PLGA Degradation Research Articles

Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

The influence of a tertiary amine, namely risperidone (pKa = 7.9) on the degradation of poly(D, L lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drug-loaded microspheres and blank microspheres in presence of free risperidone in 0.02M PBS containing 0.02% Tween®80 at 37°C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration-dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs.

The Effect of Osteochondral Regeneration Using Polymer Constructs and Continuous Passive Motion Therapy in the Lower Weight-Bearing Zone of Femoral Trocheal Groove in Rabbits

Remedying patellofemoral osteochondral defects using clinical therapy remains challenging. Construct-based and cell-based regenerative medicine with in vitro physical stimuli has been progressively implemented. However, the effect of physical stimuli in situ in knee joints with degradable constructs is still not well-documented. Therefore, we studied whether it was practical to achieve articular cartilage repair using a poly(lactic-co-glycolic acid) (PLGA) construct in addition to early short-term continuous passive motion (CPM) for treatment of full-thickness osteochondral defects in the lower-weigh bearing (LWB) zone of the femoral trocheal groove. Twenty-six rabbits were randomly allocated into either intermittent active motion (IAM) or CPM treatment groups with or without PLGA constructs, termed PLGA construct-implanted (PCI) and empty defect knee models, respectively. Gross observation, histology, inflammatory cells, which were identified using H&E staining, total collagen and alignment, studied qualitatively using Masson's trichrome staining, glycosaminoglycan (GAG), identified using Alcian blue staining, and newly formed bone, observed using micro-CT, were evaluated at 4 and 12weeks after surgery. Repair of osteochondral defects in the PCI-CPM group was more promising than all other groups. The better osteochondral defect repair in the PCI-CPM group corresponded to smooth cartilage surfaces, no inflammatory reaction, hyaline cartilaginous tissues composition, sound collagen alignment with positive collagen type II expression, higher GAG content, mature bone regeneration with osteocyte, clear tidemark formation, and better degradation of PLGA. In summary, the use of a simple PLGA construct coupled with passive motion promotes positive healing and may be a promising clinical intervention for osteochondral regeneration in LWB defects.

Nanoscaled buffering zone of charged (PLGA)n-b-bPEI micelles in acidic microclimate for potential protein delivery application

Poly(lactide-co-glycolide) (PLGA) has most often been employed for the controlled release of protein formulations because of its safety profile with non-toxic degradation products. Nevertheless, such formulations have been plagued by a local acidic microenvironment and protein–polymer interactions, which result in chemical and physical denaturation of loaded proteins and often unfavorable release profiles. This study investigated the pH change of inner PLGA microsphere (MS) using charged (PLGA)n-b-branched polyethyleneimine (bPEI) micelles. The designed micelles can be transformed into either micelle or reverse micelle (RM) depending on the solvent and RM can form microspheres. In addition, (PLGA)n-b-bPEI can be modified into (PLGA)n-b-(carboxylated bPEI) via carboxylation of the primary amines. Cationic micelle (CM) or anionic micelle (AM) was complexed with counter-charged proteins leading to nanosized particles (approximately 100nm). In the micelle/protein complexes, the micelles mostly maintained their proton buffering capacity, and consequently, prevented or delayed the typical decrease in pH caused by degradation of PLGA in aqueous solution. Reconstitutable micelle/protein complexes allowed for increased and fine-tuned protein loading (~20wt.% when using CM1 (CM prepared from PLGA36kDa-b-bPEI25kDa)/insulin complexes) in PLGA MS. In CM2 (CM prepared from (PLGA36kDa)2-b-bPEI25kDa)/insulin (4 of weight ratio (WR) of micelle to protein; WR4)-loaded PLGA MS, CM2 strongly prevented the micellar nanoenvironmental pH (pH 6.6 within 5days and then approximately pH 8.5) to be acidified in PLGA MS for 9weeks, unlike CM2-free PLGA MS. In conclusion, our findings propose that the proton buffering capacity and protein loading in PLGA MS can be tuned by controlling the complexation ratios of micelles and proteins, polymeric architectures of (PLGA)n-b-bPEI copolymers and WR of micelle/protein complexes and PLGA (or RM).

