Potential of Exosomes for Diagnosis and Treatment of Joint Disease: Towards a Point-of-Care Therapy for Osteoarthritis of the Knee

In the knee joint, articular cartilage injury can often lead to osteoarthritis of the knee (OAK). Currently, no point-of-care treatment can completely address OAK symptoms and regenerate articular cartilage to restore original functions. While various cell-based therapies are being developed to address OAK, exosomes containing various components derived from their cells of origin have attracted attention as a cell-free alternative. The potential for exosomes as a novel point-of-care treatment for OAK has been studied extensively, especially in the context of intra-articular treatments. Specific exosomal microRNAs have been identified as possibly effective in treating cartilage defects. Additionally, exosomes have been studied as biomarkers through their differences in body fluid composition between joint disease patients and healthy subjects. Exosomes themselves can be utilized as a drug delivery system through their manipulation and encapsulation of specific contents to be delivered to specific cells. Through the combination of exosomes with tissue engineering, novel sustained release drug delivery systems are being developed. On the other hand, many of the functions and activities of exosomes are unknown and challenges remain for clinical applications. In this review, the possibilities of intra-articular treatments utilizing exosomes and the challenges in using exosomes in therapy are discussed.

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A CURRENT REVIEW ON THE BIOLOGY AND TREATMENT OF ARTICULAR CARTILAGE DEFECTS (PART I & PART II)

Journal of Musculoskeletal Research ◽

10.1142/s0218957703001125 ◽

2003 ◽

Vol 07 (03n04) ◽

pp. 157-181 ◽

Cited By ~ 23

Author(s):

Craig Willers ◽

David J. Wood ◽

Ming H. Zheng

Keyword(s):

Articular Cartilage ◽

Subchondral Bone ◽

18Th Century ◽

Later Life ◽

Fibrin Clot ◽

Joint Disease ◽

Cartilage Defects ◽

Adult Males ◽

Chondrocyte Implantation ◽

Osteochondral Injury

Osteochondral injury occurs predominantly in physically active young adult males. Injury to the articular cartilage and/or subchondral bone may not only cause acute joint disease resulting in osseous intracapsular (synovitis) or extracapsular pain, but may also act to spawn arthritic conditions in later life. Since the 18th century, such injury has proven difficult to treat clinically, and much therapy has been essentially palliative. Past treatments such as abrasion arthroplasty, drilling, microfracture and arthroscopic lavage have been useful in removing articular debris and promoting the formation of the fibrin clot used in most native repair mechanisms. However, the limitation of these techniques is their inability to restore the damaged cartilage and subchondral bone to their normal tissue architecture. Recent developments in tissue engineering have concentrated on the utilization of autologous chondrocyte implantation, biomaterials and growth factors to promote the regeneration of biomechanically superior hyaline articular cartilage. This paper reviews the etiology, repair biology and therapeutic techniques of cartilage and/or osteochondral injury over the previous decades, and attempts to provide insight into interesting new research directions which offer much potential for improved treatment of these troublesome lesions.

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How Well Does MRI Predict Chondral Lesions in Patients with Femoroacetabular Impingement? An Analysis of 545 Cases (137)

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967121s00276 ◽

2021 ◽

Vol 9 (10_suppl5) ◽

pp. 2325967121S0027

Author(s):

Mia Hagen ◽

William Hannay ◽

Quinn Saluan ◽

T. Sean Lynch ◽

Robert Westermann ◽

...

Keyword(s):

