Clinical Trial of using Umbilical cord Stem Cells for Osteoarthritic Patients

The article was originally written by:

Yong-Beom Park (Department of Orthopedic Surgery, Chung-Ang University Hospital, ChungAng University College of Medicine, Seoul, Republic of Korea), Chul-Won Ha (Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Research Institute, Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea), Choong-Hee Lee (Department of Orthopedic Surgery), Young Cheol Yoon (Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea), Yong-Geun Park (Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea).

Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results From a Clinical Trial for Safety and Proof-of-Concept With 7 Years of Extended Follow-Up.

SIGNIFICANCE STATEMENT

This paper reports the results of the first-in-human clinical trial investigating a stem cell-based medicinal product (a composite of culture-expanded allogeneic human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel). The application of the stem cell-based medicinal product showed promising efficacy in terms of durable cartilage regeneration. Clinical outcomes were improved and stable, and no significant adverse events were observed over 7 years of follow-up. There are currently no effective regenerative options for cartilage loss in osteoarthritis; thus, the researchers believe that this stem cell-based medicinal product could provide a novel therapeutic option to regenerate worn cartilage lesions in osteoarthritis. The results of this early phase clinical trial warrant further investigation with a larger number of patients.

MATERIALS AND METHODS

Study Design and Participants

This study was an open-label, single-arm, single-center, phase I/II clinical trial with a 24-week follow-up period. In addition, the researchers performed long-term follow-up to assess safety and efficacy over 7 years. Patients diagnosed with osteoarthritis of the knee joint with Kellgren-Lawrence (K-L) grade 3 and painful full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4 lesions), which were not responsive to more than 6 months of palliative treatment, were eligible to participate. Other inclusion criteria were visual analog scale (VAS) score for pain between 40 and 60 mm during screening; a cartilage defect larger than 2 cm2; swelling, tenderness, and limited range of motion lower than grade 2; adequate blood coagulation activity; and adequate renal and hepatic function. Participants were excluded based on the following criteria: autoimmune or inflammatory joint disease; ligament instability higher than grade 2; a history of infection, surgery, or radiation therapy in the knee joint within the past 6 weeks; enrollment in any other clinical trial within the past 4 weeks; immunosuppressant use within the past 6 weeks; corticosteroid or viscosupplementation injections to the affected knee within the past 3 months; or current pregnancy or lactation.

Two groups were studied to ensure safety of the participants and to determine the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT) of the study medicinal product (a composite of allogeneic hUCB-MSCs and HA hydrogel). The first three participants were assigned to receive low-dose MSCs (group A), and the next three were assigned to receive high dose MSCs (group B). One participant in the low-dose group did not consent to 12-week arthroscopy; thus one more participant was assigned to receive low-dose MSCs (group A) to fulfill the requirement for proceeding to the high-dose trial. The doses and cell concentrations were selected based on previous animal studies. The allogeneic hUCB-MSCs were transplanted at a dose of 500 ml/cm2 of the defect area with a cell concentration of 0.5 3 107 cells per milliliter. DLT was defined as any case with 2 or more of the following severe adverse reactions after transplantation: swelling, tenderness, limited range of motion, and pain of the knee joint. This study was reviewed and approved by the Korean Food and Drug Administration (FDA) and the institutional review board at Samsung Medical Center, Seoul, South Korea. Informed consent was obtained from all participants before enrollment in this study.

Preparation of hUCB-MSCs

The medicinal product (hUCB-MSCs-HA hydrogel composite) was produced under Good Manufacturing Practice guidelines, which were approved by the regulatory authority, and provided as an investigational new drug by Medipost. Human umbilical cord blood was collected from umbilical veins at the time of neonatal delivery, with informed consent from the mother, and stored in a cord blood bank. The hUCB-MSCs were isolated and characterized according to previously published methods. Mononuclear cells were separated by density gradient centrifugation at 550g for 30 minutes using a Ficoll-Hypaque solution (density, 1.077 g/ml; Sigma-Aldrich, St. Louis,MO, http://www.sigmaaldrich.com). Isolated mononuclear cells were washed, suspended in minimum essential medium (a-MEM; Thermo Fisher Scientific Life Sciences, Waltham, MA, http://www.thermofisher.com) supplemented with 10% fetal bovine serum (FBS; GE Healthcare Life Sciences, Pittsburgh, PA, http://www.gelifesciences.com), and then seeded into culture flasks at a concentration of 5 3 106 cells per cm2 . Cultures were maintained at 37°C in a humidified atmosphere containing 5% CO2, with a change of culture medium twice per week. Colonies of spindle-shaped cells formed approximately 2 weeks after plating. Cells were trypsinized (0.25% trypsin; GE Healthcare Life Sciences), washed, and resuspended in culture medium (a-MEM supplemented with 10% FBS) when the monolayer of MSC colonies reached 80% confluence.

Application of the Stem Cell-Based Medicinal Product

A standard arthroscopic examination was performed to assess cartilage defects. Then, the cartilage defect site was exposed through a small longitudinal arthrotomy. Multiple drill holes (5 mm in diameter and 5 mm deep) were made approximately 2–3 mm apart at the cartilage defect site of the femoral condyle. The study drug was implanted in the drill holes of the lesion from the base to the surface. In the case of a kissing lesion, the composite was only transplanted in the femoral lesion because of dose limitation in terms of cell numbers. The wound was then closed and a splint was applied.

Postoperative Rehabilitation

Patients were encouraged to perform quadriceps-setting and straight leg-raising exercises starting immediately after surgery. Active and active-assisted range of motion exercise and nonweight-bearing ambulation of the operated knee with a walking aid was started on postoperative day 1. Nonweight-bearing ambulation was recommended for 12 weeks post-transplantation to protect the repair tissue.

RESULTS

Baseline and Treatment Characteristics

Seven participants received a hUCB-MSCs and HA hydrogel composite transplantation between November 2, 2005, and May 12, 2007. The mean age of the participants was 58.7 years, and their mean BMI was 26.4 kg/m2. The average defect size was 4.9 cm2 in group A and 7.3 cm2 in group B. Group A participants were implanted with 1.15–1.25 3 107 hUCB-MSCs, and group B participants were implanted with 1.65–2.00 3 107 hUCB-MSCs according to the size of the articular cartilage defect. Six participants consented to join the extended follow-up study after the 6-month visit. One participant in group A opted out of the extended follow-up study because she was satisfied with the current status of her knee and did not want additional examinations.

The initial version of the article was written by Yong-Beom Park, Chul-Won Ha, Choong-Hee Lee, Young Cheol Yoon, Yong-Geun Park. Published by Wiley Periodicals, Inc. on behalf of AlphaMed Press. You can read the initial version of the article by this link.