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Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes

International Orthopaedics volume 39, pages 1639–1643 (2015)Cite this article

Abstract

Purpose

Clinical studies in diabetic patients have demonstrated that there is a high incidence of complications in distal tibia and ankle fracture treatments. One strategy to mitigate issues with wound healing and infection in diabetic patients is to use a percutaneous technique in which autologous, bone marrow-derived, concentrated cells are injected at the site of non-unions.

Methods

Eighty-six ankle non-union in diabetic patients were treated with bone marrow mesenchymal stem cells (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes of the 86 diabetic non-union patients treated with BMC were compared with 86 diabetic matched non-unions treated with a standard bone iliac crest autograft.

Results

Treatment with BMC promoted non-union healing in 70 among 86 diabetic patients (82.1 %) with a low number of complications. Of the 86 diabetic patients treated with iliac bone graft, 53 (62.3 %) had healing; major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections.

Conclusions

In diabetic patients with ankle non-unions, treatment with BM-MSCs from bone marrow concentrate may be preferable in view of the high risks of major complications after open surgery and iliac bone grafting, and improved healing rates compared with standard iliac bone autograft treatment.

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References

  1. Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87:1430–1437

    Article  PubMed  Google Scholar 

  2. Liu M, Chao HZ (2008) Mesenchymal stem cells: biology and clinical potential in diabetes therapy. J Cell Mol Med 12(4):1155–1168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Lechner A, Habener JF (2003) Stem/progenitor cells derived from adult tissues: potential for the treatment of diabetes mellitus. Am J Physiol Endocrinol Metab 284:E259–E266

    Article  CAS  PubMed  Google Scholar 

  4. Volarevic V, Arsenijevic N, Lukic M, Stojkovic ML (2011) Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 29:5–10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76–79

    Article  PubMed  Google Scholar 

  6. Boddenberg U (2004) [Healing time of foot and ankle fractures in patients with diabetes mellitus: literature review and report on own cases]. Zentralbl Chir 129:453–459

    Article  CAS  PubMed  Google Scholar 

  7. Flynn JM, Rodriguez-del Rio F, Pizá PA (2000) Closed ankle fractures in the diabetic patient. Foot Ankle Int 21:311–319

    CAS  PubMed  Google Scholar 

  8. Ganesh SP, Pietrobon R, Cecilio WA, Pan D, Lightdale N, Nunley JA (2005) The impact of diabetes on patient outcomes after ankle fracture. J Bone Joint Surg Am 87:1712–1718

    Article  PubMed  Google Scholar 

  9. Gandhi A, Liporace F, Azad V, Mattie J, Lin SS (2006) Diabetic fracture healing. Foot Ankle Clin 11:805–824

    Article  PubMed  Google Scholar 

  10. McCormack RG, Leith JM (1998) Ankle fractures in diabetics. Complications of surgical management. J Bone Joint Surg Br 80:689–692

    Article  CAS  PubMed  Google Scholar 

  11. Jones KB, Maiers-Yelden KA, Marsh JL, Zimmerman MB, Estin M, Saltzman CL (2005) Ankle fractures in patients with diabetes mellitus. J Bone Joint Surg (Br) 87:489–495

    Article  CAS  Google Scholar 

  12. Cofield RH, Morrison MJ, Beabout JW (1983) Diabetic neuroarthropathy in the foot: patient characteristics and patterns of radiographic change. Foot Ankle 4:15–22

    Article  CAS  PubMed  Google Scholar 

  13. Armstrong DG, Todd WF, Lavery LA, Harkless LB, Bushman TR (1997) The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. J Am Podiatr Med Assoc 87:272–278

    Article  CAS  PubMed  Google Scholar 

  14. Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL (1999) Clinical examination for the detection of protective sensation in the feet of diabetic patients International Cooperative Group for Clinical Examination Research. J Gen Intern Med 14:418–424

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fabrin J, Larsen K, Holstein PE (2000) Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care 23:796–800

    Article  CAS  PubMed  Google Scholar 

  16. American Diabetes Association (2003) Peripheral arterial disease in people with diabetes. Diabetes Care 26:3333–3341

    Article  Google Scholar 

  17. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D, American Diabetes Association (2005) Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956–962

