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- Rikard, S. M., et al.
(author)
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Multiple computational modeling approaches for prediction of wound healing dynamics following pharmacologic intervention
- 2017
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In: Biomedical Engineering Society (BMES) annual meeting, Phoenix, AZ, USA, 11-14 October 2017.
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Conference paper (peer-reviewed)abstract
- Diabetic wounds are known to have a delayed course of wound healing. We have recently demonstrated that injection of a synthetic modified RNA (modRNA) that enhances VEGF-A protein expression accelerates healing of full-thickness cutaneous wounds in db/db diabetic mice. Here, we compare two different computational modeling approaches to explore how the dosing amount and time course affect the rate of wound healing. We show that a partial differential equation (PDE) model is appropriate for questions concerning spatial resolution of healing throughout the wound, while a nonlinear mixed effect model (NLME) is more appropriate for capturing population level variations in healing rate when dealing with a sparse data set. Both models display sensitivity to varying dosing amount and timing.
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- Sun, ND, et al.
(author)
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Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 17509-
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Journal article (peer-reviewed)abstract
- Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo. Using multi-parametric photoacoustic microscopy, we show that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. Moreover, we evaluate the bioactivity of AZD8601 in a mouse model of diabetic wound healing in vivo. Using a boron nanoparticle-based tissue oxygen sensor, we show that sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing.
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