Victoria Hamilton

 Introduction: Osteoarthritis (OA) is the most common joint disorder in the world (global prevalence 3.8%) and significantly contributes to disability globally.^1–3 OA of the knee (KOA) has the highest incidence in the body, with a lifetime risk of approximately 45%.³ Mesenchymal stem cells (MSCs) are heterogenous stem cells that can differentiate into cartilage and other connective tissues.²  Damage to articular cartilage causes joint inflammation; chronic inflammation can cause osteoarthritis, and endogenous cartilage is poorly understood.^1,2  End-stage OA is usually treated with joint replacement, but using synovium-derived MSCs (SDSCs) to treat OA is a prolific research area, though not yet fully understood.^2,4  SDSCs can travel to the sites of cartilage injury, adhere to injured cartilage, and promote superficial and full-thickness cartilage repair. Further research is needed to determine how SDSCs contribute to cartilage repair.⁴ Methods: This literature review explores current SDSC treatment for KOA and proposes a method for harvesting and expanding SDSCs, constructing a scaffold-free tissue engineered construct (TEC), and implanting the construct in human subjects.  First, I review the proliferative capacity of New Zealand White Rabbit-derived MSCs from various lineages (bone, adipose tissue, synovium-derived, etc.).⁵  Then, I examine a study regarding ex vivo expansion of human cells collected via synovium-direct biopsy, arthroscopic trocar shaver blade filtrate, or synovial fluid, and determine if these cells proliferate/form TECs better under low oxygen tension (LOT) or normal oxygen tension (NOT) conditions.^6,7  Finally, I review the first in-human study where scaffold-free TECs are implanted over chondral knee lesions.⁸ Results: Synovium-derived MSCs are superior in chondrogenesis, osteogenesis, myogenesis, and tenogenesis  than those derived from bone marrow, adipose tissue, rotator cuff, ligament, and tendon.⁵  Human SDSCs from arthroscopic trocar shaver blade filtrate showed significant ex vivo expansion.⁶ LOT-TEC showed more proliferation with hyaline-like (not fibrous) cartilage than TEC under NOT conditions.⁷  SDSC-derived scaffold-free TECs implanted in patients with symptomatic chondral knee lesions were safe and effective—chondral lesions filled with tissue alike surrounding cartilage, and patients reported improvements in pain and function.⁸  Conclusion: Human SDSCs from arthroscopic shaver-blade filtrate (reusing what was once waste), expanded under LOT conditions (physiologically similar the avascular joint), can be used to build scaffold-free TECs, which are safer and more economical than scaffolded TECs.^5–7  Implanting these TEC over symptomatic chondral knee lesions is safe and improves patients’ quality of life.⁸  Of note, high-dose steroid therapy temporarily reduces SDSC chondrogenic capacity and should be considered when harvesting SDSCs.⁹

1. To K, Zhang B, Romain K, Mak C, Khan W. Synovium-Derived Mesenchymal Stem Cell Transplantation in Cartilage Regeneration: A PRISMA Review of in vivo Studies. Front Bioeng Biotechnol. 2019;7:314. doi:10.3389/fbioe.2019.00314
2. Zupan J, Drobnič M, Stražar K. Synovium-Derived Mesenchymal Stem/Stromal Cells and their Promise for Cartilage Regeneration. In: Turksen K, ed. Cell Biology and Translational Medicine, Volume 6. Vol 1212. Springer International Publishing; 2019:87-106. doi:10.1007/5584_2019_381
3. Doyle EC, Wragg NM, Wilson SL. Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. Published online January 31, 2020. doi:10.1007/s00167-020-05859-z
4. McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat Rev Rheumatol. 2017;13(12):719-730. doi:10.1038/nrrheum.2017.182
5. Bami M, Sarlikiotis T, Milonaki M, et al. Superiority of synovial membrane mesenchymal stem cells in chondrogenesis, osteogenesis, myogenesis and tenogenesis in a rabbit model. Injury. Published online March 9, 2020. doi:10.1016/j.injury.2020.03.022
6. Ferro T, Santhagunam A, Madeira C, Salgueiro JB, da Silva CL, Cabral JMS. Successful isolation and ex vivo expansion of human mesenchymal stem/stromal cells obtained from different synovial tissue-derived (biopsy) samples. J Cell Physiol. 2019;234(4):3973-3984. doi:10.1002/jcp.27202
7. Yasui Y, Chijimatsu R, Hart DA, et al. Preparation of Scaffold-Free Tissue-Engineered Constructs Derived from Human Synovial Mesenchymal Stem Cells Under Low Oxygen Tension Enhances Their Chondrogenic Differentiation Capacity. Tissue Eng Part A. 2016;22(5-6):490-500. doi:10.1089/ten.tea.2015.0458
8. Shimomura K, Yasui Y, Koizumi K, et al. First-in-Human Pilot Study of Implantation of a Scaffold-Free Tissue-Engineered Construct Generated From Autologous Synovial Mesenchymal Stem Cells for Repair of Knee Chondral Lesions. Am J Sports Med. 2018;46(10):2384-2393. doi:10.1177/0363546518781825
9. Yasui Y, Hart DA, Sugita N, et al. Time-Dependent Recovery of Human Synovial Membrane Mesenchymal Stem Cell Function After High-Dose Steroid Therapy: Case Report and Laboratory Study. Am J Sports Med. 2018;46(3):695-701. doi:10.1177/0363546517741307