Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

There is a clinical need for new, more effective treatments for chronic wounds in diabetic patients. Lack of epithelial cell migration is a hallmark of nonhealing wounds, and diabetes often involves endothelial dysfunction. Therefore, targeting re-epithelialization, which mainly involves keratinocytes, may improve therapeutic outcomes of current treatments. In this study, we present an integrin-binding prosurvival peptide derived from angiopoietin-1, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), as a therapeutic candidate for diabetic wound treatments by demonstrating its efficacy in promoting the attachment, survival, and collective migration of human primary keratinocytes and the activation of protein kinase B Akt and MAPKp42/44. The QHREDGS peptide, both as a soluble supplement and when immobilized in a substrate, protected keratinocytes against hydrogen peroxide stress in a dose-dependent manner. Collective migration of both normal and diabetic human keratinocytes was promoted on chitosan–collagen films with the immobilized QHREDGS peptide. The clinical relevance was demonstrated further by assessing the chitosan–collagen hydrogel with immobilized QHREDGS in full-thickness excisional wounds in a db/db diabetic mouse model; QHREDGS showed significantly accelerated and enhanced wound closure compared with a clinically approved collagen wound dressing, peptide-free hydrogel, or blank wound controls. The accelerated wound closure resulted primarily from faster re-epithelialization and increased formation of granulation tissue. There were no observable differences in blood vessel density or size within the wound; however, the total number of blood vessels was greater in the peptide-hydrogel–treated wounds. Together, these findings indicate that QHREDGS is a promising candidate for wound-healing interventions that enhance re-epithelialization and the formation of granulation tissue.

Download Full-text

Diabetic wound regeneration using heparin-mimetic peptide amphiphile gel in db/db mice

Biomaterials Science ◽

10.1039/c7bm00251c ◽

2017 ◽

Vol 5 (7) ◽

pp. 1293-1303 ◽

Cited By ~ 11

Author(s):

Berna Senturk ◽

Burak M. Demircan ◽

Alper D. Ozkan ◽

Sehmus Tohumeken ◽

Tuncay Delibasi ◽

...

Keyword(s):

High Risk ◽

Chronic Wounds ◽

Diabetic Patients ◽

Diabetic Wound ◽

Peptide Amphiphile ◽

Efficient Treatment ◽

Mimetic Peptide ◽

Leg Amputation

There is an urgent need for more efficient treatment of chronic wounds in diabetic patients especially with a high risk of leg amputation.

Download Full-text

Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin

AJP Cell Physiology ◽

10.1152/ajpcell.00042.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. C295-C305 ◽

Cited By ~ 10

Author(s):

James White ◽

Theresa Guerin ◽

Hollie Swanson ◽

Steven Post ◽

Haining Zhu ◽

...

Keyword(s):

Nitric Oxide ◽

Myristic Acid ◽

Acetylcholine Receptors ◽

Diabetic Mouse ◽

No Synthase ◽

Diabetic Patients ◽

No Production ◽

Dependent Manner ◽

Endothelial No Synthase ◽

Stimulation Of

In the current study, we examined whether diabetes affected the ability of HDL to stimulate nitric oxide (NO) production. Using HDL isolated from both diabetic humans and diabetic mouse models, we found that female HDL no longer induced NO synthesis, despite containing equivalent amounts of estrogen as nondiabetic controls. Furthermore, HDL isolated from diabetic females and males prevented acetylcholine-induced stimulation of NO generation. Analyses of both the human and mouse diabetic HDL particles showed that the HDLs contained increased levels of myristic acid. To determine whether myristic acid associated with HDL particles was responsible for the decrease in NO generation, myristic acid was added to HDL isolated from nondiabetic humans and mice. Myristic acid-associated HDL inhibited the generation of NO in a dose-dependent manner. Importantly, diabetic HDL did not alter the levels of endothelial NO synthase or acetylcholine receptors associated with the cells. Surprisingly, diabetic HDL inhibited ionomycin-induced stimulation of NO production without affecting ionomycin-induced increases in intracellular calcium. Further analysis indicated that diabetic HDL prevented calmodulin from interacting with endothelial NO synthase (eNOS) but did not affect the activation of calmodulin kinase or calcium-independent mechanisms for stimulating eNOS. These studies are the first to show that a specific fatty acid associated with HDL inhibits the stimulation of NO generation. These findings have important implications regarding cardiovascular disease in diabetic patients.

