Combined Autologous Chondrocyte and Bone Marrow Mesenchymal Stromal Cell Implantation in the Knee: An 8-year Follow Up of Two First-In-Man Cases

Abstract

Autologous chondrocyte implantation (ACI) has been used to treat cartilage defects for >20 years, with promising clinical outcomes. Here, we report two first-in-man cases (patient A and B) treated with combined autologous chondrocyte and bone marrow mesenchymal stromal cell implantation (CACAMI), with 8-year follow up. Two patients with International Cartilage Repair Society (ICRS) grade III–IV cartilage lesions underwent a co-implantation of autologous chondrocytes and bone marrow-derived mesenchymal stromal cells (BM-MSCs) between February 2008 and October 2009. In brief, chondrocytes and BM-MSCs were separately isolated and culture-expanded in a good manufacturing practice laboratory for a period of 2–4 weeks. Cells were then implanted in combination into cartilage defects and patients were clinically evaluated preoperatively and postoperatively, using the self-reported Lysholm knee score and magnetic resonance imaging (MRI). Postoperative Lysholm scores were compared with the Oswestry risk of knee arthroplasty (ORKA) scores. Patient A also had a second-look arthroscopy, at which time a biopsy of the repair site was taken. Both patients demonstrated a significant long-term improvement in knee function, with postoperative Lysholm scores being consistently higher than ORKA predictions. The most recent Lysholm scores, 8 years after surgery were 100/100 (Patient A) and 88/100 (Patient B), where 100 represents a fully functioning knee joint. Bone marrow lesion (BML) volume was shown to decrease on postoperative MRIs in both patients. Cartilage defect area increased in patient A, but declined initially for patient B, slightly increasing again 2 years after treatment. The repair site biopsy taken from patient A at 14 months postoperatively, demonstrated a thin layer of fibrocartilage covering the treated defect site. The use of a combination of cultured autologous chondrocytes and BM-MSCs appears to confer long-term benefit in this two-patient case study. Improvements in knee function perhaps relate to the observed reduction in the size of the BML.

Microvalve Bioprinting of MSC-Chondrocyte Co-Cultures

“…The printing process was successfully used to generate cultures of the MSC and chondrocyte cell lines in both monoculture and co-culture. Models were generated using cell lines to provide a platform that could be used to research the impact of MSCs on cartilage tissue formation and chondrocyte cell therapies [ 5 , 10 , 48 , 49 ]. The intention here was not to create a cartilage tissue model, but broadly to replicate the cell seeding densities that would be delivered to a defect site in ACI, to assess in a simplified co-culture the effect of MSCs on chondrocytes.…”

“…A minimum cell density of approximately 1 million cells per cm 2 is commonly used during ACI procedures [ 9 ]. Recent research has examined the impact of combined autologous chondrocyte and bone marrow-derived mesenchymal stromal cell (MSC) implantation at the defect site, with the hypothesis being that the involvement of the MSCs will improve the repair, through their chondrogenic potential, and/or through the secretion of soluble factors which suppress immune reactions and stimulate endogenous stromal cells [ 10 ].…”

Microvalve bioprinting of MSC-Chondrocyte Co-Cultures

“…The printing process was successfully used to generate cultures of the MSC and chondrocyte cell lines in both monoculture and co-culture. Models were generated using cell lines to provide a platform that could be used to research the impact of MSCs on cartilage tissue formation and chondrocyte cell therapies [5,10,50,51]. The intention here was not to create a cartilage tissue model, but broadly to replicate the cell seeding densities that would be delivered to a defect site in ACI, to assess in a simplified co-culture the effect of MSCs on chondrocytes.…”

“…A minimum cell density of approximately 1 million cells per cm 2 is commonly used during ACI procedures [9]. Recent research has examined the im-pact of combined autologous chondrocyte and bone marrow derived mesenchymal stromal cell (MSC) implantation at the defect site, with the hypothesis being that the involvement of the MSCs will improve the repair, through their chondrogenic potential, and/or through the secretion of soluble factors which suppress immune reactions and stimulate endogenous stromal cells [10].…”

Intermediate frequency electrotherapy stimulation to the medial femoris muscle for functional recovery of knee joint after anterior cruciate ligament reconstruction

“… The thigh circumference 10 cm above the upper edge of the patella before and after the treatment. scores to evaluate the knee joint function 9 before and after treatment (the highest score being 100 for the best function). Knee ranges of motion measurements before and after treatment.…”