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Regenerative Medicine

Autologous fat grafting for nerve regeneration and neuropathic pain: current state from bench-to-bedside

    Amir Dehdashtian

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Jarred V Bratley

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Shelby R Svientek

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Theodore A Kung

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Tariq M Awan

    Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Paul S Cederna

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA

    &
    Stephen WP Kemp

    *Author for correspondence: Tel.: (734) 764 8750;

    E-mail Address: swpkemp@med.umich.edu

    Department of Surgery, Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI 48109, USA

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA

    Published Online:https://doi.org/10.2217/rme-2020-0103

    Despite recent advances in microsurgical techniques, functional recovery following peripheral nerve injury remains slow and inadequate. Poor peripheral nerve regeneration not only leaves patients with significant impairments, but also commonly leads to the development of debilitating neuropathic pain. Recent research has demonstrated the potential therapeutic benefits of adipose-derived stem cells, to enhance nerve regeneration. However, clinical translation remains limited due to the current regulatory burdens of the US FDA. A reliable and immediately translatable alternative is autologous fat grafting, where native adipose-derived stem cells present in the transferred tissue can potentially act upon regenerating axons. This review presents the scope of adipose tissue-based therapies to enhance outcomes following peripheral nerve injury, specifically focusing on their role in regeneration and ameliorating neuropathic pain.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Foster CH, Karsy M, Jensen MR, Guan J, Eli I, Mahan MA. Trends and cost-analysis of lower extremity nerve injury using the National Inpatient Sample. Neurosurgery 85(2), 250–256 (2019).
    • 2. Taylor CA, Braza D, Rice JB, Dillingham T. The incidence of peripheral nerve injury in extremity trauma. Am. J. Phys. Med. Rehabil. 87(5), 381–385 (2008).
    • 3. Dahlin L. Techniques of peripheral nerve repair. Scand. J. Surg. 97(4), 310–316 (2008).
    • 4. Schmidhammer R, Zandieh S, Hopf R et al. Alleviated tension at the repair site enhances functional regeneration: the effect of full range of motion mobilization on the regeneration of peripheral nerves—histologic, electrophysiologic and functional results in a rat model. J. Trauma Acute Care Surg. 56(3), 571–584 (2004).
    • 5. Yi C, Dahlin LB. Impaired nerve regeneration and Schwann cell activation after repair with tension. Neuroreport 21(14), 958–962 (2010).
    • 6. Dahlin LB. The role of timing in nerve reconstruction. Int. Rev. Neurobiol. 109, 151–164 (2013).
    • 7. Grinsell D, Keating C. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. BioMed Res. Int. 2014, 13 (2014).
    • 8. Fowler JR, Lavasani M, Huard J, Goitz RJ. Biologic strategies to improve nerve regeneration after peripheral nerve repair. J. Reconstr. Microsurg. 31(04), 243–248 (2015).
    • 9. Kubiak CA, Kung TA, Brown DL, Cederna PS, Kemp SW. State-of-the-art techniques in treating peripheral nerve injury. Plast. Reconstr. Surg. 141(3), 702–710 (2018).
    • 10. Wei Z, Fei Y, Su W, Chen G. Emerging role of Schwann cells in neuropathic pain: receptors, glial mediators and myelination. Front. Cell. Neurosci. 13, 116 (2019).
