Subchondral Drilling Diameter During CARTISTEM Implantation for Knee Cartilage Defects

Eligible adults with persistent knee pain and medial-compartment cartilage defects scheduled for CARTISTEM implantation will be recruited at the Department of Orthopedic Surgery, Severance Hospital. Computer-generated randomization will allocate 60 participants equally between two parallel groups. Recruitment is planned for one year, follow-up for 12 months after surgery, and the overall research period for three years after approval.

The experimental group will undergo subchondral drilling with a 2-mm drill alone. The active comparator group will undergo sequential drilling with 4-mm and 2-mm drills. Both groups will receive allogeneic human umbilical cord blood-derived mesenchymal stem cells mixed with sodium hyaluronate hydrogel and implanted into the drilled holes and over the cartilage defect. High tibial osteotomy may accompany implantation when clinically indicated.

Baseline assessments include demographics, clinical scores, standing knee radiographs, lower-limb alignment radiographs, and MRI. Arthroscopy at surgery will document lesion location, size, and ICRS lesion grade. IKDC, pain VAS, Lysholm, and KOOS assessments are scheduled at 3, 6, and 12 months. Radiographic assessments are scheduled at 6 and 12 months, and MRI at 12 months. Second-look arthroscopy is limited to participants undergoing plate removal after concomitant high tibial osteotomy.

Non-inferiority will be assessed using the between-group difference in the 12-month IKDC score and its 95% confidence interval, with a 10.3-point margin. Adverse events will be assessed at postoperative visits.

Participants are masked to the allocated drilling technique. Assessors of secondary imaging, arthroscopic, and histological outcomes are masked to allocation and evaluate coded participant information. The operating surgeon is aware of allocation. No biopsy or genetic analysis is planned.

Research funding: MEDIPOST; total study budget: KRW 60,000,000.

• 2-mm subchondral drilling (Procedure), also known as 2-mm subchondral drilling with CARTISTEM implantation, Small-diameter subchondral drilling, CARTISTEM implantation: Under general or spinal anesthesia, the cartilage defect is exposed and prepared. Subchondral holes are drilled with a 2-mm drill alone. Allogeneic umbilical cord blood-derived mesenchymal stem cells are mixed with sodium hyaluronate hydrogel, placed into the drilled holes, and applied over the defect. The same cell product preparation is used in both arms. High tibial osteotomy may precede implantation when indicated.
• Sequential 4-mm and 2-mm subchondral drilling (Procedure), also known as Sequential 4-mm and 2-mm subchondral drilling with CARTISTEM implantation, Combined-diameter subchondral drilling; CARTISTEM implantation.: Under general or spinal anesthesia, the cartilage defect is exposed and prepared. Subchondral holes are made using sequential 4-mm and 2-mm drilling. The same allogeneic umbilical cord blood-derived mesenchymal stem cell and sodium hyaluronate hydrogel preparation is implanted into the holes and over the defect. High tibial osteotomy may precede implantation when indicated.

Primary outcomes

• IKDC Subjective Knee Evaluation score at 12 months after surgery [12 months after surgery. Additional protocol measurements occur at 3 and 6 months.]: The IKDC Subjective Knee Evaluation score assesses participant-reported knee symptoms and function on a 0-100 scale. Higher scores indicate better function and fewer symptoms. The primary non-inferiority comparison uses the 12-month between-group difference and its 95% confidence interval, with a prespecified margin of 10.3 points.

Secondary outcomes

• Pain visual analog scale [Baseline and 3, 6, and 12 months after surgery]: Knee pain assessed using a 10-cm visual analog scale (VAS), recorded from 0 to 10: 0 = no pain; 10 = worst imaginable pain. Higher scores indicate greater pain. Scores and changes from baseline are assessed.
• Lysholm knee score [Baseline and 3, 6, and 12 months after surgery]: Patient-reported knee symptoms and function measured using the Lysholm knee score, ranging from 0 to 100; higher scores indicate better knee function.
• Knee injury and Osteoarthritis Outcome Score (KOOS) [Baseline and 3, 6, and 12 months after surgery]: The original 42-item Knee injury and Osteoarthritis Outcome Score (KOOS) assesses pain, symptoms, activities of daily living, sport/recreation, and knee-related quality of life. Each of the five subscales is scored separately from 0 to 100; higher scores indicate fewer symptoms and better function.
• MOCART 2.0 knee score [12 months after surgery]: MRI assessment of cartilage repair using the MOCART 2.0 knee score, ranging from 0 to 100; higher scores indicate more favorable repair tissue morphology.
• Subchondral edema assessment [12 months after surgery]: Subchondral edema assessed on MRI using the relevant MOCART 2.0 subscale.
• Presence of subchondral cysts [12 months after surgery]: Presence or absence of subchondral cysts on MRI.
• Presence of subchondral insufficiency fracture [12 months after surgery]: Presence or absence of subchondral insufficiency fracture on MRI.
• ICRS Cartilage Repair Assessment [At second-look arthroscopy during plate removal, planned at 12 months]: ICRS Cartilage Repair Assessment at second-look arthroscopy during plate removal in participants with concomitant high tibial osteotomy. Defect filling, integration with adjacent cartilage, and macroscopic appearance are each scored from 0 to 4 and summed to a total of 0 to 12; higher scores indicate better cartilage repair. Overall repair is classified from Grade I (normal) to Grade IV (severely abnormal).
• Kellgren-Lawrence grade [Baseline and 6 and 12 months after surgery]: Radiographic osteoarthritis assessed using the Kellgren-Lawrence grade, ranging from 0 to 4; higher grades indicate more severe osteoarthritis.
• Hip-knee-ankle angle [Baseline and 6 and 12 months after surgery]: Lower-limb alignment measured as the hip-knee-ankle angle, in degrees, on standing full-length radiographs.

Sex: All, ages: 19 Years to any

Inclusion Criteria:

1. Age 19 years or older.
2. Knee pain for at least 3 months despite conservative treatment, including medication or physical therapy.
3. Medial-compartment knee arthritis or articular cartilage defects judged to be the main cause of symptoms.
4. Imaging-confirmed medial-compartment cartilage defects for which CARTISTEM implantation has been decided.
5. Voluntary written informed consent by the participant or legally authorized representative after understanding the study.

Exclusion Criteria:

1. Surgery for knee cartilage injury within 1 year before screening.
2. Ligament instability requiring simultaneous ligament surgery.
3. Kellgren-Lawrence grade IV osteoarthritis on weight-bearing anteroposterior knee radiographs.
4. Mechanical-axis varus deformity of 5 degrees or greater, unless corrected by simultaneous high tibial osteotomy.
5. Autoimmune or inflammatory arthritis, including rheumatoid arthritis.
6. Inability to undergo MRI.
7. Body mass index of 35 kg/m² or greater.
8. Inability to adequately understand the study explanation, including illiteracy or a language barrier.
9. Age younger than 19 years.