Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Ward, W. Kenneth; Hansen, Jillian C.; Massoud, Ryan G.; Engle, J. Michael; Takeno, Marc; Hauch, Kip D.

doi:10.1002/jbm.a.32651

Cited by 22 publications

(31 citation statements)

References 29 publications

(37 reference statements)

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“…Similar results were found in reports by Klueh et al where the inflammation around implanted sensor probes was diminished when Dex was locally delivered [20]. Moreover, several studies have reported on a decrease in macrophage density as a function of Dex release from indwelling microdialysis probes and osmotic pumps [36–38]. …”

Section: Discussionsupporting

confidence: 86%

Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo

et al. 2016

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Continuous glucose sensors offer the promise of tight glycemic control for insulin dependent diabetics; however, utilization of such systems has been hindered by issues of tissue compatibility. Here we report on the in vivo performance of implanted glucose sensors coated with Dexamethasone-loaded (Dex-loaded) porous coatings employed to mediate the tissue-sensor interface. Two animal studies were conducted to 1) characterize the tissue modifying effects of the porous Dex-loaded coatings deployed on sensor surrogate implants, and 2) investigate the effects of the same coatings on the in vivo performance of Medtronic MiniMed SOF-SENSOR™ glucose sensors. The tissue response to implants was evaluated by quantifying macrophage infiltration, blood vessel formation, and collagen density around implants. Sensor function was assessed by measuring changes in sensor sensitivity and time lag, calculating the Mean Absolute Relative Difference (MARD) for each sensor treatment, and performing functional glucose challenge test at relevant time points. Implants treated with porous Dex-loaded coatings diminished inflammation and enhanced vascularization of the tissue surrounding the implants. Functional sensors with Dex-loaded porous coatings showed enhanced sensor sensitivity over a 21-day period when compared to controls. Enhanced sensor sensitivity was accompanied with an increase in sensor signal lag and MARD score. These results indicate that Dex-loaded porous coatings were able to elicit an attenuated tissue response, and that such tissue microenvironment could be conducive towards extending the performance window of glucose sensors in vivo.

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Section: Discussionsupporting

confidence: 86%

Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo

et al. 2016

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“…Prior studies have shown that local Dex delivery is able to improve sensor performance past the “break-in period” by decreasing leukocyte migration and inflammation at the implant site (19, 22, 23, 25, 38). However, when Dex is delivered over the long-term (>1 month) the drug can act as an angiostatic agent leading to reduced microvessel density, vasodilation, and increased vascular permeability at the implant site.…”

Section: Discussionmentioning

confidence: 99%

“…Attenuation of inflammation contends that the benefits of minimizing the deleterious effects of acute inflammation on sensor function outweigh the potential advantages of engineering the tissue response. One strategy for the attenuation of acute inflammation involves the local release of anti-inflammatory mediators such as nitric oxide, non-steroidal anti-inflammatory drugs, and glucocorticoids (17-19). …”

Section: Introductionmentioning

confidence: 99%

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors

2014

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Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release, and bioactivity characterization of tubular, porous dexamethasone (Dex) releasing polyurethane coatings designed to attenuate local inflammation in the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy (SEM) and Micro-computed tomography (Micro-CT) showed a controlled porosity and coating thickness. In vitro drug release from coatings monitored over two weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.

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“…There are numerous examples of the use of dexamethasone to reduce inflammation in a biomaterials context [14, 28–31]. However, the endpoint analyses in these studies are frequently histological analysis of H&E and Masson’s Trichrome stains.…”

Section: Introductionmentioning

confidence: 99%

Localized delivery of dexamethasone-21-phosphate via microdialysis implants in rat induces M(GC) macrophage polarization and alters CCL2 concentrations

Keeler¹,

Durdik²,

Stenken³

2015

Acta Biomaterialia

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Microdialysis sampling probes were implanted into the subcutaneous space on the dorsal side of male Sprague Dawley rats to locally deliver dexamethasone-21-phosphate (Dex) with the aim of altering in vivo macrophage polarization. Macrophage polarization is of significant interest in the field of biomaterials since wound healing macrophages are a possible means to extend implant life as well as improve tissue remodeling to an implant. Quantitative analysis of CCL2 in collected dialysates, gene expression and immunohistochemistry performed on the tissue surrounding the microdialysis implant were used to evaluate if Dex polarized macrophages. Dex infusion down regulated IL-6 and CCL2 gene expression and decreased CCL2 concentrations in dialysates collected at the implant site. Dex appeared to have no significant effect on the gene regulation of CD163, a commonly used M2c macrophage surface marker; Arg2; and iNOS2. However, Dex infusion was effective at increasing the number of CD 163+ cells surrounding the implanted microdialysis probe. This work demonstrates the use of microdialysis sampling to deliver agents such as Dex to alter macrophage polarization in vivo while allowing the ability to collect cytokines in the surrounding microenvironment.

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Controlled release of dexamethasone from subcutaneously‐implanted biosensors in pigs: Localized anti‐inflammatory benefit without systemic effects

Cited by 22 publications

References 29 publications

Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo

Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors

Localized delivery of dexamethasone-21-phosphate via microdialysis implants in rat induces M(GC) macrophage polarization and alters CCL2 concentrations

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