Costal Chondrocyte–Derived Pellet-Type Autologous Chondrocyte Implantation versus Microfracture for Repair of Articular Cartilage Defects: A Prospective Randomized Trial

Objective To compare the efficacy and safety of costal chondrocyte–derived pellet-type autologous chondrocyte implantation (CCP-ACI) with microfracture (MFx) for repair of articular cartilage defects of the knee. Design Thirty subjects with an International Cartilage Repair Society (ICRS) grade 3 to 4 chondral defect (2-10 cm2 in area; ≤4 cm3 in volume) were randomized at a ratio of 2:1 (CCP-ACI:MFx). Twenty patients were allocated in the CCP-ACI group and 10 patients in the MFx group. CCP-ACI was performed by harvesting costal cartilage at least 4 weeks before surgery. Implantation was performed without any marrow stimulation. Efficacy and safety were assessed at weeks 8, 24, and 48 after surgery according to the magnetic resonance observation of cartilage repair tissue (MOCART) score and clinical outcomes. Results MOCART scores improved from baseline to 24 and 48 weeks postoperatively in both treatment groups. The improvement in MOCART scores in the CCP-ACI group was significantly greater than that in the MFx group at 24 and 48 weeks (39.1 vs 21.8 and 43.0 vs 24.8, respectively). The proportions of complete defect repair and complete integration were significantly higher in the CCP-ACI group than the MFx group at 48 weeks. Improvement in Lysholm score and KOOS subscores, including Function (Sports and Recreational Activity) and knee-related quality of life was significantly greater in the CCP-ACI group than the MFx group at 48 weeks (35.4 vs 31.5, 35.7 vs 28.5, and 27.9 vs 11.6, respectively). Conclusion Treatment of cartilage defects with CCP-ACI yielded satisfactory cartilage tissue repair outcomes, with good structural integration with native cartilage tissue shown by magnetic resonance imaging at 24 and 48 weeks after surgery. Level of Evidence Level 1: Randomized controlled study.

Costal Chondrocyte–Derived Pellet-Type Autologous Chondrocyte Implantation for Treatment of Articular Cartilage Defect

Background: Because articular chondrocyte-based autologous chondrocyte implantations (ACIs) have restrictively restored articular cartilage defects, alternative cell sources as a new therapeutic option for cartilage repair have been introduced. Purpose: To assess whether implantation of a costal chondrocyte–derived pellet-type (CCP) ACI allows safe, functional, and structural restoration of full-thickness cartilage defects in the knee. Study Design: Case series; Level of evidence, 4. Methods: In this first-in-human study, 7 patients with symptomatic, full-thickness cartilage lesions were enrolled. The chondrocytes isolated from the patients’ costal cartilage were expanded, followed by 3-dimensional pellet culture to prepare the CCP-ACI. Implantation of the pellets was performed via minimal arthrotomy and secured with a fibrin sealant. Clinical scores, including the International Knee Documentation Committee (IKDC) subjective, Lysholm, and Tegner activity scores, were estimated preoperatively and at 1, 2, and 5 years postoperatively. High-resolution magnetic resonance imaging was also performed to evaluate cartilage repair as well as to calculate the MOCART (magnetic resonance observation of cartilage repair tissue) score. Results: The costal chondrocytes of all patients formed homogeneous-sized pellets, which showed the characteristics of the hyaline cartilaginous tissue with lacunae-occupied chondrocytes surrounded by glycosaminoglycan and type II collagen-rich extracellular matrix. There were no treatment-related serious adverse events during the 5-year follow-up period. Significant improvements were seen in all clinical scores from preoperative baseline to the 5-year follow-up (IKDC subjective score, 34.67 to 75.86; Lysholm score, 34.00 to 85.33; Tegner activity score, 1.17 to 4.67; and MOCART score, 28.33 to 83.33). Two patients had complete defect filling on magnetic resonance imaging evaluation at 1 year. Moreover, at 5 years postoperatively, complete defect filling was observed in 4 patients, and hypertrophy or incomplete defect filling (50%-100%) was observed in 2 patients. Conclusion: The overall results of this clinical study suggest that CCP-ACI can emerge as a promising therapeutic option for articular cartilage repair with good clinical outcomes and structural regeneration and with stable results at midterm follow-up. Registration: NCT03517046 ( ClinicalTrials.gov identifier)

