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Background: Autologous conditioned plasma (ACP) is a commercially available platelet concentrate with promising results from clinical trials., Purpose: To evaluate the clinical outcome after 3 consecutive injections of ACP in patients with knee osteoarthritis (OA) and study the influence of ACP composition and different patient factors as predictors of treatment effect., Study Design: Case series; Level of evidence, 4., Methods: This prospective case series included 260 patients (307 knees) who received ACP treatment for knee OA. The mean patient age was 51 ± 10 years. Improvement up to 12 months' follow-up was measured using the Knee injury and Osteoarthritis Outcome Score (KOOS). ACP composition was analyzed in 100 patients. The predictive value of age, sex, history of knee trauma, Kellgren-Lawrence OA grade, body mass index, and ACP composition was evaluated using generalized estimating equations., Results: The mean overall KOOS improved from 38 ± 14 at baseline to 45 ± 18 at 3 months, 45 ± 18 at 6 months, and 43 ± 18 at 12 months (all P < .05); 40% of patients achieved an improvement above the minimal clinically important difference (MCID) of 8 after 6 months and 33% after 12 months. The variation in ACP composition did not correlate with KOOS ( P > .05). Older age led to a greater clinical benefit (β = 0.27; P = .05), whereas bilateral treatment predicted worse outcomes (β = -5.6; P < .05)., Conclusion: The improvement in KOOS after treatment with ACP did not reach the MCID in most study patients. Older age was a predictor for better outcomes. The composition of ACP varied between patients but did not predict outcomes within the evaluated range. The study findings show the limited benefit of ACP treatment for knee OA and call for caution with routine use in clinical practice., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This research was supported by the Dutch Arthritis Foundation (grant No. LLP-12). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Osteoarthritis (OA) is a disabling condition that affects billions of people worldwide and places a considerable burden on patients and on society owing to its prevalence and economic cost. As cartilage injuries are generally associated with the progressive onset of OA, robustly effective approaches for cartilage regeneration are necessary. Despite extensive research, technical development and clinical experimentation, no current surgery-based, material-based, cell-based or drug-based treatment can reliably restore the structure and function of hyaline cartilage. This paucity of effective treatment is partly caused by a lack of fundamental understanding of why articular cartilage fails to spontaneously regenerate. Thus, research studies that investigate the mechanisms behind the cartilage regeneration processes and the failure of these processes are critical to instruct decisions about patient treatment or to support the development of next-generation therapies for cartilage repair and OA prevention. This Review provides a synoptic and structured analysis of the current hypotheses about failure in cartilage regeneration, and the accompanying therapeutic strategies to overcome these hurdles, including some current or potential approaches to OA therapy., (© 2023. Springer Nature Limited.)

In native healthy hyaline cartilage, the chondrocytes are surrounded by a pericellular matrix that has a distinct composition and function compared to the hyaline cartilage extracellular matrix. The chondrocyte together with its pericellular matrix is called a chondron. The type VI collagen, which is the main component of the pericellular matrix, is resistant to enzymatic digestion by pure collagenase and dispase that do digest the extracellular matrix. Therefore, this combination of enzymes can be used to enzymatically isolate chondrons from hyaline cartilage. Chondrons have a high potential for cartilage tissue engineering. This chapter describes in detail how chondrons can be isolated from hyaline cartilage for further use., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Allogeneic mesenchymal stromal cells (MSCs) are used in the 1-stage treatment of articular cartilage defects. The aim of this study is to investigate whether transport of mitochondria exists between chondrocytes and MSCs and to investigate whether the transfer of mitochondria to chondrocytes contributes to the mechanism of action of MSCs., Design: Chondrocytes and MSCs were stained with MitoTracker, and CellTrace was used to distinguish between cell types. The uptake of fluorescent mitochondria was measured in cocultures using flow cytometry. Transport was visualized using fluorescence microscopy. Microvesicles were isolated and the presence of mitochondria was assessed. Mitochondria were isolated from MSCs and transferred to chondrocytes using MitoCeption. Pellets of chondrocytes, chondrocytes with transferred MSC mitochondria, and cocultures were cultured for 28 days. DNA content and proteoglycan content were measured. Mitochondrial DNA of cultured pellets and of repair cartilage tissue was quantified., Results: Mitochondrial transfer occurred bidirectionally within the first 4 hours until 16 hours of coculture. Transport took place via tunneling nanotubes, direct cell-cell contact, and extracellular vesicles. After 28 days of pellet culture, DNA content and proteoglycan deposition were higher in chondrocyte pellets to which MSC mitochondria were transferred than the control groups. No donor mitochondrial DNA was traceable in the biopsies, whereas an increase in MSC mitochondrial DNA was seen in the pellets., Conclusions: These results suggest that mitochondrial transport plays a role in the chondroinductive effect of MSCs on chondrocytes in vitro. However, in vivo no transferred mitochondria could be traced back after 1 year.

