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Page 4 of 8 García Botero et al. Plast Aesthet Res 2018;5:15 I http://dx.doi.org/10.20517/2347-9264.2018.09

The risk of bias was examined with the SIGN data analysis strategy, which assesses the internal validity
and the quality assurance for each clinical study. A descriptive analysis was performed on the effective
granulation in patients treated with fibrin matrix and with and without growth factors. The incidence of
effective granulation was defined as those ulcers that healed completely or formed granulation tissue on ≥ 75%
of the initial ulcer size. The mean time to healing or formation of granulation tissue was analyzed by using
the Kaplan-Meier estimator. Absolute and relative frequencies were used to analyze the numbers of fibrin
matrix applications required for effective granulation and its secondary consequences.

RESULTS
The literature searched in MEDLINE by using the MESH term, restricted to human reports and without
restrictions to dates or types of study, identified 14 articles [Table 1]. Of these, five were selected by title,
which fulfilled the objective of the present study, but only three were relevant to our study [9,14,15] . Analysis of
abstracts from 12 articles, showed that management of venous ulcers were performed with different products,
such as platelet-derived, platelet-enriched plasma or non-fibrin matrices. Since those 12 articles did not focus
in fibrin matrix with autologous growth factors, they were excluded from the review.

From the three relevant articles found in MEDLINE [9,14,15] , the O’Connell et al. study was a pilot study,
[9]
assessing the use of fibrin matrix and autologous growth factors for a period of 16 weeks, in 21 patients
with chronic ulcers on lower limbs of different etiologies, including venous, arterial or a combination of
both. Patients with ulcers of diabetic origin were included also, which was one of our exclusion criteria.
In their pilot study, 66.7% of patients with venous ulcers showed completed ulcer healing within 7.1 weeks
(median = 6 weeks). The second article, from the same group as the pilot study, was a description of the
Cascade® product that they used in the original study . The third article, from Hartmann et al. , primarily
[15]
[14]
assessed a series of cases of seven patients with chronic venous ulcers treated with cultured keratinocytes
transplanted in fibrin matrix. Results showed complete ulcer healing in 4 of 7 ulcers, with a mean healing
time of 14.5 weeks; however, it was not possible to conclude that completed ulcer healing was a consequence
of the presence of fibrin matrix or cultured keratinocytes.

The search in EMBASE database identified 35 articles, from which 4 were selected by title [Table 1]. The
remaining 31 articles did not meet the search criteria and did not evaluate the intervention objective of the
present systematic literature review. From 4 of the articles identified by their title, 3 were relevant and were
the same articles found in the MEDLINE database search [9,14,15] . The search in COCHRANE (Central Register
of Controlled Trials) identified 1 review of 3 randomized controlled trials assessing the cost effectiveness of
using different fibrin matrices, such as bovine collagen matrix with neonatal keratinocytes, acellular matrix
and poly-n-acetyl glucosamine matrices, on venous ulcers in lower limbs .
[16]
The search of protocols and ongoing clinical trials at ClinicalTrial.gov database by using the MESH terms
did find any reports [Table 2]. Similarly, the search in Spanish and Portuguese at the LILACS database did
not find studies reported in either of the two languages [Table 1].

None of the four relevant articles selected by their summary met the criteria for inclusion as described in the
material and methods section, and did not evaluate the intervention objective projected for our study [Table 3];
therefore, these articles were excluded from the review.

DISCUSSION
The primary treatment for venous ulcers involves application of compression therapy using bandages or
compression hosiery . In addition to compression therapy, different dressing types are applied beneath the
[13]
compression bandage or hosiery, to enhance ulcer healing by creating a humid environment and controlling