Sustained, localized salicylic acid delivery enhances diabetic bone regeneration via prolonged mitigation of inflammation

Abstract

Diabetes is a metabolic disorder caused by insulin resistance and/or deficiency and impairs bone quality and bone healing due to altered gene expression, reduced vascularization, and prolonged inflammation. No effective treatments for diabetic bone healing are currently available, and most existing treatments do not directly address the diabetic complications that impair bone healing. We recently demonstrated that sustained and localized delivery of salicylic acid (SA) via an SA-based polymer provides a low-cost approach to enhance diabetic bone regeneration. Herein, we report mechanistic studies that delve into the biological action and local pharmacokinetics of SA-releasing polymers shown to enhance diabetic bone regeneration. The results suggest that low SA concentrations were locally maintained at the bone defect site for more than 1 month. As a result of the sustained SA release, a significantly reduced inflammation was observed in diabetic animals, which in turn, yielded reduced osteoclast density and activity, as well as increased osteoblastogenesis. Based upon these results, localized and sustained SA delivery from the SA-based polymer effectively improved bone regeneration in diabetic animals by affecting both osteoclasts and osteoblasts, thereby providing a positive basis for clinical treatments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2595-2603, 2016.

Immunomodulatory ECM-like Microspheres for Accelerated Bone Regeneration in Diabetes Mellitus

“…Moreover, a number of the efforts on DM-associated bone regeneration have ignored the vital fact that DM is a chronic inflammatory disease and have adopted the similar growth factor-delivery approaches developed for bone regeneration under normal healing conditions. Those approaches are directly targeted at osteoblast or osteoclast cells, and the critical role of inflammation control under diabetic condition was neglected, leading to limited improvement of the healing process. ,,, Although several studies examined the delivery of anti-inflammation agents, such as salicylic acid, simvastatin, and tumor necrosis factor (TNF) inhibitors, − they failed to recognize the fact that impaired macrophage polarization is the fundamental cause of prolonged inflammation, which subsequently suppresses osteogenic differentiation. In this study, we provided a unique immunomodulatory approach that targeted macrophages to accelerate bone healing under DM condition.…”

Enhanced osteogenesis of 3D printed β-TCP scaffolds with Cissus Quadrangularis extract-loaded polydopamine coatings

“…In contrast to this, the total amount of CQE released in pH 7.4 was 12.5, 14, and 15% for TCP, PD2, and PD10, respectively. The burst release behavior in acidic conditions can be beneficial as CQE and the ketosteroids it contains have shown possible anti-inflammatory properties (Bhujade et al, 2012), and mitigating the initial inflammatory response can be beneficial in accelerating the healing process (Yu et al, 2016).…”

Sustained Release of Salicylic Acid for Halting Peri-Implantitis Progression in Healthy and Hyperglycemic Systemic Conditions: A Gottingen Minipig Model

“…Biodegradable and bioabsorbable polymeric carriers designed for drug transporters, such as salicylic acid poly­(anhydride-ester) (SAPAE), have emerged as safe and efficient therapies that control the rate, time, and place of drug release, being amenable to various formulations for drug delivery and handling. ,,,− The local and sustained release of drugs may represent a breakthrough for increasing the predictability of peri-implantitis treatment, as demonstrated by the current results, encouraging future investigations to evaluate the benefits of using different dosages and/or protocols as well as different types of drugs and/or drug combinations. A previous study has also demonstrated the positive effects of adding SAPAE powder to grafted areas in small animal models for either healthy or hyperglycemic systemic conditions, which along with the current data encourages future highly translational studies to investigate the benefits of associating local and sustained release of anti-inflammatory drugs in regenerative procedures …”

“…Furthermore, the application of SAPAE around implants halted peri-implantitis progression, as treated groups presented significantly lower levels of probing depth relative to untreated groups after approximately 10–15 days of therapy for healthy and metabolically compromised minipigs, with almost 30% reduction in the probing depth. The rationale behind the positive result lies in the sustained local release of salicylic acid from SAPAE that inhibits inflammatory pathways. ,− Salicylic acid has been shown to decrease the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reducing the production of pro-inflammatory cytokines (IL and TNF-α), that impair bone metabolism and enhance bone resorption, as mentioned above, thus providing a more favorable scenario for bone regeneration. , Also, the more evident effect of SAPAE on metabolically compromised conditions, MS and T2DM, might be potentially associated with the chronic disease-enhanced inflammatory state, where the salicylic acid anti-inflammatory effect could have led to a greater difference between the experimental and control groups …”