Co-encapsulation and sustained-release of four components in ginkgo terpenes from injectable PELGE nanoparticles

It is difficult to develop injectable sustained delivery systems for herbal medicines because of their composition complexity. Encapsulating various compounds with different physiochemical properties and achieving their synchronized and sustained release seem too hard to realize. In this paper, an injectable nanoparticulate system based on an mPEG–PLGA–mPEG (PELGE) platform was prepared for co-encapsulation and sustained release of four active components (ginkgolides A, B, C and bilobalide) in Ginkgo biloba extract. Different carriers were screened by macrophage uptake experiment for their ability to be long-circulation. Drug loaded nanoparticles were prepared with 10% PEG2000 modified PLGA by a co-precipitation method. The encapsulation efficiency of the total ginkgo terpenes (GT) in the optimal formulation was 78.84±2.06% with a loading dose of 11.90±0.31mg/150mg PELGE. The particles exhibited a spherical shape with a mean diameter of 123.3±44.0nm and zeta potential of −30.86±2.49mV. Sustained and synchronized release of the four components from PELGE nanoparticles was observed both in vitro and in vivo, which was mainly contributed to the long circulation of PEGylated nanoparticles and the slow degradation of PLGA. The half-life time of the four terpenoid compounds were also significantly improved by incorporation into PELGE nanoparticles. The results indicate that a PELGE nanoparticle is a promising carrier system for sustained and synchronized release of herbal medicines containing multiple components.

Fabrication of drug-loaded polymer microparticles with arbitrary geometries using a piezoelectric inkjet printing system

Carrier geometry is a key parameter of drug delivery systems and has significant impact on the drug release rate and interaction with cells and tissues. Here we present a piezoelectric inkjet printing system as a simple and convenient approach for fabrication of drug-loaded polymer microparticles with well-defined and controlled shapes. The physical properties of paclitaxel (PTX)-loaded poly(lactic-co-glycolic acid) (PLGA) inks, such as volatility, viscosity and surface tension, were optimized for piezoelectric inkjet printing, and PTX-loaded PLGA microparticles were fabricated with various geometries, such as circles, grids, honeycombs, and rings. The resulting microparticles with 10% (w/w) PTX exhibited a fairly homogeneous shape and size. The microparticle fabrication by piezoelectric inkjet printing was precise, reproducible, and highly favorable for mass production. The microparticles exhibited a biphasic release profile with an initial burst due to diffusion and a subsequent, slow second phase due to degradation of PLGA. The release rate was dependent on the geometry, mainly the surface area, with a descending rate order of honeycomb>grid, ring>circle. The PTX-loaded microparticles showed a comparable activity in inhibiting the growth of HeLa cells. Our results demonstrate that a piezoelectric inkjet printing system would provide a new approach for large-scale manufacturing of drug carriers with a desired geometry.

Characterization and in vitro release of cyclosporine-A from poly(D,L-lactide-co-glycolide implants obtained by solvent/extraction evaporation

Cyclosporine-A-loaded PLGA implants were developed intended for ocular route. Implants were prepared using solvent extraction/evaporation technique followed by casting of the cake into rods in a heated surface. XRD patterns showed that cyclosporine-A was completely incorporated into PLGA. FTIR and DSC results indicated alterations on drug molecular conformation aiming to reach the most stable thermodynamic conformation at polymer/drug interface. Implants provided controlled/sustained in vitro release of the drug. During the first 7 weeks, the drug release was controlled by the diffusion of the cyclosporine-A; and between 7-23 week period, the drug diffusion and degradation of PLGA controlled the drug release.

Mesoporous Silicon‐PLGA Composite Microspheres for the Double Controlled Release of Biomolecules for Orthopedic Tissue Engineering

AbstractIn this study, poly(dl‐lactide‐co‐glycolide)/porous silicon (PLGA/pSi) composite microspheres, synthesized by a solid‐in‐oil‐in‐water (S/O/W) emulsion method, are developed for the long‐term controlled delivery of biomolecules for orthopedic tissue engineering applications. Confocal and fluorescent microscopy, together with material analysis, show that each composite microsphere contained multiple pSi particles embedded within the PLGA matrix. The release profiles of fluorescein isothiocyanate (FITC)‐labeled bovine serum albumin (FITC‐BSA), loaded inside the pSi within the PLGA matrix, indicate that both PLGA and pSi contribute to the control of the release rate of the payload. Protein stability studies show that PLGA/pSi composite can protect BSA from degradation during the long term release. We find that during the degradation of the composite material, the presence of the pSi particles neutralizes the acidic pH due to the PLGA degradation by‐products, thus minimizing the risk of inducing inflammatory responses in the exposed cells while stimulating the mineralization in osteogenic growth media. Confocal studies show that the cellular uptake of the composite microspheres is avoided, while the fluorescent payload is detectable intracellularly after 7 days of co‐incubation. In conclusion, the PLGA/pSi composite microspheres offer an additional level of controlled release and could be ideal candidates as drug delivery vehicles for orthopedic tissue engineering applications.