    • 11. Dubový P. Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction. Ann. Anat. 193(4), 267–275 (2011).
    • 12. Kuffler DP. Mechanisms for reducing neuropathic pain. Mol. Neurobiol. 57(1), 67–87 (2020).
    • 13. Frostick SP, Yin Q, Kemp GJ. Schwann cells, neurotrophic factors and peripheral nerve regeneration. Microsurgery 18(7), 397–405 (1998).
    • 14. Gordon T. Nerve regeneration: understanding biology and its influence on return of function after nerve transfers. Hand Clin. 32(2), 103–117 (2016).
    • 15. Sulaiman OA, Gordon T. Role of chronic Schwann cell denervation in poor functional recovery after nerve injuries and experimental strategies to combat it. Neurosurgery 65(Suppl. 4), A105–A114 (2009).
    • 16. Lopez‐Verrilli MA, Picou F, Court FA. Schwann cell‐derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61(11), 1795–1806 (2013).
    • 17. Li R, Liu Z, Pan Y, Chen L, Zhang Z, Lu L. Peripheral nerve injuries treatment: a systematic review. Cell Biochem. Biophys. 68(3), 449–454 (2014).
    • 18. Kubiak CA, Grochmal J, Kung TA, Cederna PS, Midha R, Kemp SW. Stem‐cell–based therapies to enhance peripheral nerve regeneration. Muscle Nerve 61(4), 449–459 (2020).
    • 19. Walocko FM, Khouri Jr RK, Urbanchek MG, Levi B, Cederna PS. The potential roles for adipose tissue in peripheral nerve regeneration. Microsurgery 36(1), 81–88 (2016).
    • 20. Forouzanfar F, Amin B, Ghorbani A et al. New approach for the treatment of neuropathic pain: fibroblast growth factor 1 gene‐transfected adipose‐derived mesenchymal stem cells. Eur. J. Pain 22(2), 295–310 (2018).
    • 21. Faroni A, Terenghi G, Reid AJ. Adipose-derived stem cells and nerve regeneration: promises and pitfalls. Int. Rev. Neurobiol. 108, 121–136 (2013).
    • 22. Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell. Res. Ther. 8(1), 145 (2017).
    • 23. Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H. Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone‐marrow stromal cells. Eur. J. Neurosci. 14(11), 1771–1776 (2001).
    • 24. Xu Y, Liu Z, Liu L et al. Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro. BMC Neurosci. 9(1), 21 (2008).
    • 25. Radtke C, Schmitz B, Spies M, Kocsis J, Vogt P. Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. Int. J. Dev. Neurosci. 27(8), 817–823 (2009).
    • 26. Wei Y, Gong K, Zheng Z et al. Schwann‐like cell differentiation of rat adipose‐derived stem cells by indirect co‐culture with Schwann cells in vitro. Cell Prolif. 43(6), 606–616 (2010).
    • 27. Kalbermatten DF, Schaakxs D, Kingham PJ, Wiberg M. Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat. Cell Tissue Res. 344(2), 251–260 (2011).
    • 28. Tomita K, Madura T, Sakai Y, Yano K, Terenghi G, Hosokawa K. Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy. Neuroscience 236, 55–65 (2013).
    • 29. Sun F, Zhou K, Mi W-J, Qiu J-H. Combined use of decellularized allogeneic artery conduits with autologous transdifferentiated adipose-derived stem cells for facial nerve regeneration in rats. Biomaterials 32(32), 8118–8128 (2011).
    • 30. Tomita K, Madura T, Mantovani C, Terenghi G. Differentiated adipose‐derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation. J. Neurosci. Res. 90(7), 1392–1402 (2012).
    • 31. Di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, Kalbermatten DF. Adipose-derived stem cells enhance peripheral nerve regeneration. J. Plast. Reconstr. Aesthet. Surg. 63(9), 1544–1552 (2010).
    • 32. Orbay H, Tobita M, Mizuno H. Mesenchymal stem cells isolated from adipose and other tissues: basic biological properties and clinical applications. Stem Cells Int. 2012, 461718 (2012).
