Porous silicon oxide–PLGA composite microspheres for sustained ocular delivery of daunorubicin

A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO₂) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA–DNR microspheres without pSiO₂, and pSiO₂ microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water emulsion method have mean diameters of 52.33 ± 16.37 μm for PLGA–pSiO₂_21/40–DNR and the mean diameter of 49.31 ± 8.87 μm for PLGA–pSiO₂_6/20–DNR. The mean size, 26.00 ± 8 μm, of PLGA–DNR was significantly smaller, compared with the other two (P < 0.0001). Optical microscopy revealed that PLGA–pSiO₂–DNR microspheres contained multiple pSiO₂ particles. In vitro release experiments determined that control PLGA–DNR microspheres completely released DNR within 38 days and control pSiO₂–DNR microparticles (with no PLGA coating) released DNR within 14 days, while the PLGA–pSiO₂–DNR microspheres released DNR for 74 days. Temporal release profiles of DNR from PLGA–pSiO₂ composite particles indicated that both PLGA and pSiO₂ contribute to the sustained release of the payload. The PLGA–pSiO₂ composite displayed a more constant rate of DNR release than the pSiO₂ control formulation, and displayed a significantly slower release of DNR than either the PLGA or pSiO₂ formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with antiproliferation compounds such as DNR.     

Evaluation of antibiotic releasing porous polymethylmethacrylate space maintainers in an infected composite tissue defect model

This study evaluated the in vitro and in vivo performance of antibiotic-releasing porous polymethylmethacrylate (PMMA)-based space maintainers comprising a gelatin hydrogel porogen and a poly(dl-lactic-co-glycolic acid) (PLGA) particulate carrier for antibiotic delivery. Colistin was released in vitro from either gelatin or PLGA microparticle loaded PMMA constructs, with gelatin-loaded constructs releasing colistin over approximately 7 days and PLGA microparticle-loaded constructs releasing colistin for up to 8 weeks. Three formulations with either burst release or extended release at different doses were tested in a rabbit mandibular defect inoculated with Acinetobacter baumannii (2 × 10⁷ colony forming units ml^?1). In addition, one material control that released antibiotic but was not inoculated with A. baumannii was tested. A. baumannii was not detectable in any animal after 12 weeks on culture of the defect, saliva, or blood. Defects with high dose extended release implants had greater soft tissue healing compared with defects with burst release implants, with 8 of 10 animals showing healed mucosae compared with 2 of 10 respectively. Extended release of locally delivered colistin via a PLGA microparticle carrier improved soft tissue healing compared with implants with burst release of colistin from a gelatin carrier.     

Biodegradable microfiber implants delivering paclitaxel for post-surgical chemotherapy against malignant glioma

Paclitaxel-loaded biodegradable implants in the form of microfiber discs and sheets were developed using electrospinning technique and investigated against malignant glioma in vitro and in vivo. The fibrous matrices not only provide greater surface area to volume ratio for effective drug release rates but also give the much needed implantability into tumor resected cavity in post-surgical glioma chemotherapy. Poly-(d,l-lactide-co-glycolide) (PLGA) 85:15 co-polymer was used to fabricate microfiber disc (MFD) and microfiber sheet (MFS) and PLGA 50:50 co-polymer was used to fabricate submicrofiber disc (SFD) and submicrofiber sheet (SFS) to avail different drug release properties. All the dosage forms showed sustained paclitaxel release over 80 days in vitro with a small initial burst. Sheets exhibited a relatively higher initial burst compared to discs probably due to the lower compactness. Also, submicrofibers showed higher release against microfiber due to higher surface area to volume ratio and higher degradation rate. Apoptosis study confirmed the advantage of sustained release of paclitaxel from fiber matrices compared to acute Taxol^® administration. Animal study confirmed inhibited tumor growth of 75, 78, 69 and 71% for MFD, SFD, MFS and SFS treated groups over placebo control groups after 24 days of tumor growth. Thus these implants may play a crucial role in the local chemotherapy of brain tumors.     

pH- and thermosensitive thin lipid layer coated mesoporous magnetic nanoassemblies as a dual drug delivery system towards thermochemotherapy of cancer

