Transdermal deferoxamine prevents pressure-induced diabetic ulcers

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

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Updates in Diabetic Wound Healing, Inflammation, and Scarring

Seminars in Plastic Surgery ◽

10.1055/s-0041-1731460 ◽

2021 ◽

Author(s):

Nina Dasari ◽

Austin Jiang ◽

Anna Skochdopole ◽

Jayer Chung ◽

Edward Reece ◽

...

Keyword(s):

Wound Healing ◽

Disease Process ◽

Wound Dehiscence ◽

Diabetic Patients ◽

Wound Infections ◽

Diabetic Wound ◽

Complex Process ◽

Diabetic Wound Healing ◽

Almost All ◽

Diabetic Wounds

AbstractDiabetic patients can sustain wounds either as a sequelae of their disease process or postoperatively. Wound healing is a complex process that proceeds through phases of inflammation, proliferation, and remodeling. Diabetes results in several pathological changes that impair almost all of these healing processes. Diabetic wounds are often characterized by excessive inflammation and reduced angiogenesis. Due to these changes, diabetic patients are at a higher risk for postoperative wound healing complications. There is significant evidence in the literature that diabetic patients are at a higher risk for increased wound infections, wound dehiscence, and pathological scarring. Factors such as nutritional status and glycemic control also significantly influence diabetic wound outcomes. There are a variety of treatments available for addressing diabetic wounds.

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The Role of Matrix Metalloproteinases in Diabetic Wound Healing in relation to Photobiomodulation

Journal of Diabetes Research ◽

10.1155/2016/2897656 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 51

Author(s):

Sandra Matabi Ayuk ◽

Heidi Abrahamse ◽

Nicolette Nadene Houreld

Keyword(s):

Wound Healing ◽

Matrix Metalloproteinases ◽

Vascular Complications ◽

Diabetic Patients ◽

Main Function ◽

Diabetic Wound ◽

Impaired Wound Healing ◽

Inflammatory Phase ◽

Diabetic Wound Healing

The integration of several cellular responses initiates the process of wound healing. Matrix Metalloproteinases (MMPs) play an integral role in wound healing. Their main function is degradation, by removal of damaged extracellular matrix (ECM) during the inflammatory phase, breakdown of the capillary basement membrane for angiogenesis and cell migration during the proliferation phase, and contraction and remodelling of tissue in the remodelling phase. For effective healing to occur, all wounds require a certain amount of these enzymes, which on the contrary could be very damaging at high concentrations causing excessive degradation and impaired wound healing. The imbalance in MMPs may increase the chronicity of a wound, a familiar problem seen in diabetic patients. The association of diabetes with impaired wound healing and other vascular complications is a serious public health issue. These may eventually lead to chronic foot ulcers and amputation. Low intensity laser irradiation (LILI) or photobiomodulation (PBM) is known to stimulate several wound healing processes; however, its role in matrix proteins and diabetic wound healing has not been fully investigated. This review focuses on the role of MMPs in diabetic wound healing and their interaction in PBM.

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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.

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Angiogenic Nanoscaffold Accelerates Diabetic Wound Healing and Improves Wound Tissue Strength in db/db Mice

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206874 ◽

2009 ◽

Cited By ~ 1

Author(s):

Swathi Balaji ◽

Abdul Q. Sheikh ◽

Lee Morris ◽

Foong Y. Lim ◽

Timothy M. Crombleholme ◽

...

Keyword(s):

Wound Healing ◽

Healing Process ◽

Wound Healing Process ◽

Diabetic Patients ◽

Diabetic Wound ◽

Normal Wound Healing ◽

Inflammatory Phase ◽

Diabetic Wound Healing ◽

Ecm Degradation ◽

Chronic Ulcers

Chronic ulcers are a leading cause of morbidity in diabetic patients. Diabetes is associated with major changes in the wound microenvironment and disruption of normal wound healing process, characterized by a prolonged inflammatory phase with elevated levels of wound proteases and increased degradation of extracellular matrix (ECM) components [1]. This impedes wound healing due to a lack of provisional matrix, impaired recruitment and survival of endothelial (EC) and endothelial precursor (EPC) cells, and insufficient neovascularization, resulting in delayed healing. Therefore, strategies focused on restoring the diabetic wound microenvironment by decreasing ECM degradation and promoting neovascularization are promising for development of new therapies to treat chronic diabetic ulcers.

