Prevention of foreign body reaction in a pre-clinical large animal model

Kastellorizios, Michail; Papadimitrakopoulos, Fotios; Burgess, Diane J.

doi:10.1016/j.jconrel.2015.01.038

Cited by 44 publications

(35 citation statements)

References 45 publications

(55 reference statements)

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“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 and collagen deposition from day 7. A fibrous capsule can be seen from day 14 onwards, which was rich in cell content, identified as activated fibroblasts upon higher-magnification analysis of the tissue sections which is in accordance with previous work 30 . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 encapsulation was visible in any of the tissue samples, and the implants were surrounded by normal subcutaneous tissue which consists of collagen fibers and adipose tissue.…”

Section: Preparation Of Composite Coatingssupporting

confidence: 91%

“…Our group has previously studied FBR to PLGA microsphere/PVA hydrogel composite coatings in Gottingen minipigs, with a focus on inter-species differences between minipigs and rats 30 . It was determined that minipigs require higher levels of dexamethasone released in the local 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 microenvironment to prevent FBR compared to rats (0.11 mg for one month in rats vs 0.22 mg for 2 weeks in minipigs).…”

Section: Discussionmentioning

confidence: 99%

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Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig

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The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one-month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment.

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Section: Preparation Of Composite Coatingssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig

et al. 2015

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“…Various approaches have been attempted to overcome the foreign body reaction to extend the life-time of glucose sensors. These include application of biocompatible coatings (Kastellorizios et al, 2015a; Wang et al, 2013), release of anti-inflammatory drugs (Bhardwaj et al, 2010; Galeska et al, 2005; Patil et al, 2004; Zolnik and Burgess, 2008) as well as delivery of angiogenic agents (Laschke et al, 2014; Patil et al, 2007). …”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo performance of dexamethasone loaded PLGA microspheres prepared using polymer blends

Wang

Burgess

2015

International Journal of Pharmaceutics

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The foreign body reaction is the major cause of the dysfunction and relatively short lifetime associated with implanted glucose biosensors. An effective strategy to maintain sensor functionality is to apply biocompatible coatings that elute drug to counter the negative tissue reactions. This has been achieved using dexamethasone releasing poly (lactic-co-glycolic acid) (PLGA) microspheres embedded in a poly vinyl alcohol (PVA) hydrogel coating. Accordingly, the biosensor lifetime relies on the duration and dose of drug release from the coating. To achieve long-term drug release mixed populations of microspheres have been used. In the current study, microspheres were prepared by blending low (25 KDa) and high (113 KDa) molecular weight PLGA at different mass ratios to overcome problems associated with mixing multiple populations of microspheres. “Real-time” in vitro studies demonstrated dexamethasone release for approximately 5 months. An accelerated method with discriminatory ability was developed to shorten drug release to less than 2 weeks. An in vivo pharmacodynamics study demonstrated efficacy against the foreign body reaction for 4.5 months. Such composite coatings composed of PLGA microspheres prepared using polymer blends could potentially be used to ensure long-term performance of glucose sensors.

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“…Moreover, composites were implanted approximately 2 cm apart. This has been shown to prevent any interference between different groups, for example dexamethasone released from a nearby composite did not reduce the inflammatory response of control composites (containing no drug) [13,[15][16][17]22].…”

Section: Discussionmentioning

confidence: 99%

“…The FBR and its prevention have been a research focus during the past decades; the most common method to prevent the FBR is by the continuous administration of an anti-inflammatory agent, most commonly dexamethasone [6,[13][14][15][16][17]. Dexamethasone is popular due to its high efficacy and potency which result in only small amounts of the drug being required for long-term action.…”

Section: Introductionmentioning

confidence: 99%

Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants

Kastellorizios

Papadimitrakopoulos

Burgess

2015

Journal of Controlled Release

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Prevention of foreign body reaction in a pre-clinical large animal model

Cited by 44 publications

References 45 publications

Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig

Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig

In vitro and in vivo performance of dexamethasone loaded PLGA microspheres prepared using polymer blends

Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants

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