A new pH-sensitive and thermosensitive dual drug delivery system consisting of thin lipid layer encapsulated mesoporous magnetite nanoassemblies (MMNA) has been developed which can deliver two anticancer drugs simultaneously. The formulation of lipid layer used is 5:2:2:2 w/w, DPPC:cholesterol:DSPE-PEG₂₀₀₀:MMNA. The structure, morphology and magnetic properties of MMNA and lipid coated MMNA (LMMNA) were thoroughly characterized. This hybrid system was investigated for its ability to carry two anticancer drugs as well as its ability to provide heat under an alternating current magnetic field (ACMF). A very high loading efficiency of up to ∼81% of doxorubicin hydrochloride (DOX) with an ∼0.02 mg mg⁻¹ loading capacity and ∼60% of paclitaxel (TXL) with an ∼0.03 mg mg⁻¹ loading capacity are obtained with LMMNA. A sustained release of drug is observed over a period of 172 h, with better release, of ∼88:53% (DOX:TXL), at pH 4.3 compared to the ∼28:26% (DOX:TXL) in physiological conditions (pH 7.4). An enhanced release of ∼72 and ∼68% is recorded for DOX and TXL, respectively, during the first hour with the application of an ACMF (∼43 °C). A greater in vitro cytotoxic effect is observed with the two drugs compared to them individually in HeLa, MCF-7 and HepG2 cancer cells. With the application of an ACMF for 10 min, the cell killing efficiency is improved substantially due to simultaneous thermo- and chemotherapy. Confocal microscopy confirms the internalization of drug loaded MMNA and LMMNA by cells and their morphological changes during thermochemotherapy.     

Therapeutic foam scaffolds incorporating biopolymer-shelled mesoporous nanospheres with growth factors

A novel therapeutic scaffolding system of engineered nanocarriers within a foam matrix for the long-term and sequential delivery of growth factors is reported. Mesoporous silica nanospheres were first functionalized to have an enlarged mesopore size (12.2 nm) and aminated surface, which was then shelled by a biopolymer, poly(lactic acid) (PLA) or poly(ethylene glycol) (PEG), via electrospraying. The hybrid nanocarrier was subsequently combined with collagen to produce foam scaffolds. Bovine serum albumin (BSA), used as a model protein, was effectively loaded within the enlarged nanospheres. The biopolymer shell substantially prolonged the release period of BSA (2–3 weeks from shelled nanospheres vs. within 1 week from bare nanospheres), and the release rate was highly dependent on the shell composition (PEG > PLA). Collagen foam scaffolding of the shelled nanocarrier further slowed down the protein release, while enabling the incorporation of a rapidly releasing protein, which is effective for sequential protein delivery. Acidic fibroblast growth factor (aFGF), loaded onto the shelled-nanocarrier scaffolds, was released over a month at a highly sustainable rate, profiling a release pattern similar to that of BSA. The biological activity of the aFGF was evidenced by the significant proliferation of osteoblastic precursor cells in the aFGF-releasing scaffolds. Furthermore, the aFGF-delivering scaffolds implanted in rat subcutaneous tissue for 2 weeks showed a substantially enhanced invasion of fibroblasts with a homogeneous population. Taken together, it is concluded that the biopolymer encapsulation of mesoporous nanospheres effectively prolongs the release of growth factors over weeks to a month, providing a nanocarrier platform for a long-term growth factor delivery. Moreover, the foam scaffolding of the nanocarrier system is a potential therapeutic three-dimensional matrix for cell culture and tissue engineering.     

Poly(lactic-co-glycolic acid) electrospun fibrous meshes for the controlled release of retinoic acid

Poly(lactic-co-glycolic acid) (PLGA) meshes loaded with retinoic acid (RA) were prepared by applying the electrospinning technique. The purpose of the present work was to combine the biological effects of RA and the advantages of electrospun meshes to enhancing the mass transfer features of controlled release systems and cell interaction with polymeric scaffolds. The processing conditions for the fabrication of three-dimensional meshes were optimized by studying their influence on mesh morphology. Tensile testing showed that RA loading influenced the meshes’ mechanical properties by increasing their strength and rigidity. Moreover, the drug release and degradation profiles of the electrospun systems were compared to analogous RA-loaded PLGA films prepared by solvent casting. The results of this study highlight that the electrospun meshes preserved their fibrous structure after 4 months under in vitro physiological conditions and showed a sustained controlled release of the loaded agent in comparison to that observed for cast films. The bioactivity of the loaded RA was investigated on murine preosteoblasts cells by evaluating its influence on cell proliferation and morphology.     

Mechanical properties and dual drug delivery application of poly(lactic-co-glycolic acid) scaffolds fabricated with a poly(β-amino ester) porogen

Polymeric scaffolds that are biocompatible and biodegradable are widely used for tissue engineering applications. Scaffolds can be further enhanced by enabling the release of one or more drugs to stimulate regeneration or for the treatment of a specific disease or condition. In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres were mixed with poly(β-amino ester) (PBAE) particles to create novel hybrid scaffolds capable of dual release of drug and growth factor. Fast-degrading PBAE particles loaded with the drug ketoprofen acted as porogens that provided a rapid 12 h release. The PLGA microspheres were loaded with a growth factor, bone morphogenetic protein 2, and fused together around the porogens to create a slow-degrading matrix that provided sustained release lasting 70 days. Drug release was further tailored by varying the amount of porogen added to the scaffold. Bioactivity measurements demonstrated that the scaffold fabrication technique did not damage the drug or protein. The compressive modulus was affected by the amount of porogen added, extending from 50 to 111 MPa for loadings from 60 to 40% PBAE, and after 5 days of degradation, it decreased to 0.6 to 1.1 kPa when the porogen was gone. PLGA containing a quick-degrading porogen can be used to release two drugs while developing a porous microarchitecture for cell ingrowth with in a matrix capable of maintaining a compressive modulus applicable for soft tissue implants.     

Sequentially releasing dual-drug-loaded PLGA–casein core/shell nanomedicine: Design,synthesis, biocompatibility and pharmacokinetics

The present study reports an engineered poly-l-lactide-co-glycolic acid (PLGA)–casein polymer–protein hybrid nanocarrier 190 ± 12 nm in size entrapping a combination of chemically distinct (hydrophobic/hydrophilic) model drugs. A simple emulsion–precipitation route was adopted to prepare nearly monodispersed nanoparticles with distinct core/shell morphology entrapping paclitaxel (Ptx) in the core and epigallocatechin gallate (EGCG) in the shell, with the intention of providing a sequential and sustained release of these drugs. The idea was that an early release of EGCG would substantially increase the sensitivity of Ptx to cancer, thereby providing improved therapeutics at lower concentrations, with less toxicity. The hemo- and immunocompatibility of the core/shell nanomedicine was established in this study. The core/shell nanoparticles injected via the tail vein in Sprague–Dawley rats did not reveal any organ toxicity as was evident from histopathological evaluations of the major organs. In vivo pharmacokinetic studies in rats by high-performance liquid chromatography confirmed a sustained and sequential release of both the drugs in plasma, indicating prolonged circulation of the nanomedicine and enhanced availability of the drugs when compared to the bare drugs. Overall, the polymer–protein multilayered nanoparticles proved to be a promising platform for nanopolypharmaceutics.     

Effects of protein molecular weight on the intrinsic material properties and release kinetics of wet spun polymeric microfiber delivery systems