    Article  PubMed  Google Scholar 

  18. Follak N, Kloting L, Wolf E, Merk H (2004) Delayed remodeling in the early period of fracture healing in spontaneously diabetic BB/OK rats depending on the diabetic metabolic state. Histol Histopathol 19:473–486

    CAS  PubMed  Google Scholar 

  19. Lu H, Kraut D, Gerstenfeld LC, Graves DT (2003) Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinology 144:346–352

    Article  CAS  PubMed  Google Scholar 

  20. Follak N, Klöting I, Merk H (2005) Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats. Diabetes Metab Res Rev 21:288–296

    Article  PubMed  Google Scholar 

  21. Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, Leone CW, Morgan EF, Gerstenfeld LC, Einhorn TA, Graves DT (2007) Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res 22:560–568

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Johnson JE (1998) Operative treatment of neuropathic arthropathy of the foot and ankle. J Bone Joint Surg Am 80:1700–1709

    Google Scholar 

  23. Jones KB, Maiers-Yelden KA, Marsh JL, Zimmerman MB, Estin M, Saltzman CL (2005) Ankle fractures in patients with diabetes mellitus. J Bone Joint Surg (Br) 87:489–495

    Article  CAS  Google Scholar 

  24. Ganesh SP, Pietrobon R, Cecilio WA, Pan D, Lightdale N, Nunley JA (2005) The impact of diabetes on patient outcomes after ankle fracture. J Bone Joint Surg Am 87:1712–1718

    Article  PubMed  Google Scholar 

  25. Gandhi A, Liporace F, Azad V, Mattie J, Lin SS (2006) Diabetic fracture healing. Foot Ankle Clin 11:805–824

    Article  PubMed  Google Scholar 

  26. Costigan W, Thordarson DB, Debnath UK (2007) Operative management of ankle fractures in patients with diabetes mellitus. Foot Ankle Int 28:32–37

    Article  PubMed  Google Scholar 

  27. Mueller SM, Glowacki J (2001) Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J Cell Biochem 82:583–590

    Article  CAS  PubMed  Google Scholar 

  28. Muschler GF, Nitto H, Boehm CA, Easley KA (2001) Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 19:117–125

    Article  CAS  PubMed  Google Scholar 

  29. Bartsch T, Brehm M, Zeus T, Kogler G, Wernet P, Strauer BE (2007) Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 96(12):891–899

    Article  CAS  PubMed  Google Scholar 

  30. Chochola M, Pytlik R, Kobylka P, Skalicka L, Kideryova L, Beran S, Varejka P, Jirat S, Koivanek J, Aschermann M et al (2008) Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia. Int Angiol 27(4):281–290

    CAS  PubMed  Google Scholar 

  31. De Vriese AS, Billiet J, Van Droogenbroeck J, Ghekiere J, De Letter JA (2008) Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a caucasian population with atherosclerosis obliterans. J Intern Med 263(4):395–403

    Article  PubMed  Google Scholar 

  32. Blotter RH, Connolly E, Wasan A, Chapman MW (1999) Acute complications in the operative treatment of isolated ankle fractures in patients with diabetes mellitus. Foot Ankle Int 20:687–694

    Article  CAS  PubMed  Google Scholar 

  33. Ebihara Y, Ishikawa K, Mochizuki S, Tanaka R, Manabe A, Iseki T, Maekawa T, Tsuji K (2014) Allogeneic stem cell transplantation for patients with acute myeloid leukaemia developing from severe congenital neutropenia. Br J Haematol 164(3):459–461. doi:10.1111/bjh.12638

    Article  PubMed  Google Scholar 

  34. Mei S, Haitsma J, Dos Santos C et al (2010) Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 182:1047–1057

    Article  CAS  PubMed  Google Scholar 

  35. Murphy MB, Moncivais K, Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45:e54. doi:10.1038/emm.2013.94

    Article  PubMed Central  PubMed  Google Scholar 

  36. Holmes GB Jr, Hill N (1994) Fractures and dislocations of the foot and ankle in diabetics associated with Charcot joint changes. Foot Ankle Int 15:182–185

    Article  PubMed  Google Scholar 

  37. Jani MM, Ricci WM, Borrelli J Jr, Barrett SE, Johnson JE (2003) A protocol for treatment of unstable ankle fractures using transarticular fixation in patients with diabetes mellitus and loss of protective sensibility. Foot Ankle Int 24:838–844

    PubMed  Google Scholar 

  38. Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res 232:210–216

    PubMed  Google Scholar 

  39. Perry MD, Taranow WS, Manoli A 2nd, Carr JB (2005) Salvage of failed neuropathic ankle fractures: use of large-fragment fibular plating and multiple syndesmotic screws. J Surg Orthop Adv 14:85–91

    CAS  PubMed  Google Scholar 

  40. Pinzur MS, Noonan T (2005) Ankle arthrodesis with a retrograde femoral nail for Charcot ankle arthropathy. Foot Ankle Int 26:545–549

    PubMed  Google Scholar 

  41. Schon LC, Marks RM (1995) The management of neuroarthropathic fracture dislocations in the diabetic patient. Orthop Clin N Am 26:375–392

    CAS  Google Scholar 

  42. Schon LC, Easley ME, Weinfeld SB (1998) Charcot neuroarthropathy of the foot and ankle. Clin Orthop Relat Res 349:116–131

    Article  PubMed  Google Scholar 

  43. Schepers T, De Vries MR, Van Lieshout EM, Van der Elst M (2013) The timing of ankle fracture surgery and the effect on infectious complications; a case series and systematic review of the literature. Int Orthop 37(3):489–494. doi:10.1007/s00264-012-1753-9

    Article  PubMed Central  PubMed  Google Scholar 

  44. Le Nail LR, Stanovici J, Fournier J, Splingard M, Domenech J, Rosset P (2014) Percutaneous grafting with bone marrow autologous concentrate for open tibia fractures: analysis of forty three cases and literature review. Int Orthop 10.1007/s00264-014-2342-x(9):1845–1853

    Article  Google Scholar 

  45. Wang X, Wang Y, Gou W, Lu Q, Peng J, Lu S (2013) Role of mesenchymal stem cells in bone regeneration and fracture repair: a review. Int Orthop Dec 37(12):2491–2498. doi:10.1007/s00264-013-2059-2

    Article  Google Scholar 

  46. Gómez-Barrena E, Solá CA, Bunu CP (2014) Regulatory authorities and orthopaedic clinical trials on expanded mesenchymal stem cells. Int Orthop 38(9):1803–1809. doi:10.1007/s00264-014-2332-z

    Article  PubMed  Google Scholar 

  47. Hinsenkamp M, Collard JF (2015) Growth factors in orthopaedic surgery: demineralized bone matrix versus recombinant bone morphogenetic proteins. Int Orthop 39(1):137–147. doi:10.1007/s00264-014-2562-0

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Ted Sand and Richard Suzuki and the other members of Celling Biosciences for the review of the final manuscript, and their help in translation.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Henri-Mondor Hospital, University of Paris, Créteil Cedex, France

    Philippe Hernigou, Isaac Guissou, Alexandre Poignard, Nathalie Chevallier, Helene Rouard & Charles Henri Flouzat Lachaniette

  2. Orthopaedic Department, Juntendo University, Tokyo, Japan

    Yasuhiro Homma

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  1. Philippe Hernigou
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  2. Isaac Guissou
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  3. Yasuhiro Homma
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  4. Alexandre Poignard
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  7. Charles Henri Flouzat Lachaniette
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Correspondence to Philippe Hernigou.

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Hernigou, P., Guissou, I., Homma, Y. et al. Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes. International Orthopaedics (SICOT) 39, 1639–1643 (2015). https://doi.org/10.1007/s00264-015-2738-2

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  • DOI: https://doi.org/10.1007/s00264-015-2738-2

Keywords

  • Ankle fracture
  • Non-union
  • Diabetes
  • Mesenchymal stem cells
  • Bone graft
  • Bone marrow aspiration in diabetic patients