Validation of USP apparatus 4 method for microsphere in vitro release testing using Risperdal ® Consta ®

The current manuscript addresses the need for a validated in vitro release testing method for controlled release parenteral microspheres. A USP apparatus 4 method was validated with the objective of possible compendial adaptation for microsphere in vitro release testing. Commercial microspheres (Risperdal ® Consta ®) were used for method validation. Accelerated and real-time release tests were conducted. The accelerated method had significantly reduced test duration and showed a good correlation with the real-time release profile (with limited number of sample analysis). Accelerated conditions were used for method validation (robustness and reproducibility). The robustness testing results revealed that release from the microspheres was not flow rate dependent and was not affected by minor variations in the method (such as cell preparation technique, amount of microspheres, flow-through cell size and size of glass beads). The significant difference in the release profile with small variations (±0.5 °C) in temperature was shown to be due to a change in risperidone catalyzed PLGA degradation in response to temperature. The accelerated method was reproducible as changing the system/equipment or the analyst did not affect the release profile. This work establishes the suitability of the modified USP apparatus 4 for possible compendial adaptation for drug release testing of microspheres.

Investigation on structural integrity of PLGA during ammonolysis-based microencapsulation process

The objective of this study was to gain insights into the structural integrity of PLGA during an ammonolysis-based microencapsulation process. PLGA (lactide:glycolide ratio = 75:25; M w = 25,925 g/mol) was dissolved in ethyl acetate or isopropyl formate (3–6 ml), which was emulsified in an aqueous phase. Ammonia, being added to the emulsions, reacted with the dispersed solvents to yield water-miscible solvents. Consequently, emulsion droplets were solidified into microspheres. To evaluate the impact of ammonia upon PLGA, the molar ratio of ammonia to a dispersed solvent varied from 1 to 2 and 3. After preparation of microspheres by the ammonolysis-based procedure, the lactide:glycolide composition and Mw of PLGA were analyzed by 1H NMR and GPC. Our results demonstrated that ammonia did indeed catalyze the cleavage of PLGA ester bonds during microencapsulation. Strikingly, PLGA degradation was affected by solvent type and volume, as well as ammonia concentration. For instance, when 6 ml of ethyl acetate was used and the molar ratio of ammonia to the solvent was 3, the glycolide content and M w of the microspheres considerably decreased to 17.56% and 10,814 g/mol, respectively. There were little changes in these terms, however, when microspheres were prepared using 3 ml of isopropyl formate and an equimolar amount of ammonia. Depending upon microencapsulation conditions, progesterone encapsulation efficiency ranged from 71.6 to 98.8%. Also, its release behavior was significantly influenced by ammonolysis-related process parameters. Our study demonstrated that all these contrasting results arose from differences in solvent reactivity toward ammonolysis, the rate of microsphere solidification, and the availability of ammonia to PLGA ester linkages.

Comparative study on the enzymatic degradation of poly(lactic-co-glycolic acid) by hydrolytic enzymes based on the colorimetric quantification of glycolic acid

The enzyme-catalysed cleavage of ester bonds of poly(lactic-co-glycolic acid) (PLGA) has been monitored by an improved approach for the quantification of glycolic acid as indicator of copolymer hydrolysis. Glycolic acid released into the degradation medium was determined colorimetrically using chromotropic acid. The assay established is sensitive, as well as being both rapid and economical. The proposed method was applied to assess enzymatic degradation of a series of PLGA polyesters containing different proportions of monomers, end groups of PLGA chains and molecular weights. Among 22 commercially available hydrolytic enzymes (i.e. esterases, lipases and proteases) from different sources, the lipases from Candida antarctica, Candida cylindracea, Candida rugosa, Mucor miehei, Rhizopus arrhizus and porcine pancreas and the esterase from M. miehei all had a significant effect on PLGA degradation, often increasing the rate of ester bond cleavage by a factor of 25 compared to non-enzymatic hydrolysis. The most remarkable substrate specificity was observed for C. antarctica lipase with the rate of degradation being directly proportional to the glycolic acid content. In contrast, degradation by M. miehei esterase and R. arrhizus lipase were nearly independent of PLGA structure.

