Title

關節內注射間葉幹細胞於治療動物創傷性及退化性關節病之實證醫學研究與犬隻臨床應用之效用評估

Translated Titles

Evidence-based study of intra-articular mesenchymal stem cell injection in animals with traumatic and degenerative arthropathies and evaluation of clinical therapeutic effects in dogs

DOI

10.6342/NTU.2011.02536

Authors

蔡聲揚

Key Words

間葉幹細胞 ; 成體幹細胞 ; 關節注射 ; 骨關節炎 ; 退化性關節病 ; 實證醫學 ; mesenchymal stem cell ; adult stem cell ; intraarticular injection ; osteoarthritis ; degenerative joint disease ; evidence-based medicine

PublicationName

臺灣大學臨床動物醫學研究所學位論文

Volume or Term/Year and Month of Publication

2011年

Academic Degree Category

碩士

Advisor

葉力森

Content Language

繁體中文

Chinese Abstract

骨關節炎(osteoarthritis, OA),又稱退化性關節病(degenerative joint disease, DJD)是一種非炎症性退化性的關節軟骨病變,無論人或動物,此疾病皆為中老年族群中最常見的問題之一。軟骨本身很差的再生能力再加上目前仍無有效逆轉病程的治療方式,也造成了骨關節炎在處理上的複雜性。 由於幹細胞具有分化的能力,能夠藉由新生組織,達到適當修復及癒合的效果,近年來已受到再生醫學領域的高度關注。以關節注射方式植入幹細胞,屬微創的外科治療方式,就機制上來說,間葉幹細胞有能力促進軟骨的新生及抑制關節內的發炎反應,進而延緩甚至改善關節炎的病程,故有機會成為關節炎治療的替代療法之一。 本研究第一部分,將利用系統性文獻搜尋的方法,以實證醫學的角度,探討動物關節內注射間葉幹細胞於治療骨關節病之臨床成效。研究共納入11篇動物相關研究文獻,種別包含鼠、兔、豬、羊、馬及犬隻,文中詳列出文獻所提之受試動物、研究材料、評估方式、試驗結果…等,並以美國FDA網站公布之實證醫學指導原則,針對各文獻實驗設計及研究方法的品質做分級。結果顯示,因相關研究極少,且各研究間之實驗異質性大,無法進行統合分析提出一有效之結論,不過就個別研究成果來看,以關節內注射提供間葉幹細胞的治療方式,大多數結果顯示的確能在關節內進行某種程度的組織修復效果。 第二部分的研究,將利用豬隻脂肪來源的異種間葉幹細胞,治療犬隻骨關節炎,並評估其治療效果。受試動物包含三隻臨床上患有膝部退化性骨關節炎的犬隻,以關節注射方式,植入每個關節約500萬個間葉幹細胞。關節炎病程評估方式包括:主觀性之骨科學檢查評量、飼主問卷評量,以及客觀性之放射學檢查與犬隻步態測力板分析。結果顯示在經過間葉幹細胞關節注射治療的三隻犬隻,無論是骨科學檢查、飼主問卷及測力板數據皆顯示能減緩膝部骨關節炎之症狀,進而達到患肢功能上的改善。 雖然以關節內注射間葉幹細胞之治療方式於實驗動物及臨床上的初步成果皆顯示有某種程度的治療效果,然而間葉幹細胞關節內作用機制尚未完全被證實,因此在將此療法納入常規治療前,其治療劑量、合適療程、介入時間點…等相關資訊,仍需經過日後更多大規模臨床試驗的證實。