Download Full-text

Strain-Programmable Patch for Diabetic Wound Healing

10.1101/2021.06.07.447423 ◽

2021 ◽

Author(s):

Georgios Theocharidis ◽

Hyunwoo Yuk ◽

Heejung Roh ◽

Liu Wang ◽

Ikram Mezghani ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Ex Vivo ◽

Numerical Models ◽

Diabetic Patients ◽

Diabetic Wound ◽

Memory Mechanism ◽

Culture Models ◽

Diabetic Wound Healing

Chronic wounds with impaired healing capability such as diabetic foot ulcers (DFU) are devastating complications in diabetic patients, inflicting rapidly growing clinical and economic burdens in aging societies. Despite recent advances in therapeutic approaches, limited benefits of the existing solutions highlight the critical need for novel therapeutic solutions for diabetic wound healing. Here we propose a strain-programmable patch capable of rapid robust adhesion on and programmable mechanical contraction of wet wounded tissues over days to offer a new therapeutic platform for diabetic wounds. The strain-programmable patch, consisting of a dried bioadhesive layer and a pre-stretched elastomer backing, implements a hydration-based shape-memory mechanism to achieve both uniaxial and biaxial contractions and stress remodeling of wet wounds in a programmable manner. We develop theoretical and numerical models to rationally guide the strain-programming and mechanical modulation of wounds. In vivo rodent and ex vivo human skin culture models validate the programmability and efficacy of the proposed platform and identify mechanisms of action for accelerated diabetic wound healing.

Download Full-text

Flax Fiber Hydrophobic Extract Inhibits Human Skin Cells Inflammation and Causes Remodeling of Extracellular Matrix and Wound Closure Activation

BioMed Research International ◽

10.1155/2015/862391 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 6

Author(s):

Monika Styrczewska ◽

Anna Kostyn ◽

Anna Kulma ◽

Grazyna Majkowska-Skrobek ◽

Daria Augustyniak ◽

...

Keyword(s):

Fatty Acids ◽

Extracellular Matrix ◽

Wound Healing ◽

Wound Closure ◽

Chronic Wounds ◽

Flax Fiber ◽

Great Promise ◽

Dependent Manner ◽

Skin Cells ◽

Anti Inflammatory

Inflammation is the basis of many diseases, with chronic wounds amongst them, limiting cell proliferation and tissue regeneration. Our previous preclinical study of flax fiber applied as a wound dressing and analysis of its components impact on the fibroblast transcriptome suggested flax fiber hydrophobic extract use as an anti-inflammatory and wound healing preparation. The extract contains cannabidiol (CBD), phytosterols, and unsaturated fatty acids, showing great promise in wound healing. Inin vitroproliferation and wound closure tests the extract activated cell migration and proliferation. The activity of matrix metalloproteinases in skin cells was increased, suggesting activation of extracellular components remodeling. The expression of cytokines was diminished by the extract in a cannabidiol-dependent manner, butβ-sitosterol can act synergistically with CBD in inflammation inhibition. Extracellular matrix related genes were also analyzed, considering their importance in further stages of wound healing. The extract activated skin cell matrix remodeling, but the changes were only partially cannabidiol- andβ-sitosterol-dependent. The possible role of fatty acids also present in the extract is suggested. The study shows the hydrophobic flax fiber components as wound healing activators, with anti-inflammatory cannabidiol acting in synergy with sterols, and migration and proliferation promoting agents, some of which still require experimental identification.

