As biomaterial therapies emerge to address adipose tissue dysfunction that underlies metabolic disease, the immune response to these systems must be established. As a potential therapy, we are investigating resveratrol delivery from porous poly(lactide-co-glycolide) scaffolds designed to integrate with adipose tissue. Resveratrol was selected for its ability to protect mice and primates from high fat diet and broad anti-inflammatory properties. Herein, we report fabrication of scaffolds with high resveratrol loading that are stable and active for up to one year. In vitro release profiles indicate that drug release is biphasic with a burst release over 3 days followed by a plateau. Surprisingly, we find that PLG scaffold implanted into adipose tissue of mice promotes an anti-inflammatory environment characterized by high arginase-1 and low TNF-α and IL-6 compared to naïve unmanipulated fat. Resveratrol delivery from the scaffold augments this antiinflammatory environment by decreasing monocyte and lymphocyte numbers at the implant site and increasing expression of IL-10 and IL-13, cytokines that promote healthy adipose tissue. In terms of therapeutic applications, implant of scaffolds designed to release resveratrol into the visceral fat decreases MCP-1 expression in mice fed a high fat diet, a molecule that drives both local and systemic inflammation during obesity. Taken together, resveratrol delivery to adipose tissue using poly(lactide-co-glycolide) scaffolds is a promising therapeutic strategy for the treatment of adipose tissue inflammation that drives metabolic disease.

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Lipid overload of the adipose tissue, which can be caused by overnutrition, underlies metabolic disease. We hypothesized that increasing the energy demand of adipose tissue is a promising strategy to combat excessive lipid accumulation. Resveratrol, a natural polyphenol, activates lipid catabolism in fat tissue; however, its clinical success is hindered by poor bioavailability. Here, we implanted resveratrol releasing poly(lactide‐co‐glycolide) scaffolds into epididymal fat to overcome its poor bioavailability with the goal of enhancing local lipid catabolism. In lean mice, resveratrol scaffolds decreased adipocyte size relative to scaffolds with no drug, a response that correlated with AMP kinase activation. Immunohistochemistry indicated that macrophages and multinucleated giant cells within the scaffold expressed carnitine palmitoyltransferase 1 (CPT1) at higher levels than other cells in the adipose tissue. Furthermore, resveratrol increased CPT1 levels in cultured macrophages. Taken together, we propose that resveratrol scaffolds decrease adipocyte size because resveratrol increases lipid utilization in scaffold‐infiltrating immune cells, possibly through elevating CPT1 levels or activity. In a follow‐up study, mice that received resveratrol scaffolds 28‐day prior to a high‐fat diet exhibited decreased weight gain, adipose tissue expansion, and adipocyte hypertrophy compared to mice with control scaffolds. Notably, this scaffold‐based strategy required a single resveratrol administration compared to the daily regiment generally needed for oral administration. These results indicate that localized delivery of metabolism modulating agents to the adipose tissue may overcome issues with bioavailability and that the role of biomaterials should be further investigated in this therapeutic strategy for metabolic disease.

Ectopic lipid accumulation, the deposition of lipids in lean tissue, is linked to type 2 diabetes through an association with insulin resistance. It occurs when adipose tissue fails to meet lipid storage needs and there is lipid spillover into tissues not equipped to store them. Ectopic lipid contributes to organ dysfunction because lipids can interfere with insulin signaling and other signaling pathways. Clinical studies indicate that decreasing ectopic lipids through diet and exercise is effective in treating type 2 diabetes; however, its prevalence continues to rise. We propose that strategies to improve lipid handling in the adipose tissue would be adjunctive to healthy lifestyle modification and may address difficulties in treating type 2 diabetes and other syndromes spurred by ectopic lipid. Herein, we investigate biomaterial implants as a means to increase lipid utilization in adipose tissue through the recruitment of highly metabolic cells. Poly(lactide-co-glycolide) scaffolds were implanted into the epididymal fat of mice fed a high fat diet that overwhelms the adipose tissue and promotes ectopic lipid accumulation. Over 5 weeks, mice with scaffolds gained less weight compared to mice without scaffolds and were protected from hyperinsulinemia. These effects correlated with a 53% decrease in triglyceride in the gastrocnemius and a 25% decrease in the liver. Scaffolds increased CPT1A protein levels in the epididymal fat and histology revealed high expression of CTP1A in the cells infiltrating the scaffold relative to the rest of the fat pad. In addition, lacing the scaffold with resveratrol increased CPT1A expression in the epididymal fat over scaffolds with no drug; however, this did not result in further decreases in weight gain or ectopic lipid. Mechanistically, we propose that the cellular activity caused by scaffold implant mitigates the lipid load imposed by the high fat diet and leads to a substantial decrease in lipid accumulation in the muscle and liver. In conclusion, this study establishes that a tissue engineering approach to modulate lipid utilization in the epididymal fat tissue can mitigate ectopic lipid accumulation in mice fed a high fat diet with positive effects on weight gain and whole-body insulin resistance.