Autologous micro-fragmented adipose tissue for the treatment of diabetic foot minor amputations: a randomized controlled single-center clinical trial (MiFrAADiF)

Roberto Lonardi, Nicola Leone, Stefano Gennai, Giulia Trevisi Borsari, Tea Covic, Roberto Silingardi, Roberto Lonardi, Nicola Leone, Stefano Gennai, Giulia Trevisi Borsari, Tea Covic, Roberto Silingardi

Abstract

Background: The diabetic foot ulcer (DFU) is one of the most prevalent complications of diabetes mellitus and often develops severe effects that can lead to amputation. A non-healing "minor" amputation often precedes a major amputation resulting in a negative impact on the function and quality of life of the patients. Stem cell-based therapies have emerged as a promising option to improve healing, and the adipose tissue is an abundant and easy to access source. The injection of autologous micro-fragmented adipose tissue at the amputation stump of a diabetic population undergoing a lower limb minor amputation was evaluated and compared with the standard care.

Methods: In this randomized controlled trial with two arms (parallel assignment) and no masking, 114 patients undergoing a lower limb minor amputation were randomized to standard of care or to micro-fragmented adipose tissue injection prepared using a minimal manipulation technique (Lipogems®) in a closed system. Clinical outcomes were determined monthly up to 6 months. Primary endpoint of the study was the evaluation of the healing rate and time after the minor amputation. Secondary endpoints included the assessment of safety, feasibility, technical success, relapse rate, skin tropism, and intensity of pain.

Results: At 6 months, 80% of the micro-fragmented adipose tissue-treated feet healed and 20% failed as compared with the control group where 46% healed and 54% failed (p = 0.0064). No treatment-related adverse events nor relapses were documented, and technical success was achieved in all cases. The skin tropism was improved in the treatment group, and the pain scale did not differ between the two groups.

Conclusion: The results of this randomized controlled trial suggest that the local injection of autologous micro-fragmented adipose tissue is a safe and valid therapeutic option able to improve healing rate following minor amputations of irreversible DFU. The technique overcomes several stem cell therapy-related criticisms and its potential in wound care should be better evaluated and the therapeutic indications could be expanded.

Trial registration: ClinicalTrials.gov number: NCT03276312. Date of registration: September 8, 2017 (retrospectively registered).

Keywords: Adipose tissue; Amputation; Diabetes mellitus; Peripheral arterial disease; Peripheral vascular diseases.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
MiFrAADiF trial flow diagram, inclusion and exclusion criteria
Fig. 2
Fig. 2
Kaplan-Meier showing healing probability over time
Fig. 3
Fig. 3
Kaplan-Meier showing visual analogue scale (VAS) over time

