Designed biodegradable hydrogel structures prepared by stereolithography using poly(ethylene glycol)/poly(D,L-lactide)-based resins

Designed three-dimensional biodegradable poly(ethylene glycol)/poly(D,L-lactide) hydrogel structures were prepared for the first time by stereolithography at high resolutions. A photopolymerisable aqueous resin comprising PDLLA-PEG-PDLLA-based macromer, visible light photo-initiator, dye and inhibitor in DMSO/water was used to build the structures. Porous and non-porous hydrogels with well-defined architectures and good mechanical properties were prepared. Porous hydrogel structures with a gyroid pore network architecture showed narrow pore size distributions, excellent pore interconnectivity and good mechanical properties. The structures showed good cell seeding characteristics, and human mesenchymal stem cells adhered and proliferated well on these materials.

PLGA-based microparticles for the sustained release of BMP-2

The development of growth factor delivery strategies to circumvent the burst release phenomenon prevalent in most current systems has driven research towards encapsulating molecules in resorbable polymer matrices. For these polymer release techniques to be efficacious in a clinical setting, several key points need to be addressed. This present study has investigated the encapsulation of the growth factor, BMP-2 within PLGA/PLGA-PEG-PLGA microparticles. Morphology, size distribution, encapsulation efficiency and release kinetics were investigated and we have demonstrated a sustained release of bioactive BMP-2. Furthermore, biocompatibility of the PLGA microparticles was established and released BMP-2 was shown to promote the differentiation of MC3T3-E1 cells towards the osteogenic lineage to a greater extent than osteogenic supplements (as early as day 10 in culture), as determined using alkaline phosphatase and alizarin red assays. This study showcases a potential BMP-2 delivery system which may now be translated into more complex delivery systems, such as 3D, mechanically robust scaffolds for bone tissue regeneration applications.

Polycaprolactone microspheres as carriers for dry powder inhalers : effect of surface coating on aerosolization of salbutamol sulfate

This study reports the factors controlling aerosolization of salbutamol sulfate (SS) from mixtures with polycaprolactone (PCL) microspheres fabricated using an emulsion technique with polyvinyl alcohol (PVA) as stabilizer. The fine particle fraction (FPF) of SS from PCL measured by a twin-stage impinger was unexpectedly found to be zero, although scanning electron microscopy showed that the drug coated the entire microsphere. Precoating the microspheres with magnesium stearate (MgSt) excipient solutions (1%–2%) significantly increased (p < 0.05, n = 5) the FPF of SS (11.4%–15.4%), whereas precoating with leucine had a similar effect (FPF = 11.3 ± 1.1%), but was independent of the solution concentration. The force of adhesion (by atomic force microscopy) between the PCL microspheres and SS was reduced from 301.4 ± 21.7 nN to 110.9 ± 30.5 nN and 121.8 ± 24.6 nN, (p < 0.05, n = 5) for 1% and 2% MgSt solutions, respectively, and to 148.1 ± 21.0 nN when coated with leucine. The presence of PVA on the PCL microspheres (detected by X-ray photoelectron spectroscopy) affected the detachment of SS due to strong adhesion between the two, presumably due to capillary forces acting between them. Precoating the microspheres with excipients increased the FPF significantly by reducing the drug–carrier adhesion. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:733–745, 2012

Studies on the effect of the size of polycaprolactone microspheres for the dispersion of Salbutamol Sulfate from dry powder inhaler formulations

Purpose: To study the effect of the size of the surface-coated polycaprolactone (PCL) microparticle carriers on the aerosolization and dispersion of Salbutamol Sulfate (SS) from Dry Powder Inhaler (DPI) formulations. Methods: The microparticles were fabricated using an emulsion technique in four different sizes (25, 48, 104 and 150 μm) and later coated with Magnesium stearate (MgSt) and leucine. They were characterized by laser diffraction and SEM. The Fine Particle Fraction (FPF) of SS from powder mixtures was determined by a Twin Stage Impinger (TSI). Results: As the carrier size increased from 25 μm to 150 μm, the FPF of the SS delivered by the coated PCL particles increased approximately four fold. A linear relationship was found between the FPF and Volume mean Diameter (VMD) of the particles over this range. Conclusions: The dispersion behaviour of SS from PCL carriers was dependent on the inherent size of the carriers and the increased FPF of SS with increased carrier size probably reflects the higher mechanical forces produced due to the carrier-carrier collisions or collisions between the carrier particles and the internal walls of the inhaler during aerosolization.

