Fat as an Adjunct in Nerve Surgery

Peripheral nerve surgery involves suturing an injured nerve to itself or to another nerve end-to-end or side-to-end to promote regeneration of the damaged nerve. Nerve surgeries include repair, grafting, transfer, and decompression. Poor outcomes of nerve surgery can occur if the nerve incompletely heals, which can result in motor and/or sensory deficits depending on the type of nerve. Adipose tissue has been exploratively used as an adjunct to peripheral nerve surgery in an attempt to provide additional support to repaired nerves and promote the healing process. 

Adipose tissue contains Adipose-Derived Stem Cells (ADSCs), which supply the regenerative properties of the tissue. ADSCs can produce exosomes occupied with transcripts for various neural growth factors to aid in Schwann cell proliferation and, ultimately, axon regrowth [1]. Stem cells in adipose tissue have demonstrated ability to express Brain-Derived Neurotrophic Factor (BDNF), Glial-Derived Neurotrophic Factor (GDNF), Ciliary Neurotrophic Factor (CNTF), basic Fibroblasts Growth Factor (bFGF), insulin-like growth factor 1 (IGF-1), Nerve Growth Factor (NGF) and neutrophin-3 and -4 (NT-3, NT-4) which correlated with increases in axon sprouting [2]. In vivo, ADSCs exhibit migration to sites distal to the injury, which is where Wallerian degeneration and subsequent axon regrowth occur [3]. Schwann cells are responsible for myelination in the peripheral nervous system. ADSCs present in adipose tissue have been shown to support existing Schwann cells at the site of injury, as well as possess the ability to differentiate into Schwann-like cells themselves [4,5]. Additionally, fat grafting after sciatic nerve surgery in rats resulted in decreased scar tissue growth [6]. Adhesions around the site of surgical nerve repair can lead to worse outcomes by restricting free movement, so minimizing scar tissue is an added benefit provided by ADSCs. 

In a recent review, our group explored the literature regarding the use of adipose tissue and ADSCs in conjunction with peripheral nerve surgeries in animal studies [7]. Studies of surgical repairs, grafts, Tissue-Engineered Nerve Grafts (TENGs), and transfers that used fat grafting or ADSC injection near the site of repair were evaluated. Some of the most compelling nerve repair studies showed improved functional recovery on a swim test at 2 and 6 weeks with ADSC injection near the repair site and increased functional recovery determined by pin prick test after fat grafting [8,9]. Nerve grafting animal studies with ADSC supplementation obtained results revealing more myelin fibers, increased distal muscle responsiveness on electromyography, and reduced reinnervation time compared to controls [10,11]. Numerous experiments utilizing ADSCs with TENGs had positive results, but all studies had small sample sizes with the largest sample size being n=16. Notably, nerve transfers in conjunction with ADSCs correlated functional outcomes with histological results, which provides a more powerful level of evidence. Abbas et al. correlated vibrissae motor performances with histological results of facial nerve transfers with and without ADSCs [12]. Additionally, Yang et al., correlated modified grooming test results to evaluate various shoulder movements and elbow flexion with histological results of brachial plexus C7 nerve transfers with and without ADSC seeding in engineered nerve grafts [13]. Animal studies provide insight to the mechanisms of action of the ADSCs in adipose tissue on damaged and regenerating peripheral nerves on a level that is not always attainable or ethical in human studies. 

Though more animal studies exist, a small number of human studies concerning the use of fat grafting concomitant with peripheral nerve surgery are present in the literature. Of the types of peripheral nerve surgery, use of fat grafting with nerve release for decompression surgery seems the most explored, likely exploiting the ability of adipose tissue to reduce scar tissue formation. A retrospective study of 40 patients regarding the use of free fat grafts in secondary surgical decompression of recalcitrant carpal tunnel syndrome concluded there to be no benefit of fat grafted groups compared to controls [14]. Fat grafted patients reported more scar sensitivity immediately after surgery, but long term follow up revealed no difference in scar sensitivity between fat grafted patients and controls. A study of three patients undergoing secondary decompression of median or ulnar nerves with ADSC injection noted gradual sensory recovery at 36 months with no reported adverse effects [15]. Though promising results were obtained, the study would hold more power if ADSC supplemented patient results were compared to control patient results. 

