Slower Release Rate Research Articles

Slow Release of Menthol Using Sorbents Developed from Microwave Graphene Oxide

Menthol is a key ingredient in many of the traditional Thai aroma products such as potpourri and herbal air freshener. However, it suffers from the rapid evaporation and sublimation loss. In this work, microwave graphene oxide (mGO) has been prepared as sorbent and tested for the slow release of menthol. Menthol was loaded into microwave graphene oxide at loading ratios of 1:0.5 and 1:1. The release performance of the mGO as compared to traditional essential oil reed diffuser and the pure menthol was studied by monitoring the menthol weight loss at the temperature of 80°C until all of the menthol evaporated using thermogravimetric analysis. It was found that mGO can significantly slow down the menthol release rate compared to that of the pure menthol by up to eight times slower. The interaction and adsorption mechanism of the menthol-loaded microwave graphene oxide was also studied using Fourier Transform Infrared Spectroscopy (FTIR) which indicates that menthol adsorbs strongly onto the mGO leading to the slow release rate.

Drug release profiles of modified MCM-41 with superparamagnetic behavior correlated with the employed synthesis method

Mesoporous materials with superparamagnetic properties were successfully synthesized by two different methods: direct incorporation (DI) and wet impregnation (WI). The synthetized solids were evaluated as host of drugs for delivery systems and their physicochemical properties were characterized by XRD, ICP, N2 adsorption-desorption, spectroscopies of UV–Vis DR, FT-IR and their magnetic properties were measured. Indomethacin (IND) was incorporated into the materials and the kinetic of the release profiles was studied by applying the Pepas and Sahlin model. In this sense, materials modified by DI, particularly that with hydrothermal treatment, showed the higher adsorption capacity and slower release rate. This behavior could be associated to the synthesis method used that allowed a high percentage of silanol groups available in the solids surface, which can interact with the IND molecule. This feature coupled with the superparamagnetic behavior; make these materials very interesting for drug delivery systems.

Synchronization of Nitrogen Supply with Demand by Wheat Using Sewage Sludge as Organic Amendment in an Inceptisol

Nitrogen (N) is the most important essential nutrient for plant growth. Intensive agriculture requires large quantities of N mainly applied through commercial fertilizers like urea. However, the N use efficiency (NUE) hardly exceeds 50% under best management practices. Use of organics as N source to increase NUE is a very promising approach. The present investigation was carried out to study the mineralization and subsequent release of N from sewage sludge for synchronization with crop demand and to evaluate its effectiveness for maximization of NUE by wheat. Sewage sludge was collected from Okhla sewage sludge treatment plant, Delhi, characterized and incubated in an Inceptisol along with fertilizer N to monitor the release pattern of N. A pot culture experiment was also conducted to evaluate the efficiency of sludge for synchronization of N supply with the demand of wheat crop. Incubation experiment revealed that the sludge amended soil released significantly higher amounts of NH4+-N as well as NO3−-N than that of control. Release of NH4+-N from the sludge treated soil was slow during the first 15 days of incubation, then it increased and reached its maxima at around 45 days, after which it decreased sharply. Release of NO3−-N was slow during the first 15 days of incubation, followed by a high release rate up to 45 days and a slow release rate beyond 45 days. Pot culture experiment revealed that maximum yield, N content and uptake by wheat was obtained when the soil was treated with sludge along with fertilizer N @ 100 mg kg−1 soil but those were statistically at par with the results obtained using sludge along with fertilizer N @ 50 mg kg−1 soil. The same treatment i.e. sludge along with fertilizer N @ 50 mg kg−1 soil, also showed the highest N recovery (50%). This treatment also showed significantly higher yield and N uptake over the sole fertilizer treatment i.e. N @ 100 mg kg−1 soil along with recommended dose of P and K. Hence, with sludge amendment fertilizer N requirement could be curtailed by 50% and might be implicative for better NUE.

Transformation from single-mesoporous to dual-mesoporous organosilica nanoparticles.

Transformation from single-mesoporous to dual-mesoporous structured organosilica nanoparticles can be achieved by simply varying the volume fraction of ethanol in the synthesis system, using lauryl sulfonate betaine and sodium dodecyl sulfonate as dual-templates. Core-shell structured dual-mesoporous organosilica nanoparticles possess smaller mesopores (4.0 nm) in the shell and flower-like larger mesopores (46 nm) in the core. Owing to the unique mesostructure, dual-mesoporous organosilica nanoparticles show a high loading capacity and a slow release rate for cargo molecules. The large mesopores on the inside can provide a large storage space for the guest molecules and the small mesopores in the outer shell act as a natural valve, slowing the release. In addition, both single-mesoporous and dual-mesoporous organosilica nanoparticles, exhibit low cell toxicity and excellent cell permeability.

Quality by Design (QbD) Approach for Development of Co-Processed Excipient Pellets (MOMLETS) By Extrusion-Spheronization Technique.

