Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages

Jiang, Kaiyuan; Weaver, Jessica D.; Li, Yangjunyi; Chen, Xiongjian; Liang, Jia-Pu; Stabler, Cherie L.

doi:10.1016/j.biomaterials.2016.11.004

Cited by 134 publications

(128 citation statements)

References 42 publications

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“…Jiang et al [129] showed that long term (90 days) effects could be achieved by just 10–30 days of controlled release of dexamethasone, an anti-inflammatory glucocorticoid, from synthetic scaffolds encapsulating pancreatic islet cells for cell transplantation therapy of diabetes. However, release of dexamethasone from the scaffold in this study was characterized in vitro, which may be different than in vivo conditions [129, 130]. Another critical quality control issue for drug-releasing implants will be dose.…”

Section: Unresolved Questions: Obstacles and Opportunitiesmentioning

confidence: 99%

“…Another critical quality control issue for drug-releasing implants will be dose. In the islet transplantation study, low doses of released dexamethasone improved graft survival, while high doses excessively suppressed macrophage infiltration, thus hindering vascularization and graft integration and reducing islet cell survival [129]. Presumably, too low of a dose would fail to sufficiently modulate macrophage behavior.…”

Section: Unresolved Questions: Obstacles and Opportunitiesmentioning

confidence: 99%

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Macrophage-based therapeutic strategies in regenerative medicine

Spiller

Koh

2017

Advanced Drug Delivery Reviews

251

193

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Mounting evidence suggests that therapeutic cell and drug delivery strategies designed to actively harness the regenerative potential of the inflammatory response have great potential in regenerative medicine. In particular, macrophages have emerged as a primary target because of their critical roles in regulating multiple phases of tissue repair through their unique ability to rapidly shift phenotypes. Herein, we review macrophage-based therapies, focusing on the translational potential for cell delivery of ex vivo-activated macrophages and delivery of molecules and biomaterials to modulate accumulation and phenotype of endogenous macrophages. We also review current obstacles to progress in translating basic findings to therapeutic applications, including the need for improved understanding of context-dependent macrophage functions and the myriad factors that regulate macrophage phenotype; potential species-specific differences (e.g. humans versus mice); quality control issues; and the lack of standardized procedures and nomenclature for characterizing macrophages. Looking forward, the inherent plasticity of macrophages represents a daunting challenge for harnessing these cells in regenerative medicine therapies but also great opportunity for improving patient outcomes in a variety of pathological conditions.

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Section: Unresolved Questions: Obstacles and Opportunitiesmentioning

confidence: 99%

Section: Unresolved Questions: Obstacles and Opportunitiesmentioning

confidence: 99%

Macrophage-based therapeutic strategies in regenerative medicine

Spiller

Koh

2017

Advanced Drug Delivery Reviews

251

193

View full text Add to dashboard Cite

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“…The absolute Dex release followed a similar kinetic release pattern (Figure F–H). A quantity of 45 μg of Dex localized at the site of engraftment, 24‐hour posttransplant, was our drug delivery target, based on previous literature and was achieved (46.6 ± 2.8 μg) when 2 mg lyophilized Dex‐micelles at a concentration of 5 mg/mL were implanted. Localized Dex + micelles under the KC were evident by histological analysis of kidneys procured 14 days postinfusion (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…Higher doses inhibit the host cells infiltration and prevent healthy tissue remodeling around the implant, while hindering the insulin secretion capacity of the islets . Local delivery of high Dex dosages impairs foreign body responses by suppressing cell migration; however, this potent suppression also hinders angiogenesis and wound healing, leading to poor graft integration . Furthermore, Dex inhibits insulin secretion through distal actions, by decreasing the efficacy of calcium on the secretory process .…”

Section: Discussionmentioning

confidence: 99%

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Co-localized immune protection using dexamethasone-eluting micelles in a murine islet allograft model

Kuppan

Kelly

Polishevska

et al. 2020

American Journal of Transplantation

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The broad application of ß cell transplantation for type 1 diabetes is hindered by the requisite of lifelong systemic immunosuppression. This study examines the utility of localized islet graft drug delivery to subvert the inflammatory and adaptive immune responses. Herein, we have developed and characterized dexamethasone (Dex) eluting Food and Drug Administration‐approved micro‐Poly(lactic‐co‐glycolic acid) micelles and examined their efficacy in a fully major histocompatibility complex‐mismatch murine islet allograft model. A clinically relevant dose of 46.6 ± 2.8 μg Dex per graft was confirmed when 2 mg of micelles was implemented. Dex‐micelles + CTLA‐4‐Ig (n = 10) resulted in prolonged allograft function with 80% of the recipients demonstrating insulin independence for 60 days posttransplant compared to 40% in empty micelles + CTLA‐4‐Ig recipients (n = 10, P = .06). Recipients of this combination therapy (n = 8) demonstrated superior glucose tolerance profiles, compared to empty micelles + CTLA‐4‐Ig recipients (n = 4, P < .05), and significantly reduced localized intragraft proinflammatory cytokine expression. Histologically, increased insulin positive and FOXP3+ T cells were observed in Dex‐micelles + CTLA‐4‐Ig grafts compared to empty micelles + CTLA‐4‐Ig grafts (P < .01 and P < .05, respectively). Localized drug delivery via micelles elution has the potential to alter the inflammatory environment, enhances allograft survival, and may be an important adjuvant approach to improve clinical islet transplantation outcomes.

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A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation

Razavi

Primavera

Kevadiya

et al. 2020

Adv Funct Materials

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The aim of this article is to develop, characterize, and test a novel 3D bioscaffold matrix that can accommodate pancreatic islets and provide them with a continuous, controlled, and steady source of oxygen to prevent hypoxia-induced damage following transplantation. Hence, a collagen-based cryogel bioscaffold that incorporates calcium peroxide (CPO) into its matrix is made. The optimal concentration of CPO integrated into bioscaffolds is 0.25 wt% and this generates oxygen at 0.21 ± 0.02 × 10 -3 m day -1 (day 1), 0.19 ± 0.01 × 10 -3 m day -1 (day 6), 0.13 ± 0.03 × 10 -3 m d -1 (day 14), and 0.14 ± 0.02 × 10 -3 m d -1 (day 21). Accordingly, islets seeded into cryogel-CPO bioscaffolds have a significantly higher viability and function compared to islets seeded into cryogel alone bioscaffolds; these findings are supported by data from quantitative computational modeling. When syngeneic islets are transplanted into the epididymal fat pad (EFP) of diabetic mice, the cryogel-0.25 wt%CPO bioscaffold improves islet function with diabetic animals re-establishing glycemic control. Mice transplanted with cryogel-0.25 wt%CPO bioscaffolds show faster responses to intraperitoneal glucose injections and have a higher level of insulin content in their EFP compared to those transplanted with islets alone (P < 0.05). The novel oxygen-generating bioscaffold (i.e., cryogel-0.25 wt%CPO) therefore provides a biostable and biocompatible 3D microenvironment for islets which can facilitate islet survival and function at extra-hepatic sites of transplantation.

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Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages

Cited by 134 publications

References 42 publications

Macrophage-based therapeutic strategies in regenerative medicine

Macrophage-based therapeutic strategies in regenerative medicine

Co-localized immune protection using dexamethasone-eluting micelles in a murine islet allograft model

A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation

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