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Stem cell transplantation for articular cartilage repair

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Mesenchymal stem cells (MSCs) are multipotent cells found in multiple human adult tissues including bone marrow, synovial tissues, and adipose tissues. Since they are derived from the mesoderm, they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue.[1] MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells [1], or stem cells isolated from adult humans that can be transplanted into damaged tissue.

Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone.[2][3][4] Recent research demonstrates that articular cartilage may be able to be repaired via percutaneous introduction of mesenchymal stem cells (MSC’s).[5]

Current Research

Research into MSC’s has exploded in recent years. As an example, a PubMed search for the year 1999 reveals about 90 papers published under the MESH heading of “Mesenchymal Stem Cells”, the same search ran for the year 2007 reveals more than 4,000 entries. The most commonly used source of MSC’s is bone marrow aspirate. Most of the adult bone marrow consists of blood cells in various stages of differentiation.[6] These marrow components can be divided into plasma, red blood cells, platelets, and nucleated cells. The adult stem cell fraction is present in the nucleated cells of the marrow. Most of these cells are CD34+ heme progenitors (destined to differentiate into blood components), while very few are actually MSC’s capable of differentiating into bone, cartilage, or muscle. As a result, that leaves the very small number of MSC’s in the marrow as cells capable of differentiating into tissues of interest to joint preservation.[7] Of note, this may be one of the reasons that commercially available centrifuge systems that concentrate marrow nucleated cells have not shown as much promise in animal research for cartilage repair as have approaches where MSC’s are expanded in culture to greater numbers.

Mesenchymal Stem Cell Applications

Marrow nucleated cells are used every day in regenerative orthopedics. The knee microfracture surgery technique popularized by Steadman[8] relies on the release of these cells into a cartilage lesion to initiate fibrocartilage repair in osteochondral defects.[9] In addition, this cell population has also been shown to assist in the repair of non-union fractures.[10] For this application, bed side centrifugation is commonly used. Again, these techniques produce a very dilute MSC population, usually a yield of 1 in 10,000-1,000,000 of the nucleated cells.[11] Despite this low number of MSC’s, isolated bone marrow nucleated cells implanted into degenerated human peripheral joints have shown some promise for joint repair.[12] As the number of MSC’s that can be isolated from bone marrow is fairly limited, most research in cartilage regeneration has focused on the use of culture expanded cells.[13][14] This method can expand cell numbers by 100-10,000 fold over several weeks. Once these MSCs are ready for re-implanation, they are usually transferred with growth factors to allow for continued cell growth and engraftment to the damaged tissue. At some point, a signal is introduced (either in culture or after transplant to the damaged tissue) for the cells to differentiate into the end tissue (in this discussion, cartilage).

Recent developments

Until recently, the use of cultured mesenchymal stem cells to regenerate cartilage has been primarily in research with animal models. There are now, however, two published case reports of the above technique being used to successfully regenerate articular and meniscus cartilage in human knees.[15][16] This technique has yet to be shown effective in a study involving a larger group of patients, however the same team of researchers have published a large safety study (n=227) showing fewer complications than would normally be associated with surgical procedures. [17]

Another team used a similar technique for cell extraction and ex vivo expansion but cells were embedded within a collagen gel before being surgically re-implanted. They reported a case study in which a full-thickness defect in the articular cartilage of a human knee was successfully repaired.[18]

Recent Developments using Peripheral Blood Stem Cells

While the use of cultured mesenchymal stem cells has shown promising results, a more recent study using uncultured MSC’s has resulted in full thickness, histologically confirmed hyaline cartilage regrowth. Dr. Khay-Yong Saw and his team evaluated the quality of the repair knee cartilage after arthroscopic microdrilling (also microfracture) surgery followed by post-operative injections of autologous peripheral blood progenitor cells (PBPC) in combination with hyaluronic acid(HA).[19] PBPC’s are a blood product containing MSC’s, which is obtained by mobilizing stem cells into the peripheral blood. In February 2011, the team published the results of a 5 patient case series. All five patients showed evidence of hyaline cartilage regeneration at second-look arthroscopy and subsequent biopsy, including 2 patients with full thickness bipolar or kissing lesions. The authors propose that the microdrilling surgery creates a blood clot scaffold on which injected PBPC’s can be recruited and enhance chondrogenesis at the site of the contained lesion. They explain that the significance of this cartilage regeneration protocol is that it is successful in patients with historically difficult-to-treat grade IV bipolar or bone-on-bone osteochondral lesions.