Over the past two decades, evidence has emerged for the existence of a distinct population of endogenous progenitor cells in adult articular cartilage, predominantly referred to as articular cartilage-derived progenitor cells (ACPCs). This progenitor population can be isolated from articular cartilage of a broad range of species, including human, equine, and bovine cartilage. In vitro, ACPCs possess mesenchymal stromal cell (MSC)-like characteristics, such as colony forming potential, extensive proliferation, and multilineage potential. Contrary to bone marrow-derived MSCs, ACPCs exhibit no signs of hypertrophic differentiation and therefore hold potential for cartilage repair. As no unique cell marker or marker set has been established to specifically identify ACPCs, isolation and characterization protocols vary greatly. This systematic review summarizes the state-of-the-art research on this promising cell type for use in cartilage repair therapies. It provides an overview of the available literature on endogenous progenitor cells in adult articular cartilage and specifically compares identification of these cell populations in healthy and osteoarthritic (OA) cartilage, isolation procedures, in vitro characterization, and advantages over other cell types used for cartilage repair. The methods for the systematic review were prospectively registered in PROSPERO (CRD42020184775)., (© 2022. The Author(s).)

Objective: Articular cartilage-derived progenitor cells (ACPCs) are a potential new cell source for cartilage repair. This study aims to characterize endogenous ACPCs from healthy and osteoarthritic (OA) cartilage, evaluate their potential for cartilage regeneration, and compare this to cartilage formation by chondrocytes., Design: ACPCs were isolated from full-thickness healthy and OA human cartilage and separated from the total cell population by clonal growth after differential adhesion to fibronectin. ACPCs were characterized by growth kinetics, multilineage differentiation, and surface marker expression. Chondrogenic redifferentiation of ACPCs was compared with chondrocytes in pellet cultures. Pellets were assessed for cartilage-like matrix production by (immuno)histochemistry, quantitative analyses for glycosaminoglycans and DNA content, and expression of chondrogenic and hypertrophic genes., Results: Healthy and OA ACPCs were successfully differentiated toward the adipogenic and chondrogenic lineage, but failed to produce calcified matrix when exposed to osteogenic induction media. Both ACPC populations met the criteria for cell surface marker expression of mesenchymal stromal cells (MSCs). Healthy ACPCs cultured in pellets deposited extracellular matrix containing proteoglycans and type II collagen, devoid of type I collagen. Gene expression of hypertrophic marker type X collagen was lower in healthy ACPC pellets compared with OA pellets., Conclusions: This study provides further insight into the ACPC population in healthy and OA human articular cartilage. ACPCs show similarities to MSCs, yet do not produce calcified matrix under well-established osteogenic culture conditions. Due to extensive proliferative potential and chondrogenic capacity, ACPCs show potential for cartilage regeneration and possibly for clinical application, as a promising alternative to MSCs or chondrocytes.

Meniscus injury and meniscectomy are strongly related to osteoarthritis, thus there is a clinical need for meniscus replacement. The purpose of this study is to create a meniscus scaffold with micro-scale circumferential and radial fibres suitable for a one-stage cell-based treatment. Poly-caprolactone-based scaffolds with three different architectures were made using melt electrowriting (MEW) technology and their in vitro performance was compared with scaffolds made using fused-deposition modelling (FDM) and with the clinically used Collagen Meniscus Implants ® (CMI ® ). The scaffolds were seeded with meniscus and mesenchymal stromal cells (MSCs) in fibrin gel and cultured for 28 d. A basal level of proteoglycan production was demonstrated in MEW scaffolds, the CMI ® , and fibrin gel control, yet within the FDM scaffolds less proteoglycan production was observed. Compressive properties were assessed under uniaxial confined compression after 1 and 28 d of culture. The MEW scaffolds showed a higher Young's modulus when compared to the CMI ® scaffolds and a higher yield point compared to FDM scaffolds. This study demonstrates the feasibility of creating a wedge-shaped meniscus scaffold with MEW using medical-grade materials and seeding the scaffold with a clinically-feasible cell number and -type for potential translation as a one-stage treatment.

Meniscus injuries can be highly debilitating and lead to knee osteoarthritis. Progenitor cells from the meniscus could be a superior cell type for meniscus repair and tissue-engineering. The purpose of this study is to characterize meniscus progenitor cells isolated by differential adhesion to fibronectin (FN-prog). Human osteoarthritic menisci were digested, and FN-prog were selected by differential adhesion to fibronectin. Multilineage differentiation, population doubling time, colony formation, and MSC surface markers were assessed in the FN-prog and the total meniscus population (Men). Colony formation was compared between outer and inner zone meniscus digest. Chondrogenic pellet cultures were performed for redifferentiation. FN-prog demonstrated multipotency. The outer zone FN-prog formed more colonies than the inner zone FN-prog. FN-prog displayed more colony formation and a higher proliferation rate than Men. FN-prog redifferentiated in pellet culture and mostly adhered to the MSC surface marker profile, except for HLA-DR receptor expression. This is the first study that demonstrates differential adhesion to fibronectin for the isolation of a progenitor-like population from the meniscus. The high proliferation rates and ability to form meniscus extracellular matrix upon redifferentiation, together with the broad availability of osteoarthritis meniscus tissue, make FN-prog a promising cell type for clinical translation in meniscus tissue-engineering.