    • 33. J Salgado A, L Reis R, Sousa N, M Gimble J. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr. Stem Cell Res. Ther. 5(2), 103–110 (2010).
    • 34. Kapur SK, Katz AJ. Review of the adipose derived stem cell secretome. Biochimie 95(12), 2222–2228 (2013).
    • 35. Sowa Y, Kishida T, Imura T et al. Adipose-derived stem cells promote peripheral nerve regeneration in vivo without differentiation into Schwann-like lineage. Plast. Reconstr. Surg. 137(2), 318e–330e (2016).
    • 36. Di Summa PG, Kalbermatten DF, Pralong E, Raffoul W, Kingham PJ, Terenghi G. Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts. Neuroscience 181, 278–291 (2011).
    • 37. Hsieh S-C, Chang C-J, Cheng W-T, Tseng T-C, Hsu S-H. Effect of an epineurial-like biohybrid nerve conduit on nerve regeneration. Cell Transplant. 25(3), 559–574 (2016).
    • 38. Schaakxs D, Kalbermatten DF, Pralong E, Raffoul W, Wiberg M, Kingham PJ. Poly‐3‐hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair. J. Tissue Eng. Regen. Med. 11(3), 812–821 (2017).
    • 39. Wang Y, Zhao Z, Ren Z et al. Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci. Lett. 514(1), 96–101 (2012).
    • 40. Syu W-Z, Hueng D-Y, Chen W-L, Chan JY-H, Chen S-G, Huang S-M. Adipose-derived neural stem cells combined with acellular dermal matrix as a neural conduit enhances peripheral nerve repair. Cell Transplant. 28(9-10), 1220–1230 (2019).
    • 41. Masgutov R, Masgutova G, Mukhametova L et al. Allogenic adipose derived stem cells transplantation improved sciatic nerve regeneration in rats: autologous nerve graft model. Front. Pharmacol. 9, 86 (2018).
    • 42. Carriel V, Garrido-Gómez J, Hernández-Cortés P et al. Combination of fibrin-agarose hydrogels and adipose-derived mesenchymal stem cells for peripheral nerve regeneration. J. Neural Eng. 10(2), 026022 (2013).
    • 43. Liu Y, Dong R, Zhang C et al. Therapeutic effects of nerve leachate-treated adipose-derived mesenchymal stem cells on rat sciatic nerve injury. Exp. Ther. Med. 19(1), 223–231 (2020).
    • 44. Kim D-Y, Choi Y-S, Kim S-E et al. In vivo effects of adipose-derived stem cells in inducing neuronal regeneration in Sprague-Dawley rats undergoing nerve defect bridged with polycaprolactone nanotubes. J. Korean Med. Sci. 29(Suppl. 3), S183–S192 (2014).
    • 45. Watanabe Y, Sasaki R, Matsumine H, Yamato M, Okano T. Undifferentiated and differentiated adipose‐derived stem cells improve nerve regeneration in a rat model of facial nerve defect. J. Tissue Eng. Regen. Med. 11(2), 362–374 (2017).
    • 46. Zhang R, Rosen JM. The role of undifferentiated adipose-derived stem cells in peripheral nerve repair. Neural Regen. Res. 13(5), 757 (2018).
    • 47. Shimizu M, Matsumine H, Osaki H et al. Adipose‐derived stem cells and the stromal vascular fraction in polyglycolic acid‐collagen nerve conduits promote rat facial nerve regeneration. Wound Repair Regen. 26(6), 446–455 (2018).
    • 48. Matsumine H, Numakura K, Climov M, Watanabe Y, Giatsidis G, Orgill DP. Facial‐nerve regeneration ability of a hybrid artificial nerve conduit containing uncultured adipose‐derived stromal vascular fraction: an experimental study. Microsurgery 37(7), 808–818 (2017). • While SVF contains a lower concentration of ADSCs, it was still able to improve nerve regeneration similar to the purified and cultured ADSCs in rats.
    • 49. Suganuma S, Tada K, Hayashi K et al. Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration. J. Orthop. Sci. 18(1), 145–151 (2013).