References

    1. Boulton Andrew JM, Vileikyte Loretta, Ragnarson-Tennvall Gunnel, Apelqvist Jan. The global burden of diabetic foot disease. The Lancet. 2005;366(9498):1719–1724. doi: 10.1016/S0140-6736(05)67698-2.
    1. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders: a clinical practice guideline (2006 revision) J. Foot Ankle Surg. 2006;45:S1–S66. doi: 10.1016/S1067-2516(07)60001-5.
    1. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63:3S–21S. doi: 10.1016/j.jvs.2015.10.003.
    1. Snyder RJ, Hanft JR. Diabetic foot ulcers—effects on quality of life, costs, and mortality and the role of standard wound care and advanced-care therapies in healing: a review. Ostomy Wound Manage. 2009;55:28.
    1. Thorud JC, Jupiter DC, Lorenzana J, et al. Reoperation and reamputation after transmetatarsal amputation: a systematic review and meta-analysis. J. Foot Ankle Surg. 2016;55:1007–1012. doi: 10.1053/j.jfas.2016.05.011.
    1. Margolis DJ, Malay DS, Hoffstad OJ, et al. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008. 2011.
    1. Schaper N, Van Netten J, Apelqvist J, et al. Prevention and management of foot problems in diabetes: a Summary Guidance for Daily Practice 2015, based on the IWGDF guidance documents. Diabetes Res Clin Pract. 2017;124:84–92. doi: 10.1016/j.diabres.2016.12.007.
    1. Schaper NC, Apelqvist J, Bakker K. The international consensus and practical guidelines on the management and prevention of the diabetic foot. Curr. Diab. Rep. 2003;3:475–479. doi: 10.1007/s11892-003-0010-4.
    1. Bakker K., Apelqvist J., Schaper N. C. Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes/Metabolism Research and Reviews. 2012;28:225–231. doi: 10.1002/dmrr.2253.
    1. Shu X, Shu S, Tang S, et al. Efficiency of stem cell based therapy in the treatment of diabetic foot ulcer: a meta-analysis. Endocr J. 2018;65:403–413. doi: 10.1507/endocrj.EJ17-0424.
    1. Cao Yue, Gang Xiaokun, Sun Chenglin, Wang Guixia. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. Journal of Diabetes Research. 2017;2017:1–10.
    1. Didangelos T, Koliakos G, Kouzi K, et al. Accelerated healing of a diabetic foot ulcer using autologous stromal vascular fraction suspended in platelet-rich plasma. Regen Med. 2018;13:277–281. doi: 10.2217/rme-2017-0069.
    1. Lopes L, Setia O, Aurshina A, et al. Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research. Stem Cell Res Ther. 2018;9:188. doi: 10.1186/s13287-018-0938-6.
    1. Jeffcoate WJ, Vileikyte L, Boyko EJ, et al. Current challenges and opportunities in the prevention and management of diabetic foot ulcers. Diabetes Care. 2018;41:645–652. doi: 10.2337/dc17-1836.
    1. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–15. doi: 10.1016/j.stem.2011.06.008.
    1. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–1084. doi: 10.1002/jcb.20886.
    1. Gimble JM, Guilak F, Bunnell BA. Clinical and preclinical translation of cell-based therapies using adipose tissue-derived cells. Stem Cell Res Ther. 2010;1:1. doi: 10.1186/scrt19.
    1. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–4295. doi: 10.1091/mbc.e02-02-0105.
    1. Ebrahimian TG, Pouzoulet F, Squiban C, et al. Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing. Arterioscler Thromb Vasc Biol. 2009;29:503–510. doi: 10.1161/ATVBAHA.108.178962.
    1. Marfia G, Navone SE, Di Vito C, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 2015;11:183–206. doi: 10.1080/15476278.2015.1126018.
    1. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–228. doi: 10.1089/107632701300062859.
    1. Ährlund-Richter L, De Luca M, Marshak DR, et al. Isolation and production of cells suitable for human therapy: challenges ahead. Cell Stem Cell. 2009;4:20–26. doi: 10.1016/j.stem.2008.11.012.
    1. Arcidiacono JA, Blair JW, Benton KA. US Food and Drug Administration international collaborations for cellular therapy product regulation. Stem Cell Res Ther. 2012;3:1. doi: 10.1186/scrt129.
    1. Oberbauer E, Steffenhagen C, Wurzer C, et al. Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. Cell Regeneration. 2015;4:1. doi: 10.1186/s13619-015-0020-0.
    1. Sensebé L, Bourin P, Tarte K. Good manufacturing practices production of mesenchymal stem/stromal cells. Hum Gene Ther. 2010;22:19–26. doi: 10.1089/hum.2010.197.
    1. Gutowski KA, Force AFGT. Current applications and safety of autologous fat grafts: a report of the ASPS fat graft task force. Plast Reconstr Surg. 2009;124:272–280. doi: 10.1097/PRS.0b013e3181a09506.
    1. Bianchi F, Maioli M, Leonardi E, et al. A new nonenzymatic method and device to obtain a fat tissue derivative highly enriched in pericyte-like elements by mild mechanical forces from human lipoaspirates. Cell Transplant. 2013;22:2063–2077. doi: 10.3727/096368912X657855.