Dr. Saw and his team are currently conducting a larger randomized trial and working towards beginning a multicenter study. The work of the Malaysian research team is gaining international attention.[20]

References

  1. ^ Szilvassy SJ. (2003). "The biology of hematopoietic stem cells". Arch Med Res. 34 (6): 446–60. doi:10.1016/j.arcmed.2003.06.004. PMID 14734085.
  2. ^ Buckwalter JA, Mankin HJ (1998). "Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation". Instr Course Lect. 47: 487–504. PMID 9571450.
  3. ^ Johnstone B, Yoo JU (1999). "Autologous mesenchymal progenitor cells in articular cartilage repair". Clin Orthop Relat Res. 367 (Suppl): S156–62. doi:10.1097/00003086-199910001-00017. PMID 10546644.
  4. ^ Luyten FP. (2004). "Mesenchymal stem cells in osteoarthritis". Current Opinion in Rheumatology. 16 (5): 599–603. doi:10.1097/01.bor.0000130284.64686.63. PMID 15314501.
  5. ^ Walsh CJ, Goodman D, Caplan AI, Goldberg VM (1999). "Meniscus regeneration in a rabbit partial meniscectomy model". Tissue Eng. 5 (4): 327–37. doi:10.1089/ten.1999.5.327. PMID 10477855.
  6. ^ Verfaillie C, Blakolmer K, McGlave P (1990). "Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma". J Exp Med. 172 (2): 509–2. doi:10.1084/jem.172.2.509. PMC 2188338. PMID 2373991.
  7. ^ "What is joint preservation?". Joint Preservation Blog.
  8. ^ "Steadman Clinic - Sports Medicine and Orthopaedic Surgery for Knee, Shoulder and Hip".
  9. ^ Steadman JR, Ramappa AJ, Maxwell RB, Briggs KK (2007). "An arthroscopic treatment regimen for osteoarthritis of the knee". Arthroscopy. 23 (9): 948–55. doi:10.1016/j.arthro.2007.03.097. PMID 17868833.
  10. ^ Bruder SP, Fink DJ, Caplan AI (1994). "Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy". J Cell Biochem. 56 (3): 283–94. doi:10.1002/jcb.240560303. PMID 7876320.
  11. ^ D'Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA (1999). "Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow". J Bone Miner Res. 14 (7): 1115–22. doi:10.1359/jbmr.1999.14.7.1115. PMID 10404011.
  12. ^ Centeno CJ, Kisiday J, Freeman M, Schultz JR (2006). "Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study". Pain Physician. 9 (3): 253–6. PMID 16886034.
  13. ^ Gao J, Caplan AI (2003). "Mesenchymal stem cells and tissue engineering for orthopaedic surgery". La Chirurgia degli organi di movimento. 88 (3): 305–16. PMID 15146948.
  14. ^ Xiang Y, Zheng Q, Jia BB, Huang GP, Xu YL, Wang JF, Pan ZJ (2007). "Ex vivo expansion and pluripotential differentiation of cryopreserved human bone marrow mesenchymal stem cells". J Zhejiang Univ Sci B. 8 (2): 136–36. doi:10.1631/jzus.2007.B0136. PMC 1791057. PMID 17266190.
  15. ^ Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D (2008). "Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells" (PDF). Pain Physician. 11 (3): 343–53. PMID 18523506.
  16. ^ Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M (2008). "Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone". Am J Case Rep. 9: CR246–251.
  17. ^ Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W (2010). "Safety and Complications Reporting on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique". Current Stem Cell Research and Therapy. 5 (1): 81–93. doi:10.2174/157488810790442796. PMID 19951252.
  18. ^ Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, Ohgushi H, Wakitani S, Kurosaka M (2007). "Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells". Osteoarthritis and Cartilage. 15 (2): 226–231. doi:10.1016/j.joca.2006.08.008. PMID 17002893.
  19. ^ Saw, KY; Anz A; Merican S; Tay YG; Ragavanaidu K; Jee CS; McGuire DA (Epub 2011 Feb 19). "Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic Acid after arthroscopic subchondral drilling: a report of 5 cases with histology". Arthroscopy. 27 (4): 493–506. doi:10.1016/j.arthro.2010.11.054. PMID 21334844. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Wey Wen, Lim. "Generating New Cartilage". The Star. Retrieved 6 May 2011.
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