Skin Graft Donor Site and Use of Polydeoxyribonucleotide as a Treatment for Skin Regeneration: A Randomized, Controlled, Double-Blind, Clinical Trial

Giovambattista De Aloe, MD; Pietro Rubegni, MD; Maurizio Biagioli, MD; Paolo Taddeucci, MD; Michele Fimiani, MD

Disclosures

Wounds. 2004;16(8) 

In This Article

Abstract and Introduction

The effect of polydeoxyribonucleotide (PDRN) vs. placebo on the wound healing process in patients undergoing skin grafts during reconstructive surgery was evaluated. In this double-blind, placebo-controlled study, 58 patients of both sexes subjected to skin grafts were studied and randomly allocated in two homogeneous groups treated with standard therapy plus PDRN (3mL ampoule contains PDRN mg. 5.625) or placebo. PDRN or placebo were administered by intramuscular injection once daily for 10 days and by perilesional infiltration at Days 1 and 5, postoperatively. Checks were carried out at the end of surgery and after 5, 10, 14, and 21 days. The primary end point of the trial was the rate of repair of the graft donor site. At the beginning, the two groups were homogeneous in terms of age, sex, and size of the graft donor site. On Day 10, the surface of the reepithelized area was 26.7 ± 6.2cm2 (mean ± SD) in the PDRN group and 20.7 ± 6.7cm2 in the placebo group (p <0.01 between groups). On Day 14, the graft donor site was completely reepithelized in 17 out of 29 (58.6%) patients treated with PDRN and in 5 out of 29 (17.2%) patients treated with placebo (p <0.01 between groups). At the end of the trial, all graft donor sites appeared to be clinically healed. The data of the trial show the stimulation action of PDRN on tissue repair processes, with no significant side-effects. A more regular regression of pain symptoms was also observed in the PDRN group (p <0.01 between groups on Days 10 and 14).

Polydeoxyribonucleotide (PDRN) (Placentex Integro, Mastelli Srl-Sanremo, Italy) is a preparation used in therapy as a tissue repair stimulating agent in diseases characterized by a loss of substance, such as chronic wounds[1,2,3] and burns.[4] It consists of low molecular weight deoxyribonucleic acid (DNA) fractions that can be defined as deoxyribonucleotide linear polymers that are combined by phosphodiester bonds whose monomeric units are the purine and pyrimidine nucleotides. The compound is extracted from the sperm of trout bred for human food purposes and is then purified and sterilized to obtain an over 95-percent pure active principle without pharmacologically active proteins and peptides (Registration Dossier, Ministry of Health). The PDRN trophic effect is attributed to the nucleotides by which it is formed.[5] A link between nucleotides and wound healing had already been established at the beginning of the 1990s.[6,7,8,9] The stimulating effect of the extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) on cell multiplication, DNA synthesis, and wound healing has also been specified.[6] It has been demonstrated that the nucleic acids of damaged cells, released in the extracellular environment, are rapidly lysated into nucleotides that trigger a repair response by modulating its development.[7] The same nucleotides are able to activate different cell types[8] and to promote the repair of the solutions of continuity.[8,9,10] There is evidence that the stimulation of type A2 purinergic receptors accelerates wound healing,[11,12,13,14] and it is well documented that PDRN and nucleotides stimulate cell regeneration and cell metabolic activity by acting as A2 receptors agonists.[15,16] Nucleotides promote cell regeneration also stimulating the synthesis of new nucleic acids necessary for cell duplication. The preformed nucleotides, in fact, activate the "salvage" metabolic pathways (reuse of nucleotides as such with a considerable energy saving) as an alternative to the traditional metabolic pathways of the ex-novo synthesis[17,18] (nucleotide neosynthesis starting from amino acids with a high-energy consumption). The activation of "salvage" pathways enables a quicker synthesis of nucleic acids with a lower energy consumption.[19]

In-vitro studies have shown that PDRN can stimulate the growth of human fibroblast primary cultures at concentrations of 20-100mg/mL and that cell proliferation is at least partly mediated by stimulating type A2 purinergic receptors[5,15] and by activating "salvage" pathways. A recent study documented the stimulation effect of PDRN on the osteoblasts in culture, and it also showed that this effect is dramatically reduced by pretreating the cells with 3,7-dimethyl-1-propargylxanthine (DMPX),[20] an A2a selective receptor antagonist. In one of our previous pilot study,[21] it was observed that the administration of PDRN by intramuscular and perilesional route in patients who underwent skin grafts was associated with a significant increase of the reepithelization rate of the skin graft donor site.

The purpose of this randomized, double-blind, placebo-controlled clinical study was to evaluate the activity of PDRN on the wound healing process in patients undergoing skin graft for reconstructive surgery.

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