Meniscus regeneration could be enhanced by targeting meniscus cells and mesenchymal stromal cells (MSCs) with the right growth factors. Combining these growth factors with the Collagen Meniscus Implant (CMI®) could accelerate cell ingrowth and tissue formation in the implant and thereby improve clinical outcomes. Using a transwell migration assay and a micro-wound assay, the effect of insulin-like growth factor-1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1), fibroblast growth factor, and platelet lysate (PL) on migration and proliferation of meniscus cells and MSCs was assessed. The formation of extracellular matrix under influence of the above-mentioned growth factors was assessed after 28 days of culture of both MSCs and meniscus cells. As a proof of concept, the CMI® was functionalized with a VEGF binding peptide and coated with platelet-rich plasma (PRP) for clinical application. Our results demonstrate that PDGF, TGF-β1, and PL stimulate migration, proliferation, and/or extracellular matrix production of meniscus cells and MSCs. Additionally, the CMI® was successfully functionalized with a VEGF binding peptide and PRP which increased migration of meniscus cell and MSC into the implant. This study demonstrates proof of concept of functionalizing the CMI® with growth factor binding peptides. A CMI® functionalized with the right growth factors holds great potential for meniscus replacement after partial meniscectomy., (© 2021 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons Ltd.)

Background and purpose - Platelet-rich plasma (PRP) is broadly used in the treatment of knee osteoarthritis, but clinical outcomes are highly variable. We evaluated the effectiveness of intra-articular injections with Autologous Conditioned Plasma (ACP), a commercially available form of platelet-rich plasma, in a tertiary referral center. Second, we aimed to identify which patient factors are associated with clinical outcome. Patients and methods - 140 patients (158 knees) with knee osteoarthritis (Kellgren and Lawrence grade 0-4) were treated with 3 intra-articular injections of ACP. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (Numeric Rating Scale; NRS), and general health (EuroQol 5 Dimensions; EQ5D) were assessed at baseline and 3, 6, and 12 months' follow-up. The effect of sex, age, BMI, Kellgren and Lawrence grade, history of knee trauma, and baseline KOOS on clinical outcome at 6 and 12 months was determined using linear regression. Results - Mean KOOS increased from 37 at baseline to 44 at 3 months, 45 at 6 months, and 43 at 12 months' follow-up. Mean NRS-pain decreased from 6.2 at baseline to 5.3 at 3 months, 5.2 at 6 months, and 5.3 at 12 months. EQ5D did not change significantly. There were no predictors of clinical outcome. Interpretation - ACP does not lead to a clinically relevant improvement (exceeding the minimal clinically important difference) in patients suffering from knee osteoarthritis. None of the investigated factors predicts clinical outcome.

Background: Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). "Instant MSC Product accompanying Autologous Chondron Transplantation" (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the efficacy of IMPACT to nonsurgical treatment for the treatment of large (2-8 cm 2 ) articular cartilage defects in the knee., Methods: Sixty patients will be randomized to receive nonsurgical care or IMPACT. After 9 months of nonsurgical care, patients in the control group are allowed to receive IMPACT surgery. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (numeric rating scale, NRS), and EuroQol five dimensions five levels (EQ5D-5 L) will be used to compare outcomes at baseline and 3, 6, 9, 12, and 18 months after inclusion. Cartilage formation will be assessed at baseline, and 6 and 18 months after inclusion using MRI. An independent rheumatologist will monitor the onset of a potential inflammatory response. (Severe) adverse events will be recorded. Lastly, the difference between IMPACT and nonsurgical care in terms of societal costs will be assessed by monitoring healthcare resource use and productivity losses during the study period. A health economic model will be developed to estimate the incremental cost-effectiveness ratio of IMPACT vs. nonsurgical treatment in terms of costs per quality adjusted life year over a 5-year time horizon., Discussion: This study is designed to evaluate the efficacy of IMPACT compared to nonsurgical care. Additionally, safety of IMPACT will be assessed in 30 to 60 patients. Lastly, this study will evaluate the cost-effectiveness of IMPACT compared to nonsurgical care., Trial Registration: NL67161.000.18 [Registry ID: CCMO] 2018#003470#27 [EU-CTR; registered on 26 March 2019] NCT04236739 [ ClinicalTrials.gov ] [registered after start of inclusion; 22 January 2020].

