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Page 2 of 9 Kawakibi et al. Plast Aesthet Res 2023;10:48 https://dx.doi.org/10.20517/2347-9264.2022.120

scleroderma, limited to the skin and underlying tissue, and systemic scleroderma, which includes internal
[2,3]
organ involvement . All patients experience some degree of cutaneous involvement of the face and hands
regardless of scleroderma subtype, which results in significant aesthetic and functional concerns for
[1,4]
patients . Current oral and topical therapies have been shown to have some efficacy in slowing the
progression of the cutaneous manifestations of scleroderma; however, these therapies have limited efficacy
and do not reverse skin fibrosis .
[5-7]
AFT has been used safely for decades in facial rejuvenation and, more recently, has become a highly
efficacious surgical procedure performed to optimize breast reconstructions, scar treatments, hand
rejuvenation, and correction of deformities related to congenital anomalies [8-15] . Adipose tissue is composed
of mature adipocytes and a heterogenous stromal vascular fraction (SVF), which includes ASCs,
[16]
preadipocytes, endothelial cells, immune cells, and hematopoietic stem cells . ASCs have recently been
shown to have immunomodulatory, angiogenic, and regenerative potential. Given its rich source of growth
factors, it is believed that AFT can mitigate inflammation, promote angiogenesis, and reverse skin fibrosis in
scleroderma patients, in addition to providing structural volume restoration [9,17] .

PATHOPHYSIOLOGY AND CURRENT TREATMENT OF SCLERODERMA
Scleroderma is the result of microvascular dysfunction and immune cell activation that leads to progressive
tissue fibrosis. In early stages, immune inflammation is characterized by immune cell infiltration leading to
increased levels of proinflammatory cytokines and growth factors (TGF-β, IL-10, PDGF) [18-20] . The degree of
[20]
mononuclear cell infiltration correlates with the severity and progression of skin thickening . The
widespread inflammation eventually results in vascular damage to small arteries and arterioles with intima
swelling and proliferation, which all lead to blood vessel narrowing [18,21-23] . This vascular injury leads to
chronic hypoxia and ischemic changes that result in the differentiation of fibroblasts into
myofibroblasts [24,25] . Myofibroblasts play a critical role in the pathologic changes associated with scleroderma
and are thought to be in a persistently activated state, depositing extracellular matrix proteins that lead to
skin fibrosis [26-29] . Fibrosis generally affects the lower dermis first, prior to spreading to deeper structures and
[19]
leading to skin thickening and hair follicle injury .

Current treatments for scleroderma are systemic. Immunomodulatory agents target the overactive immune
system, antiplatelet and vasodilatory agents improve circulation, and antifibrinolytic agents decrease fibrosis
by targeting collagen synthesis . These agents have been used alone or in combination, depending on the
[30]
severity of symptoms. However, medical management of scleroderma remains challenging given the
significant side effects of the medications and their limited efficacy in preventing and treating the skin
changes seen in scleroderma . Side effects of current medical therapies include systemic toxicity, chronic
[30]
immune suppression, and bleeding . Moreover, the extensive skin fibrosis seen in scleroderma limits the
[19]
perfusion of systemic medications to the dermis and restricts their efficacy . Current systemic treatments
[19]
have also shown to be ineffective at reversing skin fibrosis or improving contour irregularities in
scleroderma, prompting the need to identify alternative therapies.

THE SCIENCE OF FAT GRAFTING
AFT has the potential to attenuate and reverse the pathophysiologic processes that underly scleroderma.
ASCs have strong immunomodulatory effects that mitigate the widespread inflammation essential to the
progression of scleroderma [31-36] . ASCs also exhibit pro-angiogenic effects by secreting growth factors that
synergistically interact with endothelial cells to stimulate rapid neoangiogenesis [9,19,37,38] . This enhanced blood
vessel formation has the potential to revascularize fibrotic skin in scleroderma patients and promote tissue
regeneration [19,39] . With respect to skin fibrosis, ASCs are a host for matrix metalloproteinases and various