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this occurred, the application of a topical immunologic
suppressant like 5‑fluorouracil ointment would have been
recommended.

In the literature, other studies have reported clinical
outcomes for cellular skin substitutes on various other
scaffolds in the treatment of chronic leg and foot diabetic
ulcers. [17‑20] The differences among these studies in results,
methods, products, cost‑effectiveness ratio, and follow‑up
period are highlighted in Table 3. However, comparison of
the effectiveness is difficult to perform given the extreme
variation in protocols (e.g., skin substitutes were used
multiple times on the same ulcer in some studies, or the
end of the study was not fixed until 100% wound healing
Figure 3: At t1 (9 days postoperative), 50% reduction of dimensions and was achieved). [21‑23] However, some clinical features have
improvement of wound bed emerged from these studies regarding the use of cellular
skin substitutes in the management of chronic diabetic
ulcers. The role of allogeneic keratinocytes appears to
be central in the cellular therapy of diabetic wounds,
although good results have been reported with the use
of autologous cells. [24,25] Unlike allogeneic substitutes,
autologous sheets are not available for use immediately,
a skin biopsy is required, and longer times are necessary
for cell processing, with the ever‑present risk of ischemia
or osteomyelitis. Cellular skin substitutes are formed
by two elements: cells and scaffold. In the “dynamic
reciprocity” model, the extracellular matrix emerges
as capable of influencing wound healing, acting on the
others two characters, cells and signal factors. Thus,
[26]
the scaffold and cells are both fundamental in the clinical
outcome of skin substitutes. Hyaluronic acid is a central
Figure 4: At t2 (23 days postoperative), further reduction of the ulcer molecule in human skin, and its functions are diverse.
Hyaluronan influences hydration of the extracellular
matrix, due to its hydroscopic characteristics, and
contributes to the physical and mechanical properties
of the dermis. Hyaluronic acid interacts with a number
of receptors, resulting in the activation of signaling
cascades that influence cell migration, proliferation,
and gene expression. Further, fetal‑like regenerative
wound healing is characterized by a large amount of
hyaluronic acid deposition. From these observations, a
membrane composed of completely esterified hyaluronic
acid was developed, and was shown to support growth
of keratinocytes in vitro and biocompatibility in vivo.
[27]
Prior studies on cellular therapy for diabetic wounds have
emphasized repeated debridement, control of bacterial
growth, careful moisture balance to prevent maceration,
Figure 5: At t3 (45 days postoperative), complete healing of the ulcer
blood pressure control, management of blood glucose,
and perfusion of the extremity. Wound bed preparation
in interesting clinical outcomes. Cultured keratinocytes remains central for cellular skin substitutes application
were, in fact, resistant to bacterial colonization in and efficacy.
excised burns and chronic ulcers. In such settings and
[16]
considering the cost of this new product, allogeneic The present case series study on skin substitutes based
keratinocytes on a hyaluronic acid scaffold could be on hyaluronic acid scaffold for the therapy of chronic
considered a second‑line treatment in case of prior diabetic leg and foot ulcers allows investigation of the
treatment failure. clinical results, in order to find evidence for treatment
perspectives, and stimulate biochemical research in the
Fortunately, we had no cases of immunologic response field of regenerative medicine. Comprehensive studies will
to these allogeneic products in our case series. Had be necessary to evaluate the cost‑effectiveness of these

78 Plast Aesthet Res || Vol 1 || Issue 2 || Sep 2014