Vonk, Lucienne A

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.

Background: Long-term clinical evaluation of patient outcomes can steer treatment choices and further research for cartilage repair. Using mesenchymal stromal cells (MSCs) as signaling cells instead of stem cells is a novel approach in the field. Purpose: To report the 5-year follow-up of safety, clinical efficacy, and durability after treatment of symptomatic cartilage defects in the knee with allogenic MSCs mixed with recycled autologous chondrons in first-in-human study of 1-stage cartilage repair. Study Design: Case series; Level of evidence, 4. Methods: This study is an investigator-driven study aiming at the feasibility and safety of this innovative cartilage repair procedure. Between 2013 and 2014, a total of 35 patients (mean ± SD age, 36 ± 8 years) were treated with a 1-stage cartilage repair procedure called IMPACT (Instant MSC Product Accompanying Autologous Chondron Transplantation) for a symptomatic cartilage defect on the femoral condyle or trochlear groove. Subsequent follow-up after initial publication was performed annually using online patient-reported outcome measures with a mean follow-up of 61 months (range, 56-71 months). Patient-reported outcome measures included the KOOS (Knee injury and Osteoarthritis Outcome Score), visual analog scale for pain, and EuroQol–5 Dimensions. All clinical data and serious adverse events, including additional treatment received after IMPACT, were recorded. A failure of IMPACT was defined as a chondral defect of at least 20% of the index lesion with a need for a reintervention including a surgical procedure or an intra-articular injection. Results: Using allogenic MSCs, no signs of a foreign body response or serious adverse reactions were recorded after 5 years. The majority of patients showed statistically significant and clinically relevant improvement in the KOOS and all its subscales from baseline to 60 months: overall, 57.9 ± 16.3 to 78.9 ± 17.7 ( P < .001); Pain, 62.3 ± 18.9 to 79.9 ± 20.0 ( P = .03); Function, 61.6 ± 16.5 to 79.4 ± 17.3 ( P = .01); Activities of Daily Living, 69.0 ± 19.0 to 89.9 ± 14.9 ( P < .001); Sports and Recreation, 32.3 ± 22.6 to 57.5 ± 30.0 ( P = .02); and Quality of Life, 25.9 ± 12.9 to 55.8 ± 26.8 ( P < .001). The visual analog scale score for pain improved significantly from baseline (45.3 ± 23.6) to 60 months (15.4 ± 13.4) ( P < .001). Five cases required reintervention. Conclusion: This is the first study showing the midterm safety and efficacy of the proof of concept that allogenic MSCs augment 1-stage articular cartilage repair. The absence of serious adverse events and the clinical outcome support the longevity of this unique concept. These data support MSC-augmented chondron transplantation (IMPACT) as a safe 1-stage surgical solution that is considerably more cost-effective and a logistically advantageous alternative to conventional 2-stage cell-based therapy for articular chondral defects in the knee.

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.

Objective: To investigate the preclinical feasibility of using bio-airbrush technology for the fully arthroscopic treatment of cartilage defects with a combination of cells and biomaterials. Design: A combination of in vitro , ex vivo , and cadaveric in situ experiments was performed, to evaluate the preclinical feasibility of using bio-airbrush technology for cartilage repair. Cartilage matrix production after airbrushing cells was evaluated. Subsequently, the influence of different spray parameters on successful defect fill was studied. Finally, the surgical feasibility of using bio-airbrush technology was evaluated in situ in cadaveric knees. Results: The most important findings of the presented study are that the matrix producing capacity of the cells was not hampered by airbrushing, air pressure and defect location were important parameters to consider, and using the bio-airbrush was found to be surgically feasible in a CO 2 -insufflated arthroscopic procedure in cadaveric knees. Conclusions: Bio-airbrush using CO 2 arthroscopy would facilitate fully arthroscopic application of (cell laden) two-component in situ gelating biomaterials to cartilage defects, as a treatment for cartilage repair. This would shift the conventional procedures, which are commonly performed using a (mini-)arthrotomy, toward arthroscopy. Impact Statement This study shows that a bio-airbrush can be a clinically feasible instrument for the use in cell transplantations to repair knee cartilage defects. This technology would enable a shift from cartilage repair procedures, which are mostly performed using an arthrotomy, toward a fully arthoscopic approach. In addition, the technology presented could possibly be translated to other fields of research where controlled in situ deposition of cells is required, such as treatment of burn wounds/ulcers/others. Our research has shown that the use of an airbrush is safe, without harming cell viability and performance.

Purpose: To test the technical aspects and feasibility of seeding a combination of meniscus cells isolated from a rapid digestion protocol and mesenchymal stromal cells (MSCs) (20:80 ratio) into a meniscus scaffold for the development of a one-stage arthroscopic procedure for meniscus regeneration. Methods: A cadaveric study was performed using nine fresh frozen human cadaveric knee joints. Two different arthroscopic cell-seeding methods were applied to the Collagen Meniscus Implant (CMI ® ) as carrier scaffold: either (1) seeding before arthroscopic surgical implantation of the scaffold or (2) after implantation of the scaffold. The cells were injected inside the scaffold, using fast green-stained fibrin glue as carrier, to macroscopically visualize the amount of fibrin glue. Macroscopic pictures and confocal microscopy analyses were used to determine cell distribution and viability. In addition, the DNA content in the cell-seeded scaffold was determined. In addition, different concentrations of Liberase were examined to find the optimal concentration for rapid digestion of meniscus tissue. Results: Macroscopically, seeding before implantation showed a better distribution of fast green-stained fibrin glue carrier than seeding the scaffold before surgical implantation. In addition, it resulted in significantly more cells and a better cell distribution compared with seeding the scaffold after arthroscopic implantation. Both seeding methods did not affect cell viability. After rapid digestion, 0.0125% Liberase resulted in the highest cell isolation efficiency. Conclusions: This study demonstrates that living human meniscus cells can be isolated efficiently, combined with MSCs in 20:80 ratio, and uniformly delivered into a currently available meniscus scaffold. This scaffold can then be arthroscopically implanted, creating a one-stage solution for partial meniscal deficiency. Impact Statement Meniscus injury remains the most common indication for orthopedic surgery, but loss of functioning meniscus tissue is strongly correlated with development of early osteoarthritis. However, current clinical options for tissue engineering of the meniscus are limited. This study demonstrates the feasibility of combining human meniscus cells with mesenchymal stromal cells to enhance a meniscus scaffold for meniscus regeneration in a one-stage solution for partial meniscal deficiency.