Modified Magnesium Hydroxide Nanoparticles Inhibit the Inflammatory Response to Biodegradable Poly(lactide- co-glycolide) Implants.

Biodegradable polymers have been extensively used in biomedical applications, ranging from regenerative medicine to medical devices. However, the acidic byproducts resulting from degradation can generate vigorous inflammatory reactions, often leading to clinical failure. We present an approach to prevent acid-induced inflammatory responses associated with biodegradable polymers, here poly(lactide- co-glycolide), by using oligo(lactide)-grafted magnesium hydroxide (Mg(OH)2) nanoparticles, which neutralize the acidic environment. In particular, we demonstrated that incorporating the modified Mg(OH)2 nanoparticles within degradable coatings on drug-eluting arterial stents efficiently attenuates the inflammatory response and in-stent intimal thickening by more than 97 and 60%, respectively, in the porcine coronary artery, compared with that of drug-eluting stent control. We also observed that decreased inflammation allows better reconstruction of mouse renal glomeruli in a kidney tissue regeneration model. Such modified Mg(OH)2 nanoparticles may be useful to extend the applicability and improve clinical success of biodegradable devices used in various biomedical fields.

Controlled release of paclitaxel using a drug-eluting stent through modulation of the size of drug particles in vivo.

Drug-eluting stents (DESs) are generally used in percutaneous coronary intervention. Paclitaxel (PTX) is widely used in DESs to suppress neointima, which causes restenosis. However, the PTX release profile is slow owing to its hydrophobic properties, resulting in negative effects on re-endothelialization in vessels. In this study, we assessed the effects of the controlled release of PTX particles of specific sizes on in-stent restenosis (ISR). PTX particle sizes were controlled by adjusting the evaporating temperature of the solvent from 25 to 80°C during ultrasonic coating, and DESs were prepared. The properties of prepared films and DESs were analyzed, and cell viability was assessed in vitro and in vivo. Poly(lactic-co-glycolic acid) (PLGA)/PTX500-loaded stents showed the most rapid release for 58 days, and smaller drug particles exhibited lower PTX release rates. In vivo, PLGA/PTX50-, PLGA/PTX250-, and PLGA/PTX500-loaded stents showed good efficacy for alleviating ISR as compared with bare metal stents and PLGA/PTX5-loaded stents. However, PLGA/PTX250- and PLGA/PTX500-loaded stents exhibited strut exposure and reduced recovery of the vascular compared with PLGA/PTX50-loaded stents. PTX drug particles of approximately 50 nm were most effective in vivo, and the control of particle size is a promising strategy for improving the performance of PTX-eluting stents. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2275-2283, 2018.

A poly(lactide) stereocomplex structure with modified magnesium oxide and its effects in enhancing the mechanical properties and suppressing inflammation.

Biodegradable polymers such as poly(L-lactide) (PLLA) have been widely utilized as materials for biomedical applications. However, the relatively poor mechanical properties of PLLA and its acid-induced cell inflammation brought about by the acidic byproducts during biodegradation pose severe problems. In this study, these drawbacks of PLLA are addressed using a stereocomplex structure, where oligo-D-lactide-grafted magnesium hydroxide (MgO-ODLA) is synthesized by grafting d-lactide onto the surface of magnesium hydroxide, which is then blended with a PLLA film. The structure, morphology, pH change, thermal and mechanical properties, in-vitro cytotoxicity, and inflammation effect of the MgO-ODLAs and their PLLA composites are evaluated through various analyses. The PLLA/MgO70-ODLA30 (0-20 wt%) composite with a stereocomplex structure shows a 20% increase in its tensile strength and an improvement in the modulus compared to its oligo-L-lactide (PLLA/MgO70-OLLA30) counterpart. The interfacial interaction parameter of PLLA/MgO70-ODLA30 (5.459) has superior properties to those of PLLA/MgO70-OLLA30 (4.013) and PLLA/Mg(OH)2 (1.774). The cell cytotoxicity and acid-induced inflammatory response are suppressed by the neutralizing effect of the MgO-ODLAs. In addition, the inflammatory problem caused by the rapid acidification of the stereocomplex structure is also addressed. As a result, the stereocomplex structure of the MgO-ODLA/PLLA composite can be used to overcome the problems associated with the biomedical applications of PLLA films.

Biodegradable poly(l-lactide) composites by oligolactide-grafted magnesium hydroxide for mechanical reinforcement and reduced inflammation.

Biodegradable polymers, such as poly(l-lactide) (PLLA), are very useful in many biomedical applications. However, their degradation by-products have been much of a concern as they are the sources of inflammatory reactions in the body. In this work, we suggest a novel composite system composed of PLLA and oligolactide-grafted magnesium hydroxide (Mg-OLA) that can overcome drawbacks caused by poor mechanical properties and inflammatory response of PLLA for biomedical applications. Mg-OLAs were synthesized by ring opening polymerization and the structure, morphology, pH change, thermal, and mechanical properties were analyzed using FTIR, SEM, pH meter, TGA, and UTM. In particular, the tensile strength and modulus of PLLA/Mg80-OLA20 (0-20 wt%) were higher than those of PLLA/magnesium hydroxide. The PLLA/Mg80-OLA20 composite was also very effective in neutralizing the acidic environment caused by the degradable by-product of the PLLA matrix. In vitro cell viability and the expression levels of COX-2 and IL-6 proteins in the PLLA composites were also evaluated. Cell viability increased to around 100% with increasing the amount of Mg80-OLA20 from 0 to 20 wt%. The expression levels of IL-6 and COX-2 were reduced dramatically when increasing the proportion of Mg80-OLA20 from 0 to 50 wt%. As a result, the incorporation of Mg-OLAs into the PLLA matrix could reinforce the mechanical properties as well as reduce the inflammatory response of the hybrid PLLA. Therefore, this hybrid composite system blending oligomer-grafted magnesium hydroxide in biodegradable polymers would be a promising strategy for avoiding current fatal problems in biomedical applications.