Download Full-text

Fibrin Glue Enhances Adipose-Derived Stromal Cell Cytokine Secretion and Survival Conferring Accelerated Diabetic Wound Healing

Stem Cells International ◽

10.1155/2018/1353085 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Ursula Hopfner ◽

Matthias M. Aitzetmueller ◽

Philipp Neßbach ◽

Michael S. Hu ◽

Hans-Guenther Machens ◽

...

Keyword(s):

Wound Healing ◽

Fibrin Glue ◽

Stromal Cell ◽

Wound Closure ◽

Chronic Wounds ◽

Imaging System ◽

Diabetic Wound ◽

Diabetic Wound Healing

Introduction. Although chronic wounds are a major personal and economic burden, treatment options are still limited. Among those options, adipose-derived stromal cell- (ASC-) based therapies rank as a promising approach but are restricted by the harsh wound environment. Here we use a commercially available fibrin glue to provide a deliverable niche for ASCs in chronic wounds. Material and Methods. To investigate the in vitro effect of fibrin glue, cultivation experiments were performed and key cytokines for regeneration were quantified. By using an established murine chronic diabetic wound-healing model, we evaluated the influence of fibrin glue spray seeding on cell survival (In Vivo Imaging System, IVIS), wound healing (wound closure kinetics), and neovascularization of healed wounds (CD31 immunohistochemistry). Results. Fibrin glue seeding leads to a significantly enhanced secretion of key cytokines (SDF-1, bFGF, and MMP-2) of human ASCs in vitro. IVIS imaging showed a significantly prolonged murine ASC survival in diabetic wounds and significantly accelerated complete wound closure in the fibrin glue seeded group. CD31 immunohistochemistry revealed significantly more neovascularization in healed wounds treated with ASCs spray seeded in fibrin glue vs. ASC injected into the wound bed. Conclusion. Although several vehicles have shown to successfully act as cell carrier systems in preclinical trials, regulatory issues have prohibited clinical usage for chronic wounds. By demonstrating the ability of fibrin glue to act as a carrier vehicle for ASCs, while simultaneously enhancing cellular regenerative function and viability, this study is a proponent of clinical translation for ASC-based therapies.

Download Full-text

Healing Effects of Photobiomodulation on Diabetic Wounds

Applied Sciences ◽

10.3390/app9235114 ◽

2019 ◽

Vol 9 (23) ◽

pp. 5114

Author(s):

Nicolette Houreld

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Chronic Wounds ◽

Diabetic Patients ◽

Diabetic Wound ◽

Recurrence Rates ◽

Speed Up ◽

Diabetic Wound Healing ◽

Underlying Mechanisms ◽

Diabetic Wounds

Diabetic patients frequently develop chronic ulcers of the lower extremities, which are a frequent cause for hospitalization and amputation, placing strain on patients, their families, and healthcare systems. Present therapies remain a challenge, with high recurrence rates. Photobiomodulation (PBM), which is the non-invasive application of light at specific wavelengths, has been shown to speed up healing of chronic wounds, including diabetic foot ulcers (DFUs). PBM produces photophysical and photochemical changes within cells without eliciting thermal damage. It has been shown to promote tissue regeneration and speed up wound repair by reducing inflammation and oxidative stress, accelerating cell migration and proliferation, and promoting extracellular matrix production and release of essential growth factors. The shortage of rigorous, well-designed clinical trials makes it challenging to assess the scientific impact of PBM on DFUs, and lack of understanding of the underlying mechanisms also hinders the conventional use of this therapy. This review gives a glimpse into diabetic wound healing and PBM, and the effects of PBM on diabetic wound healing.