Wet spun microfibers have great potential for the design of multifunctional controlled release scaffolds. Understanding aspects of drug delivery and mechanical strength, specific to protein molecular weight, may aid in the optimization and development of wet spun fiber platforms. This study investigated the intrinsic material properties and release kinetics of poly(l-lactic acid) (PLLA) and poly(lactic-co-glycolic acid) (PLGA) wet spun microfibers encapsulating proteins with varying molecular weights. A cryogenic emulsion technique developed in our laboratory was used to encapsulate insulin (5.8 kDa), lysozyme (14.3 kDa) and bovine serum albumin (BSA, 66.0 kDa) within wet spun microfibers (～100 μm). Protein loading was found to significantly influence mechanical strength and drug release kinetics of PLGA and PLLA microfibers in a molecular-weight-dependent manner. BSA encapsulation resulted in the most significant decrease in strength and ductility for both PLGA and PLLA microfibers. Interestingly, BSA-loaded PLGA microfibers had a twofold increase (8 ± 2 MPa to 16 ± 1 MPa) in tensile strength and a fourfold increase (3 ± 1% to 12 ± 6%) in elongation until failure in comparison to PLLA microfibers. PLGA and PLLA microfibers exhibited prolonged protein release up to 63 days in vitro. Further analysis with the Korsmeyer–Peppas kinetic model determined that the mechanism of protein release was dependent on Fickian diffusion. These results emphasize the critical role protein molecular weight has on the properties of wet spun filaments, highlighting the importance of designing small molecular analogues to replace growth factors with large molecular weights.     

Fabrication and characterization of monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells for controlled drug release

Monodisperse PLGA–alginate core–shell microspheres with controlled size and homogeneous shells were first fabricated using capillary microfluidic devices for the purpose of controlling drug release kinetics. Sizes of PLGA cores were readily controlled by the geometries of microfluidic devices and the fluid flow rates. PLGA microspheres with sizes ranging from 15 to 50 μm were fabricated to investigate the influence of the core size on the release kinetics. Rifampicin was loaded into both monodisperse PLGA microspheres and PLGA–alginate core–shell microspheres as a model drug for the release kinetics studies. The in vitro release of rifampicin showed that the PLGA core of all sizes exhibited sigmoid release patterns, although smaller PLGA cores had a higher release rate and a shorter lag phase. The shell could modulate the drug release kinetics as a buffer layer and a near-zero-order release pattern was observed when the drug release rate of the PLGA core was high enough. The biocompatibility of PLGA–alginate core–shell microspheres was assessed by MTT assay on L929 mouse fibroblasts cell line and no obvious cytotoxicity was found. This technique provides a convenient method to control the drug release kinetics of the PLGA microsphere by delicately controlling the microstructures. The obtained monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells could be a promising device for controlled drug release.     

Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects

A novel methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-phenylalanine) (mPEG-b-P(Glu)-b-P(Phe)) triblock copolymer was prepared and explored as a micelle carrier for the co-delivery of paclitaxel (PTX) and cisplatin (cis-diamminedichlo-platinum, CDDP). PTX and CDDP were loaded inside the hydrophobic P(Phe) inner core and chelated to the middle P(Glu) shell, respectively, while mPEG provided the outer corona for prolonged circulation. An in vitro release profile of the PTX + CDDP-loaded micelles showed that the CDDP chelation cross-link prevented an initial burst release of PTX. The PTX + CDDP-loaded micelles exhibited a high synergism effect in the inhibition of A549 human lung cancer cell line proliferation over 72 h incubation. For the in vivo treatment of xenograft human lung tumor, the PTX + CDDP-loaded micelles displayed an obvious tumor inhibiting effect with a 83.1% tumor suppression rate (TSR%), which was significantly higher than that of a free drug combination or micelles with a single drug. In addition, more importantly, the enhanced anti-tumor efficacy of the PTX + CDDP-loaded micelles came with reduced side-effects. No obvious body weight loss occurred during the treatment of A549 tumor-bearing mice with the PTX + CDDP-loaded micelles. Thus, the polypeptide-based combination of PTX and CDDP may provide useful guidance for effective and safe cancer chemotherapy.     

Ability of polyurethane foams to support cell proliferation and the differentiation of MSCs into osteoblasts