Articular Cartilage ◽

Femoroacetabular Impingement ◽

Hip Arthroscopy ◽

Multivariate Logistic Regression Analysis ◽

Cartilage Injury ◽

Cartilage Defects ◽

Mri Findings ◽

Femoroacetabular Impingement Syndrome ◽

Articular Cartilage Injury ◽

Grade Iii

Objectives: Articular cartilage injury has been identified as a risk factor for poor outcomes following hip arthroscopy for femoroacetabular impingement syndrome (FAI). The purpose of this study was to evaluate the efficacy of magnetic resonance imaging (MRI) in detecting cartilage defects, and to identify specific MRI findings associated with cartilage injury. Methods: All patients undergoing hip arthroscopy between February 2015 and May 2017 at one institution were enrolled in a prospective cohort. Intra-articular findings were documented at the time of surgery. MRI reports were retrospectively reviewed for radiologist-reported articular cartilage, osseous or synovial abnormalities. Sensitivity and specificity of MRI findings were calculated; multivariate logistic regression analysis determined which findings were associated with high-grade chondral damage at time of arthroscopy and used to create an online risk calculator, https://orthop.washington.edu/hiprisk/. Results: Out of a total of 598 patients who underwent hip arthroscopy, 550 had MRI reports available for review (92%). Grade III and IV cartilage injuries were reported on arthroscopy in 70 patients (13%) of average age 33 ± 13 years. On univariate analyses, individual MRI findings were not found to be sensitive in detection of articular cartilage injury (mean 22%, range 1.4% – 46%), but positive findings were highly specific (mean 90%, range 76% – 99%). Multivariate analysis revealed that older age (OR 1.09 [1.06-1.11], p < .001) and osseous findings such as subchondral cyst or edema (OR 4.77 [2.51-9.05], p <.001) were most predictive of grade III and IV defects (p < .001). An example of use of the online calculator is in Figure 1. Conclusions: MRI was a specific but not sensitive tool in diagnosing articular cartilage injury. Surgeons should be aware that osseous findings such as cysts or edema are highly predictive of full-thickness cartilage loss in FAI.

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Vitrification of Intact Porcine Femoral Condyle Allografts Using an Optimized Approach

Cartilage ◽

10.1177/1947603520967077 ◽

2020 ◽

pp. 194760352096707

Author(s):

Kezhou Wu ◽

Leila Laouar ◽

Janet A. W. Elliott ◽

Nadr M. Jomha

Keyword(s):

Articular Cartilage ◽

Femoral Condyle ◽

Membrane Integrity ◽

Cartilage Defects ◽

Chondrocyte Viability ◽

Cell Membrane Integrity ◽

A Cell ◽

Vitrification Solution ◽

Femoral Condyles ◽

Osteochondral Allografts

Objective Successful preservation of articular cartilage will increase the availability of osteochondral allografts to treat articular cartilage defects. We compared the effects of 2 methods for storing cartilage tissues using 10-mm diameter osteochondral dowels or femoral condyles at −196°C: (a) storage with a surrounding vitrification solution versus (b) storage without a surrounding vitrification solution. We investigated the effects of 2 additives (chondroitin sulfate and ascorbic acid) for vitrification of articular cartilage. Design Healthy porcine stifle joints ( n = 11) from sexually mature pigs were collected from a slaughterhouse within 6 hours after slaughtering. Dimethyl sulfoxide, ethylene glycol, and propylene glycol were permeated into porcine articular cartilage using an optimized 7-hour 3-step cryoprotectant permeation protocol. Chondrocyte viability was assessed by a cell membrane integrity stain and chondrocyte metabolic function was assessed by alamarBlue assay. Femoral condyles after vitrification were assessed by gross morphology for cartilage fractures. Results There were no differences in the chondrocyte viability (~70%) of 10-mm osteochondral dowels after vitrification with or without the surrounding vitrification solution. Chondrocyte viability in porcine femoral condyles was significantly higher after vitrification without the surrounding vitrification solution (~70%) compared to those with the surrounding vitrification solution (8% to 36%). Moreover, articular cartilage fractures were not seen in femoral condyles vitrified without surrounding vitrification solution compared to fractures seen in condyles with surrounding vitrification solution. Conclusions Vitrification of femoral condyle allografts can be achieved by our optimized approach. Removing the surrounding vitrification solution is advantageous for vitrification outcomes of large size osteochondral allografts.

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Extracellular Vesicles and Their Potential Significance in the Pathogenesis and Treatment of Osteoarthritis

Pharmaceuticals ◽

10.3390/ph14040315 ◽

2021 ◽

Vol 14 (4) ◽

pp. 315

Author(s):

Anne-Mari Mustonen ◽

Petteri Nieminen

Keyword(s):

