Local Delivery of PHD2 siRNA from ROS‐Degradable Scaffolds to Promote Diabetic Wound Healing

Martin, John R.; Nelson, Christopher E.; Gupta, Mukesh Kumar; Yu, Fang; Sarett, Samantha M.; Hocking, Kyle M.; Pollins, Alonda C.; Nanney, Lillian B.; Davidson, Jeffrey M.; Guelcher, Scott A.; Duvall, Craig L.

doi:10.1002/adhm.201600820

Cited by 75 publications

(58 citation statements)

References 58 publications

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“…These results are consistent with the oxidation-induced transition of poly(propylene sulfide) (Figure S12, Supporting Information) to more hydrophilic poly(propylene sulfoxide) and poly(propylene sulfone) upon ROS exposure, [22] while ester groups are relatively inert to oxidative environments. [23] …”

Section: Resultsmentioning

confidence: 99%

“…Similar bulk biomaterials that are specifically degraded by cell-generated ROS have been shown to promote enhanced tissue regeneration compared to hydrolytically degraded biomaterial implants since the ROS-sensitive constructs directly tie material breakdown to cellular infiltration. [23] In an analogous manner, ROS-degradable PDN gels appear to mediate specific, on-demand drug delivery in response to local cellular infiltration and are well suited for future exploration in tissue regenerative applications.…”

Section: Resultsmentioning

confidence: 99%

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Thermogelling, ABC Triblock Copolymer Platform for Resorbable Hydrogels with Tunable, Degradation‐Mediated Drug Release

Gupta

Martin

Dollinger

et al. 2017

Adv Funct Materials

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Clinical application of injectable, thermoresponsive hydrogels is hindered by lack of degradability and controlled drug release. To overcome these challenges, a family of thermoresponsive, ABC triblock polymer-based hydrogels has been engineered to degrade and release drug cargo through either oxidative or hydrolytic/enzymatic mechanisms dictated by the “A” block composition. Three ABC triblock copolymers are synthesized with varying “A” blocks, including oxidation-sensitive poly(propylene sulfide), slow hydrolytically/enzymatically degradable poly(ε-caprolactone), and fast hydrolytically/enzymatically degradable poly(D,L-lactide-co-glycolide), forming the respective formulations PPS135-b-PDMA152-b-PNIPAAM225 (PDN), PCL85-b-PDMA150-b-PNIPAAM150 (CDN), and PLGA60-b-PDMA148-b-PNIPAAM152 (LGDN). For all three polymers, hydrophilic poly(N,N-dimethylacrylamide) and thermally responsive poly(N-isopropylacrylamide) comprise the “B” and “C” blocks, respectively. These copolymers form micelles in aqueous solutions at ambient temperature that can be preloaded with small molecule drugs. These solutions quickly transition into hydrogels upon heating to 37 °C, forming a supra-assembly of physically crosslinked, drug-loaded micelles. PDN hydrogels are selectively degraded under oxidative conditions while CDN and LGDN hydrogels are inert to oxidation but show differential rates of hydrolytic/enzymatic decomposition. All three hydrogels are cytocompatible in vitro and in vivo, and drug-loaded hydrogels demonstrate differential release kinetics in vivo corresponding with their specific degradation mechanism. These collective data highlight the potential cell and drug delivery use of this tunable class of ABC triblock polymer thermogels.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Thermogelling, ABC Triblock Copolymer Platform for Resorbable Hydrogels with Tunable, Degradation‐Mediated Drug Release

Gupta

Martin

Dollinger

et al. 2017

Adv Funct Materials

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“…In the early stage of wound diabetic healing, ROS levels increase, but the activity of antioxidant enzymes does not increase, which will cause a significant increase in oxidative stress in the wound environment . It is more noteworthy that persistent hyperglycemia and infection in diabetic wounds elevate the levels of AGEs in the blood, which directly bring about excessive ROS accumulation .…”

Section: Causes and Healing Of Woundsmentioning

confidence: 99%

“…Among all of them, the effect of ROS on healing of chronic wounds is one of the most typical representatives . ROS are highly reactive molecules, which are important participants in wound healing, ranging from the initial signal that stimulates immune response to the signal pathway that triggers redox‐dependent intracellular oxidation and resistance to invasive bacteria . However, the oxidative stress caused by a large amount of ROS can lead to the oxidation of lipids, proteins, and nucleic acids .…”

Section: Antioxidation In Chronic Wound Healingmentioning

confidence: 99%

Advances and Impact of Antioxidant Hydrogel in Chronic Wound Healing

Han

et al. 2020

Adv Healthcare Materials

449

305

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The accelerating and thorough treatment of chronic wounds still represents a major unmet medical need owing to the complex symptoms resulting from metabolic disorder of the wound microenvironment. Although numerous strategies and bioactive hydrogels are developed, an effective and widely used method of chronic wound treatment remains a bottleneck. With the aim to accelerate chronic wound healing, many hydrogel dressings with antioxidant functions have emerged and are proven to accelerate wound healing, especially for chronic wound repair. The new strategy in chronic wound treatment brought by antioxidant hydrogels is of great significance to human health. Here, the application of antioxidant hydrogels in the repair of chronic wounds is discussed systematically, aiming to provide an important theoretical reference for the further breakthrough of chronic wound healing.

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“…Although RNA interference is a promising therapeutic strategy, its use in wound healing has been limited. There have been several reports of improved wound healing outcomes upon gene silencing of matrix metalloproteinases (MMPs) and prolyl hydroxylase domain protein 2 . In separate studies, siRNA loaded in hydrogel dressings has induced modest knockdown of other gene targets, including xanthine dehydrogenase and the tumor suppressor gene, p53, in the diabetic wound.…”

Section: Introductionmentioning

confidence: 99%

Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice

Kasiewicz

Whitehead

2018

Bioengineering & Transla Med

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Diabetes mellitus is a mounting concern in the United States, as are the mortality and morbidity that result from its complications. Of particular concern, diabetes patients frequently suffer from impaired wound healing and resultant nonhealing diabetic foot ulcers. These ulcers overproduce tumor necrosis factor α (TNFα), which reduces wound bed cell migration and proliferation while encouraging apoptosis. Herein, we describe the use of siRNA‐loaded lipid nanoparticles (LNPs) as a potential wound treatment to combat an overzealous immune response and facilitate wound closure. LNPs were formulated with an ionizable, degradable lipidoid and siRNA specific for TNFα. Topical application of nanoparticles reduced TNFα mRNA expression in the wound by 40–55% in diabetic and nondiabetic mice. In diabetic mice, this TNFα knockdown accelerated wound healing compared to untreated controls. Together, these results serve as proof‐of‐concept that RNA interference therapy using LNPs can reduce the severity and duration of chronic diabetic wounds.

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Local Delivery of PHD2 siRNA from ROS‐Degradable Scaffolds to Promote Diabetic Wound Healing

Cited by 75 publications

References 58 publications

Thermogelling, ABC Triblock Copolymer Platform for Resorbable Hydrogels with Tunable, Degradation‐Mediated Drug Release

Thermogelling, ABC Triblock Copolymer Platform for Resorbable Hydrogels with Tunable, Degradation‐Mediated Drug Release

Advances and Impact of Antioxidant Hydrogel in Chronic Wound Healing

Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice

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