International Orthopaedics

, Volume 39, Issue 8, pp 1639–1643 | Cite as

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

  • Philippe HernigouEmail author
  • Isaac Guissou
  • Yasuhiro Homma
  • Alexandre Poignard
  • Nathalie Chevallier
  • Helene Rouard
  • Charles Henri Flouzat Lachaniette
Original Paper



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.


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.


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.


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.


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



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.


  1. 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 87:1430–1437PubMedCrossRefGoogle Scholar
  2. 2.
    Liu M, Chao HZ (2008) Mesenchymal stem cells: biology and clinical potential in diabetes therapy. J Cell Mol Med 12(4):1155–1168PubMedCentralPubMedCrossRefGoogle Scholar
  3. 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–E266PubMedCrossRefGoogle Scholar
  4. 4.
    Volarevic V, Arsenijevic N, Lukic M, Stojkovic ML (2011) Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 29:5–10PubMedCentralPubMedCrossRefGoogle Scholar
  5. 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 289:76–79PubMedCrossRefGoogle Scholar
  6. 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 129:453–459PubMedCrossRefGoogle Scholar
  7. 7.
    Flynn JM, Rodriguez-del Rio F, Pizá PA (2000) Closed ankle fractures in the diabetic patient. Foot Ankle Int 21:311–319PubMedGoogle Scholar
  8. 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 87:1712–1718PubMedCrossRefGoogle Scholar
  9. 9.
    Gandhi A, Liporace F, Azad V, Mattie J, Lin SS (2006) Diabetic fracture healing. Foot Ankle Clin 11:805–824PubMedCrossRefGoogle Scholar
  10. 10.
    McCormack RG, Leith JM (1998) Ankle fractures in diabetics. Complications of surgical management. J Bone Joint Surg Br 80:689–692PubMedCrossRefGoogle Scholar
  11. 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) 87:489–495CrossRefGoogle Scholar
  12. 12.
    Cofield RH, Morrison MJ, Beabout JW (1983) Diabetic neuroarthropathy in the foot: patient characteristics and patterns of radiographic change. Foot Ankle 4:15–22PubMedCrossRefGoogle Scholar
  13. 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 87:272–278PubMedCrossRefGoogle Scholar
  14. 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 14:418–424PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Fabrin J, Larsen K, Holstein PE (2000) Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care 23:796–800PubMedCrossRefGoogle Scholar
  16. 16.
    American Diabetes Association (2003) Peripheral arterial disease in people with diabetes. Diabetes Care 26:3333–3341CrossRefGoogle Scholar
  17. 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 28:956–962PubMedCrossRefGoogle Scholar
  18. 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 19:473–486PubMedGoogle Scholar
  19. 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 144:346–352PubMedCrossRefGoogle Scholar
  20. 20.
    Follak N, Klöting I, Merk H (2005) Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats. Diabetes Metab Res Rev 21:288–296PubMedCrossRefGoogle Scholar
  21. 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 22:560–568PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Johnson JE (1998) Operative treatment of neuropathic arthropathy of the foot and ankle. J Bone Joint Surg Am 80:1700–1709Google Scholar
  23. 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) 87:489–495CrossRefGoogle Scholar
  24. 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 87:1712–1718PubMedCrossRefGoogle Scholar
  25. 25.
    Gandhi A, Liporace F, Azad V, Mattie J, Lin SS (2006) Diabetic fracture healing. Foot Ankle Clin 11:805–824PubMedCrossRefGoogle Scholar
  26. 26.
    Costigan W, Thordarson DB, Debnath UK (2007) Operative management of ankle fractures in patients with diabetes mellitus. Foot Ankle Int 28:32–37PubMedCrossRefGoogle Scholar
  27. 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 82:583–590PubMedCrossRefGoogle Scholar
  28. 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 19:117–125PubMedCrossRefGoogle Scholar
  29. 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):891–899PubMedCrossRefGoogle Scholar
  30. 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):281–290PubMedGoogle Scholar
  31. 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):395–403PubMedCrossRefGoogle Scholar
  32. 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 20:687–694PubMedCrossRefGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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 182:1047–1057PubMedCrossRefGoogle Scholar
  35. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 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 15:182–185PubMedCrossRefGoogle Scholar
  37. 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 24:838–844PubMedGoogle Scholar
  38. 38.
    Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res 232:210–216PubMedGoogle Scholar
  39. 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 14:85–91PubMedGoogle Scholar
  40. 40.
    Pinzur MS, Noonan T (2005) Ankle arthrodesis with a retrograde femoral nail for Charcot ankle arthropathy. Foot Ankle Int 26:545–549PubMedGoogle Scholar
  41. 41.
    Schon LC, Marks RM (1995) The management of neuroarthropathic fracture dislocations in the diabetic patient. Orthop Clin N Am 26:375–392Google Scholar
  42. 42.
    Schon LC, Easley ME, Weinfeld SB (1998) Charcot neuroarthropathy of the foot and ankle. Clin Orthop Relat Res 349:116–131PubMedCrossRefGoogle Scholar
  43. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 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):1845–1853CrossRefGoogle Scholar
  45. 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 CrossRefGoogle Scholar
  46. 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 PubMedCrossRefGoogle Scholar
  47. 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 PubMedCrossRefGoogle Scholar

Copyright information

© SICOT aisbl 2015

Authors and Affiliations

  • Philippe Hernigou
    • 1
    Email author
  • Isaac Guissou
    • 1
  • Yasuhiro Homma
    • 2
  • Alexandre Poignard
    • 1
  • Nathalie Chevallier
    • 1
  • Helene Rouard
    • 1
  • Charles Henri Flouzat Lachaniette
    • 1
  1. 1.Department of Orthopaedic Surgery, Henri-Mondor HospitalUniversity of ParisCréteil CedexFrance
  2. 2.Orthopaedic DepartmentJuntendo UniversityTokyoJapan

Personalised recommendations