Peripheral nerve injuries present challenges in healing even after surgical correction and can prove disabling [16]. Novel ideas about how to improve nerve surgery outcomes are becoming increasingly explored. ADSCs present in adipose tissue have shown promising regenerative properties on peripheral nerves and the nerve microenvironment in vitro, in animal experiments, and in some human studies. For now, animal studies correlating functional outcomes with histological observations provide the most powerful and convincing evidence for the use of fat in conjunction with peripheral nerve surgery. More human studies, especially randomized control trials, will need to be performed to draw conclusions on the usefulness of fat grafting as an adjunct to peripheral nerve surgery in humans.

1. Liu CY, Yin G, Sun YD, Lin YF, Xie Z, et al. (2020) Effect of exosomes from adipose-derived stem cells on the apoptosis of Schwann cells in peripheral nerve injury. CNS Neurosci Ther 26: 189-196.
2. Widgerow AD, Salibian AA, Lalezari S, Evans GR (2013) Neuromodulatory nerve regeneration: adipose tissue-derived stem cells and neurotrophic mediation in peripheral nerve regeneration. J Neurosci Res 91: 1517-1524.
3. Dong S, Feng S, Chen Y, Chen M, Yang Y, et al. (2021) Nerve Suture Combined With ADSCs Injection Under Real-Time and Dynamic NIR-II Fluorescence Imaging in Peripheral Nerve Regeneration in vivo. Front Chem 9: 676928.
4. Kingham PJ, Kolar MK, Novikova LN, Novikov LN, Wiberg M (2014) Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev 23: 741-754.
5. di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, et al. (2010) Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg 63: 1544-1552.
6. Cherubino M, Pellegatta I, Crosio A, Valdatta L, Geuna S, et al. (2017) Use of human fat grafting in the prevention of perineural adherence: Experimental study in athymic mouse. PLoS One 12: 0176393.
7. Podsednik A, Cabrejo R, Rosen J (2022) Adipose Tissue Uses in Peripheral Nerve Surgery. Int J Mol Sci 23: 644.
8. Schweizer R, Schnider JT, Fanzio PM, Tsuji W, Kostereva N, et al. (2020) Effect of Systemic Adipose-derived Stem Cell Therapy on Functional Nerve Regeneration in a Rodent Model. Plast Reconstr Surg Glob Open 8: 2953.
9. Tuncel U, Kostakoglu N, Turan A, Cevik B, Cayli, et al. (2015) 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: 1181-1191.
10. Masgutov R, Masgutova G, Mullakhmetova A, Zhuravleva M, Shulman, et al. (2019) Adipose-Derived Mesenchymal Stem Cells Applied in Fibrin Glue Stimulate Peripheral Nerve Regeneration. Front Med (Lausanne) 6: 68.
11. Fujii K, Matsumine H, Osaki H, Ueta Y, Kamei W, et al. (2020) Accelerated outgrowth in cross-facial nerve grafts wrapped with adipose-derived stem cell sheets. J Tissue Eng Regen Med 14: 1087-1099.
12. Abbas OL, Borman H, Uysal CA, Gonen ZB, Aydin L, et al. (2016) Adipose-Derived Stem Cells Enhance Axonal Regeneration through Cross-Facial Nerve Grafting in a Rat Model of Facial Paralysis. Plast Reconstr Surg 138: 387-396.
13. Yang JT, Fang JT, Li L, Chen G, Qin BG, et al. (2019) Contralateral C7 transfer combined with acellular nerve allografts seeded with differentiated adipose stem cells for repairing upper brachial plexus injury in rats. Neural Regen Res 14: 1932-1940.
14. Impelmans JMBE, Burke FD (2001) The use of free fat grafts in recalcitrant carpal tunnel: a retrosepctive study. Eur J Plast Surg 24: 12-17.
15. Krzesniak NE, Sarnowska A, Figiel-Dabrowska A, Osiak K, Domanska-Janik K, et al. (2021) Secondary release of the peripheral nerve with autologous fat derivates benefits for functional and sensory recovery. Neural Regen Res 16: 856-864.
16. Walocko FM, Khouri RK Jr, Urbanchek MG, Levi B, Cederna PS (2016) The potential roles for adipose tissue in peripheral nerve regeneration. Microsurgery 36: 81-88.