Background: Anterior cruciate ligament (ACL) tear and meniscal injury often co-occur. The protective effect of early ACL reconstruction (ACLR) on meniscal injury and its repair is not clear. Critical literature review can support or change clinical strategies and identify gaps in the available evidence., Purpose: To assess the protective effect of ACLR on the meniscus and provide clinical guidelines for managing ACL tears and subsequent meniscal injury. We aimed to answer the following questions: (1) Does ACLR protect the meniscus from subsequent injury? (2) Does early ACLR reduce secondary meniscal injury compared with delayed ACLR? (3) Does ACLR protect the repaired meniscus?, Study Design: Systematic review; Level of evidence, 4., Methods: A systematic review was performed through use of MEDLINE and Embase electronic databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included ACL , reconstruction , and meniscus . Studies describing primary ACLR and nonoperative treatment in adult patients were included, as well as studies indicating timing of ACLR. The included articles were assessed individually for risk of bias through use of the modified Cochrane Risk of Bias and MINORS (Methodological Index for Nonrandomized Studies) tools., Results: One level 2 randomized controlled trial and several level 3 and 4 studies indicated a protective effect of ACLR on meniscal injury compared with nonoperative treatment. There was weak (level 3) evidence of the protective effect of early ACLR on the meniscus. Meniscal repair failure was less frequent in patients with ACL reconstruction than in patients with ACL deficiency (level 4)., Conclusion: The evidence collected in this review suggests a protective effect of ACLR for subsequent meniscal injury (level 2 evidence). ACLR should be performed within 3 months of injury (level 3 evidence). Meniscal injury requiring surgical repair in the ACL-deficient knee should be treated with repair accompanied by ACLR (level 3 evidence). The paucity of level 2 studies prevents the formation of guidelines based on level 1 evidence. There is a strong clinical need for randomized or prospective trials to provide guidelines on timing of ACLR and meniscal repair., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This research was supported by the Dutch Arthritis Foundation (LLP-12 and LLP-22). L.A.V. is employed by CO.DON AG. A.J.K. has received research support from Aesculap/B.Braun, Ceterix, Exactech, Gemini Medical, and Histogenics; consulting fees from Arthrex, JRF Ortho, and Vericel; speaking fees from Arthrex; royalties from Arthrex; and honoraria from Vericel; is a board or committee member for the Musculoskeletal Transplant Foundation; and has stock/stock options in Responsive Arthroscopy. D.B.F.S. has received research support from JRF Ortho. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Background: Meniscus damage can be caused by trauma or degeneration and is therefore common among patients of all ages. Repair or regeneration of the menisci could be of great importance not only for pain relief or regaining function but also to prevent degenerative disease and osteoarthritis. Current treatment does not offer consistent long-term improvement. Although preclinical research focusing on augmentation of meniscal tear repair and regeneration after meniscectomy is encouraging, clinical translation remains difficult., Purpose: To systematically evaluate the literature on in vivo meniscus regeneration and explore the optimal cell sources and conditions for clinical translation. We aimed at thorough evaluation of current evidence as well as clarifying the challenges for future preclinical and clinical studies., Study Design: Systematic review., Methods: A search was conducted using the electronic databases of MEDLINE, Embase, and the Cochrane Collaboration. Search terms included meniscus , regeneration , and cell-based ., Results: After screening 81 articles based on title and abstract, 51 articles on in vivo meniscus regeneration could be included; 2 additional articles were identified from the references. Repair and regeneration of the meniscus has been described by intra-articular injection of multipotent mesenchymal stromal (stem) cells from adipose tissue, bone marrow, synovium, or meniscus or the use of these cell types in combination with implantable or injectable scaffolds. The use of fibrochondrocytes, chondrocytes, and transfected myoblasts for meniscus repair and regeneration is limited to the combination with different scaffolds. The comparative in vitro and in vivo studies mentioned in this review indicate that the use of allogeneic cells is as successful as the use of autologous cells. In addition, the implantation or injection of cell-seeded scaffolds increased tissue regeneration and led to better structural organization compared with scaffold implantation or injection of a scaffold alone. None of the studies mentioned in this review compare the effectiveness of different (cell-seeded) scaffolds., Conclusion: There is heterogeneity in animal models, cell types, and scaffolds used, and limited comparative studies are available. The comparative in vivo research that is currently available is insufficient to draw strong conclusions as to which cell type is the most promising. However, there is a vast amount of in vivo research on the use of different types of multipotent mesenchymal stromal (stem) cells in different experimental settings, and good results are reported in terms of tissue formation. None of these studies compare the effectiveness of different cell-scaffold combinations, making it hard to conclude which scaffold has the greatest potential., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution.