Efficacy and Safety of Autologous Cell Therapies for Knee Cartilage Defects (Autologous Stem Cells, Chondrocytes or the Two): Randomized Controlled Trial Design

Richardson, James B.; Wright, Karina; Wales, Johanna; Kuiper, Jan Herman; McCarthy, Helen; Gallacher, Peter; Harrison, Paul E.; Roberts, Sally

doi:10.2217/rme-2017-0032

Cited by 16 publications

(19 citation statements)

References 52 publications

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“…We are currently assessing BM-MSCs versus UC-MSCs in pre-clinical in vivo cartilage injury and osteoarthritis models. Autologous culture-expanded BM-MSCs are also being assessed in a randomised clinical trial for cartilage repair, comparing their efficacy versus the current cell therapy ‘gold standard’, autologous chondrocyte implantation (ACI), alone or in combination in the ASCOT trial [18]. BM-MSCs have been used clinically both in autologous [19] and in allogeneic transplantations [20, 21], whereas UC-MSC therapies are being developed as an allogeneic treatment option [22].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells

et al. 2019

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BackgroundThe manufacture of mesenchymal stem/stromal cells (MSCs) for clinical use needs to be cost effective, safe and scaled up. Current methods of expansion on tissue culture plastic are labour-intensive and involve several ‘open’ procedures. We have used the closed Quantum® hollow fibre bioreactor to expand four cultures each of MSCs derived from bone marrow (BM) and, for the first time, umbilical cords (UCs) and assessed extensive characterisation profiles for each, compared to parallel cultures grown on tissue culture plastic.MethodsBone marrow aspirate was directly loaded into the Quantum®, and cells were harvested and characterised at passage (P) 0. Bone marrow cells were re-seeded into the Quantum®, harvested and further characterised at P1. UC-MSCs were isolated enzymatically and cultured once on tissue culture plastic, before loading cells into the Quantum®, harvesting and characterising at P1. Quantum®-derived cultures were phenotyped in terms of immunoprofile, tri-lineage differentiation, response to inflammatory stimulus and telomere length, as were parallel cultures expanded on tissue culture plastic.ResultsBone marrow cell harvests from the Quantum® were 23.1 ± 16.2 × 106 in 14 ± 2 days (P0) and 131 ± 84 × 106 BM-MSCs in 13 ± 1 days (P1), whereas UC-MSC harvests from the Quantum® were 168 ± 52 × 106 UC-MSCs after 7 ± 2 days (P1). Quantum®- and tissue culture plastic-expanded cultures at P1 adhered to criteria for MSCs in terms of cell surface markers, multipotency and plastic adherence, whereas the integrins, CD29, CD49c and CD51/61, were found to be elevated on Quantum®-expanded BM-MSCs. Rapid culture expansion in the Quantum® did not cause shortened telomeres when compared to cultures on tissue culture plastic. Immunomodulatory gene expression was variable between donors but showed that all MSCs upregulated indoleamine 2, 3-dioxygenase (IDO).ConclusionsThe results presented here demonstrate that the Quantum® can be used to expand large numbers of MSCs from bone marrow and umbilical cord tissues for next-generation large-scale manufacturing, without impacting on many of the properties that are characteristic of MSCs or potentially therapeutic. Using the Quantum®, we can obtain multiple MSC doses from a single manufacturing run to treat many patients. Together, our findings support the development of cheaper cell-based treatments.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1202-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells

et al. 2019

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“…The patient-reported Lysholm score may have some limitations associated with its subjectivity. However, our group and many others consistently use such a subjective patient-reported outcome as the primary outcome of clinical trials 16,17,22 . The reason being that ultimately, how the patient feels about their knee function, is the most important clinical observation and metric of treatment success/failure.…”

Section: Discussionmentioning

confidence: 99%

“…Cartilage and bone marrow aspiration harvest and final cell yields are summarized in Table 2. Chondrocytes and BM-MSCs were released for implantation upon conformance to expect morphological characteristics and if cell populations were at least 90% viable, as assessed by trypan blue exclusion (as described in detail in a published current clinical trial) 16 .…”

Section: Methodsmentioning

confidence: 99%

“…Then chondrocytes were passaged a further 1 or 2 times and prepared for Table 2. Chondrocytes and BM-MSCs were released for implantation upon conformance to expect morphological characteristics and if cell populations were at least 90% viable, as assessed by trypan blue exclusion (as described in detail in a published current clinical trial) 16 . Patient A underwent a second arthroscopic procedure, in which the chondral defect on the medial femoral condyle was debrided.…”

Section: Surgical Procedures and Cell Therapy Deliverymentioning

confidence: 99%

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

et al. 2019

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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.

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“…r The Clinical Trial Report, "Efficacy and safety of autologous cell therapies for knee cartilage defects (autologous stem cells, chondrocytes or the two): randomized controlled trial design" [7]. r The Perspective entitled, "The European General Data Protection Regulation: challenges and considerations for iPSC researchers and biobanks" [8].…”

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confidence: 99%

Introducing Volume 13 of Regenerative Medicine

Price-Evans

2018

Regen. Med.

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Efficacy and Safety of Autologous Cell Therapies for Knee Cartilage Defects (Autologous Stem Cells, Chondrocytes or the Two): Randomized Controlled Trial Design

Cited by 16 publications

References 52 publications

A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells

A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells

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

Introducing Volume 13 of Regenerative Medicine

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