Clinical phase I/II trial of SVF therapy for cartilage regeneration: A cellular therapy with novel 3D MRI imaging for evaluating chondral defect of knee osteoarthritis

Abstract

Background: The clinical applications of stromal vascular fraction (SVF) therapy for osteoarthritis (OA) have attracted academic and clinical attention. However, data of the effects of stromal vascular fraction therapy on regeneration of degenerated cartilage are limited in the literature. Meanwhile, there is a great need for a simple and non-invasive evaluation method to analyze the changes of joint cartilage qualitatively and quantitatively in clinical trials. This study entitled "stromal vascular fraction Therapy for Human Knee Osteoarthritis" was registered in ClinicalTrial.gov # NCT05019378. Materials and Methods: We designed and conducted a single center, open labeled clinical phase I/II study, and 6 osteoarthritis patients with both knee cartilage defect I-II were enrolled in this study. The two knees of each patient were randomly assigned to autologous stromal vascular fraction treatment group or non-treatment control group to evaluate the safety and therapeutic effect of stromal vascular fraction therapy for human knee osteoarthritis. We have also established a novel protocol to provide 3D MRI imaging for human knee cartilage enabling us to qualitatively and quantitatively evaluate cartilage degeneration and regeneration in this study. Results: The qualitative and quantitative evaluation of 3D Magnetic Resonance Imaging (MRI) imaging of knee cartilage demonstrated that the stromal vascular fraction therapy reduced the cartilage defects; and significant increase of cartilage value both in defect cartilage area and whole cartilage area of treated group and significant increase of thickness and area of both femoral and tibia cartilage in vertical sections of the stromal vascular fraction treated Group at 12 and 24 W post treatment in cartilage defect I-II osteoarthritis patients. Conclusion: This clinical phase I/II study indicated that stromal vascular fraction therapy is a safe clinical procedure and provided evidence that the stromal vascular fraction therapy significantly facilitated cartilage regeneration, opening the opportunity to a phase III trial investigating authentic efficacy of the procedure. This study is the first qualitative and quantitative evaluation of the efficacy of autologous stromal vascular fraction cellular therapy on cartilage regeneration. Through early and definite diagnosis of knee osteoarthritis patients, and providing safe and efficient therapy to facilitate cartilage regeneration, we will be able to control or reverse cartilage degeneration and completely change the epidemiology of osteoarthritis worldwide.

Keywords: 3D MRI imaging; cartilage regeneration; clinical trial; osteoarthritis; stromal vascular fraction (SVF).

FIGURE 1

Establishment of human knee joint MRI 3D models and 3D spatial alignment method. (A) Establishment of human knee joint MRI 3D models: (a,b) The detection range from the femoral condyle to the tibial plateau of knee joint is selected in coronal plane and sagittal plane of MRI; (c–e) region growing method is used to obtain the contour curves of all planes of the detection range; (f,g) Based on the gray scale thresholds of cartilage or bone, the scanning sequences of cartilage or bone within the selected region are identified respectively. (h,i) the cartilage and bone 3D MRI models are generated. (B). Establishment of 3D spatial alignment method: (j-n) 3-matic was applied to spatially align the MRI image data I and II based on osteogenic section to ensure that the cartilage section is registered in the same 3D spatial domain.

FIGURE 2

Qualitative analysis of femoral cartilage and tibial cartilage. (A–C) The articular cartilage was determined with the articular surface of femur or tibia as the reference template, (D,E) the damage of cartilage were qualitatively analyzed based on the defect of articular cartilage.

FIGURE 3

Quantitative analysis method of articular cartilage at different time periods. Define the borderline of defect cartilage area (A) or entire articular cartilage area (B), and the volume changes between two different periods could be measured and compared. (C) The knee joint was coronal incised at the anterior and posterior positions, the cross-sectional area of cartilage, as well as the thickness of femoral cartilage and tibial cartilage at each position could be measured respectively.

FIGURE 4

Qualitative analysis of femoral cartilage and tibial cartilage defects of 6 enrolled patients. (A) Patient 1: female, 69 years, BMI = 23.5. (B) Patient 2: female, 69 years, BMI = 20. (C) Patient 3: female, 64 years, BMI = 23.8. (D) Patient 4: female, 59 years, BMI = 29.2. (E) Patient 5: female, 59 years, BMI = 27.3. (F) Patient 6: male, 53 years, BMI = 25.0. After a single injection of SVF the femur and/or tibia cartilage defects of all 6 patients show improvement, some show significant reduction at 12 and 24 weeks post therapy in comparison with pretreatment. In contrast, most the defects of untreated group show deterioration and some new defects are noted.

FIGURE 5

Radiologic evaluation of articular cartilage: volume, area and thickness. (A) Volume change of damaged cartilage. (B) Volume change of total articular cartilage. (C) Thickness of femoral cartilage in section 1. (D) Thickness of tibial cartilage in section 1. (E) Area of articular cartilage in section 1. (F) Thickness of femoral cartilage in section 2. (G) Thickness of tibial cartilage in section 2. (H) Area of articular cartilage in section 2. The volume of damaged cartilage and total cartilage, thickness and area of articular cartilage improved significantly in SVF treated group at 12 and 24 weeks as compared to baseline, while no significant difference was observed in control group.

FIGURE 6

The trend in WOMAC score and Lysholm score from 0 to 24 W. (A) WOMAC Score: the decreasing trend of WOMAC is obvious between 0 and 12 weeks, and leveled off gradually at 12–24 weeks. (B) Lysholm score: The constant increase was observed from 0 to 12 weeks; thereafter, a relative stability was recorded.