Cross-linked poly(trimethylene carbonate-co-L-lactide) as a biodegradable, elastomeric scaffold for vascular engineering applications

A series of copolymers of trimethylene carbonate (TMC) and l-lactide (LLA) were synthesized and evaluated as scaffolds for the production of artificial blood vessels. The polymers were end-functionalized with acrylate, cast into films, and cross-linked using UV light. The mechanical, degradation, and biocompatibility properties were evaluated. High TMC polymers showed mechanical properties comparable to human arteries (Young’s moduli of 1.2–1.8 MPa and high elasticity with repeated cycling at 10% strain). Over 84 days degradation in PBS, the modulus and material strength decreased gradually. The polymers were nontoxic and showed good cell adhesion and proliferation over 7 days using human mesenchymal stem cells. When implanted into the rat peritoneal cavity, the polymers elicited formation of tissue capsules composed of myofibroblasts, resembling immature vascular smooth muscle cells. Thus, these polymers showed properties which were tunable and favorable for vascular tissue engineering, specifically, the growth of artificial blood vessels in vivo.

Increased generation of platelet-derived microparticles following percutaneous transluminal coronary angioplasty

Platelet-derived microparticles (PMPs) which are produced during platelet activation contribute to coagulation1 and bind to traumatized endothelium in an animal model2. Such endothelial injury occurs during percutaneous transluminal coronary angioplasty (PTCA), a procedure which restores the diameter of occluded coronary arteries using balloon inflations. However, re-occlusions subsequently develop in 20-25% of patients3, although this is limited by treatment with anti-platelet glycoprotein IIb/IIIa receptor drugs such as abciximab4. However, abciximab only partially decreases the need for revascularisation5, and therefore other mechanisms appear to be involved. As platelet activation occurs during PTCA, it is likely that PMPs may be produced and contribute to restenosis. This study population consisted of 113 PTCA patients, of whom 38 received abciximab. Paired peripheral arterial blood samples were obtained from the PTCA sheath: 1) following heparinisation (baseline); and 2) subsequent to all vessel manipulation (post-PTCA). Blood was prepared with an anti-CD61 (glycoprotein IIIa) fluorescence conjugated antibody to identify PMPs using flow cytometry, and PMP results expressed as a percentage of all CD61 events. The level of PMPs increased significantly from baseline following PTCA in the without abciximab group (paired t test, P=0.019). However, there was no significant change in the level of PMPs following PTCA in patients who received abciximab. Baseline clinical characteristics between patient groups were similar, although patients administered abciximab had more complex PTCA procedures, such as increased balloon inflation pressures (ANOVA, P=0.0219). In this study, we have clearly demonstrated that the level of CD61-positive PMPs increased during PTCA. This trend has been demonstrated previously, although a low sample size prevented statistical significance being attained6. The results of our work also demonstrate that there was no increase in PMPs after PTCA with abiciximab treatment. The increased PMPs may adhere to traumatized endothelium, contributing to re-occlusion of the arteries, but this remains to be determined. References: (1) Holme PA, Brosstad F, Solum NO. Blood Coagulation and Fibrinolysis. 1995;6:302-310. (2) Merten M, Pakala R, Thiagarajan P, Benedict CR. Circulation. 1999;99:2577-2582. (3) Califf RM. American Heart Journal.1995;130:680-684. (4) Coller BS, Scudder LE. Blood. 1985;66:1456-1459. (5) Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT on behalf of the EPIC investigators. Lancet. 1994;343:881-886. (6) Scharf RE, Tomer A, Marzec UM, Teirstein PS, Ruggeri ZM, Harker LA. Arteriosclerosis and Thrombosis. 1992;12:1475-87.

Hydrocarbon plasma for treatment of biodegradable food containers

A newly developed middle-frequency (2 MHz) inductively coupled plasma (ICP) source with internal oscillating current is used to treat biodegradable food packaging surfaces. Initially hydrophilic packaging turns to hydrophobic after being processed by ICP plasma. The investigation of optical emission from hydrocarbon radicals in the Ar/ CH4 plasma helps us to understand the property of the hydrophobicity of the surfaces. © 2008 IEEE.

Encapsulation of Hydrocortisone and Mesalazine in Zein Microparticles

Zein was investigated for use as an oral-drug delivery system by loading prednisolone into zein microparticles using coacervation. To investigate the adaptability of this method to other drugs, zein microparticles were loaded with hydrocortisone, which is structurally related to prednisolone; or mesalazine, which is structurally different having a smaller LogP and ionizable functional groups. Investigations into the in vitro digestibility, and the electrophoretic profile of zein, and zein microparticles were conducted to shed further insight on using this protein as a drug delivery system. Hydrocortisone loading into zein microparticles was comparable with that reported for prednisolone, but mesalazine loading was highly variable. Depending on the starting quantities of hydrocortisone and zein, the average amount of microparticles equivalent to 4 mg hydrocortisone, (a clinically used dose), ranged from 60-115 mg, which is realistic and practical for oral dosing. Comparatively, an average of 2.5 g of microparticles was required to deliver 250 mg of mesalazine (a clinically used dose), so alternate encapsulation methods that can produce higher and more precise mesalazine loading are required. In vitro protein digestibility revealed that zein microparticles were more resistant to digestion compared to the zein raw material, and that individual zein peptides are not preferentially coacervated into the microparticles. In combination, these results suggest that there is potential to formulate a delivery system based on zein microparticles made using specific subunits of zein that is more resistant to digestion as starting material, to deliver drugs to the lower gastrointestinal tract.

