Chronic Leg Ulcers: Are Tissue Engineering and Biomaterials Science the Solution?

Chronic leg ulcers (CLUs) are full thickness wounds that usually occur between the ankle and knee, fail to heal after 3 months of standard treatment, or are not entirely healed at 12 months. CLUs present a considerable burden on patients, subjecting them to severe pain and distress, while healthcare systems suffer immense costs and loss of resources. The poor healing outcome of the standard treatment of CLUs generates an urgent clinical need to find effective solutions for these wounds. Tissue Engineering and Biomaterials Science offer exciting prospects for the treatment of CLUs, using a broad range of skin substitutes or scaffolds, and dressings. In this review, we summarize and discuss the various types of scaffolds used clinically in the treatment of CLUs. Their structure and therapeutic effects are described, and for each scaffold type representative examples are discussed, supported by clinical trials. Silver dressings are also reviewed due to their reported benefits in the healing of leg ulcers, as well as recent studies on new dermal scaffolds, reporting on clinical results where available. We conclude by arguing there is a further need for tissue-engineered products specifically designed and bioengineered to treat these wounds and we propose a series of properties that a biomaterial for CLUs should possess, with the intention of focusing efforts on finding an effective treatment.

Decellularised scaffolds: just a framework? Current knowledge and future directions.

The use of decellularised matrices as scaffolds offers the advantage of great similarity with the tissue to be replaced. Moreover, decellularised tissues and organs can be repopulated with the patient's own cells to produce bespoke therapies. Great progress has been made in research and development of decellularised scaffolds, and more recently, these materials are being used in exciting new areas like hydrogels and bioinks. However, much effort is still needed towards preserving the original extracellular matrix composition, especially its minor components, assessing its functionality and scaling up for large tissues and organs. Emphasis should also be placed on developing new decellularisation methods and establishing minimal criteria for assessing the success of the decellularisation process. The aim of this review is to critically review the existing literature on decellularised scaffolds, especially on the preparation of these matrices, and point out areas for improvement, finishing with alternative uses of decellularised scaffolds other than tissue and organ reconstruction. Such uses include three-dimensional ex vivo platforms for idiopathic diseases and cancer modelling.

Annexin A12-26 Treatment Improves Skin Heterologous Transplantation by Modulating Inflammation and Angiogenesis Processes.

Skin graft successful depends on reduction of local inflammation evoked by the surgical lesion and efficient neovascularization to nutrition the graft. It has been shown that N-terminal portion of the Annexin A1 protein (AnxA1) with its anti-inflammatory properties induces epithelial mucosa repair and presents potential therapeutic approaches. The role of AnxA1 on wound healing has not been explored and we investigated in this study the effect of the peptide Ac2-26 (N-terminal AnxA1 peptide Ac2-26; AnxA12-26) on heterologous skin scaffolds transplantation in BALB/c mice, focusing on inflammation and angiogenesis. Treatment with AnxA12-26, once a day, from day 3-60 after scaffold implantation improved the take of the implant, induced vessels formation, enhanced gene and protein levels of the vascular growth factor-A (VEGF-A) and fibroblast influx into allograft tissue. It also decreased pro- while increasing anti-inflammatory cytokines. The pro-angiogenic activity of AnxA12-26 was corroborated by topical application of AnxA12-26 on the subcutaneous tissue of mice. Moreover, treatment of human umbilical endothelial cells (HUVECs) with AnxA12-26 improved proliferation, shortened cycle, increased migration and actin polymerization similarly to those evoked by VEGF-A. The peptide treatment instead only potentiated the tube formation induced by VEGF-A. Collectively, our data showed that AnxA12-26 treatment favors the tissue regeneration after skin grafting by avoiding exacerbated inflammation and improving the angiogenesis process.

The essential role of annexin A1 mimetic peptide in the skin allograft survival.

Immunosuppressive drugs have a critical role in inhibiting tissue damage and allograft rejection. Studies have demonstrated the anti-inflammatory effects of the annexin A1 (AnxA1) in the regulation of transmigration and apoptosis of leucocytes. In the present study, an experimental skin allograft model was used to evaluate a potential protective effect of AnxA1 in transplantation survival. Mice were used for the skin allograft model and pharmacological treatments were carried out using either the AnxA1 mimetic peptide Ac2-26, with or without cyclosporine A (CsA), starting 3 days before surgery until rejection. Graft survival, skin histopathology, leucocyte transmigration and expression of AnxA1 and AnxA5 post-transplantation were analysed. Pharmacological treatment with Ac2-26 increased skin allograft survival related with inhibition of neutrophil transmigration and induction of apoptosis, thereby reducing the tissue damage compared with control animals. Moreover, AnxA1 and AnxA5 expression increased after Ac2-26 treatment in neutrophils. Interestingly, the combination of Ac2-26 and cyclosporine A showed similar survival of transplants when compared with the cyclosporine A group, which could be attributed to a synergistic effect of both drugs. Investigations in vitro revealed that cyclosporine A inhibited extracellular-signal-regulated kinase (ERK) phosphorylation induced by Ac2-26 in neutrophils. Overall, the results suggest that AnxA1 has an essential role in augmenting the survival of skin allograft, mainly owing to inhibition of neutrophil transmigration and enhancement of apoptosis. This effect may lead to the development of new therapeutic approaches relevant to transplant rejection.

Mesenteric microcirculatory dysfunctions and translocation of indigenous bacteria in a rat model of strangulated small bowel obstruction.

PURPOSE: Bacterial translocation has been shown to occur in critically ill patients after extensive trauma, shock, sepsis, or thermal injury. The present study investigates mesenteric microcirculatory dysfunctions, the bacterial translocation phenomenon, and hemodynamic/metabolic disturbances in a rat model of intestinal obstruction and ischemia. METHODS: Anesthetized (pentobarbital 50 mg/kg, i.p.) male Wistar rats (250-350 g) were submitted to intestinal obstruction or laparotomy without intestinal obstruction (Sham) and were evaluated 24 hours later. Bacterial translocation was assessed by bacterial culture of the mesenteric lymph nodes (MLN), liver, spleen, and blood. Leukocyte-endothelial interactions in the mesenteric microcirculation were assessed by intravital microscopy, and P-selectin and intercellular adhesion molecule (ICAM)-1 expressions were quantified by immunohistochemistry. Hematocrit, blood gases, lactate, glucose, white blood cells, serum urea, creatinine, bilirubin, and hepatic enzymes were measured. RESULTS: About 86% of intestinal obstruction rats presented positive cultures for E. coli in samples of the mesenteric lymph nodes, liver, and spleen, and 57% had positive hemocultures. In comparison to the Sham rats, intestinal obstruction induced neutrophilia and increased the number of rolling (approximately 2-fold), adherent (approximately 5-fold), and migrated leukocytes (approximately 11-fold); this increase was accompanied by an increased expression of P-selectin (approximately 2-fold) and intercellular adhesion molecule-1 (approximately 2-fold) in the mesenteric microcirculation. Intestinal obstruction rats exhibited decreased PaCO2, alkalosis, hyperlactatemia, and hyperglycemia, and increased blood potassium, hepatic enzyme activity, serum urea, creatinine, and bilirubin. A high mortality rate was observed after intestinal obstruction (83% at 72 h vs. 0% in Sham rats). CONCLUSION: Intestinal obstruction and ischemia in rats is a relevant model for the in vivo study of mesenteric microcirculatory dysfunction and the occurrence of bacterial translocation. This model parallels the events implicated in multiple organ dysfunction (MOD) and death.

Mesenteric microcirculatory dysfunctions and translocation of indigenous bacteria in a rat model of strangulated small bowel obstruction

PRUPOSE: Bacterial translocation has been shown to occur in critically ill patients after extensive trauma, shock, sepsis, or thermal injury. The present study investigates mesenteric microcirculatory dysfunctions, the bacterial translocation phenomenon, and hemodynamic/metabolic disturbances in a rat model of intestinal obstruction and ischemia. METHODS: Anesthetized (pentobarbital 50 mg/kg, i.p.) male Wistar rats (250-350 g) were submitted to intestinal obstruction or laparotomy without intestinal obstruction (Sham) and were evaluated 24 hours later. Bacterial translocation was assessed by bacterial culture of the mesenteric lymph nodes (MLN), liver, spleen, and blood. Leukocyte-endothelial interactions in the mesenteric microcirculation were assessed by intravital microscopy, and P-selectin and intercellular adhesion molecule (ICAM)-1 expressions were quantified by immunohistochemistry. Hematocrit, blood gases, lactate, glucose, white blood cells, serum urea, creatinine, bilirubin, and hepatic enzymes were measured. RESULTS: About 86 percent of intestinal obstruction rats presented positive cultures for E. coli in samples of the mesenteric lymph nodes, liver, and spleen, and 57 percent had positive hemocultures. In comparison to the Sham rats, intestinal obstruction induced neutrophilia and increased the number of rolling (~2-fold), adherent (~5-fold), and migrated leukocytes (~11-fold); this increase was accompanied by an increased expression of P-selectin (~2-fold) and intercellular adhesion molecule-1 (~2-fold) in the mesenteric microcirculation. Intestinal obstruction rats exhibited decreased PaCO2, alkalosis, hyperlactatemia, and hyperglycemia, and increased blood potassium, hepatic enzyme activity, serum urea, creatinine, and bilirubin. A high mortality rate was observed after intestinal obstruction (83 percent at 72 h vs. 0 percent in Sham rats). CONCLUSION: Intestinal obstruction and ischemia in rats is a relevant model for ...

Esofagite química e ulcerações esofágicas associadas ao uso de alendronato sódio / Esophageal quimical and ulceration esophageal associated to the use of alendronate of sodium

Objetivo: O presente trabalho enfoca o perfil do paciente que utiliza o alendronato de sódio e suas possíveis queixas. Material e Métodos: Aplicação de questionário estruturado para pacientes atendidos em farmácias com manipulação e drogarias, nas regiões de Santana e Guarulhos, São Paulo. Critérios de inclusão: uso de alendronato de sódio, ambos os sexos, 45 e 80 anos. Variáveis observadas: características demográficas, origem da prescrição, prescritor, padrões de uso e queixas dos pacientes. Resultados: Pacientes entre 60-70 anos de idade, sexo feminino, praticantes de alguma atividade física. 88% relatam seguir a posologia adequadamente, 13% apresentaram queixas como: azia (mais prevalente), dor de garganta ou dificuldade ao engolir, dor no estômago e gases. A dose mais comum de alendronato de sódio foi 70mg uma vez por semana. Grande parcela dos pacientes faz uso do medicamento há mais de um ano e de outros concomitantes: antiinflamatórios (31%), analgésicos (25%), anti-hipertensivos (46%), hormônios (18%) entre outros. Conclusão: O uso incorreto do alendronato está relacionado com as reações adversas gástricas, pudemos observar que nem sempre o uso correto reduz a incidência de problemas esofágicos, portanto, tais queixas poderiam estar relacionadas ao fármaco em si.

Fatores relacionados à prescrição médica de antibióticos em farmácia pública da região Oeste da cidade de São Paulo / Factors related to prescriptions of antibiotics in a public pharmacy in the Western region of the city of São Paulo

Os antibióticos são comumente utilizados para melhorar uma infecção estabelecida e possuem a finalidade de eliminar ou impedir o crescimento bacteriano. Os riscos mais importantes relacionados ao seu uso são: reações adversas, resistência bacteriana e possíveis interações medicamentosas. Foram realizadas entrevistas com os pacientes para observar o entendimento dos mesmos sobre o uso do antibiótico e tratamento. 38,3 por cento dos pacientes são menores de 18 anos e a maioria é do sexo feminino. Um terço não compreende diagnóstico ou posologia e a maioria consultou-se com um clínico geral. Ainda há resistência na prescrição do nome genérico. Cerca de 8 por cento das receitas continham interação medicamentosa. Grande parte dos tratamentos pode estar comprometida pelo não entendimento do paciente ou presença de interação medicamentosa. A eficácia do tratamento depende de todos os profissionais de saúde, sendo necessário treinamento a esses profissionais tanto para conhecimento próprio quanto para atenção farmacêutica.

The use of antibiotics in the treatment of established infections for inhibiting or abolishing the growth of microorganism is very common. The risks related to their use include side effects, drug resistance and potential drug-drug interactions. A structured questionnaire was applied to patients in order to collect information about their understanding of the treatment and of how to use the antibiotic. As to the profile of the patients, 38.3 percent are younger than 18 years and most are females. One third does not understand the diagnosis or prescribed dosage and most of the patients had consulted with the general practitioner. Prescriptions of generic drugs continue rare, probably due to the physicians' resistance to prescribe this kind of medication. About 8 percent of prescriptions involved drug-drug interactions. Many treatments are compromised due to the lack of information provided to the patient or to drug-drug interactions. The efficiency of a treatment depends on all health professionals involved, who need to be adequately trained for providing effective pharmacy care.

[Factors related to prescriptions of antibiotics in a public pharmacy in the Western region of the city of São Paulo]. / Fatores relacionados à prescrição médica de antibióticos em farmácia pública da região Oeste da cidade de São Paulo.

The use of antibiotics in the treatment of established infections for inhibiting or abolishing the growth of microorganism is very common. The risks related to their use include side effects, drug resistance and potential drug-drug interactions. A structured questionnaire was applied to patients in order to collect information about their understanding of the treatment and of how to use the antibiotic. As to the profile of the patients, 38.3% are younger than 18 years and most are females. One third does not understand the diagnosis or prescribed dosage and most of the patients had consulted with the general practitioner. Prescriptions of generic drugs continue rare, probably due to the physicians' resistance to prescribe this kind of medication. About 8% of prescriptions involved drug-drug interactions. Many treatments are compromised due to the lack of information provided to the patient or to drug-drug interactions. The efficiency of a treatment depends on all health professionals involved, who need to be adequately trained for providing effective pharmacy care.

Lymphatic regeneration across an incisional wound: inhibition by dexamethasone and aspirin, and acceleration by a micronized purified flavonoid fraction.

Although the antiinflammatory and antiangiogenic properties of dexamethasone and acetylsalicylic acid have been studied extensively, their effects on lymphangiogenesis in regenerating tissues remain mostly unknown. We studied in rats the pharmacological modulation and the effect of a remote inflammatory stimulus on the lymphatic regeneration upon damage after a surgical procedure. A micronized purified flavonoid fraction bearing antiinflammatory and lymphagogue properties, was also used. An incisional wound and interruption of the afferent lymphatic vessels to the popliteal and axillary lymph nodes of adult rats were made in dorsal thigh and hypochondrium, respectively. The progress of lymphatic regeneration was evaluated 3, 7, 14 and 21 days after surgery. (99m)Tc-dextran lymphoscintigraphy and Evans blue dye uptake were used to evaluate the lymphatic flow and the kinetics of lymphatic regeneration. In control conditions, lymphatic regeneration took 14 days to be accomplished. In the presence of a remote inflammatory response, which conceivably yielded inflammatory mediators to the incised lymphatic vessels, that time was shortened to 7 days. In both conditions, lymphatic regeneration was inhibited by dexamethasone and acetylsalicylic acid and accelerated by the micronized purified flavonoid fraction. These findings indicate that lymphatic regeneration in an incisional wound may be significantly modulated by dexamethasone, aspirin and a micronized purified flavonoid fraction, and these results call our attention for the possibility to pharmacologically stimulate the recovery of a lymphatic failure due to a traumatic event, or to inhibit its function in order to limit the lymphatic spread of cytokines or neoplastic cells.