    1. Tassinari R, Canaider S, Pasquinelli G, et al. Lipogems, a new modality of fat tissue handling to enhance tissue repair in chronic hind limb ischemia. CellR4. 2014;2:e1289.
    1. Ceserani V, Ferri A, Berenzi A, et al. Angiogenic and anti-inflammatory properties of micro-fragmented fat tissue and its derived mesenchymal stromal cells. Vascular Cell. 2016;8:3. doi: 10.1186/s13221-016-0037-3.
    1. Cattaneo G, De Caro A, Napoli F, et al. Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2018;19:176. doi: 10.1186/s12891-018-2105-8.
    1. Russo A, Screpis D, Di Donato S, et al. Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3 year follow-up. J Exp Orthop. 2018;5:52. doi: 10.1186/s40634-018-0169-x.
    1. Benzi R, Marfia G, Bosetti M, et al. Microfractured lipoaspirate may help oral bone and soft tissue regeneration: a case report. CellR4. 2015;3:e1583.
    1. Giori A, Tremolada C, Vailati R, et al. Recovery of function in anal incontinence after micro-fragmented fat graft (Lipogems®) injection: two years follow up of the first 5 cases. CellR4. 2015;3:e1544.
    1. Naldini G, Sturiale A, Fabiani B, et al. Micro-fragmented adipose tissue injection for the treatment of complex anal fistula: a pilot study accessing safety and feasibility. Tech Coloproctol. 2018;22:107–113. doi: 10.1007/s10151-018-1755-8.
    1. Grossi P, Giarratana S, Cernei S, et al. Low back pain treated with disc decompression and autologous micro-fragmented adipose tissue: a case report. CellR4. 2016;4:e1772.
    1. Franceschini M, Castellaneta C, Mineo G. Injection of autologous micro-fragmented adipose tissue for the treatment of post-traumatic degenerative lesion of knee cartilage: a case report. CellR4. 2016;4:e1768.
    1. Raffaini M, Tremolada C. Micro fractured and purified adipose tissue graft (Lipogems®) can improve the orthognathic surgery outcomes both aesthetically and in postoperative healing. CellR4. 2014;2:e1118.
    1. Saibene A, Pipolo C, Lorusso R, et al. Transnasal endoscopic microfractured fat injection in glottic insufficiency. B-ENT. 2014;11:229–234.
    1. Striano R, Chen H, Bilbool N, et al. Non-responsive knee pain with osteoarthritis and concurrent meniscal disease treated with autologous microfragmented adipose tissue under continuous ultrasound guidance. CellR4. 2015;3:e1690.
    1. Russo A, Condello V, Madonna V, et al. Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J Exp Orthop. 2017;4:33. doi: 10.1186/s40634-017-0108-2.
    1. Dash SN, Dash NR, Guru B, et al. Towards reaching the target: clinical application of mesenchymal stem cells for diabetic foot ulcers. Rejuvenation Res. 2014;17:40–53. doi: 10.1089/rej.2013.1467.
    1. Aronowitz JA, Lockhart RA, Hakakian CS. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. Springerplus. 2015;4:713. doi: 10.1186/s40064-015-1509-2.
    1. Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res Ther. 2017;8:145. doi: 10.1186/s13287-017-0598-y.
    1. Cárdenas-Camarena L, Arenas-Quintana R, Robles-Cervantes J-A. Buttocks fat grafting: 14 years of evolution and experience. Plast Reconstr Surg. 2011;128:545–555. doi: 10.1097/PRS.0b013e31821b640b.
    1. Schreiber AK, Nones CF, Reis RC, et al. Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes. 2015;6:432. doi: 10.4239/wjd.v6.i3.432.
    1. García-Contreras M, Messaggio F, Jimenez O, et al. Differences in exosome content of human adipose tissue processed by non-enzymatic and enzymatic methods. CellR4. 2015;3:e1423.
    1. Garcia-Contreras M, Messaggio F, Mendez A, et al. Metabolomic changes in human adipose tissue derived products following non-enzymatic microfacturing. Eur Rev Med Pharmacol Sci. 2018;22:3249–3260.
    1. Vezzani B, Shaw I, Lesme H, et al. Higher pericyte content and secretory activity of microfragmented human adipose tissue compared to enzymatically derived stromal vascular fraction. Stem Cells Transl Med. 2018;7:876–886. doi: 10.1002/sctm.18-0051.
    1. Nava Sara, Sordi Valeria, Pascucci Luisa, Tremolada Carlo, Ciusani Emilio, Zeira Offer, Cadei Moris, Soldati Gianni, Pessina Augusto, Parati Eugenio, Slevin Mark, Alessandri Giulio. Long-Lasting Anti-Inflammatory Activity of Human Microfragmented Adipose Tissue. Stem Cells International. 2019;2019:1–13. doi: 10.1155/2019/5901479.
    1. Gadelkarim M, Abushouk AI, Ghanem E, et al. Adipose-derived stem cells: effectiveness and advances in delivery in diabetic wound healing. Biomed Pharmacother. 2018;107:625–633. doi: 10.1016/j.biopha.2018.08.013.

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