Clinically Relevant Cell Sources for TMJ Disc Engineering

Tissue-engineering of the temporomandibular joint (TMJ) disc aims to provide patients with TMJ disorders an option to replace diseased tissue with autologous, functional tissue. This study examined clinically relevant cell sources by comparing costal chondrocytes, dermal fibroblasts, a mixture of the two, and TMJ disc cells in a scaffoldless tissue-engineering approach. It was hypothesized that all constructs would produce matrix relevant to the TMJ disc, but the mixture constructs were expected to appear most like the TMJ disc constructs. Costal chondrocyte and mixture constructs were morphologically and biochemically superior to the TMJ disc and dermal fibroblast constructs, and their compressive properties were not significantly different. Costal chondrocyte constructs produced almost 40 times more collagen and 800 times more glycosaminoglycans than did TMJ constructs. This study demonstrates the ability of costal chondrocytes to produce extracellular matrix that may function in a TMJ disc replacement.

Effect of vanadate on cartilage-matrix proteoglycan synthesis in rabbit costal chondrocyte cultures.

The effect of vanadate on proteoglycan synthesis by cultured rabbit costal chondrocytes was examined. Rabbit chondrocytes were seeded at low densities and grown to confluency in medium supplemented with 10% fetal bovine serum, and then the serum concentration was reduced to 0.3%. At the low serum concentration, chondrocytes adopted a fibroblastic morphology. Addition of 4 microM vanadate to the culture medium induced a morphologic differentiation of the fibroblastic cells to spherical chondrocytes, and increased by two- to threefold incorporation of [35S]sulfate and [3H]glucosamine into large, chondroitin sulfate proteoglycans. The stimulation of incorporation of labeled precursors reflected real increases in proteoglycan synthesis, in that chemical analyses showed increases in the accumulation of macromolecules containing hexuronic acid and hexosamine in vanadate-maintained cultures. However, vanadate had only a marginal effect on [35S]sulfate incorporation into small proteoglycans and [3H]glucosamine incorporation into hyaluronic acid and chondroitinase AC-resistant material. These results provide evidence that vanadate selectively stimulates the synthesis of proteoglycans characteristically found in cartilage by rabbit costal chondrocyte cultures.

Sulfated proteoglycan synthesis by confluent cultures of rabbit costal chondrocytes grown in the presence of fibroblast growth factor.

We examined the effect of fibroblast growth factor (FGF) on proteoglycan synthesis by rabbit costal chondrocyte cultures maintained on plastic tissue culture dishes. Low density rabbit costal chondrocyte cultures grown in the absence of FGF gave rise at confluency to a heterogeneous cell population composed of fibroblastic cells and poorly differentiated chondrocytes. When similar cultures were grown in the presence of FGF, the confluent cultures organized into a homogenous cartilage-like tissue composed of rounded cells surrounded by a refractile matrix. The cell ultrastructure and that of the pericellular matrix were similar to those seen in vivo. The expression of the cartilage phenotype in confluent chondrocyte cultures grown from the sparse stage in the presence vs. absence of FGF was reflected by a fivefold increase in the rate of incorporation of [35S]sulfate into proteoglycans. These FGF effects were only observed when FGF was present during the cell logarithmic growth phase, but not when it was added after chondrocyte cultures became confluent. High molecular weight, chondroitin sulfate proteoglycans synthesized by confluent chondrocyte cultures grown in the presence of FGF were slightly larger in size than that produced by confluent cultures grown in the absence of FGF. The major sulfated glycosaminoglycans associated with low molecular weight proteoglycan in FGF-exposed cultures were chondroitin sulfate, while in cultures not exposed to FGF they were chondroitin sulfate and dermatan sulfate. Regardless of whether or not cells were grown in the presence or absence of FGF, the 6S/4S disaccharide ratio of chondroitin sulfate chains associated with high and low molecular weight proteoglycans synthesized by confluent cultures was the same. These results provide evidence that when low density chondrocyte cultures maintained on plastic tissue culture dishes are grown in the presence of FGF, it results in a stimulation of the expression and stabilization of the chondrocyte phenotype once cultures become confluent.