Articular Cartilage ◽

Extracellular Vesicles ◽

Articular Chondrocytes ◽

Functional Limitations ◽

Expression Patterns ◽

Biologically Active ◽

Joint Disease ◽

Cartilage Defects ◽

Matrix Deposition ◽

And Cartilage

Osteoarthritis (OA) is a chronic joint disease characterized by inflammation, gradual destruction of articular cartilage, joint pain, and functional limitations that eventually lead to disability. Join tissues, including synovium and articular cartilage, release extracellular vesicles (EVs) that have been proposed to sustain joint homeostasis as well as to contribute to OA pathogenesis. EVs transport biologically active molecules, and OA can be characterized by altered EV counts and composition in synovial fluid. Of EV cargo, specific non-coding RNAs could have future potential as diagnostic biomarkers for early OA. EVs may contribute to the propagation of inflammation and cartilage destruction by transporting and enhancing the production of inflammatory mediators and cartilage-degrading proteinases. In addition to inducing OA-related gene expression patterns in synoviocytes and articular chondrocytes, EVs can induce anti-OA effects, including increased extracellular matrix deposition and cartilage protection. Especially mesenchymal stem cell-derived EVs can alleviate intra-articular inflammation and relieve OA pain. In addition, surgically- or chemically-induced cartilage defects have been repaired with EV therapies in animal models. While human clinical trials are still in the future, the potential of actual cures to OA by EV products is very promising.

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Treatment of Unicompartmental Cartilage Defects of the Knee with Unicompartmental Knee Arthroplasty, Patellofemoral Partial Knee Arthroplasty or Focal Resurfacing

Life ◽

10.3390/life11050394 ◽

2021 ◽

Vol 11 (5) ◽

pp. 394

Author(s):

Bernhard Springer ◽

Friedrich Boettner

Keyword(s):

Articular Cartilage ◽

Conservative Treatment ◽

Knee Replacement ◽

Knee Arthroplasty ◽

Treatment Options ◽

Cartilage Defects ◽

Osteoarthritis Of The Knee ◽

Chondral Defects ◽

Focal Resurfacing ◽

Partial Knee Replacement

Focal chondral defects are common lesions of the articular cartilage. They are predominantly found on the medial femoral condyle and often progress to osteoarthritis of the knee. Various conservative treatment options are available. The conservative treatment might reduce pain and delay the progress of degenerative processes. However, restoration of the articular cartilage cannot be accomplished. If the conservative treatment fails unicompartmental arthroplasty, patellofemoral joint replacement or focal resurfacing are reasonable options to postpone total knee arthroplasty. A careful patient selection before surgery is crucial for all three treatment options. The following overview reports indications and outcomes of medial partial knee replacement, patellofemoral partial knee replacement, and focal resurfacing treatment options for focal chondral defects.

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3D Printing of Collagen/Oligomeric Proanthocyanidin/Oxidized Hyaluronic Acid Composite Scaffolds for Articular Cartilage Repair

Polymers ◽

10.3390/polym13183123 ◽

2021 ◽

Vol 13 (18) ◽

pp. 3123

Author(s):

Chung-Fei Lee ◽

Yung-Heng Hsu ◽

Yu-Chien Lin ◽

Thu-Trang Nguyen ◽

Hsiang-Wen Chen ◽

...

Keyword(s):

Hyaluronic Acid ◽

Articular Cartilage ◽

3D Printing ◽

Cartilage Repair ◽

Joint Disease ◽

Tissue Loss ◽

Cartilage Defects ◽

Natural Polymers ◽

Composite Scaffolds ◽

Articular Cartilage Repair

Articular cartilage defects affect millions of people worldwide, including children, adolescents, and adults. Progressive wear and tear of articular cartilage can lead to progressive tissue loss, further exposing the bony ends and leaving them unprotected, which may ultimately cause osteoarthritis (degenerative joint disease). Unlike other self-repairing tissues, cartilage has a low regenerative capacity; once injured, the cartilage is much more difficult to heal. Consequently, developing methods to repair this defect remains a challenge in clinical practice. In recent years, tissue engineering applications have employed the use of three-dimensional (3D) porous scaffolds for growing cells to regenerate damaged cartilage. However, these scaffolds are mainly chemically synthesized polymers or are crosslinked using organic solvents. Utilizing 3D printing technologies to prepare biodegradable natural composite scaffolds could replace chemically synthesized polymers with more natural polymers or low-toxicity crosslinkers. In this study, collagen/oligomeric proanthocyanidin/oxidized hyaluronic acid composite scaffolds showing high biocompatibility and excellent mechanical properties were prepared. The compressive strengths of the scaffolds were between 0.25–0.55 MPa. Cell viability of the 3D scaffolds reached up to 90%, which indicates that they are favorable surfaces for the deposition of apatite. An in vivo test was performed using the Sprague Dawley (SD) rat skull model. Histological images revealed signs of angiogenesis and new bone formation. Therefore, 3D collagen-based scaffolds can be used as potential candidates for articular cartilage repair.