In vitro release characteristics and cellular uptake of poly(D,L-lactic-co-glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides

The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion.

In vitro degradation rate of apatitic calcium phosphate cement with incorporated PLGA microspheres

Calcium phosphate cements (CPCs) are frequently used as bone substitute material. Despite their superior clinical handling and excellent biocompatibility, they exhibit poor degradability, which limits bone ingrowth into the implant. Microspheres were prepared from poly( d, l-lactic-co-glycolic acid) (PLGA) and included in injectable CPCs as porogens in order to enhance its macroporosity after the polymeric microspheres had degraded. Upon degradation of the PLGA microspheres, acid is produced that enhances the dissolution rate of the CPC. However, the effect of the characteristics of PLGA microspheres on the degradation rate of CPCs has never been studied before. Therefore, the purpose of the current study was to investigate the dependence of CPC degradation on the chemical and morphological characteristics of incorporated PLGA microspheres. With respect to the chemical characteristics of the PLGA microspheres, the effects of both PLGA molecular weight (5, 17 and 44 kDa) and end-group functionalization (acid-terminated or end-capped) were studied. In addition, two types of PLGA microspheres, differing in morphology (hollow vs. dense), were tested. The results revealed that, although both chemical parameters clearly affected the polymer degradation rate when embedded as hollow microspheres in CPC, the PLGA and CPC degradation rates were mainly dependent on the end-group functionalization. Moreover, it was concluded that dense microspheres were more efficient porogens than hollow ones by increasing the CPC macroporosity during in vitro incubation. By combining all test parameters, it was concluded that dense PLGA microspheres consisting of acid-terminated PLGA of 17 kDa exhibited the highest and fastest acid-producing capacity and correspondingly the highest and fastest amount of porosity. In conclusion, the data presented here indicate that the combination of dense, acid-terminated PLGA microspheres with CPC emerges as a successful combination to achieve enhanced apatitic CPC degradation.

Development of a Novel Phase Separation Technique for the Encapsulation of AZT in a Biodegradable Polymer

AZT is effective in prolonging survival and reducing the frequency and severity of opportunistic infections, but no preparation of the compound is available for sustained delivery. Poly(lactide-co-glycolide) microcapsules containing AZT have been prepared by a novel phase separation technique. Poly(dl-lactic/glycolic acid) (PLGA) was dissolved in dichloromethane; the drug was added to the solution which was then sonicated for 30 s. The polymer-drug mixture was added dropwise to a solution of silicone oil in dichloromethane with continuous stirring using a magnetic stirrer. Stirring was maintained until the dichloromethane had completely evaporated to give microcapsules which were then washed with cold petroleum ether, filtered, and freeze-dried to give a free-flowing powder. The microcapsules prepared by this method were smooth, spherical, and agglomerated; the particle size was between 25 and 300 μm. The efficiency of encapsulation was more than 90%. An in-vitro drug-release study showed that the microcapsules were free from any initial “burst effect”. An excellent sustained release was observed from the microcapsules up to 17 days followed by a burst effect between 17 and 22 days. Drug release, however, continued over a 60-day period. The phase separation method significantly improved the efficiency of encapsulation of AZT in PLGA. Although the microcapsules prepared by this method showed no initial burst effect, significant dose dumping was observed between the second and third week as a result of the rapid degradation of PLGA.