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A dual functional collagen scaffold coordinates angiogenesis and inflammation for diabetic wound healing

Biomaterials Science ◽

10.1039/d0bm00999g ◽

2020 ◽

Vol 8 (22) ◽

pp. 6337-6349

Author(s):

Ge Long ◽

Dingyang Liu ◽

Xi He ◽

Yeyu Shen ◽

Yannan Zhao ◽

...

Keyword(s):

Wound Healing ◽

Collagen Scaffold ◽

Diabetic Patients ◽

Diabetic Wound ◽

Dual Functional ◽

Persistent Inflammation ◽

Diabetic Wound Healing ◽

Diabetic Wounds ◽

Impaired Angiogenesis

Chronic diabetic wounds, which are associated with persistent inflammation and impaired angiogenesis, occur frequently in diabetic patients.

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Local reactive oxygen species scavenging improves diabetic wound healing

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2010.06.209 ◽

2010 ◽

Vol 211 (3) ◽

pp. S80

Author(s):

Denis Knobel ◽

James Lee Crawford ◽

Parag Butala ◽

Edward Henry Davidson ◽

Meredith Wetterau ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Wound Healing ◽

Reactive Oxygen ◽

Oxygen Species ◽

Diabetic Wound ◽

Diabetic Wound Healing

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Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)

Cellular and Molecular Bioengineering ◽

10.1007/s12195-021-00678-9 ◽

2021 ◽

Author(s):

S. Michaela Rikard ◽

Paul J. Myers ◽

Joachim Almquist ◽

Peter Gennemark ◽

Anthony C. Bruce ◽

...

Keyword(s):

Mathematical Model ◽

Wound Healing ◽

Spatial Distribution ◽

Surrounding Tissue ◽

Diabetic Patients ◽

Model Parameters ◽

Diabetic Wound ◽

Diabetic Wound Healing ◽

Diabetic Wounds ◽

The Impact

Abstract Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1–2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds.

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In Situ Tissue Engineering Using Angiogenic Nanoscaffold Enhances Diabetic Wound Healing in db/db Mouse Model

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-192198 ◽

2008 ◽

Author(s):

Swathi Balaji ◽

Sachin S. Vaikunth ◽

Jignesh K. Parvadia ◽

Timothy M. Crombleholme ◽

Daria A. Narmoneva

Keyword(s):

Tissue Engineering ◽

Wound Healing ◽

Attractive Alternative ◽

Diabetic Wound ◽

Diabetic Ulcer ◽

The Us ◽

Diabetic Wound Healing ◽

Bioengineered Skin ◽

Care Costs

Tissue engineering offers an attractive alternative for treatment of chronic nonhealing diabetic ulcers, which account for more than 27% of the $10.9 billion total diabetic health care costs in the US annually [1]. The harsh environment of a diabetic ulcer is characterized by reduced expression of angiogenic factors, insufficient vascularization, excess protease activity, matrix degradation and hyperglycemia-induced cell apoptosis [2]. A major factor contributing to insufficient neovascularization in diabetic nonhealing wounds may be deficiency in the recruitment of endothelial cells (ECs) and endothelial precursor cells (EPCs) to the wound site [3]. Recent studies focusing on altering the wound’s cellular and molecular environment using bone-marrow-derived stem cells, growth factors (delivered either directly or using gene or cell therapy), bioengineered skin constructs, and biological matrices, such as collagen and hyaluronic acid gels had promising wound healing outcomes [4]. These studies suggest that strategies aimed at modifying the extracellular environment of the diabetic wound to enhance cell survival and angiogenesis are promising for development of new therapies for diabetic wound healing.

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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.

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