    • 50. Mohammadi R, Azizi S, Delirezh N, Hobbenaghi R, Amini K. Transplantation of uncultured omental adipose-derived stromal vascular fraction improves sciatic nerve regeneration and functional recovery through inside-out vein graft in rats. J. Trauma Acute Care Surg. 72(2), 390–396 (2012).
    • 51. Mohammadi R, Sanaei N, Ahsan S, Rostami H, Abbasipour-Dalivand S, Amini K. Repair of nerve defect with chitosan graft supplemented by uncultured characterized stromal vascular fraction in streptozotocin induced diabetic rats. Int. J. Surg. 12(1), 33–40 (2014).
    • 52. Mohammadi R, Asadollahi A, Amini K. Uncultured undifferentiated adipose-derived nucleated cell fractions combined with inside-out artery graft accelerate sciatic nerve regeneration and functional recovery. Int. J. Oral Maxillofac. Surg. 43(9), 1161–1168 (2014).
    • 53. Kilic A, Ojo B, Rajfer RA et al. Effect of white adipose tissue flap and insulin‐like growth factor‐1 on nerve regeneration in rats. Microsurgery 33(5), 367–375 (2013).
    • 54. Tuncel U, Kostakoglu N, Turan A et al. The effect of autologous fat graft with different surgical repair methods on nerve regeneration in a rat sciatic nerve defect model. Plast. Reconstr. Surg. 136(6), 1181–1191 (2015). • Fat grafting enhanced nerve regeneration with subsequent improvement in motor and sensory functions in a rat model of nerve injury.
    • 55. Bloancă V, Ceauşu AR, Jitariu AA et al. Adipose tissue graft improves early but not late stages of nerve regeneration. In Vivo 31(4), 649–655 (2017).
    • 56. Hsueh Y-Y, Chang Y-J, Huang T-C et al. Functional recoveries of sciatic nerve regeneration by combining chitosan-coated conduit and neurosphere cells induced from adipose-derived stem cells. Biomaterials 35(7), 2234–2244 (2014).
    • 57. Liu G-B, Cheng Y-X, Feng Y-K et al. Adipose-derived stem cells promote peripheral nerve repair. Arch. Med. Sci. 7(4), 592 (2011).
    • 58. Saller MM, Huettl R-E, Mayer JM et al. Validation of a novel animal model for sciatic nerve repair with an adipose-derived stem cell loaded fibrin conduit. Neural Regen. Res. 13(5), 854 (2018).
    • 59. Strong AL, Cederna PS, Rubin JP, Coleman SR, Levi B. The current state of fat grafting: a review of harvesting, processing and injection techniques. Plast. Reconstr. Surg. 136(4), 897 (2015).
    • 60. Kuffler DP. Injury-induced effectors of neuropathic pain. Mol. Neurobiol. 57(1), 51–66 (2020).
    • 61. Feng N, Jia Y, Huang X. Exosomes from adipose-derived stem cells alleviate neural injury caused by microglia activation via suppressing NF-kB and MAPK pathway. J. Neuroimmunol. 334, 576996 (2019).
    • 62. Xie W, Strong JA, Zhang J-M. Active nerve regeneration with failed target reinnervation drives persistent neuropathic pain. eNeuro 4(1), 1–16 (2017). •• The incomplete process of nerve regeneration can be directly associated with neuropathic pain development.
    • 63. Davies AJ, Kim HW, Gonzalez-Cano R et al. Natural killer cells degenerate intact sensory afferents following nerve injury. Cell 176(4), 716–728.e718 (2019).
    • 64. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10(9), 895–926 (2009).
    • 65. Meacham K, Shepherd A, Mohapatra DP, Haroutounian S. Neuropathic pain: central vs. peripheral mechanisms. Curr. Pain Headache Rep. 21(6), 28 (2017).
    • 66. Marcol W, Kotulska K, Larysz-Brysz M, Kowalik JL. BDNF contributes to animal model neuropathic pain after peripheral nerve transection. Neurosurg. Rev. 30(3), 235–243 (2007).
    • 67. Haselbach D, Raffoul W, Larcher L, Tremp M, Kalbermatten DF, Di Summa PG. Regeneration patterns influence hindlimb automutilation after sciatic nerve repair using stem cells in rats. Neurosci. Lett. 634, 153–159 (2016).