In bone tissue reconstruction, the use of engineered constructs created by mesenchymal stem cells (MSCs) that differentiate and proliferate into three-dimensional porous scaffolds is an appealing alternative to autologous and heterologous bone grafts. Scaffolds considered in this work are represented by polyurethane (PU) foams. Two PU foams (EC-1 and EC-2) were synthesized and characterized for morphology, mechanical properties and in vitro interaction with the osteoblast-like cell line MG63 and MSCs from human bone marrow. EC-1 and EC-2 showed similar densities (0.20 g cm^?3) with different morphologies: EC-1 showed a more homogeneous pore size (average Φ = 691 μm) and distribution, with a 35% open porosity, whereas EC-2 evidenced a wide range of pore dimension, with an average pore size of 955 μm and a 74% open porosity. The compressive properties of the two foams were similar in the dry condition and both showed a strong decrease in the wet condition. In vitro tests showed good MG63 cell proliferation, as confirmed by the results of the MTT assay and scanning electron microscopy (SEM) observations, with a higher cell viability on EC-2 foam 7 days post-seeding. In the experiments with MSCs, SEM observations showed the presence of an inorganic phase deposition starting day 7 onto EC-1, day 14 onto EC-2. The inorganic particles (CaP) deposition was much more evident onto the pore surface of both foams at day 30, indicating good differentiation of MSCs into osteoblasts. Both PU foams therefore appeared to stimulate cell adhesion and proliferation in vitro, sustaining the MSCs’ growth and differentiation into osteoblasts.     

Development of highly porous large PLGA microparticles for pulmonary drug delivery

We report a new process of making highly-porous large polymeric microparticles for local drug delivery to the lungs by inhalation. Poly(lactic-co-glycolic acid) (PLGA) microparticles (average diameter, 10–20 μm) were made by the double-emulsion method. To impart favorable aerodynamic properties, an effervescent salt ammonium bicarbonate (ABC) was included in the internal aqueous phase. ABC produced highly-porous structures in the PLGA particles as it escaped as ammonia and carbon dioxide. The fine-particle fraction (FPF) of the microparticles increased as a function of the ratio of ABC to PLGA. Microparticles prepared with 7.5%w/w (ABC/PLGA) had a mass median aerodynamic diameter (MMAD) of 4.0 ± 1.2 μm and FPF of 32.0 ± 9.1% when tested with Anderson Cascade Impactor (ACI) and Rotahaler. The highly-porous large particles deposited at the ACI stages corresponding to the trachea and below. The highly-porous large particles avoided phagocytosis by macrophages, while non-porous small particles were quickly taken up by the macrophages. Unlike other encapsulation methods which employ osmogens or extractable porogens, this method could encapsulate lysozyme and doxorubicin·HCl, with high encapsulation efficiency (～100% for both lysozyme and doxorubicin), in the PLGA microparticles characterized by desirable MMAD (4.5 ± 0.6 μm lysozyme; 4.6 ± 0.4 μm doxorubicin) and FPF (29.1 ± 12.2% lysozyme; 33.8 ± 3.6% doxorubicin). Fifty-two percent of encapsulated doxorubicin was released over 4 days from the highly-porous microparticles. This method is an efficient way of making polymeric microparticles for sustained local drug delivery by inhalation.     

Dual delivery of chlorhexidine and platelet-derived growth factor-BB for enhanced wound healing and infection control

Wound treatment can require molecules that both enhance healing and control infection. As in many biomedical applications, the options for therapeutic molecules may include both hydrophilic and hydrophobic molecules. The goal of this study was to investigate a polymer system for drug delivery that simultaneously delivers platelet-derived growth factor (PDGF)-BB, a hydrophilic protein known to promote wound healing, and chlorhexidine (CHX), a hydrophobic antimicrobial agent for infection treatment. Poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared using different polymer formulations in a double emulsion process. CHX encapsulation efficiency was 19.6 ± 0.8% and 28.9 ± 1.5% for PLGA 50:50 and 85:15, respectively. The presence of CHX significantly increased PDGF-BB encapsulation efficiency relative to PDGF-BB alone. Both molecules could be released for up to 50 days and exhibited bioactivity for greater than 3 (PLGA 85:15) or 8 (PLGA 50:50) weeks using in vitro bacteria and cellular assays. An infected wound model was used to evaluate the system in vivo. Wounds treated with the dual delivery system showed decreased levels of infection and increased healing. Vascular analysis of wound tissues also showed higher levels of mature vasculature with the delivery of PDGF-BB. In conclusion, we have evaluated a drug delivery system for simultaneous delivery of hydrophobic and hydrophilic molecules and have shown that this system can improve healing and reduce bacteria levels in an infected wound model. This system could be applied to other therapeutic applications where sustained delivery of hydrophobic and hydrophilic molecules is required.     

Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration

Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis during bone regeneration, the aim of this study was to investigate if their sequential release could enhance BMP-2-induced bone formation. A composite consisting of poly(lactic-co-glycolic acid) microspheres loaded with BMP-2 embedded in a poly(propylene) scaffold surrounded by a gelatin hydrogel loaded with VEGF was used for the sequential release of the growth factors. Empty composites or composites loaded with VEGF and/or BMP-2 were implanted ectopically and orthotopically in Sprague–Dawley rats (n = 9). Following implantation, the local release profiles were determined by measuring the activity of ¹²⁵I-labeled growth factors using scintillation probes. After 8 weeks blood vessel and bone formation were analyzed using microangiography, μCT and histology. The scaffolds exhibited a large initial burst release of VEGF within the first 3 days and a sustained release of BMP-2 over the full 56-day implantation period. Although VEGF did not induce bone formation, it did increase the formation of the supportive vascular network (p = 0.03) in ectopic implants. In combination with local sustained BMP-2 release, VEGF significantly enhanced ectopic bone formation compared to BMP-2 alone (p = 0.008). In the orthotopic defects, no effect of VEGF on vascularisation was found, nor was bone formation higher by the combination of growth factors, compared to BMP-2 alone. This study demonstrates that a sequential angiogenic and osteogenic growth factor release may be beneficial for the enhancement of bone regeneration.     

Poly(l-glutamic acid)/chitosan polyelectrolyte complex porous microspheres as cell microcarriers for cartilage regeneration

In this study a novel kind of porous poly(l-glutamic acid) (PLGA)/chitosan polyelectrolyte complex (PEC) microsphere was developed through electrostatic interaction between PLGA and chitosan. By adjusting the formula parameters chitosan microspheres with an average pore size of 47.5 ± 5.4 μm were first developed at a concentration of 2 wt.% and freeze temperature of −20 °C. For self-assembly of the PEC microspheres porous chitosan microspheres were then incubated in PLGA solution at 37 °C. Due to electrostatic interaction a large amount of PLGA (110.3 μg mg⁻¹) was homogeneously absorbed within the chitosan microspheres. The developed PEC microspheres retained their original size, pore diameters and interconnected porous structure. Fourier transform infrared spectroscopy, thermal gravimetric analysis and zeta potential analysis revealed that the PEC microspheres were successfully prepared through electrostatic interaction. Compared with microspheres fabricated from chitosan, the porous PEC microspheres were shown to efficiently promote chondrocyte attachment and proliferation. After injection subcutaneously for 8 weeks PEC microspheres loaded with chondrocytes were found to produce significant more cartilaginous matrix than chitosan microspheres. These results indicate that these novel fabricated porous PLGA/chitosan PEC microspheres could be used as injectable cell carriers for cartilage tissue engineering.     

BSA-FITC-loaded microcapsules for in vivo delivery

Here we describe the preparation of BSA-FITC-loaded microcapsules as a model protein system for in vivo delivery. BSA-FITC-loaded microcapsules were prepared using a mono-axial nozzle ultrasonic atomizer, varying a number of parameters to determine optimal conditions. The preparation method chosen resulted in a BSA-FITC encapsulation efficiency of ～60% and a particle size of ～50 μm. An analysis of the microcapsules showed a BSA-FITC core surrounded by a poly(d,l-lactic-co-glycolic acid) (PLGA) shell. Injection of BSA-FITC-loaded microcapsules into rats resulted in a sustained release of BSA-FITC that maintained increased concentrations of BSA-FITC in plasma for up to 2 weeks. In contrast, the concentration of BSA-FITC in plasma after injection of BSA-FITC-only solution reached near-zero levels within 3 days. Fluorescence images of microcapsules removed at various times after implantation showed a gradual decrease of BSA-FITC in BSA-FITC-loaded microcapsules, confirming a sustained in vivo release of BSA-FITC. The duration of in vivo release and plasma concentration of BSA-FITC was correlated with the initial dose of BSA-FITC. BSA-FITC-loaded microcapsules maintained their structure for at least 4 weeks in the rat. The inflammatory response observed initially after injection declined over time. In conclusion, BSA-FITC-loaded microcapsules achieved sustained release of BSA-FITC, suggesting that microcapsules manufactured as described may be useful for in vivo delivery of pharmacologically active proteins.     

Polymeric topology and composition constrained polyether–polyester micelles for directional antitumor drug delivery

Amphiphilic linear and dumbbell-shaped poly(ethylene glycol)–poly(lactide-co-glycolide) (PEG–PLGA) copolymers were simply synthesized by the ring-opening polymerization of lactide and glycolide using PEG or tetrahydroxyl-functionalized PEG as the macroinitiator and stannous octoate as the catalyst. The copolymers spontaneously self-assembled into spherical micelles in phosphate-buffered saline at pH 7.4. The self-assembly behavior was dependent on both the polymeric topology and composition. Doxorubicin (DOX), an anthracycline antitumor drug, was loaded into micelles through nanoprecipitation. The in vitro release behavior could be adjusted by regulating the topology or composition of the copolymer, or the pH of the release medium. The effective intracellular DOX release from DOX-loaded micelles was confirmed by confocal laser scanning microscopy and flow cytometry in vitro. DOX-loaded micelles displayed great cellular proliferation inhibition efficacies after incubation for 24, 48 or 72 h. The hemolysis ratio of DOX was significantly reduced by the presence of copolymer. These properties indicated that the micelles derived from linear or dumbbell-shaped copolymers were promising candidates as smart antitumor drug carriers for malignancy therapy.     

Injectable and biodegradable thermosensitive hydrogels loaded with PHBHHx nanoparticles for the sustained and controlled release of insulin

Biodegradable PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) nanoparticles containing insulin phospholipid complex were loaded in chitosan-based thermosensitive hydrogels for long-term sustained and controlled delivery of insulin. The injectable hydrogels, prepared by adding β-glycerophosphate disodium salt (GP) solution to chitosan (CS) solution under stirring, showed a rapid solution-to-gel transition at 37 °C, a porous structure and a comparative degradation and swelling rate in vitro. In the in vitro release studies, only 19.11% of total insulin was released from the nanoparticle-loaded hydrogel (NP-CS/GP) within 31 days. However, 96.41% of total insulin was released from the free insulin-loaded hydrogel (INS-CS/GP) within 16 days. Most importantly, the hypoglycemic effect of NP-CS/GP following subcutaneous injection in diabetic rats lasted for >5 days, much longer than the effect caused by INS-CS/GP or other long-acting insulin formulations. The pharmacological availability of NP-CS/GP relative to INS-CS/GP was 379.85%, indicating that the bioavailability of insulin was significantly enhanced by NP-CS/GP gels. Therefore, biodegradable and thermosensitive NP-CS/GP gels have great potential for use in novel ultralong-acting insulin injections. In addition, the NP-loaded hydrogel system also paves the way for long-term delivery of other proteins and peptides.     

Hierarchically structured titanium foams for tissue scaffold applications

We present a novel route for producing a new class of titanium foams for use in biomedical implant applications. These foams are hierarchically porous, with both the traditional large (>300 μm) highly interconnected pores and, uniquely, wall struts also containing micron scale (0.5–5 μm) interconnected porosities. The fabrication method consists of first producing a porous oxide precursor via a gel casting method, followed by electrochemical reduction to produce a metallic foam. This method offers the unique ability to tailor the porosity at several scales independently, unlike traditional space-holder techniques. Reducing the pressure during foam setting increased the macro-pore size. The intra-strut pore size (and percentage) can be controlled independently of macro-pore size by altering the ceramic loading and sintering temperature during precursor production. Typical properties for an 80% porous Ti foam were a modulus of ～1 GPa, a yield strength of 8 MPa and a permeability of 350 Darcies, all of which are in the range required for biomedical implant applications. We also demonstrate that the micron scale intra-strut porosities can be exploited to allow infiltration of bioactive materials using a novel bioactive silica–polymer composite, resulting in a metal–bioactive silica–polymer composite.