New approaches to mapping through-thickness variations in the degradation in poly (lactide-co-glycolide)

Biodegradable poly (lactide-co-glycolide) (PLGA) copolymers have been used for many years for biomedical applications such as soluble sutures, orthopaedic implants and more recently as potential tissue scaffold materials. The rate at which the copolymers degrade can be manipulated from a period of days to months by changing the lactide/glycolic acid ratio. Degradation of PLGA copolymers occurs by hydrolysis of the ester bonds in the polymer backbone. The hydrolysis reaction is autocatalytic and is accelerated by the build up of degradation products in the bulk of the material. As a consequence, material degradation is expected to be non-uniform through the specimen thickness with the material at the centre degrading at a faster rate than at the surface. Despite many studies of PLGA degradation, information on this local variance is sparse as the techniques used to track the process are usually bulk measures. In this study, two new approaches for monitoring degradation have been developed that enable local measurements of degradation to be made throughout the specimen over an extended period of time. Chemical and mechanical variations in the structure of the polymer have been mapped using attenuated total reflectance infrared spectroscopy (ATR-FTIR) and nanoindentation. These have produced comparable results and show that the degradation rate at the centre of the specimens is almost an order of magnitude higher than at the surface.

Controlled Release of Anti-inflammatory siRNA from Biodegradable Polymeric Microparticles Intended for Intra-articular Delivery to the Temporomandibular Joint

As the next step in the development of an intra-articular controlled release system to treat painful temporomandibular joint (TMJ) inflammation, we developed several biodegradable poly(DL-lactic-co-glycolic acid) (PLGA)-based microparticle (MP) formulations encapsulating a model anti-inflammatory small interfering RNA (siRNA) together with branched poly(ethylenimine) (PEI) as a transfecting agent. The effect of siRNA loading and N:P ratio on the release kinetics of siRNA-PEI polyplexes was determined, and the size and N:P ratio of the polyplexes released over time was characterized. Polyplex-loaded PLGA MPs were prepared using an established double emulsion technique. Increasing the pH of the release samples enabled siRNA-PEI dissociation and subsequent measurement of the release of each component over 28 days. Polyplex diameter was measured for all release samples and compared to freshly prepared siRNA-PEI under simulated physiologic conditions. Systematic variation of siRNA loading and N:P ratio resulted in distinct siRNA and PEI release profiles. Polyplex diameter remained constant despite large variations in the relative amounts of siRNA and PEI. Excess PEI was sequestered through complexation with 500-1,000 nm diameter PLGA MP-derived particles, including small MPs and PLGA degradation products. These PLGA MP formulations show exciting potential as the first intra-articular TMJ controlled release system.

Incorporation of carboxylation multiwalled carbon nanotubes into biodegradable poly(lactic-co-glycolic acid) for bone tissue engineering

Biodegradable poly(lactic-co-glycolic acid) (PLGA)/carboxyl-functionalized multi-walled carbon nanotube (c-MWCNT) nanocomposites were successfully prepared via solvent casting technique. Rat bone marrow-derived mesenchymal stem cells (MSCs) were employed to assess the biocompatibility of the nanocomposites in vitro. Scanning electron microscopy (SEM) observations revealed that c-MWCNTs gave a better dispersion than unmodified MWCNTs in the PLGA matrix. Surface properties were determined by means of static contact angle, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) analysis. The presence of c-MWCNTs increased the mechanical properties of the nanocomposites. Seven-week period in vitro degradation test showed the addition of c-MWCNTs accelerated the hydrolytic degradation of PLGA. In addition, SEM proved that the cells could adhere to and spread on films via cytoplasmic processes. Compared with control groups, MSCs cultured onto PLGA/c-MWCNT nanocomposites exhibited better adhesion and viability and also displayed significantly higher production levels of alkaline phosphatase (ALP) over 21 days culture. These results demonstrated that c-MWCNTs modified PLGA films were beneficial for promoting cell growth and inducing MSCs to differentiate into osteoblasts. This work presented here had potential applications in the development of 3-D scaffolds for bone tissue engineering.

Unintended potential impact of perfect sink conditions on PLGA degradation in microparticles

