TY - JOUR
T1 - Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants
AU - Kastellorizios, Michail
AU - Papadimitrakopoulos, Fotios
AU - Burgess, Diane J.
N1 - Funding Information:
The work was financially supported by the US Army Medical Research and Materiel Command, Telemedicine & Advanced Technology Research Center , award W81XWH-09-1-0711 .
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/7/31
Y1 - 2015/7/31
N2 - Dexamethasone-releasing PLGA poly(lactic-co-glycolic acid) microsphere/PVA (polyvinyl alcohol) hydrogel composite coatings have been shown to prevent the foreign body reaction (FBR) to subcutaneous implants in small and large animal models. Such coatings were developed to extend the lifetime of implantable biosensors. However, long-term exposure of tissue to low levels of dexamethasone results in a reduction in blood vessel density due to the anti-angiogenic effect of dexamethasone. This mild effect, while not threatening to the subject's health, may interfere with analyte detection and the sensor response time over the long-term. The present work is focused on the development of coatings that deliver combinations of three tissue response modifiers (TRMs): dexamethasone, VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor). Dexamethasone, VEGF and PDGF prevent the FBR, increase angiogenesis and promote blood vessel maturation (which increases blood flow), respectively. To minimize any potential interference among these three TRMs (for example, PDGF increases fibrosis), the relative doses of dexamethasone, VEGF and PDGF were adjusted. It was determined that: a) all three TRMs are required for maximum promotion of angiogenesis, blood vessel maturation and prevention of the FBR; b) VEGF has to be administered at higher doses than PDGF; c) an increase in dexamethasone dosing must be accompanied by a proportional increase in growth factor dosing; and d) modification of the TRM ratio can achieve a constant capillary density throughout the implantation period which is important for applications such as biosensors to maintain sensitivity and a stable sensor baseline. Moreover, an osmosis-driven process for encapsulation of proteins in PLGA microspheres that showed low burst release was developed.
AB - Dexamethasone-releasing PLGA poly(lactic-co-glycolic acid) microsphere/PVA (polyvinyl alcohol) hydrogel composite coatings have been shown to prevent the foreign body reaction (FBR) to subcutaneous implants in small and large animal models. Such coatings were developed to extend the lifetime of implantable biosensors. However, long-term exposure of tissue to low levels of dexamethasone results in a reduction in blood vessel density due to the anti-angiogenic effect of dexamethasone. This mild effect, while not threatening to the subject's health, may interfere with analyte detection and the sensor response time over the long-term. The present work is focused on the development of coatings that deliver combinations of three tissue response modifiers (TRMs): dexamethasone, VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor). Dexamethasone, VEGF and PDGF prevent the FBR, increase angiogenesis and promote blood vessel maturation (which increases blood flow), respectively. To minimize any potential interference among these three TRMs (for example, PDGF increases fibrosis), the relative doses of dexamethasone, VEGF and PDGF were adjusted. It was determined that: a) all three TRMs are required for maximum promotion of angiogenesis, blood vessel maturation and prevention of the FBR; b) VEGF has to be administered at higher doses than PDGF; c) an increase in dexamethasone dosing must be accompanied by a proportional increase in growth factor dosing; and d) modification of the TRM ratio can achieve a constant capillary density throughout the implantation period which is important for applications such as biosensors to maintain sensitivity and a stable sensor baseline. Moreover, an osmosis-driven process for encapsulation of proteins in PLGA microspheres that showed low burst release was developed.
KW - Angiogenesis
KW - Dexamethasone
KW - Foreign body reaction
KW - PLGA microspheres
KW - Platelet dericed growth factor
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=84938098545&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2015.07.021
DO - 10.1016/j.jconrel.2015.07.021
M3 - Article
C2 - 26216396
AN - SCOPUS:84938098545
SN - 0168-3659
VL - 214
SP - 103
EP - 111
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -