A randomized, controlled clinical trial of autologous stromal vascular fraction cells transplantation to promote mechanical stretch-induced skin regeneration

Abstract

Background: The regeneration response of the skin to mechanical stretching in vivo has been explored in reconstructive surgery to repair large-scale deformities. The ability of the skin to regenerate limits the reconstructive outcome. Here, we propose an approach in which autologous stromal vascular fraction (SVF) cells and mechanical stretching are combined to overcome this limitation and promote skin regeneration.

Methods: This randomized, blinded, placebo-controlled clinical trial screened 22 participants undergoing tissue expansion with exhausted regeneration. Twenty eligible participants received intradermal injections of the SVF or placebo treatments. Follow-ups were conducted at 4, 8, and 12 weeks to assess efficacy and at 2 years to assess safety. The primary endpoint was the expanded skin thickness at 12 weeks. The secondary endpoints included skin thickness at 4 and 8 weeks, the expansion index (EI), and the skin texture score at 12 weeks.

Results: The skin thickness of the SVF group was significantly higher than that of the control group at both 8 weeks (mean difference 0.78 [95% CI - 1.43 to - 0.11]; p = 0.018) and 12 weeks (0.65 [95% CI - 1.30 to - 0.01]; p = 0.046). In the SVF group, the increase in skin thickness was significant at 4 weeks (0.49 [95% CI - 0.80 to - 0.06]; p = 0.010) to 8 weeks (0.45 [95% CI - 0.92 to 0.02]; p = 0.026) and maintained after 12 weeks, whereas that in the control group was reduced after 8 weeks (0.42 [95% CI - 0.07 to 0.91]; p = 0.037). The SVF group showed greater EI increases than the control group (0.50 [95% CI - 0.00 to 0.99]; p = 0.047). The skin texture scores in the SVF group were greater than those in the control group at 12 weeks. Histologically, SVF-treated expanded skin showed more proliferating cells and blood vessels, and the extracellular matrix volume increased. No severe adverse events occurred.

Conclusions: Transplantation of SVF cells can expedite the potency of mechanical stretch-induced skin regeneration and provide clinical reconstruction with plentiful tissue.

Trial registration: This trial was registered with the Chinese Clinical Trial Registry, ChiCTR2000039317 (registered 23 October 2020-retrospectively registered).

Keywords: Mechanical stretch; Skin expansion; Skin regeneration; Stem cell; Stromal vascular fraction (SVF).

Fig. 1

CONSORT flow diagram of participant recruitment

Fig. 2

The SVF injection and the changes in skin thickness. Through liposuction and enzyme digestion, the red SVF cell-pellet (shown in arrow) was harvested (a). SVF was subcutaneously injected onto the expanded skin area (b). An ultrasound was used to assess the skin thickness (results from the control group (c) and SVF group (d) at baseline and 12 weeks). The SVF group had a significant increase in the skin thickness compared to the control group at 8 to 12 weeks (e). Compared to baseline, the skin thickness in the SVF group increased significantly at 4 to 8 weeks and was maintained after 12 weeks, whereas the control group decreased after 8 weeks (f, g). A similar downward trend was found for the dermal thickness (l, m), whereas no differences in the epidermal thickness were noted between both groups (i, j).* p<0.05; ** p<0.01

Fig. 3

Changes in the EI. The EI was significantly increased in the SVF group (a). Patients in the SVF group gained significantly more skin surface area (c, d) compared with control group (b) at 12 weeks of treatment. *p<0.05

Fig. 4

Evaluation of skin texture. Patients in the SVF group had higher scores when their expanded skin texture was assessed compared to patients in the control group at 12 weeks (a). Compared to baseline, patients in the SVF group showed significantly improved skin textures (d–f) at 12 weeks posttreatment but those in the control group had no improvement (b, c). The skin texture of patients in the control group was deteriorated after 12 weeks posttreatment. This deterioration was noted by increased telangiectasia (b) and a deepening of the stretch striae (c). d Prior to study enrollment, the patient had papery skin accompanied by telangiectasia and the development of an embolism (shown by the arrow). The patient was facing expansion failure. After SVF treatment, his skin texture improved, and its thickness increased. The telangiectasia area was diminished (shown by the arrow). The patient gained further expansion until reaching the need for reconstruction. e The patient had stretch marks throughout the expanded skin at baseline. After 12 weeks of SVF treatment, the stretch striae had disappeared, and skin growth improved. f Before study enrollment, the patient’s expanded skin appeared papery with stretch striae, and expansion could not be continued. After 12 weeks of SVF treatment, the skin had increased in thickness, and the stretch marks diminished

Fig. 5

Histology and immunohistochemical staining of the expanded skin. HE staining showed that the epidermal layer in the SVF group was thicker than that in the control group (a) with the presence of an increasing rete subpapillary in the papillary layer. Masson’s trichrome staining showed that the ECM volume in the SVF group was significantly increased as the collagen fibers showed an organized distribution, whereas the collagen fibers in the control group (b) were loosely organized. PCNA + proliferating cells and CD31+ stained vessels were significantly increased in the SVF group compared to the control group (c, d). The results of the statistical analysis showed more proliferating cells (e) and blood vessels (f) in the SVF-treated skin as the volume of ECM increased (g). Scale bar in a–d, 100 μm. *p<0.05, **p<0.01