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Delayed diabetic wound healing has placed an enormous burden on society. The key factors limiting wound healing include unresolved inflammation and impaired angiogenesis. Platelet-rich plasma (PRP) gel, a popular biomaterial in the field of regeneration, has limited applications due to its non-injectable properties and rapid release and degradation of growth factors. Here, we prepared an injectable hydrogel (DPLG) based on PRP and laponite by a simple one-step mixing method. Taking advantages of the non-covalent interactions, DPLG could overcome the limitations of PRP gels, which is injectable to fill irregular injures and could serve as a local drug reservoir to achieve the sustained release of growth factors in PRP and deferoxamine (an angiogenesis promoter). DPLG has an excellent ability in accelerating wound healing by promoting macrophage polarization and angiogenesis in a full-thickness skin defect model in type I diabetic rats and normal rats. Taken together, this study may provide the ingenious and simple bioactive wound dressing with a superior ability to promote wound healing.
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Chronic diabetic wound remains a critical challenge suffering from the complicated negative microenvironments, such as high-glucose, excessive reactive oxygen species (ROS), hypoxia and malnutrition. Unfortunately, few strategies have been developed to ameliorate the multiple microenvironments simultaneously. In this study, Chlorella sp. (Chlorella) hydrogels were prepared against diabetic wounds. In vitro experiments demonstrated that living Chlorella could produce dissolved oxygen by photosynthesis, actively consume glucose and deplete ROS with the inherent antioxidants, during the daytime. At night, Chlorella was inactivated in situ by chlorine dioxide with human-body harmless concentration to utilize its abundant contents. It was verified in vitro that the inactivated-Chlorella could supply nutrition, relieve inflammation and terminate the oxygen-consumption of Chlorella-respiration. The advantages of living Chlorella and its contents were integrated ingeniously. The abovementioned functions were proven to accelerate cell proliferation, migration and angiogenesis in vitro. Then, streptozotocin-induced diabetic mice were employed for further validation. The in vivo outcomes confirmed that Chlorella could ameliorate the undesirable microenvironments, including hypoxia, high-glucose, excessive-ROS and chronic inflammation, thereby synergistically promoting tissue regeneration. Given the results above, Chlorella is considered as a tailor-made therapeutic strategy for diabetic wound healing.
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ABSTRACT This project's purpose was to evaluate the healing effects of chitosan (CS) hydrogels loaded with extracts from Aloe vera (CS+AV) and Calendula officinalis (CS+CO) on wounds of diabetic and non-diabetic Wistar rats. A total of 24 rats were used; animals were randomly divided into three diabetic and three non-diabetic groups (one control and two treated groups) and monitored for 13 days. A biopsy on the wound site was recovered to assess the collagen and n-acetyl glucosamine content. The wound area ratio was reduced since day 1 on both non-diabetic treated groups. A similar effect was observed on the diabetic group treated with CS+AV, while the diabetic group treated with CS+CO showed a reduction in wound area compared to the diabetic control until day 11 after being wounded. Collagen and n-acetyl glucosamine content were higher in every treated group. Further studies are needed to clarify the underlying mechanisms through which they promote wound healing. These results suggest that the hydrogels prepared are potential material to be used as wound dressings.
RESUMEN El propósito de este proyecto fue evaluar los efectos curativos de los hidrogeles de quitosano con extractos de Aloe vera (CS + AV) y Calendula officinalis (CS + CO) en heridas en ratas Wistar diabéticas y no diabéticas. Se utilizaron un total de 24 ratas; los animales fueron divididos aleatoriamente en tres grupos diabéticos y tres no diabéticos (un grupo control y dos tratados) y se monitorearon durante 13 días. Se recuperó una biopsia del sitio de la herida para evaluar el contenido de colágeno y n-acetilglucosamina. El área de la herida se redujo desde el día 1 en ambos grupos no diabéticos tratados. Se observó un efecto similar en el grupo diabético tratado con CS + AV, mientras que el grupo diabético tratado con CS + CO mostró una reducción del área de la herida en comparación al control diabético hasta el día 11 después de la creación de la herida. El contenido de colágeno y n-acetilglucosamina fue mayor en todos los grupos tratados. Se necesitan más estudios para aclarar los mecanismos subyacentes a través de los cuales estos tratamientos promueven la cicatrización de heridas. Estos resultados sugieren que los hidrogeles preparados son materiales con potencial para usarse como apósitos para heridas.
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Objective:To evaluate the effects of adipose-derived stem cells (ADSCs) and ADM microparticle on diabetic wound healing.Methods:ADSCs was co-cultured with ADM microparticle in vitro. The models of diabetic nude mice were established by intraperitoneal injection of STZ and the full-thickness skin defects were designed on the back. All 24 diabetic mice were randomly divided into 4 group: experimental groups were transplanted with ADSCs and ADM microparticle and the other groups were transplanted with ADSCs, ADM microparticle and blank control group was set up. On the 7th and 14 th days, the wound healing rate of 3 mice randomly selected from each group was calculated, and the thickness between dermis and epidermis was measured by hematoxylin and eosin staining. The density of neovascularization was measured by immunohistochemical staining. The differences were compared between the groups.Results:Compared to the ADSCs groups, the mice of the experimental groups showed higher cell survival rate. The wound healing rate in the experimental groups was (86.0±2.7)% (7 days) and (98.5±1.1)% (14 days), thicker dermis-epidermis distance was (99.1±1.8) μm (7 days) and (124.3±4.3) μm (14 days) ( P<0.05), and higher density of neovascularization was noted. Conclusions:The transplantation with active ADM microparticle can significantly promote neovascularization and wound healing of diabetic wound.
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As of 2020， there are more than 120 million diabetic patients in China. Diabetic wounds is one of the common complications of diabetes with increasing incidence and has the potential to cause disability and mortality. Traditional Chinese medicine （TCM） has a long history in treating diabetic wounds， demonstrating significant efficacy and safety. In recent years， increasing researchers have explored the mechanisms of polysaccharides from TCM in the repair of diabetic wounds. Polysaccharides are the main active ingredients of TCM and employ one or more blood sugar-lowering mechanisms. However， most studies focus on the repair mechanism of single polysaccharides， and there is little in-depth discussion and summary. To provide a new therapy for diabetic wounds， which meets international standards and has the characteristics of TCM， and provide reference for the clinical treatment of diabetic wounds， we reviewed relevant literature to summarize the mechanisms of TCM polysaccharides in treating diabetic wounds. The mechanisms include inhibiting inflammation to improve wound microenvironment， lowering blood sugar， promoting fibroblast migration and proliferation， regulating wound growth factor to promote angiogenesis， inhibiting oxidative stress response， and regulating immune function. Finally， we put forward some possible research directions in the future.
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Diabetic wound healing disorder，one of the common chronic complications of diabetes，seriously influences the quality of life of patients and even causes disability and death，bringing a heavy burden to the society. Chinese medicine，a unique and precious resource in China，is safe with definite effect. Oxidative stress plays an important role in the occurrence and development of diabetic wound and the disturbance of antioxidant defense mechanism is among the causes of the lingering diabetic wound. As a vital transcription factor for intracellular redox homeostasis，nuclear factor erythroid 2-related factor 2 （Nrf2） regulates oxidative/heterogenous stress and reduces inflammatory responses. Although it is unnecessary for common wound healing，it is of great importance for diabetic wound healing. Many Chinese medicinals and the active ingredients have been found to enhance diabetic wound healing by mechanisms related to activation of the Nrf2 signaling pathway. Targeted activation of Nrf2 by Chinese medicine can alleviate oxidative stress，inflammatory response，and apoptosis in diabetic wound，thereby delaying further exacerbation of symptoms. Therefore，Nrf2 is regarded as a potential target for drugs to boost diabetic wound healing. This study summarizes the relationship between the Nrf2 signaling pathway and diabetic wound and analyzes the mode of action and possible mechanisms of Chinese medicine and its active ingredients in promoting diabetic wound healing through modulating the Nrf2 pathway，which is expected to serve as a reference for developing drugs for diabetic wound based on this pathway.
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Macrophages play a crucial role in inflammatory, proliferative and reconstructive phases in wound healing. A dysfunction of macrophage could lead to a delay of healing. As the most common type of chronic wounds, the diabetic wound may ultimately result in a delayed or failed wound healing due to a high glucose microenvironment and abnormal metabolic environment. Such abnormal metabolic environment may lead to the aberrant macrophage polarization, abnormal secretion of cytokines and aberrant phagocytic function hence cause prolonged inflammation with excessive oxidative stress reaction. As the consequence, the inflammatory phase in diabetic wound is lengthy while the proliferative and reconstructive phases are usually delayed. The diabetic wound may result in enormous financial burden to patients, the healthcare and the society. This study briefly reviewed the recent research progresses at home and abroad, and analysed and summarized the roles of the dysfunction of macrophage polarization, secretion and phagocytosis in the process of diabetic wound healing.
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Objective: To study the effect and mechanism of Angelica dahurica extract (AD) on neovascularization maturation in db/db mice. Methods: Forty-eight 8-week-old male db/db mice were randomly divided into model group and A. dahurica extract-treated group, and 24 littermate male db/m mice were set as control group. A mouse model of diabetic ulcer was prepared by punching the back. The A. dahuricae extract-treated group was administered with AD 1.8 g/kg ig, and control group and model group were ig administered with the same amount of normal saline for 21 d. The healing condition of mouse wounds was recorded at 2, 4, 7, 11, 14 and 21 d after trauma. The number and maturation of new blood vessels in wound tissues was observed by HE, immunohistochemistry and immunofluorescence staining at 11 d after trauma. Expression of fork head transcription factor (FOXO1) and angiopoietin-2 (Ang-2) in wound tissues were detected by Western blotting and immunohistochemistry. According to different intervention conditions in vitro, endothelial cells were divided into normal glucose and hypoxia group, high glucose and hypoxia group, hypertonic and hypoxic group, high glucose and hypoxia + A. dahurica extract-treated group. Endothelial cells were co-cultured with pericytes under different intervention conditions, and the effects of A. dahurica intervention on endothelial cells' chemotaxis and tubular structure formation in vitro under high glucose and hypoxia were observed. Western blotting was used to detect the levels of FOXO1, p-FOXO1 and Ang-2 proteins and their upstream protein kinase B (Akt) and phosphorylation protein changes in wound tissues and endothelial cells. Results: The wound healing rate of the A. dahurica extract-treated group, the general recovery of the wound, the number of blood vessels and the maturation of new blood vessels in the wound tissue were significantly better than the model group (P < 0.05). FOXO1 and Ang-2 protein expression levels in the A. dahurica extract-treated group were significantly higher than the model group (P < 0.05); p-Akt and p-FOXO1 protein expression in the A. dahurica extract-treated group were lower than model group (P < 0.05). After A. dahurica intervention in endothelial cells under high glucose and hypoxia in vitro, the expression levels of FOXO1 and Ang-2 protein in the cells were significantly reduced (P < 0.05), p-Akt and p-FOXO1 protein expression were significantly increased (P < 0.05); In addition, A. dahurica extract could increase the chemotaxis of endothelial cells to pericytes under high glucose and hypoxia and promote the formation of tubular structures of endothelial cells and pericytes in vitro under high glucose and hypoxia. Conclusion: A. dahurica extract can promote the formation and maturation of neovascularization, so as to improve the rate and quality of wound healing in db/db mice. The mechanism may be related to the down-regulation of FOXO1/Ang-2 pathway, the recruitment of endothelial cells to pericytes, and the promotion of the maturation of wound new blood vessels.
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Background: Diabetic wound is a major socioeconomic debilitating problem in this society. Various treatment options are available but still it requires better treatment option. In diabetes mellitus the oxygenation to the tissues is reduced. In this study effects of low level laser therapy were compared with topical application of Streptococcus thermophilus on diabetic wounds that induces formation of new blood vessel and free radical scavenging system, a comparative study to get better treatment option for diabetic wounds.Methods: 18 male rats were selected and divided randomly into three groups. Diabetes was induced in all the rats by using the Alloxan monohydrate at a dose of 120mg/kg of the body weight. Group A was treated with normal saline, group B was treated with low level laser therapy and group C was treated with Streptococcus thermophilus topically. Skin tissues were collected on day three and seven, slides were prepared for microscopic examination to observe the new blood vessels formation.Results: Mean number of new blood vessel formation was observed in group B compared with group A and C. Significant vasculogenesis was seen in group B when treated with Low level laser therapy.Conclusions: In the group of low level laser therapy new blood vessel formation was seen with better wound healing. It means LLLT provides better oxygenation to the tissues by generation of new blood vessels compared with Streptococcus thermophilus and normal saline.
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Objective: This research aimed to evaluate the effect of fractionation of Merremia mammosa Lour. (Mm (Lour.)) extract on diabetic wound healing by observing the collagen synthesis process and to search the most potent fraction. Methods: Wistar rats were divided into five groups (n=5), i.e., K-(negative control), K+(positive control), K1 (ethyl acetate fraction), K2 (water fraction), and K3 (n-hexane fraction). The Mm (Lour.) was extracted with ethanol 70%, then fractionated by using three solvents which have different polarity. The rats were adapted in 7 d, then induced into diabetic by streptozotocin dose 40 mg/kg body weight. The wound was made by Morton excision method. Treatment was given every two days and a skin biopsy was done on day 11. Analysis of collagen density was done by photomicrograph of histopathology preparations in Masson’s trichome stained by using trinocular microscope with 400x magnification in 6 fields of view, then processed by imageJ software and analyzed by appropriate statistic tool. Results: The results of this research showed that fractionation of Mm (Lour.) extract significantly enhanced diabetic wound healing based on macroscopic (percentage of wound healing) and collagen density with p-value<0.05 when compared with negative control, especially the water fraction (p=0.000). The follow-up post hoc analysis showed that there was no significant (p=0.989) or there was no meaningful difference in the group of water fraction when compared to positive control. Conclusion: Water fraction is the extract fraction of Mm (Lour.) which has the most significant influence on diabetic wound healing showed by enhancement of collagen synthesis.
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Aim To observe the effectof paeoniflorin (PA) on diabetic wound healing and its mechanisms. Methods A full-thickness skin excision splint model in diabetic mice was used to study the effects of PA on diabetic wound healing and the underlying mechanism. HE staining and Masson staining were used to observe the changes of granulation tissue and collagen in wound tissues. Immunofluorescence technique was employed to detect angiogenesis in wound tissues of diabetic mice. To detect the effects of PA, human umbilical vein endothelial cells ( HUVECs) and mouse fibroblasts were cultured in vitro. MTS, BrdU and scratch assays were used to detect the effects of PA on proliferation and migration. Tube formation assays were used to detect the effects of PA on the tube formation of HUVECs. qPCR was applied to assess the expression of collagen HI, fibronectin and ot-SMA gene. Immunoflu orescence was used to detect the expression of a-SMA. Results Compared with db/db model group, the formation rate of granulation tissues and collagen and the capillary density around the wound of db/db model group treated with PA was significantly higher than that of db/db model group(P <0. 01 ). PA had no significant effect on endothelial cell proliferation, but it could markedly promote endothelial cell migration and tube formation. PA could significantly up-regulate the migration , proliferation, secretion and differentiation of fibroblasts. Conclusions PA can significantly promote diabetic wound healing, which may be related to accelerating the generation of extracellular matrix and promoting angiogenesis.
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Objective · To investigate the effects of insulin on high glucose-cultured humanmononuclear cell line THP-1 and macrophage phenotype transformation in diabetic wounds. Methods · THP-1 cells were cultured with normal (5.6 mmol/L) and high (25 mmol/L) glucose, respectively,stimulated with PMA for differentiation, and induced to M1 macrophages with LPS. After treated with insulin for 6 h, expression changes of M1 type macrophage markers inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β), as well as M2 type macrophage markers arginase1 (Arg1) and IL-10 were detected using real-time PCR andWestern blotting. High fat diet feeding plus multiple intraperitoneal injections of low dose streptozotocin (STZ) were used to induce type II diabetes rat model. After blood glucose level has been stable for five weeks, two fullthickness skin wounds with the diameter of 1cm were made on the back of DM rats. Wounds were randomly assigned to being treated with insulin (0.2 U insulin /20 μL saline) or saline (20 μL saline) using the random number table. Characteristics of macrophagephenotypes were observed 3, 7, and 25days after wounds were made. Normal rats (n=3) served as controls. Results · After being cultured with high glucose, the mRNA levels of M1 markers iNOS and TNF-α were up-regulated in LPS-induced THP-1 cells, while the mRNA levels of M2 markers Arg1 and IL-10 were down-regulated.Afterbeing treated with insulin for 6 h, mRNA levels of iNOS and TNF-α weredown-regulated, protein levels of iNOS, IL-1β were down-regulated too, while mRNAand protein levels of Arg1 and IL-10 were up-regulated. In addition, the expression level of phosphorylated NF-κB-p65 was significantly increased after high glucose culture and was significantly decreased after insulin intervention. Compared to normal rat skin wounds, the expression of iNOS in macrophages was significantly increased in wounds of diabetic rats. The expression of iNOS in macrophages was high in saline treated wounds 3 and 7 days after the wounds were made and the expression of Arg1 was low 25 days after the wounds were made. In insulin treated wounds, the expression of iNOS started to decrease on day 7 after the wounds were made and the expression of Arg1 was significantly higher than that in saline treated wounds on day 25 after the wounds were made. Conclusion · Insulin can induce macrophage phenotype transformation from M1 to M2 under high glucose condition and the mechanism may be associated with the phosphorylation of NF-κB-p65.
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In acute and chronic wounds, Katupila (Securinega leucopyrus) (Willd.) Muell is a commonly used folklore remedy in Sri Lanka and Saurashtra region of India. We report a case of Madhumehajanya Dushta Vrana (chronic diabetic wound) that was treated with local application of S. leucopyrus in paste form once daily. Wound healed within a month with normal pigmentation and minimal scar. This case also demonstrated possible antimicrobial potential in the treatment of Dushta Vrana.
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PURPOSE: Many clinical trials have shown the effectiveness of platelet releasate on chronic wounds. However, a large volume of blood must be aspirated from a patient and a platelet separator is required. Here, we hypothesized that platelet concentrate obtained from a blood bank (PCBB) would be also effective at stimulating wound healing. The purpose of this study was to investigate the effectiveness of PCBB on accelerating healing of diabetic wounds in vivo. METHODS: Round wounds of 5mm diameter were made at four sites(two wounds on the left and two on the right side) on the backs of nine diabetic mice. Three hundred million platelets suspended in 0.05ml fibrinogen were dispersed on each wound on left sides. Same amount of fibrinogen without platelets was dispersed on right side control wounds. Thereafter, 0.05ml thrombin was applied to the each wound. Ten days after wound treatment, healed wounds were excised and the extent of wound healing in each group was compared. RESULTS: Quantitative histologic analysis of epithelial gap distances revealed that PCBB treatment had greatly accelerated wound healing. Mean epithelial gap distances for PCBB treated and control wounds were 2.5x0.6mm and 3.6x0.5mm, respectively(p<0.05). CONCLUSION: Our results suggest that PCBB has potential to accelerate the healing of diabetic wounds.
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Animales , Humanos , Ratones , Bancos de Sangre , Plaquetas , Fibrinógeno , Trombina , Cicatrización de Heridas , Heridas y LesionesRESUMEN
PURPOSE: Many clinical trials have shown the effectiveness of platelet releasate on chronic wounds. However, a large volume of blood must be aspirated from a patient and a platelet separator is required. Here, we hypothesized that platelet concentrate obtained from a blood bank (PCBB) would be also effective at stimulating wound healing. The purpose of this study was to investigate the effectiveness of PCBB on accelerating healing of diabetic wounds in vivo. METHODS: Round wounds of 5mm diameter were made at four sites(two wounds on the left and two on the right side) on the backs of nine diabetic mice. Three hundred million platelets suspended in 0.05ml fibrinogen were dispersed on each wound on left sides. Same amount of fibrinogen without platelets was dispersed on right side control wounds. Thereafter, 0.05ml thrombin was applied to the each wound. Ten days after wound treatment, healed wounds were excised and the extent of wound healing in each group was compared. RESULTS: Quantitative histologic analysis of epithelial gap distances revealed that PCBB treatment had greatly accelerated wound healing. Mean epithelial gap distances for PCBB treated and control wounds were 2.5x0.6mm and 3.6x0.5mm, respectively(p<0.05). CONCLUSION: Our results suggest that PCBB has potential to accelerate the healing of diabetic wounds.