    • 68. Lee HY, Lee H-L, Yun Y et al. Human adipose stem cells improve mechanical allodynia and enhance functional recovery in a rat model of neuropathic pain. Tissue Eng. Part A 21(13-14), 2044–2052 (2015).
    • 69. Noh M-C, Stemkowski PL, Smith PA. Long-term actions of interleukin-1β on K+, Na+ and Ca2+ channel currents in small, IB4-positive dorsal root ganglion neurons; possible relevance to the etiology of neuropathic pain. J. Neuroimmunol. 332, 198–211 (2019).
    • 70. Stemkowski PL, Noh MC, Chen Y, Smith PA. Increased excitability of medium‐sized dorsal root ganglion neurons by prolonged interleukin‐1β exposure is K+ channel dependent and reversible. J. Physiol. 593(16), 3739–3755 (2015).
    • 71. Czeschik JC, Hagenacker T, Schäfers M, Büsselberg D. TNF-α differentially modulates ion channels of nociceptive neurons. Neurosci. Lett. 434(3), 293–298 (2008).
    • 72. Ratté S, Prescott SA. Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy. Curr. Opin. Neurobiol. 36, 31–37 (2016).
    • 73. Yan H, Gao W, Pan Z, Zhang F, Fan C. The expression of α-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. J. Neurotrauma 29(18), 2791–2797 (2012).
    • 74. Onode E, Uemura T, Takamatsu K et al. Nerve capping with a nerve conduit for the treatment of painful neuroma in the rat sciatic nerve. J. Neurosurg. doi:10.3171/2018.10.JNS182113 (2019) (Epub ahead of print).
    • 75. Huang S-H, Wu S-H, Chang K-P et al. Autologous fat grafting alleviates burn-induced neuropathic pain in rats. Plast. Reconstr. Surg. 133(6), 1396–1405 (2014).
    • 76. Strong AL, Agarwal S, Cederna PS, Levi B. Peripheral neuropathy and nerve compression syndromes in burns. Clin. Plast. Surg. 44(4), 793–803 (2017).
    • 77. Ji R-R, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat. Revi. Neurosci. 20(11), 667–685 (2019).
    • 78. Yu X, Liu H, Hamel KA et al. Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain. Nat. Commun. 11(1), 1–12 (2020).
    • 79. Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat. Rev. Neurosci. 19(3), 138 (2018).
    • 80. Suter MR, Wen Y-R, Decosterd I, Ji R-R. Do glial cells control pain? Neuron Glia Biol. 3(3), 255–268 (2007).
    • 81. Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J. Neurosci. 28(48), 12775–12787 (2008).
    • 82. Shih R-H, Wang C-Y, Yang C-M. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front. Mol. Neurosci. 8, 77 (2015).
    • 83. Brini AT, Amodeo G, Ferreira LM et al. Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain. Sci. Rep. 7(1), 1–15 (2017). • ADSCs and their secretomes mitigated central and peripheral neuronal inflammation and subsequently improved neuropathic pain in diabetic rats.
    • 84. Da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 20(5-6), 419–427 (2009).
    • 85. Yang J, Zhang X, Chen X, Wang L, Yang G. Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol. Ther. Nucleic Acids 7, 278–287 (2017).
    • 86. Han Y, Seyfried D, Meng Y et al. Multipotent mesenchymal stromal cell–derived exosomes improve functional recovery after experimental intracerebral hemorrhage in the rat. J. Neurosurg. 131(1), 290–300 (2018).
    • 87. Kang SK, Shin IS, Ko MS, Jo JY, Ra JC. Journey of mesenchymal stem cells for homing: strategies to enhance efficacy and safety of stem cell therapy. Stem Cells Int. 2012, 342968 (2012).
    • 88. Erba P, Terenghi G, J Kingham P. Neural differentiation and therapeutic potential of adipose tissue derived stem cells. Curr. Stem Cell Res. Ther. 5(2), 153–160 (2010).
