74% of the total variance. Interobserver and intraobserver reproducibilities for evaluations of articular cartilage and subchondral bone were acceptable. The articular cartilage integrity and chondrocyte viability factor scores were able to distinguish severe OA from normal, minimal, mild, and moderate disease. CONCLUSION: This newly developed grading scheme and resulting factors characterize a range of joint changes in mouse stifle joints that are associated with OA. Overall, the newly developed scheme is reliable and reproducible, characterizes changes in multiple tissues, and provides comprehensive information regarding a specific site in the stifle joint.

An acellular, allograft-derived meniscus scaffold in an ovine model.

PURPOSE: The purpose of this study was to develop a meniscus scaffold that has increased porosity and maintains the native meniscus extracellular matrix in an ovine model. METHODS: The medial menisci of skeletally mature ovine (n = 16) were harvested; half were made into meniscus scaffolds (n = 8), and half remained intact (n = 8). Intact and scaffold meniscus tissues were compared by use of histology, DNA content analysis, in vitro cellular biocompatibility assays, and ultrastructural analysis. An additional 16 knees were used to investigate the biomechanics of the intact meniscus compared with the meniscus scaffold. RESULTS: DNA content and histology showed a significant decrease in cellular and nuclear content in the meniscus scaffold (P < .003). Biocompatibility was supported through in vitro cellular assays. Scanning electron microscopy and micro-computed tomography showed a substantial increase in porosity and pore connectivity in the meniscus scaffold compared with the intact meniscus (P < .01). There was no statistical difference between the ultimate load or elastic modulus of the intact and meniscus scaffolds. CONCLUSIONS: In this study a meniscus scaffold was evaluated for potential clinical application as a meniscus transplant construct in an ovine model. The data showed that a decellularized meniscus scaffold with increased porosity was comparable to the intact meniscus, with an absence of in vitro cellular toxicity. Although some compositional alterations of the extracellular matrix are to be expected during processing, it is evident that many of the essential structural components remained functional with maintenance of biomechanical properties. CLINICAL RELEVANCE: This meniscus scaffold has potential for future clinical application as a meniscus transplant construct.

Freeze-dried allografts for anterior cruciate ligament reconstruction.

Freeze-dried allografts represent a viable and functional alternative to fresh-frozen allograft and autograft constructs. Compared with fresh-frozen allograft constructs, freeze-dried soft tissue allograft constructs have many advantages including limited immunogenicity, ease of graft storage, comparable mechanical properties of soft tissue constructs, and the potential for improved biologic incorporation. This article reviews the fundamental processing of freeze-dried allografts and summarizes the clinical and basic science studies supporting the safe and effective use of freeze-dried allograft constructs for anterior cruciate ligament reconstruction. It also discusses potential directions of future research on tissue-engineered anterior cruciate ligament constructs using freeze-dried tendon constructs.

Surgical treatment of chronic posteromedial instability using capsular procedures.

Patients with posteromedial corner injuries of the knee present a significant problem to the clinician. Often the symptoms of anteromedial rotatory instability may be overlooked due to concurrent anterior cruciate ligament and/or posterior cruciate ligament injuries. When addressing concurrent ligamentous injuries to the knee, the clinician may fail to isolate anteromedial rotatory instability on physical examination and imaging studies may not specifically identify damage to posteromedial corner structures. This unrecognized and untreated damage results in residual functional laxity and can potentially lead to chronic and progressive instability of the knee. This paper contains descriptions of 2 surgical techniques that address posteromedial instability. Both techniques require an understanding of posteromedial corner knee anatomy, careful preoperative planning, and extensive postoperative rehabilitation.

Future treatment of osteoarthritis.

Osteoarthritis represents an advanced stage of disease progression caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and noninflammatory pathways. The burden of this disease will increase in direct proportion to the increase in the older adult population. Research on current and experimental treatment protocols are reviewed, including the effect of hyaluronic acid in both in vitro and in vivo studies, autologous chondrocyte and osteochondral plug implantation, and gene therapy. Disease-modifying osteoarthritis drugs and in vivo studies of glucosamine and chondroitin sulfate are reviewed.

Transforming growth factor-beta1 induced alteration of skeletal morphogenesis in vivo.

Transforming growth factor beta (TGF-beta) is expressed in the growth plate and is an important regulator of chondrocyte maturation. Loss of function results in premature chondrocyte maturation both in vitro and in vivo. While TGF-beta inhibits chondrocyte maturation in cell cultures, the effect of increased TGF-beta has not been well characterized in an in vivo development model. Addition of Affi-gel agarose beads loaded with TGF-beta1 (10 ng/microl) to developing stage 24-25 chick limb buds resulted in limb shortening and altered morphology. In situ hybridization studies showed down regulation of Indian hedgehog (ihh), bone morphogenetic protein 6 (bmp6), and collagen type X (colX) expression, markers of chondrocyte maturation, in TGF-beta1 treated limbs. TGF-beta1 also decreased chondrocyte proliferation in the developing anlage. The findings confirm a critical role for TGF-beta during skeletal development. A more complete understanding of the role of TGF-beta and its down-stream signals will lead to improved understanding and treatment of cartilage diseases.

A role for the BMP antagonist chordin in endochondral ossification.

Bone morphogenetic proteins (BMPs) are ubiquitous regulators of cellular growth and differentiation. A variety of processes modulate BMP activity, including negative regulation by several distinct binding proteins. One such BMP antagonist chordin has a role in axis determination and neural induction in the early embryo. In this study, a role for chordin during endochondral ossification has been investigated. During limb development, Chordin expression was detected only at the distal ends of the skeletal elements. In cultured embryonic sternal chondrocytes, Chordin expression was related inversely to the stages of maturation. Further, treating cultured chondrocytes with chordin interfered with maturation induced by treatment with BMP-2. These results suggest that chordin may negatively regulate chondrocyte maturation and limb growth in vivo. To address this hypothesis, chordin protein was expressed ectopically in Hamburger-Hamilton (HH) stage 25-27 embryonic chick limbs. The phenotypic changes and alteration of gene expression in treated limbs revealed that overexpression of chordin protein delayed chondrocyte maturation in developing skeletal elements. In summary, these findings strongly support a role for chordin as a negative regulator of endochondral ossification.