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Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis

Nature Communications ◽

10.1038/s41467-021-24460-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yoshiaki Ito ◽

Tokio Matsuzaki ◽

Fumiaki Ayabe ◽

Sho Mokuda ◽

Ryota Kurimoto ◽

...

Keyword(s):

Articular Cartilage ◽

Mirna Target ◽

Hypoxia Inducible Factor ◽

Cartilage Degeneration ◽

Joint Disease ◽

Cartilage Homeostasis ◽

Elevated Expression ◽

A Cell ◽

Target Screening ◽

And Function

AbstractOsteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

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Point-of-care treatment of focal cartilage defects with selected chondrogenic mesenchymal stromal cells-An in vitro proof-of-concept study

Journal of Tissue Engineering and Regenerative Medicine ◽

10.1002/term.2699 ◽

2018 ◽

Vol 12 (7) ◽

pp. 1717-1727 ◽

Cited By ~ 2

Author(s):

Oliver Petters ◽

Christian Schmidt ◽

Christian Thuemmler ◽

Frank Peinemann ◽

Matthias Zscharnack ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Point Of Care ◽

Cartilage Defects ◽

Proof Of Concept ◽

Concept Study ◽

Care Treatment

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REPAIR OF ARTICULAR CARTILAGE INJURY

Biomedical Engineering Applications Basis and Communications ◽

10.4015/s1016237205000366 ◽

2005 ◽

Vol 17 (05) ◽

pp. 243-251 ◽

Cited By ~ 2

Author(s):

HONGSEN CHIANG ◽

YI-YOU HUANG ◽

CHING-CHUAN JIANG

Keyword(s):

Articular Cartilage ◽

Immune Reaction ◽

Healing Process ◽

Cartilage Defects ◽

Recipient Site ◽

Core Elements ◽

Articular Cartilage Injury ◽

Articular Cartilage Defects

Articular cartilage defects heal poorly and lead to consequences as osteoarthritis. Clinical experience has indicated that no existing medication would substantially promote the healing process, and the cartilage defect requires surgical replacement. Allograft decays quickly for multiple reasons including the preparation process and immune reaction, and the outcome is disappointing. The extreme shortage of sparing in articular cartilage has much discouraged the use of autograft, which requires modification. The concept that constructs a chondral or osteochondral construct for the replacement of injured native tissue introduces that of tissue engineering. Limited number of cells are expanded either in vitro or in vivo, and resided temporally on a scaffold of biomaterial, which also acts as a vehicle to transfer the cells to the recipient site. Three core elements constitute this technique: the cell, a biodegradable scaffold, and an environment suitable for cells to present their proposed activity. Modern researches have kept updating those elements for a better performance of such cultivation of living tissue.

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Is There a Role for Cartilage Imaging in Athletes?

Seminars in Musculoskeletal Radiology ◽

10.1055/s-0040-1708818 ◽

2020 ◽

Vol 24 (03) ◽

pp. 246-255

Author(s):

Asako Yamamoto ◽

Benjamin D. Levine ◽

Mario Padron ◽

Christine B. Chung

Keyword(s):

Articular Cartilage ◽

Morphological Changes ◽

Return To Sport ◽

Cartilage Defects ◽

Joint Stability ◽

Cartilage Imaging ◽

Athletic Ability ◽

Cartilage Extracellular Matrix ◽

Chondral Injury ◽

Articular Cartilage Injury

AbstractThis article reviews implications for cartilage imaging in athletes in the setting of (1) acute chondral injury diagnosis, (2) evaluation and follow-up of conservative and surgical therapy, and (3) evaluation of cartilage as a surrogate for meniscal function and joint stability. Focal knee cartilage defects are common in athletic populations. Athletes with articular cartilage injury may initially be able to return to sport with conservative therapy; however, a reduction of athletic ability and progression to osteoarthritis is expected in athletes with untreated severe chondral injury. For diagnostic and pre- and postsurgical evaluation purposes, morphological magnetic resonance (MR) assessment of the articular cartilage with high-resolution protocols is crucial. Although not widely implemented for clinical use, compositional MR techniques have great potential for monitoring the development and progression of biochemical and microstructural changes in cartilage extracellular matrix before gross morphological changes occur.

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