    • 89. Sacerdote P, Niada S, Franchi S et al. Systemic administration of human adipose-derived stem cells reverts nociceptive hypersensitivity in an experimental model of neuropathy. Stem Cells Dev. 22(8), 1252–1263 (2013).
    • 90. Mert T, Kurt AH, Altun İ, Celik A, Baran F, Gunay I. Pulsed magnetic field enhances therapeutic efficiency of mesenchymal stem cells in chronic neuropathic pain model. Bioelectromagnetics 38(4), 255–264 (2017).
    • 91. Huang S-H, Wu S-H, Lee S-S et al. Fat grafting in burn scar alleviates neuropathic pain via anti-inflammation effect in scar and spinal cord. PLoS ONE 10(9), 1–13 (2015).
    • 92. Lin C-H, Wu S-H, Lee S-S et al. Autologous adipose-derived stem cells reduce burn-induced neuropathic pain in a rat model. Int. J. Mol. Sci. 19(1), 34 (2018).
    • 93. Haahr MK, Jensen CH, Toyserkani NM et al. Safety and potential effect of a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label Phase I clinical trial. EBioMedicine 5, 204–210 (2016). •• SVF injection into the corpus cavernosum improved erectile dysfunction in patients whose neurovascular bundle had been severed due to the radical prostatectomy surgery.
    • 94. Salonia A, Burnett AL, Graefen M et al. Prevention and management of postprostatectomy sexual dysfunctions part 1: choosing the right patient at the right time for the right surgery. Eur. Urol. 62(2), 261–272 (2012).
    • 95. Haahr MK, Jensen CH, Toyserkani NM et al. A 12-month follow-up after a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label Phase I clinical trial. Urology 121, 203.e206–203.e213 (2018).
    • 96. Van Hecke O, Austin SK, Khan RA, Smith B, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. PAIN® 155(4), 654–662 (2014).
    • 97. Alessandri-Bonetti M, Egro FM, Persichetti P, Coleman SR, Rubin JP. The role of fat grafting in alleviating neuropathic pain: a critical review of the literature. Plast. Reconstr. Surg.Global Open 7(5), 1–8 (2019).
    • 98. Stevens PE, Dibble SL, Miaskowski C. Prevalence, characteristics and impact of postmastectomy pain syndrome: an investigation of women's experiences. Pain 61(1), 61–68 (1995).
    • 99. Caviggioli F, Maione L, Forcellini D, Klinger F, Klinger M. Autologous fat graft in postmastectomy pain syndrome. Plast. Reconstr. Surg. 128(2), 349–352 (2011).
    • 100. Maione L, Vinci V, Caviggioli F et al. Autologous fat graft in postmastectomy pain syndrome following breast conservative surgery and radiotherapy. Aesthetic Plast. Surg. 38(3), 528–532 (2014).
    • 101. Caviggioli F, Maione L, Klinger F, Lisa A, Klinger M. Autologous fat grafting reduces pain in irradiated breast: a review of our experience. Stem Cells Int. 2016, 1–5 (2016).
    • 102. Juhl AA, Karlsson P, Damsgaard TE. Fat grafting for alleviating persistent pain after breast cancer treatment: a randomized controlled trial. J. Plast. Reconstr. Aesthet. Surg. 69(9), 1192–1202 (2016). • Autologous fat grafting reduced post-mastectomy neuropathic pain and enhanced the quality of life.
    • 103. Cogliandro A, Barone M, Tenna S, Coppola MM, Persichetti P. The role of lipofilling after breast reconstruction: evaluation of outcomes and patient satisfaction with BREAST-Q. Aesthetic Plast. Surg. 41(6), 1325–1331 (2017).
    • 104. Vaienti L, Merle M, Battiston B, Villani F, Gazzola R. Perineural fat grafting in the treatment of painful end-neuromas of the upper limb: a pilot study. J. Hand Surg. 38(1), 36–42 (2013).
    • 105. Vaienti L, Amendola F, Borelli F, Zaccaria G, Cottone G. Perineural fat grafting in end-neuroma pain treatment: long-term outcomes. Eur. J. Plast. Surg. 37, 1–6 (2020).