English Abstract

Osteoarthritis, also referred as degenerative joint disease(DJD), is a disease process associated with non-inflammatory, degenerative changes in the tissues of synovial joints and loss of articular cartilage, it is a common diagnosis in the clinic of aged population in both human and veterinary medicine. The poor regenerative capacity of cartilage and no available curative treatment options complicate satisfactory management of osteoarthritis. Recently, stem cell therapy plays an important role in regenerative medicine due to its capacity to differentiate into new tissue to achieve proper tissue repair. Intra-articular injection of suspended stem cells, as a minimal invasive surgical option, could provide as an alternative therapy to osteoarthritis due to its effect of cartilage regeneration and immunomodulation mechanism, and therefore, stop or reverse the disease progression of osteoarthritis. In chapter three, we systematically review the articles related to intra-articular mesenchymal stem cell injection in animals and consider them in the light of evidence-based (veterinary) medicine. A total of 11 studies from various animal species including rat、rabbit、porcine、goat、horse and dog were included. The study materials, evaluation methods and primary outcome of each study were analysed along with the evaluation of the study design and grading of the study quality by use of the FDA’s EBM scoring system. Evaluation of efficacy in published trials was hampered by the low number of studies and their heterogeneity nature, but most of individual study shows intra-articular stem cell injection could have positive therapeutic effect to a certain degree. In chapter four, we use porcine adipose-derived mesenchymal stem cells as a stem cell source to treat canine osteoarthritis and evaluate its therapeutic effects. A total of 3 client-owned dogs with nature course of stifle degenerative joint disease were included in our study. We delivered approximately 5x106 stem cells per joint suspended in phosphate buffered saline via direct intra-articular injection. The outcome revealed that the score of doctor assessment, owner assessment, peak vertical force and vertical impulse of affect limb were functionally improved after intra-articular injection of mesenchymal stem cells. Although some studies, whether in experimental animal models or in clinical trial, have provided promising results of intra-articular stem cell therapy in osteoarthritis, the information is still limited. The actual mechanism of stem cells participating in tissue repair, optimal number of cells needed to be injected, proper therapeutic protocols or the appropriate time point of intervention still remains to be discovered in the future.