Download Full-text

Parameter-Dependency of Low-Intensity Vibration for Wound Healing in Diabetic Mice

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.654920 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rita E. Roberts ◽

Onur Bilgen ◽

Rhonda D. Kineman ◽

Timothy J. Koh

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Wound Closure ◽

Chronic Wounds ◽

Low Frequency ◽

Whole Body ◽

Diabetic Patients ◽

Diabetic Mice ◽

Low Intensity ◽

Low Intensity Vibration

Chronic wounds in diabetic patients represent an escalating health problem, leading to significant morbidity and mortality. Our group previously reported that whole body low-intensity vibration (LIV) can improve angiogenesis and wound healing in diabetic mice. The purpose of the current study was to determine whether effects of LIV on wound healing are frequency and/or amplitude dependent. Wound healing was assessed in diabetic (db/db) mice exposed to one of four LIV protocols with different combinations of two acceleration magnitudes (0.3 and 0.6 g) and two frequencies (45 and 90 Hz) or in non-vibration sham controls. The low acceleration, low frequency protocol (0.3 g and 45 Hz) was the only one that improved wound healing, increasing angiogenesis and granulation tissue formation, leading to accelerated re-epithelialization and wound closure. Other protocols had little to no impact on healing with some evidence that 0.6 g accelerations negatively affected wound closure. The 0.3 g, 45 Hz protocol also increased levels of insulin-like growth factor-1 and tended to increase levels of vascular endothelial growth factor in wounds, but had no effect on levels of basic fibroblast growth factor or platelet derived growth factor-bb, indicating that this LIV protocol induces specific growth factors during wound healing. Our findings demonstrate parameter-dependent effects of LIV for improving wound healing that can be exploited for future mechanistic and therapeutic studies.

Download Full-text

Lupeol, a Dietary Triterpene, Enhances Wound Healing in Streptozotocin-Induced Hyperglycemic Rats with Modulatory Effects on Inflammation, Oxidative Stress, and Angiogenesis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3182627 ◽

2019 ◽

Vol 2019 ◽

pp. 1-20 ◽

Cited By ~ 14

Author(s):

Fernando Pereira Beserra ◽

Ana Júlia Vieira ◽

Lucas Fernando Sérgio Gushiken ◽

Eduardo Oliveira de Souza ◽

Maria Fernanda Hussni ◽

...

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Inflammatory Cell ◽

Chronic Wounds ◽

Treated Group ◽

Diabetic Patients ◽

Impaired Wound Healing ◽

Collagen Iii ◽

Wound Healing Activity ◽

Immunohistochemical Analyses

Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-β1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.

Download Full-text

Heme Oxygenase-1 Promotes Delayed Wound Healing in Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2016/9726503 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Qing-Ying Chen ◽

Guo-Guang Wang ◽

Wei Li ◽

Yu-Xin Jiang ◽

Xiao-Hua Lu ◽

...

Keyword(s):

Heme Oxygenase ◽

Wound Closure ◽

Diabetic Rats ◽

Heme Oxygenase 1 ◽

Diabetic Patients ◽

Diabetic Wound ◽

Chronic Complications ◽

Delayed Wound Healing ◽

Wound Model ◽

Anti Inflammation

Diabetic ulcers are one of the most serious and costly chronic complications for diabetic patients. Hyperglycemia-induced oxidative stress may play an important role in diabetes and its complications. The aim of the study was to explore the effect of heme oxygenase-1 on wound closure in diabetic rats. Diabetic wound model was prepared by making an incision with full thickness in STZ-induced diabetic rats. Wounds from diabetic rats were treated with 10% hemin ointment for 21 days. Increase of HO-1 protein expression enhanced anti-inflammation and antioxidant in diabetic rats. Furthermore, HO-1 increased the levels of VEGF and ICAM-1 and expressions of CBS and CSE protein. In summary, HO-1 promoted the wound closure by augmenting anti-inflammation, antioxidant, and angiogenesis in diabetic rats.

Download Full-text

Sustained Release of Insulin-Like Growth Factor-1 from Bombyx mori L. Silk Fibroin Delivery for Diabetic Wound Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22126267 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6267

Author(s):

Meng-Jin Lin ◽

Mei-Chun Lu ◽

Hwan-You Chang

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Sustained Release ◽

Silk Fibroin ◽

Granulation Tissue ◽

Release Rate ◽

Insulin Like Growth Factor ◽

Diabetic Wound ◽

Diabetic Mice ◽

Wound Therapy

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h−1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.

Download Full-text