    • 106. Calcagni M, Zimmermann S, Scaglioni MF, Giesen T, Giovanoli P, Fakin RM. The novel treatment of SVF‐enriched fat grafting for painful end‐neuromas of superficial radial nerve. Microsurgery 38(3), 264–269 (2016).
    • 107. Zimmermann S, Fakin RM, Giovanoli P, Calcagni M. Outcome of stromal vascular fraction-enriched fat grafting compared to intramuscular transposition in painful end-neuromas of superficial radial nerve: preliminary results. Frontiers Surg. 5, 10 (2018).
    • 108. Bourne DA, Thomas RD, Bliley J et al. Amputation-site soft-tissue restoration using adipose stem cell therapy. Plast. Reconstr. Surg. 142(5), 1349–1352 (2018).
    • 109. Fredman R, Edkins RE, Hultman CS. Fat grafting for neuropathic pain after severe burns. Ann. Plast. Surg. 76, S298–S303 (2016). • Autologous fat grafting significantly reduced pain in burn patients with refractory neuropathic pain to the previous medical and surgical interventions.
    • 110. Mcfarland LV, Hubbard Winkler SL, Heinemann AW, Jones M, Esquenazi A. Unilateral upper-limb loss: satisfaction and prosthetic-device use in veterans and servicemembers from Vietnam and OIF/OEF conflicts. J. Rehabil. Res. Dev. 47(4), 299–316 (2010).
    • 111. Bavikatte G, Kulkarni J, Choukairi F, Lees V. Use of lipomodeling to forearm residuum to assist fitting of below-elbow prosthesis. J. Prosthetics Orthotics 24(1), 50–51 (2012).
    • 112. Hamed K, Giles N anderson J et al. Changes in cutaneous innervation in patients with chronic pain after burns. Burns 37(4), 631–637 (2011).
    • 113. Summer GJ, Dina OA, Levine JD. Enhanced inflammatory hyperalgesia after recovery from burn injury. Burns 33(8), 1021–1026 (2007).
    • 114. Klinger M, Caviggioli F, Klinger FM et al. Autologous fat graft in scar treatment. J. Craniofac. Surg. 24(5), 1610–1615 (2013).
    • 115. Lifchez SD, Means Jr KR, Dunn RE, Williams EH. Intra-and inter-examiner variability in performing Tinel's test. J. Hand Surg. 35(2), 212–216 (2010).
    • 116. Knoepfler PS, Turner LG. The FDA and the US direct-to-consumer marketplace for stem cell interventions: a temporal analysis. Regen. Med. 13(1), 19–27 (2018).
    • 117. Tocco I, Widgerow AD, Lalezari S, Banyard D, Shaterian A, Evans GR. Lipotransfer: the potential from bench to bedside. Ann. Plast. Surg. 72(5), 599–609 (2014).
    • 118. Dykstra JA, Facile T, Patrick RJ et al. Concise review: fat and furious: Harnessing the full potential of adipose‐derived stromal vascular fraction. Stem Cells Transl. Med. 6(4), 1096–1108 (2017). • At the current state, only autologous fat grafting is considered safe and applicable to the clinical practice.
    • 119. Berry JD, Cudkowicz ME, Windebank AJ et al. NurOwn, phase 2, randomized, clinical trial in patients with ALS: safety, clinical and biomarker results. Neurology 93(24), e2294–e2305 (2019).
    • 120. Cohen JA, Imrey PB, Planchon SM et al. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult. Scler. 24(4), 501–511 (2018).
    • 121. Levi AD, Okonkwo DO, Park P et al. Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery 82(4), 562–575 (2018).
    • 122. Levy ML, Crawford JR, Dib N, Verkh L, Tankovich N, Cramer SC. Phase I/II study of safety and preliminary efficacy of intravenous allogeneic mesenchymal stem cells in chronic stroke. Stroke 50(10), 2835–2841 (2019).
    • 123. Zuk PA, Zhu M, Ashjian P et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13(12), 4279–4295 (2002).
    • 124. Rigotti G, Marchi A, Galiè M et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast. Reconstr. Surg. 119(5), 1409–1422 (2007).
    • 125. Strem BM, Hicok KC, Zhu M et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J. Med. 54(3), 132–141 (2005).