Preparation and in vitro release of zein microparticles loaded with prednisolone for oral delivery

Zein has been proposed as a polymer for targeted-drug delivery via the oral route. Zein microparticles were loaded with prednisolone and evaluated as an oral delivery system. Microparticles were formulated using phase separation. Starting quantities of zein and prednisolone, along with the agitation method and temperature were found to significantly impact drug loading and loading efficiency. Vortex mixing produced the highest drug loading and loading efficiency. Drug release was measured in simulated conditions of the stomach and small intestine using the microparticles made with the method that best improved drug loading. In simulated stomach and small intestine conditions, prednisolone release reached almost 70 over 3 and 4h, respectively. While a clinically relevant dose may be delivered using c. 100mg of zein microparticles, prednisolone release from the microparticles indicates that they may not be suited as a controlled-or targeted-delivery system.

Increased platelet-derived microparticles in the coronary circulation of percutaneous transluminal coronary angioplasty patients

Platelet-derived microparticles that are produced during platelet activation are capable of adhesion and aggregation. Endothelial trauma that occurs during percutaneous transluminal coronary angioplasty (PTCA) may support platelet-derived microparticle adhesion and contribute to development of restenosis. We have previously reported an increase in platelet-derived microparticles in peripheral arterial blood with angioplasty. This finding raised concerns regarding the role of plateletderived microparticles in restenosis, and therefore the aim of this study was to monitor levels in the coronary circulation. The study population consisted of 19 angioplasty patients. Paired coronary artery and sinus samples were obtained following heparinization, following contrast administration, and subsequent to all vessel manipulation. Platelet-derived microparticles were identified with an anti-CD61 (glycoprotein IIIa) fluorescence-conjugated antibody using flow cytometry. There was a significant decrease in arterial platelet-derived microparticles from heparinization to contrast administration (P 0.001), followed by a significant increase to the end of angioplasty (P 0.004). However, there was no significant change throughout the venous samples. These results indicate that the higher level of platelet-derived microparticles after angioplasty in arterial blood remained in the coronary circulation. Interestingly, levels of thrombin–antithrombin complexes did not rise during PTCA. This may have implications for the development of coronary restenosis post-PTCA, although this remains to be determined.

Increased generation of platelet-derived microparticles following percutaneous transluminal coronary angioplasty

Platelet-derived microparticles that are produced during platelet activation bind to traumatized endothelium. Such endothelial injury occurs during percutaneous transluminal coronary angioplasty. Approximately 20% of these patients subsequently develop restenosis, although this is improved by treatment with the anti-platelet glycoprotein IIb/IIIa receptor drug abciximab. As platelet activation occurs during angioplasty, it is likely that platelet-derived microparticles may be produced and hence contribute to restenosis. This study population consisted of 113 angioplasty patients, of whom 38 received abciximab. Paired peripheral arterial blood samples were obtained following heparinization and subsequent to all vessel manipulation. Platelet-derived microparticles were identified using an anti-CD61 (glycoprotein IIIa) fluorescence-conjugated antibody and flow cytometry. Baseline clinical characteristics between patient groups were similar. The level of platelet-derived microparticles increased significantly following angioplasty in the group without abciximab (paired t test, P 0.019). However, there was no significant change in the level of platelet-derived microparticles following angioplasty in patients who received abciximab, despite requiring more complex angioplasty procedures. In this study, we have demonstrated that the level of platelet-derived microparticles increased during percutaneous transluminal coronary angioplasty, with no such increase with abciximab treatment. The increased platelet-derived microparticles may adhere to traumatized endothelium, contributing to re-occlusion of the arteries, but this remains to be determined.

Microparticle-mediated gene delivery for the enhanced expression of a 19-KDa fragment of merozoite surface protein 1 of Plasmodium falciparum

The 19 kDa carboxyl-terminal fragment of merozoite surface protein 1 (MSP119) is a major component of the invasion-inhibitory response in individual immunity to malaria. A novel ultrasonic atomization approach for the formulation of biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles of malaria DNA vaccines encoding MSP119 is presented here. After condensing the plasmid DNA (pDNA) molecules with a cationic polymer polyethylenimine (PEI), a 40 kHz ultrasonic atomization frequency was used to formulate PLGA microparticles at a flow rate of 18 mL h1. High levels of gene expression and moderate cytotoxicity in COS-7 cells were achieved with the condensed pDNA at a nitrogen to phosphate (N/P) ratio of 20, thus demonstrating enhanced cellular uptake and expression of the transgene. The ability of the microparticles to convey pDNA was examined by characterizing the formulated microparticles. The microparticles displayed Z-average hydrodynamic diameters of 1.50-2.10 lm and zeta potentials of 17.8-23.2 mV. The encapsulation efficiencies were between 78 and 83%, and 76 and 85% of the embedded malaria pDNA molecules were released under physiological conditions in vitro. These results indicate that PLGA-mediated microparticles can be employed as potential gene delivery systems to antigen-presenting cells in the prevention of malaria.