Topic Category 獸醫專業學院 > 臨床動物醫學研究所
生物農學 > 獸醫
Reference
  1. 1. Abdel-Hamid M, and Hussein MR. Enhancement of the repair of meniscal wounds in the red-white zone (middle third) by the injection of bone marrow cells in canine animal model. Int J Exp Pathol 86: 117-123, 2005.
    連結:
  2. 2. Aigner T, Soder S, Gebhard PM, McAlinden A, and Haag J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis-structure, chaos and senescence. Nat Clin Pract Rheumatol 3: 391-399, 2007.
    連結:
  3. 3. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 43: 9-15, 2003.
    連結:
  4. 4. Aragon CL, Hofmeister EH, and Budsberg SC. Systematic review of clinical trials of treatments for osteoarthritis in dogs. J Am Vet Med Assoc 230: 514-521, 2007.
    連結:
  5. 5. Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K, Smith A, and Kadiyala S. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg 85: 1927, 2003.
    連結:
  6. 6. Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, and Mullner M. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ 172: 1039, 2005.
    連結:
  7. 7. Barry FP. Mesenchymal stem cell therapy in joint disease. Novartis Found Symp 249: 86–96, 2003.
    連結:
  8. 8. Bayliss MT, Howat S, Davidson C, and Dudhia J. The organization of aggrecan in human articular cartilage. J Biol Chem 275: 6321, 2000.
    連結:
  9. 9. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, and Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2: 1469-1493, 2006.
    連結:
  10. 10. Bierer TL, and Bui LM. Improvement of arthritic signs in dogs fed green-lipped mussel (Perna canaliculus). J Nutr 132: 1634S, 2002.
    連結:
  11. 11. Lozier SM and Menard M. Arthrocentesis and synovial fluid analysis. In: Bojrab MJ, edi. Current techniques in small animal surgery. 4th ed. Williams & Wilkins, United states, 1057-1062, 1998.
    連結:
  12. 12. Boon AJ, Smith J, Dahm DL, Sorenson EJ, Larson DR, Fitz-Gibbon PD, Dykstra DD, and Singh JA. Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthritis: a pilot study. PM&R 2: 268-276, 2010.
    連結:
  13. 13. Brainard BM, Meredith CP, Callan MB, Budsberg SC, Shofer FS, Driessen B, and Otto CM. Changes in platelet function, hemostasis, and prostaglandin expression after treatment with nonsteroidal anti-inflammatory drugs with various cyclooxygenase selectivities in dogs. Am J Vet Res 68: 251-257, 2007.
    連結:
  14. 15. Budsberg SC, Johnston SA, Schwarz P, DeCamp CE, and Claxton R. Efficacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 214: 206, 1999.
    連結:
  15. 18. Caplan AI, and Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 98: 1076-1084, 2006.
    連結:
  16. 19. Chen X, Armstrong MA, and Li G. Mesenchymal stem cells in immunoregulation. Immunol Cell Biol 84: 413-421, 2006.
    連結:
  17. 20. Chung DJ, Choi CB, Lee SH, Kang EH, Lee JH, Hwang SH, Han H, Choe BY, and Lee SY. Intraarterially delivered human umbilical cord blood derived mesenchymal stem cells in canine cerebral ischemia. J Neurosci Res 87: 3554-3567, 2009.
    連結:
  18. 22. Crook T, McGowan C, and Pead M. Effect of passive stretching on the range of motion of osteoarthritic joints in 10 labrador retrievers. Vet Rec 160: 545, 2007.
    連結:
  19. 23. Dahlberg J, Fitch G, Evans R, McClure S, and Conzemius M. The evaluation of extracorporeal shockwave therapy in naturally occurring osteoarthritis of the stifle joint in dogs. Vet Comp Orthop Traumatol 18: 147, 2005.
    連結:
  20. 24. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, Dragoo JL, Ashjian P, Thomas B, and Benhaim P. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 174: 101-109, 2000.
    連結:
  21. 25. DeCamp CE. Kinetic and kinematic gait analysis and the assessment of lameness in the dog. Vet Clin North Am Small Anim Pract 27: 825-840, 1997.
    連結:
  22. 26. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, and Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838, 2002.
    連結:
  23. 27. Doig PA, Purbrick KA, Hare JE, and McKeown DB. Clinical efficacy and tolerance of meloxicam in dogs with chronic osteoarthritis. Can Vet J 41: 296, 2000.
    連結:
  24. 28. Echigo R, Mochizuki M, Nishimura R, and Sasaki N. Suppressive effect of hyaluronan on chondrocyte apoptosis in experimentally induced acute osteoarthritis in dogs. J Vet Med Sci 68: 899-902, 2006.
    連結:
  25. 29. Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, Blair SN, Berman BM, Fries JF, and Weinberger M. Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med 133: 726, 2000.
    連結:
  26. 30. Friedenstein A, Piatetzky-Shapiro I, and Petrakova K. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 16: 381, 1966.
    連結:
  27. 32. Fritsch DA, Allen TA, Dodd CE, Jewell DE, Sixby KA, Leventhal PS, Brejda J, and Hahn KA. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. J Am Vet Med Assoc 236: 535-539, 2010.
    連結:
  28. 33. Goldring MB. The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43: 1916-1926, 2000.
    連結:
  29. 34. Haan JJ, Goring RL, and Beale BS. Evaluation of polysulfated glycosaminoglycan for the treatment of hip dysplasia in dogs. Vet Surg 23: 177-178, 1994.
    連結:
  30. 35. Hadley HS, Wheeler JL, and Petersen SW. Effects of intra-articular botulinum toxin type A (Botox®) in dogs with chronic osteoarthritis. Vet Comp Orthop Traumatol 4: 254-258, 2010.
    連結:
  31. 36. Hanson PD, Brooks KC, Case J, Conzemius M, Gordon W, Schuessler J, Shelley B, Sifferman R, Drag M, and Alva R. Efficacy and safety of firocoxib in the management of canine osteoarthritis under field conditions. Vet Ther 7: 127, 2006.
    連結:
  32. 37. Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, and Brisby H. Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine 34: 141, 2009.
    連結:
  33. 39. Hielm-Bjorkman A, Raekallio M, Kuusela E, Saarto E, Markkola A, and Tulamo R. Double-blind evaluation of implants of gold wire at acupuncture points in the dog as a treatment for osteoarthritis induced by hip dysplasia. Vet Rec 149: 452, 2001.
    連結:
  34. 40. Holmes M, and Cockcroft P. Evidence-based veterinary medicine 1. Why is it important and what skills are needed? In Practice 26: 28, 2004.
    連結:
  35. 41. Holtsinger R, Parker R, Beale B, and Friedman R. The therapeutic efficacy of carprofen (Rimadyl-V) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Traumatol 5: 140-144, 1992.
    連結:
  36. 42. Innes J, Barr A, and Sharif M. Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Vet Rec 146: 433, 2000.
    連結:
  37. 43. Innes JF, Clayton J, and Lascelles BDX. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec 166: 226-230, 2010.
    連結:
  38. 44. Jeffcott L, Rossdale P, Freestone J, Frank C, and Towers-Clark P. An assessment of wastage in Thoroughbred racing from conception to 4 years of age. Equine Vet J 14: 185-198, 1982.
    連結:
  39. 45. Johnston SA. Osteoarthritis. Joint anatomy, physiology, and pathobiology. Vet Clin North Am Small Anim Pract 27: 699-723, 1997.
    連結:
  40. 46. Johnston SA. Osteoarthritis. Joint anatomy, physiology, and pathobiology. Vet Clin North Am Small Anim Pract 27: 699-723, 1997.
    連結:
  41. 47. Jordan K, Arden N, Doherty M, Bannwarth B, Bijlsma J, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, and Kaklamanis P. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Ann Rheum Dis 62: 1145, 2003.
    連結:
  42. 48. Kan I, Melamed E, and Offen D. Autotransplantation of bone marrow-derived stem cells as a therapy for neurodegenerative diseases. In: Andreeff M, ed. Bone Marrow-Derived Progenitors. Springer, Germany, 219-242, 2007.
    連結:
  43. 49. Kapatkin AS, Tomasic M, Beech J, Meadows C, Boston RC, Mayhew PD, Powers MY, and Smith GK. Effects of electrostimulated acupuncture on ground reaction forces and pain scores in dogs with chronic elbow joint arthritis. J Am Vet Med Assoc 228: 1350-1354, 2006.
    連結:
  44. 50. Kealy RD, Lawler DF, Ballam JM, Lust G, Biery DN, Smith GK, and Mantz SL. Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. J Am Vet Med Assoc 217: 1678-1680, 2000.
    連結:
  45. 51. Keene BW. Editorial: Towards evidence based veterinary medicine. J Vet Intern Med 14: 118-119, 2000.
    連結:
  46. 52. Khan KS, Kunz R, Kleijnen J, and Antes G. Systematic reviews to support evidence-based medicine: how to review and apply findings of healthcare research. Royal Society of Medicine Press, England, 2003.
    連結:
  47. 53. Kim HJ, Park JB, Lee JK, Park EY, Park EA, Riew KD, and Rhee SK. Transplanted xenogenic bone marrow stem cells survive and generate new bone formation in the posterolateral lumbar spine of non-immunosuppressed rabbits. Eur Spine J 17: 1515-1521, 2008.
    連結:
  48. 54. Koerner J, Nesic D, Romero JD, Brehm W, Mainil Varlet P, and Grogan SP. Equine peripheral blood derived progenitors in comparison to bone marrow derived mesenchymal stem cells. Stem Cells 24: 1613-1619, 2006.
    連結:
  49. 55. Kuroiwa T, Kakishita E, Hamano T, Kataoka Y, Seto Y, Iwata N, Kaneda Y, Matsumoto K, Nakamura T, and Ueki T. Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function. J Clin Invest 107: 1365-1386, 2001.
    連結:
  50. 56. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, and Ringden O. HLA expression and immunologic propertiesof differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31: 890-896, 2003.
    連結:
  51. 57. Lipscomb V, Pead M, Muir P, AliAbadi F, and Lees P. Clinical efficacy and pharmacokinetics of carprofen in the treatment of dogs with osteoarthritis. Vet Rec 150: 684, 2002.
    連結:
  52. 58. Lo GH, LaValley M, McAlindon T, and Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis. J Am Med Assoc 290: 3115, 2003.
    連結:
  53. 59. Mahowald ML, Krug HE, Singh JA, and Dykstra D. Intra-articular Botulinum Toxin Type A: A new approach to treat arthritis joint pain. Toxicon 54: 658-667, 2009.
    連結:
  54. 60. Mahowald ML, Singh JA, and Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res 9: 179-188, 2006.
    連結:
  55. 61. Majumdar MK, Keane-Moore M, Buyaner D, Hardy WB, Moorman MA, McIntosh KR, and Mosca JD. Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10: 228-241, 2003.
    連結:
  56. 62. Mansa S, Palmer E, Grondahl C, Lonaas L, and Nyman G. Long-term treatment with carprofen of 805 dogs with osteoarthritis. Vet Rec 160: 427, 2007.
    連結:
  57. 63. Marshall WG, Hazewinkel HAW, Mullen D, De Meyer G, Baert K, and Carmichael S. The effect of weight loss on lameness in obese dogs with osteoarthritis. Vet Res Commun 34: 241-253, 2010.
    連結:
  58. 64. McLaughlin RM, Jr., Miller CW, Taves CL, Hearn TC, Palmer NC, and Anderson GI. Force plate analysis of triple pelvic osteotomy for the treatment of canine hip dysplasia. Vet Surg 20: 291-297, 1991.
    連結:
  59. 66. Mlacnik E, Bockstahler BA, Muller M, Tetrick MA, Nap RC, and Zentek J. Effects of caloric restriction and a moderate or intense physiotherapy program for treatment of lameness in overweight dogs with osteoarthritis. J Am Vet Med Assoc 229: 1756-1760, 2006.
    連結:
  60. 67. Moreau M, Dupuis J, Bonneau N, and Desnoyers M. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 152: 323, 2003.
    連結:
  61. 69. Mueller M, Bockstahler B, Skalicky M, Mlacnik E, and Lorinson D. Effects of radial shockwave therapy on the limb function of dogs with hip osteoarthritis. Vet Rec 160: 762, 2007.
    連結:
  62. 70. Mulrow CD. Systematic reviews: synthesis of best evidence for health care decisions. Amer College of Physicians, United States, 1998.
    連結:
  63. 71. Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, and Barry F. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum 46: 704-713, 2002.
    連結:
  64. 72. Murphy JM, Fink DJ, Hunziker EB, and Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 48: 3464-3474, 2003.
    連結:
  65. 73. Nell T, Bergman J, Hoeijmakers M, Laar P, and Horspool L. Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation. J Small Anim Pract 43: 208-212, 2002.
    連結:
  66. 74. Niemeyer P, Schonberger TS, Hahn J, Kasten P, Fellenberg J, Suedkamp N, Mehlhorn AT, Milz S, and Pearce S. Xenogenic transplantation of human mesenchymal stem cells in a critical size defect of the sheep tibia for bone regeneration. Tissue Eng Part A 16: 33-43, 2009.
    連結:
  67. 75. Noth U, Steinert AF, and Tuan RS. Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol 4: 371-380, 2008.
    連結:
  68. 76. Peterson KD, and Keefe TJ. Effects of meloxicam on severity of lameness and other clinical signs of osteoarthritis in dogs. J Am Vet Med Assoc 225: 1056-1060, 2004.
    連結:
  69. 77. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, and Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 284: 143, 1999.
    連結:
  70. 78. Pollmeier M, Toulemonde C, Fleishman C, and Hanson P. Clinical evaluation of firocoxib and carprofen for the treatment of dogs with osteoarthritis. Vet Rec 159: 547, 2006.
    連結:
  71. 79. Quinn MM, Keuler NS, Lu Y, Faria MLE, Muir P, and Markel MD. Evaluation of agreement between numerical rating scales visual analogue scoring scales, and force plate gait analysis in dogs. Vet Surg 36: 360-367, 2007.
    連結:
  72. 80. Raghunath J, Rollo J, Sales KM, Butler PE, and Seifalian AM. Biomaterials and scaffold design: key to Tissue Eng cartilage. Biotechnol Appl Biochem 46: 73-84, 2007.
    連結:
  73. 81. Read R, Cullis-Hill D, and Jones M. Systemic use of pentosan polysulphate in the treatment of osteoarthritis. J Small Anim Pract 37: 108-114, 1996.
    連結:
  74. 83. Ribitsch I, Burk J, Delling U, Geißler C, Gittel C, Jülke H, and Brehm W. Basic science and clinical application of stem cells in veterinary medicine. Adv Biochem Eng Biotechnol, 123: 219-263, 2010.
    連結:
  75. 84. Rossignol J, Boyer C, Thinard R, Remy S, Dugast AS, Dubayle D, Dey ND, Boeffard F, Delecrin J, and Heymann D. Mesenchymal stem cells induce a weak immune response in the rat striatum after allo or xenotransplantation. J Cell Mol Med 13: 2547-2558, 2009.
    連結:
  76. 85. Roush JK, Cross AR, Renberg WC, Dodd CE, Sixby KA, Fritsch DA, Allen TA, Jewell DE, Richardson DC, and Leventhal PS. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. J Am Vet Med Assoc 236: 67-73, 2010.
    連結:
  77. 86. Roush JK, Dodd CE, Fritsch DA, Allen TA, Jewell DE, Schoenherr WD, Richardson DC, Leventhal PS, and Hahn KA. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. J Am Vet Med Assoc 236: 59-66, 2010.
    連結:
  78. 88. Ryan JM, Barry FP, Murphy JM, and Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2: 8, 2005.
    連結:
  79. 90. Sanderson R, Beata C, Flipo R, Genevois J, Macias C, Tacke S, Vezzoni A, and Innes J. Systematic review of the management of canine osteoarthritis. Vet Rec 164: 418, 2009.
    連結:
  80. 91. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, and Martin BJ. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 73: 1919-1926, 2002.
    連結:
  81. 92. Singh JA, Mahowald ML, and Noorbaloochi S. Intra-articular botulinum toxin A for refractory shoulder pain: a randomized, double-blinded, placebo-controlled trial. Transl Res 153: 205-216, 2009.
    連結:
  82. 94. Smith GK, Paster ER, Powers MY, Lawler DF, Biery DN, Shofer FS, McKelvie PJ, and Kealy RD. Lifelong diet restriction and radiographic evidence of osteoarthritis of the hip joint in dogs. J Am Vet Med Assoc 229: 690-693, 2006.
    連結:
  83. 95. Smith GN, Mickler EA, Myers SL, and Brandt KD. Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine post-traumatic osteoarthritis. J Rheumatol 28: 1341, 2001.
    連結:
  84. 96. Smith Jr GN, Myers SL, Brandt KD, and Mickler EA. Effect of intraarticular hyaluronan injection in experimental canine osteoarthritis. Arthritis Rheum 41: 976-985, 1998.
    連結:
  85. 97. Steinert AF, Ghivizzani SC, Rethwilm A, Tuan RS, Evans CH, and Noth U. Major biological obstacles for persistent cell-based regeneration of articular cartilage. Arthritis Res Ther 9: 213, 2007.
    連結:
  86. 98. Thrall DE. Textbook of veterinary diagnostic radiology. Saunders company, United States, 2007.
    連結:
  87. 99. Todhunter R, and Lust G. Synovial joint anatomy, biology, and pathobiology. In: Auer JA ed. Equine surgery. 3rd ed. Saunders, United States, 844-866, 1992.
    連結:
  88. 100. Tse WT, Pendleton JD, Beyer WM, Egalka MC, and Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75: 389, 2003.
    連結:
  89. 101. Uccelli A, Pistoia V, and Moretta L. Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol 28: 219-226, 2007.
    連結:
  90. 102. Van Baar ME, Assendelft WJJ, Dekker J, Oostendorp RAB, and Bijlsma JWJ. Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a systematic review of randomized clinical trials. Arthritis Rheum 42: 1361-1369, 1999.
    連結:
  91. 103. Vasseur P, Johnson A, Budsberg S, Lincoln J, Toombs J, Whitehair J, and Lentz E. Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 206: 807, 1995.
    連結:
  92. 104. Wang L, Li Y, Chen X, Chen J, Gautam SC, Xu Y, and Chopp M. MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 7: 113-117, 2002.
    連結:
  93. 105. Waxman AS, Robinson DA, Evans RB, Hulse DA, Innes JF, and Conzemius MG. Relationship between objective and subjective asessment of limb function in normal dogs with an experimentally induced lameness. Vet Surg 37: 241-246, 2008.
    連結:
  94. 107. Yoshimura H, Muneta T, Nimura A, Yokoyama A, Koga H, and Sekiya I. Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res 327: 449-462, 2007.
    連結:
  95. 108. Zhang W, Moskowitz R, Nuki G, Abramson S, Altman R, Arden N, Bierma-Zeinstra S, Brandt K, Croft P, and Doherty M. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16: 137-162, 2008.
    連結:
  96. 109. 王貞棣。關節內注射高分子量玻尿酸治療膝部骨關節炎之實證醫學與分子機轉研究。博士論文,國立台灣大學臨床醫學研究所,台北,台灣,2006。
    連結:
  97. 110. 徐偉岸,鍾國彪。實證醫學研究之系統性回顧方法評論-療效研究之品質評估。醫護科技學刊,7卷3期, p. 307-316,2005。
    連結:
  98. 111. 謝青峰。重複試驗之疲勞因子對犬隻測力板垂直反作用力數據之影響。碩士論文,國立台灣大學獸醫學研究所臨床組,台北,台灣,2008。
    連結:
  99. 14. Brandt KD, Smith GN, and Myers SL. Hyaluronan injection affects neither osteoarthritis progression nor loading of the OA knee in dogs. Biorheology 41: 493-502, 2004.
  100. 16. Budsberg SC, Verstraete MC, and Soutas-Little RW. Force plate analysis of the walking gait in healthy dogs. Am J Vet Res 48: 915-918, 1987.
  101. 17. Bui LM, and Bierer TL. Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Vet Ther 4: 397-407, 2003.
  102. 21. Cockcroft PD and Holmes MA. Handbook of evidence-based veterinary medicine. Wiley Online Library, 2003.
  103. 31. Frisbie D, and Smith R. Clinical update on the use of mesenchymal stem cells in equine orthopaedics. Equine Vet J 42: 86-89, 2010.
  104. 38. Herthel DJ. Enhanced suspensory ligament healing in 100 horses by stem cells and other bone marrow components. 47th Annu Meet Am Assoc Equine Pract, 2001, p. 319-321.
  105. 65. McLaughlin RM, and Roush JK. Diagnosing osteoarthritis. Vet Med 97: 120-133, 2002.
  106. 68. Moreau M, Dupuis J, Bonneau NH, and Lecuyer M. Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthrosis in dogs. Can Vet J 45: 133, 2004.
  107. 82. Reyes M, and Verfaillie C. Turning marrow into brain: Generation of glial and neuronal cells from adult bone marrow mesenchymal stem cells. Blood 94: 377a, 1999.
  108. 87. Rumph PF, Lander JE, Kincaid SA, Baird DK, Kammermann JR, and Visco DM. Ground reaction force profiles from force platform gait analyses of clinically normal mesomorphic dogs at the trot. Am J Vet Res 55: 756-761, 1994.
  109. 89. Ryan WG, Moldave K, and Carithers D. Clinical effectiveness and safety of a new NSAID, firocoxib: A 1,000 dog study. Vet Ther 7: 119, 2006.
  110. 93. Smith G, Myers SL, Brandt KD, Mickler EA, and Albrecht ME. Effect of intraarticular hyaluronan injection on vertical ground reaction force and progression of osteoarthritis after anterior cruciate ligament transection. J Rheumatol 32: 325, 2005.
  111. 106. Willard MD, and Tvedten H. Small animal clinical diagnosis by laboratory methods. Saunders, St. Louis, 2004.