Yet, no standardized test method for drug release measurements from PLGA-based microparticles has been generally agreed on, or described by the regulatory authorities. Often, perfect sink conditions are provided in vitro to avoid artificial drug saturation effects. However, the maintenance of such conditions might strongly affect PLGA degradation. The involved physicochemical processes are complex and the potential impact of perfect sink conditions is not yet well understood. Differently sized, highly porous, carbamazepine- and ibuprofen-loaded PLGA microparticles were prepared by a W/O/W emulsion solvent extraction/evaporation technique. The initial drug loading was intentionally low (3–4%) so that the two drugs were molecularly dispersed within the polymeric matrices (monolithic solutions). This was important to be able to exclude potential limited drug solubility effects on the resulting release kinetics. Drug release into phosphate buffer pH 7.4 was measured under perfect sink conditions. SEC, DSC and SEM were used to characterize polymer degradation. The decrease in the average polymer molecular weight, glass transition temperature as well as changes in the inner and outer morphology of the PLGA microparticles were strongly affected by the bulk fluid's volume. In the case of the poorly water-soluble drug carbamazepine, much lower “microparticle mass:phosphate buffer volume” ratios were required to maintain perfect sink conditions, resulting in stable pH values within the bulk fluid, slower PLGA degradation and, thus, lower drug release rates. Thus, great care has to be taken when defining the conditions for in vitro drug release measurements from PLGA-based microparticles, avoiding potentially artificial conditions for polymer degradation.

Effect of degradation of PLGA and PLGA/β-TCP scaffolds on the growth of osteoblasts

Osteoblasts were cultured on porous scaffolds of poly(L-lactide-co-glycolide) (PLGA) and PLGA/β-tricalcium phosphate (β-TCP) to evaluate their cytocompatibility. The proliferation of the cells on both scaffolds was examined before and after in vitro degradation for 4, 8 and 12 weeks under static (shaking water bath) and dynamic (cyclic loading) conditions. Results indicate that porous PLGA and PLGA/β-TCP scaffolds have good biocompatibility and can be used as effective templates for guiding the growth of osteoblasts. The degradation of the scaffolds affects the proliferation of osteoblasts and the cell viability decreased with the degradation time.

PLGA Erosion: Solubility- or Diffusion-Controlled?

To calculate the degradation time-dependent formation of water-soluble PLGA oligomers and to evaluate the relation between calculated oligomer formation and actual erosion of a PLGA-based delivery system. A proper model of the erosion process would be expected to facilitate forecasting of drug release profiles from PLGA matrices due to the close relationship of erosional mass loss and drug release described in the literature. The molecular weight distribution (MWD), degradation and erosion behaviour of PLGA were characterized by gel permeation chromatography. PLGA was characterized by a lognormal distribution of mass fractions of individual molecular weights. Implementation of the pseudo-first-order reaction kinetics into the MWD function facilitated calculating the formation of water-soluble oligomers during degradation. The calculated soluble oligomer formation agreed excellently with measured erosional mass loss of a PLGA matrix in aqueous buffer, which suggested that the bulk erosion process was solely controlled by the kinetic of the formation of soluble oligomers and thus solubility-controlled and not diffusion-limited as conventionally assumed. The accurately calculated formation of soluble PLGA oligomers was in excellent agreement with the actual erosional mass loss of a PLGA matrix, suggesting that bulk erosion of PLGA represents a degradation-controlled dissolution process.

Effect of medium-chain triglycerides on the release behavior of Endostar ® encapsulated PLGA microspheres

The incomplete release of Endostar ® from PLGA microspheres was observed in our previous study. In the present study, we focused on the effect of medium-chain triglycerides (MCT) on the in vitro/ in vivo release behavior of Endostar ® encapsulated PLGA microspheres, which were prepared by a water-in-oil-in-water (W/O/W) double-emulsion method with or without MCT. The in vitro accumulated release of Endostar ® from microspheres co-encapsulated with 30% MCT was found to be 79.04% after a 30-day incubation period in PBS (pH 7.4) at 37 °C. However, the accumulated release of Endostar ® from MCT-free microspheres was found to be only 32.22%. Pouches containing Endostar ® encapsulated PLGA microspheres were implanted subcutaneously in rats. The effect of MCT on the in vivo release showed a similar trend to the in vitro release. After 30 days, only 9.87% of the total encapsulated Endostar ® was retained in microspheres co-encapsulated with 30% MCT, while 42.25% of Endostar ® was retained in MCT-free microspheres. The co-encapsulation of MCT provided the microspheres with a porous surface, which significantly improved the in vitro/i n vivo release of Endostar ® from PLGA microspheres. In addition, in vitro experiments showed that MCT co-encapsulated PLGA microspheres had more inter-connected pores, faster degradation of PLGA, and faster swelling of microspheres, which helped to explain the mechanism of the effect of MCT on improving the release of Endostar ® from PLGA microspheres.