Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microfracture for Large, Full-Thickness Cartilage Defects in Older Patients: A Multicenter Randomized Clinical Trial and Extended 5-Year Clinical Follow-up

Abstract

Background: There is currently no optimal method for cartilage restoration in large, full-thickness cartilage defects in older patients.

Purpose: To determine whether implantation of a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and 4% hyaluronate (UCB-MSC-HA) will result in reliable cartilage restoration in patients with large, full-thickness cartilage defects and whether any clinical improvements can be maintained up to 5 years postoperatively.

Study design: Randomized controlled trial; Level of evidence, 1.

Methods: A randomized controlled phase 3 clinical trial was conducted for 48 weeks, and the participants then underwent extended 5-year observational follow-up. Enrolled were patients with large, full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4) in a single compartment of the knee joint, as confirmed by arthroscopy. The defect was treated either with UCB-MSC-HA implantation through mini-arthrotomy or with microfracture. The primary outcome was proportion of participants who improved by ≥1 grade on the ICRS Macroscopic Cartilage Repair Assessment (blinded evaluation) at 48-week arthroscopy. Secondary outcomes included histologic assessment; changes in pain visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) score from baseline; and adverse events.

Results: Among 114 randomized participants (mean age, 55.9 years; 67% female; body mass index, 26.2 kg/m²), 89 completed the phase 3 clinical trial and 73 were enrolled in the 5-year follow-up study. The mean defect size was 4.9 cm² in the UCB-MSC-HA group and 4.0 cm² in the microfracture group (P = .051). At 48 weeks, improvement by ≥1 ICRS grade was seen in 97.7% of the UCB-MSC-HA group versus 71.7% of the microfracture group (P = .001); the overall histologic assessment score was also superior in the UCB-MSC-HA group (P = .036). Improvement in VAS pain, WOMAC, and IKDC scores were not significantly different between the groups at 48 weeks, however the clinical results were significantly better in the UCB-MSC-HA group at 3- to 5-year follow-up (P < .05). There were no differences between the groups in adverse events.

Conclusion: In older patients with symptomatic, large, full-thickness cartilage defects with or without osteoarthritis, UCB-MSC-HA implantation resulted in improved cartilage grade at second-look arthroscopy and provided more improvement in pain and function up to 5 years compared with microfracture.

Registration: NCT01041001, NCT01626677 (ClinicalTrials.gov identifier).

Keywords: cartilage restoration; full-thickness cartilage defect; mesenchymal stem cells; microfracture; umbilical cord blood.

Figure 1.

Surgical implantation procedure for the allogeneic human umbilical cord blood–derived mesenchymal stem cell and 4% hyaluronate (UCB-MSC-HA) composite. (A) Preoperative weightbearing (WB) posteroanterior radiograph (Rosenberg view) shows osteophyte formation of the right knee of a 54-year-old female patient. She had previously undergone a total knee arthroplasty for her left knee. (B) The same radiographic view taken at 5-year follow-up shows maintenance of restored medial joint space without significant deterioration. (C) Arthroscopic inspection and confirmation of International Cartilage Repair Society (ICRS) grade 4 cartilage defect at the initial examination. (D) Mini-arthrotomy and measurement of the size of the full-thickness cartilage defect in the medial femoral condyle of the patient’s right knee. (E) Multiple drilling with a drill bit of 5-mm diameter, which is larger than the diameter of holes made during standard microfracture at the subchondral bone. The large drill holes were mainly made for containment of the UCB-MSC-HA composite. (F) Implantation of the UCB-MSC-HA composite in the 5-mm drill holes. (G, H) Restored articular cartilage at 48 weeks after implantation, which was assessed as ICRS grade 3 in this case. (I) Safranin O staining showing abundant presence of glycosaminoglycan in the restored cartilaginous tissue. (J) Type II collagen immunostaining showing abundant type II collagen in the restored cartilaginous tissue.

Figure 2.

CONSORT (Consolidated Standards of Reporting Trials) flow diagram of study participants. (A) Phase 3 clinical trial of 48 weeks. (B) Observational extended follow-up study of 60 months. *Some of the participants were lost to follow-up at specific follow-up time points only (eg, a participant who was “lost to follow-up” at the 36- and 48-month timepoints could have been included at the 60-month timepoint, and vice versa). AE, adverse event; UCB-MSCs-HA, umbilical cord blood–derived mesenchymal stem cells and 4% hyaluronate.

Figure 3.

Clinical outcomes from baseline to 60-month follow-up in the umbilical cord blood–derived mesenchymal stem cells and 4% hyaluronate (UCB-MSC-HA) versus microfracture groups. Vertical bars indicate 95% CIs for the mean scores. (A) Visual analog scale (VAS) for pain; (B) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); and (C) International Knee Documentation Committee (IKDC) score. ^§2-sample t test. *Wilcoxon rank-sum test on score changes from baseline to the time point. **2-sample t test on score changes from baseline to the time point. ^#Sample sizes for follow-up study (36, 48, and 60 months) include missing data replacements using last observation carried forward (LOCF). The numbers in parentheses indicate the participants assessed at each time point.

Appendix Figure A1.

Preparation of umbilical cord blood–derived mesenchymal stem cell and 4% hyaluronate (UCB-MSC-HA) composite. (A) UCB-MSC and the HA hydrogel were transported in a portable refrigerator to the hospital on the day of surgery. (B) Cells were aspirated from the cell-containing vial before mixture. (C) Aspirated cells were transferred to the bottle containing the HA sponge, and (D) the cells and HA sponge were mixed gently. (E) Prepared UCB-MSC-HA composite formed a gel. (F) UCB-MSC-HA composite was transferred into a syringe for implantation. (G) UCB-MSC-HA composite was implanted into the drill holes. (H) The hydrogel of UCB-MSC-HA composite could be kept in the drill holes without additional paste material. Bone bleeding within the drill holes could permeate into the hydrogel that formed clots intermingled with the hydrogel.