Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.

https://escholarship.org/content/qt76m4g3q5/qt76m4g3q5.pdf?t=oe66jy

Repair and tissue engineering techniques for articular cartilage

Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 10(7) cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.1634

Intra‐Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof‐of‐Concept Clinical Trial

Mesenchymal stem cells (MSC) hold great potential for regenerative medicine because of their ability for self-renewal and differentiation into tissue-specific cells such as osteoblasts, chondrocytes, and adipocytes. MSCs orchestrate tissue development, maintenance and repair, and are useful for musculoskeletal regenerative therapies to treat age-related orthopedic degenerative diseases and other clinical conditions. Importantly, MSCs produce secretory factors that play critical roles in tissue repair that support both engraftment and trophic functions (autocrine and paracrine). The development of uniform protocols for both preparation and characterization of MSCs, including standardized functional assays for evaluation of their biological potential, are critical factors contributing to their clinical utility. Quality control and release criteria for MSCs should include cell surface markers, differentiation potential, and other essential cell parameters. For example, cell surface marker profiles (surfactome), bone-forming capacities in ectopic and orthotopic models, as well as cell size and granularity, telomere length, senescence status, trophic factor secretion (secretome), and immunomodulation, should be thoroughly assessed to predict MSC utility for regenerative medicine. We propose that these and other functionalities of MSCs should be characterized prior to use in clinical applications as part of comprehensive and uniform guidelines and release criteria for their clinical-grade production to achieve predictably favorable treatment outcomes for stem cell therapy. Stem Cells Translational Medicine 2017;6:2173-2185.

/pdf/concise-review-multifaceted-characterization-of-human-2rcqfk9c60.pdf

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine.

Human platelet lysate: Replacing fetal bovine serum as a gold standard for human cell propagation?

Background: Osteoarthritis (OA) is a cartilage degenerative process, involving the immune system, producing local inflammatory reactions, with production of pro-inflammatory cytokines and metalloproteinases. No treatment is still available to improve or reverse the process. Stem cell therapy opened new horizons for treatment of many incurable diseases. Mesenchymal stem cells (MSCs) due to their multi-lineage potential, immunosuppressive activities, limited immunogenicity and relative ease of growth in culture, have attracted attentions for clinical use. Aim: The aim of this study was to examine whether MSC transplantation could reverse the OA process in the knee joint. The project was approved by the Tehran University of Medical Sciences Research Committee and Ethical Committee. Patients and Methods: Four patients with knee osteoarthritis were selected for the study. They were aged 55, 57, 65 and 54 years, and had moderate to severe knee OA. After their signed written consent, 30 mL of bone marrow were taken and cultured for MSC growth. After having enough MSCs in culture (4‐5 weeks) and taking in consideration all safety measures, cells were injected in one knee of each patient. Results: The walking time for the pain to appear improved for three patients and remained unchanged for one. The number of stairs they could climb and the pain on visual analog scale improved for all of them. On physical examination, the improvement was mainly for crepitus. It was minor for the improvement of the range of motion. Conclusion: Results were encouraging, but not excellent. Improvement of the technique may improve the

Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients

BACKGROUND The ability to repair tissue via percutaneous means may allow interventional pain physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will highlight the developments in cellular medicine that may soon permit interventional pain management physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using these technologies OBJECTIVE To determine if isolated and expanded human autologous mesenchymal stem cells could effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees. DESIGN Case Study SETTING Private Interventional Pain Management practice. METHODS An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then percutaneously injected into the subject's knee with MRI proven degenerative joint disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical and radiographic changes. RESULTS At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on MRI, as well as increased range of motion and decreased modified VAS pain scores. CONCLUSION The described process of autologous mesenchymal stem cell culture and percutaneous injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.

https://www.kumc.edu/Documents/msctc/Centeno%20Pain%20Physician.%202008%20.pdf

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Much progress has been made in regenerative medicine for the symptomatic treatment of KOA, including products containing stromal vascular fraction (SVF) and platelet-rich plasma (PRP). The aim of this study was to evaluate clinical and radiological findings after the application of autologous conditioned adipose tissue (ACA) and leukocyte-poor PRP (LP-PRP) in patients with mild to moderate KOA. A total of 16 patients (eight male and eight female) with changes related to KOA on the magnetic resonance imaging (MRI), but without severe osteophytosis, full-thickness cartilage loss, or subchondral bone involvement were included in this study. Patients received an intraarticular, ultrasound-guided injection of ACA and LP-PRP. Clinical scores, including a visual analog scale for pain (VAS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated at baseline and at the three and six month follow-ups showing a statistically significant improvements at three and six months post-intervention. Furthermore, the delayed gadolinium-enhanced MRI of the cartilage (dGEMRIC) indices were evaluated at baseline and at the three and six month follow-ups showing no significant changes after treatment with ACA and LP-PRP, which were actually equal to the dGEMRIC indices measured in the control group (hyaluronic acid applied in contralateral knees without osteoarthritis). ACA with LP-PRP presents a viable minimally invasive therapeutic option for the clinical improvement of mild to moderate KOA. However, MFAT produced by different systems is likely to differ in cellular content, which can directly affect the paracrine effect (cytokine secretion) of mesenchymal stem cells and consequently the regeneration process.

/pdf/results-of-treating-mild-to-moderate-knee-osteoarthritis-1tv9awg8.pdf

Results of Treating Mild to Moderate Knee Osteoarthritis with Autologous Conditioned Adipose Tissue and Leukocyte-Poor Platelet-Rich Plasma

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Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

Results of Treating Mild to Moderate Knee Osteoarthritis with Autologous Conditioned Adipose Tissue and Leukocyte-Poor Platelet-Rich Plasma