BackgroundThe presence of infections is one of the main factors that leads to delays in healing or non-closure of cutaneous wounds. Although the goal of antibiotic use is to treat or prevent infection, there is currently no agreement on the effectiveness of these products.AimThe aim of this study was to evaluate the efficacy of antibiotic use during the healing process of skin wounds in animal models not intentionally infected, as well as to analyze the advances and limitations of the studies carried out in this field.Main methodsThis systematic review was performed according to the PRISMA guidelines, using a structured search on the MedLine (PubMed) and Scopus platforms to retrieve studies published until August 29, 2018, 13:35p.m. The studies included were limited to those that used excision or incision wound models and that were not intentionally infected. The data for the animal models, antibiotic used, and the main results of the studies were extracted, and compared where possible. Bias analysis and methodological quality assessments were examined through the SYRCLE’s Risk of Bias tool.Key findingsTwenty-seven studies were selected. Overall, the effects of the antibiotic on the wound decreased inflammatory cell infiltration and promoted an increased number of fibroblasts, extracellular matrix constituents, re-epithelialization and tissue strength. A great deal of important information about the methodology was not presented, such as: the statistical analysis used, the animal model (sex and age), antibiotic dosage, blinding and randomization of the animals chosen.SignificanceBased on the results found, we believe that antibiotic therapy can be considered a viable alternative for the treatment of cutaneous wounds. However, current evidence obtained from the methodological quality analysis points towards a high risk of bias. This is due to the incomplete characterization of the experimental design and treatment protocol, which compromises the reproducibility of the studies.

Cytokines and growth factors are known to play an important role in the skin wound closure process; however, in knockout organisms, the levels of these molecules can undergo changes that result in the delay or acceleration of this process. Therefore, we systematically reviewed evidence from preclinical studies about the main immunoregulatory molecules involved in skin repair through the analysis of the main mechanisms involved in the depletion of immunoregulatory genes, and we carried out a critical analysis of the methodological quality of these studies. We searched biomedical databases, and only original studies were analyzed according to the PRISMA guidelines. The included studies were limited to those which used knockout animals and excision or incision wound models without intervention. A total of 27 studies were selected; data for animal models, gene depletion, wound characteristics, and immunoregulatory molecules were evaluated and compared whenever possible. Methodological quality assessments were examined using the ARRIVE and SYRCLE’s bias of risk tool. In our review, the extracellular molecules act more negatively in the wound healing process when silenced and the metabolic pathway most affected involved in these processes was TGF-β/Smad, and emphasis was given to the importance of the participation of macrophages in TGF-β signaling. Besides that, proinflammatory molecules were more evaluated than anti-inflammatory ones, and the main molecules evaluated were, respectively, TGF-β1, followed by VEGF, IL-6, TNF-α, and IL-1β. Overall, most gene depletions delayed wound healing, negatively influenced the concentrations of proinflammatory cytokines, and consequently promoted a decrease of inflammatory cell infiltration, angiogenesis, and collagen deposition, compromising the formation of granulation tissue. The studies presented heterogeneous data and exhibited methodological limitations; therefore, mechanistic and highly controlled studies are required to improve the quality of the evidence.

The main objective of this study was to investigate the action of doxycycline hyclate (Dx) in the skin wound healing process in Wistar rats. We investigated the effect of Dx on inflammatory cell recruitment and production of inflammatory mediators via in vitro and in vivo analysis. In addition, we analyzed neovascularization, extracellular matrix deposition, and antioxidant potential of Dx on cutaneous repair in Wistar rats. Male animals ( n = 15 ) were divided into three groups with five animals each (protocol: 72/2017), and three skin wounds (12 mm diameter) were created on the back of the animals. The groups were as follows: C, received distilled water (control); Dx1, doxycycline hyclate (10 mg/kg/day); and Dx2, doxycycline hyclate (30 mg/kg/day). The applications were carried out daily for up to 21 days, and tissues from different wounds were removed every 7 days. Our in vitro analysis demonstrated that Dx led to macrophage proliferation and increased N-acetyl-β-D-glucosaminidase (NAG) production, besides decreased cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and metalloproteinases (MMP), which indicates that macrophage activation and COX-2 inhibition are possibly regulated by independent mechanisms. In vivo, our findings presented increased cellularity, blood vessels, and the number of mast cells. However, downregulation was observed in the COX-2 and PGE2 expression, which was limited to epidermal cells. Our results also showed that the downregulation of this pathway benefits the oxidative balance by reducing protein carbonyls, malondialdehyde, nitric oxide, and hydrogen peroxide (H2O2). In addition, there was an increase in the antioxidant enzymes (catalase and superoxide dismutase) after Dx exposure, which demonstrates its antioxidant potential. Finally, Dx increased the number of types I collagen and elastic fibers and reduced the levels of MMP, thus accelerating the closure of skin wounds. Our findings indicated that both doses of Dx can modulate the skin repair process, but the best effects were observed after exposure to the highest dose.

Background. Skin wounds are closely correlated with opportunistic infections and sepsis risk. Due to the need of more efficient healing drugs, animal peptides are emerging as new molecular platforms to accelerate skin wound closure and to prevent and control bacterial infection. Aim. The aim of this study was to evaluate the preclinical evidence on the impact of animal peptides on skin wound healing. In addition, we carried out a critical analysis of the studies’ methodological quality. Main Methods. This systematic review was performed according to the PRISMA guidelines, using a structured search on the PubMed-Medline, Scopus, and Web of Science platforms to retrieve studies published until August 25, 2020 at 3 : 00 pm. The studies included were limited to those that used animal models, investigated the effect of animal peptides with no association with other compounds on wound healing, and that were published in English. Bias analysis and methodological quality assessments were examined through the SYRCLE’s RoB tool. Results. Thirty studies were identified using the PRISMA workflow. In general, animal peptides were effective in accelerating skin wound healing, especially by increasing cellular proliferation, neoangiogenesis, colagenogenesis, and reepithelialization. Considering standardized methodological quality indicators, we identified a marked heterogeneity in research protocols and a high risk of bias associated with limited characterization of the experimental designs. Conclusion. Animal peptides show a remarkable healing potential with biotechnological relevance for regenerative medicine. However, rigorous experimental approaches are still required to clearly delimit the mechanisms underlying the healing effects and the risk-benefit ratio attributed to peptide-based treatments.

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A busca por um tratamento eficaz para feridas cutâneas tem como objetivo promover o fechamento rápido e eficaz da ferida e a formação de uma cicatriz forte e resistente. O tratamento de feridas cutâneas pode variar de acordo com a profundidade e extensão das lesões. Em geral, os cuidados incluem a limpeza da área e o uso de medicamentos ou até mesmo curativos especiais. No entanto, os tratamentos atuais têm se mostrado ineficazes no controle da infecção e da dor, o que limita o processo de cicatrização de feridas. Então, o objetivo deste trabalho foi investigar o efeito de peptídeos obtidos de animais, em especial da pele de rã-touro Lithobates catesbeianus (Shaw, 1802), no processo de cicatrização de feridas. Inicialmente, foi realizada uma revisão sistemática seguindo as diretrizes PRISMA, para investigar as evidências pré-clínicas de peptídeos animais na cicatrização de feridas cutâneas. A plataforma SYRCLE’s RoB tool foi utilizada para análise de viés e qualidade metodológica dos estudos. Foram selecionados trinta estudos para extração dos dados. Em geral, os peptídeos animais foram eficazes em acelerar a cicatrização de feridas cutâneas por atuar na estimulação da proliferação celular, neoangiogênese, colagenogênese, reepitelização e contração da ferida. No entanto, observamos um alto risco de viés associado à caracterização limitada dos protocolos experimentais. Em seguida, foi realizada a investigação de uma fração peptídica isolada do hidrolisado de tripsina da pele de rã-touro no processo de cicatrização de feridas, utilizando análises in vitro e in vivo. Foram identificadas 71 sequências peptídicas relacionadas com proteínas desta espécie. Nos testes in vitro utilizando células de murinos, os peptídeos da fração investigada foram eficazes em promover a proliferação celular. No experimento in vivo, a fração peptídica foi eficiente em promover a contração da ferida, aumentar a proliferação celular e a síntese de colágeno, bem como reduzir a resposta inflamatória e o estresse oxidativo. Em conclusão, a fração peptídica isolada do hidrolisado de tripsina da pele da rã-touro foi eficiente no controle do processo inflamatório e consequentemente na promoção do fechamento rápido e eficaz da ferida. Palavras-chave: Proliferação. Hidrólise enzimática. Cicatrização. Revisão sistemática.