Microcrystalline cellulose (MCC) is an excellent excipient for the production of pellets by extrusion spheronization. However, it causes slow release rate of poorly water soluble drugs from pellets. Co-processed excipient prepared by spray drying (US4744987; US5686107; WO2003051338) and coprecipitation technique (WO9517831) are patented. The objective of present study was to develop co-processed MCC pellets (MOMLETS) by extrusion-spheronization technique using the principle of Quality by Design (QbD). Co-processed excipient core pellets (MOMLETS) were developed by extrusion spheronization technique using Quality by Design (QbD) approach. BCS class II drug (telmisartan) was layered onto it in a fluidized bed processor. Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) for pellets were identified. Risk assessment was reported using Ishikawa diagram. Plackett Burman design was used to check the effect of seven independent variables; superdisintegrant, extruder speed, ethanol: water, spheronizer speed, extruder screen, pore former and MCC: lactose; on percentage drug release at 30 min. Pareto chart and normal probability plot was constructed to identify the significant factors. Box-Behnken design (BBD) using three most significant factors (Extruder screen size, type of superdisintegrant and type of pore former) was used as an optimization design. The control space was identified in which desired quality of the pellets can be obtained. Co-processed excipient core pellets (MOMLETS) were successfully developed by QbD approach. Versatility, Industrial scalability and simplicity are the main features of the proposed research.

Comparative studies on osmosis based encapsulation of sodium diclofenac in porcine and outdated human erythrocyte ghosts

The objective of our study was to develop controlled drug delivery system based on erythrocyte ghosts for amphiphilic compound sodium diclofenac considering the differences between erythrocytes derived from two readily available materials – porcine slaughterhouse and outdated transfusion human blood. Starting erythrocytes, empty erythrocyte ghosts and diclofenac loaded ghosts were compared in terms of the encapsulation efficiency, drug releasing profiles, size distribution, surface charge, conductivity, surface roughness and morphology. The encapsulation of sodium diclofenac was performed by an osmosis based process – gradual hemolysis. During this process sodium diclofenac exerted mild and delayed antihemolytic effect and increased potassium efflux in porcine but not in outdated human erythrocytes. FTIR spectra revealed lack of any membrane lipid disorder and chemical reaction with sodium diclofenac in encapsulated ghosts. Outdated human erythrocyte ghosts with detected nanoscale damages and reduced ability to shrink had encapsulation efficiency of only 8%. On the other hand, porcine erythrocyte ghosts had encapsulation efficiency of 37% and relatively slow drug release rate. More preserved structure and functional properties of porcine erythrocytes related to their superior encapsulation and release performances, define them as more appropriate for the usage in sodium diclofenac encapsulation process.

Liposomal Doxorubicin Delivery Systems: Effects of Formulation and Processing Parameters on Drug Loading and Release Behavior.

Liposomes can serve as promising carriers for targeting delivery and controlled release of anti-cancer drugs. Doxorubicin-loaded liposomes have achieved enhanced efficacy in some solid tumors due to EPR effect with prolonged circulation and reduced toxicity. In this study the effects of liposomal structure have been investigated on the loading efficiency and controlled release behavior. Liposomes with various compositions were prepared through a thin film hydration method, and extruded to large unilamellar vesicles (LUVs) with mean particle size (Z ave~ 100 nm) by high-pressure extrusion technique. Then, doxorubicin was loaded into liposomes using remote active loading strategy. The loading efficiency and drug release behavior were evaluated using various parameters such as medium pH, liposome compositions and cholesterol concentrations. Liposomes prepared with different compositions showed high levels of drug encapsulation. Drug loading efficiencies (>90%) achieved with high final drug/lipid ratio (0.18-0.2). Faster release was observed at pH 5.5 when compared to pH 7.4 for all formulations. The fastest release rate was observed for unsaturated lipid (<48hr) and the slowest release rate was observed for saturated lipids with high phase transition temperature such as 1, 2-distearoylphosphatidylcholine (DSPC) and hydrogenated soy phosphatidylcholine (HSPC) (10-18 days). The sustained release was observed for liposomal formulations containing cholesterol. In conclusion, we have demonstrated that drug release rate could be controlled by manipulating the composition of liposomal structures.

A comparative study between melt granulation/compression and hot melt extrusion/injection molding for the manufacturing of oral sustained release thermoplastic polyurethane matrices

During this project 3 techniques (twin screw melt granulation/compression (TSMG), hot melt extrusion (HME) and injection molding (IM)) were evaluated for the manufacturing of thermoplastic polyurethane (TPU)-based oral sustained release matrices, containing a high dose of the highly soluble metformin hydrochloride.Whereas formulations with a drug load between 0 and 70% (w/w) could be processed via HME/(IM), the drug content of granules prepared via melt granulation could only be varied between 85 and 90% (w/w) as these formulations contained the proper concentration of binder (i.e. TPU) to obtain a good size distribution of the granules. While release from HME matrices and IM tablets could be sustained over 24h, release from the TPU-based TSMG tablets was too fast (complete release within about 6h) linked to their higher drug load and porosity. By mixing hydrophilic and hydrophobic TPUs the in vitro release kinetics of both formulations could be adjusted: a higher content of hydrophobic TPU was correlated with a slower release rate. Although mini-matrices showed faster release kinetics than IM tablets, this observation was successfully countered by changing the hydrophobic/hydrophilic TPU ratio. In vivo experiments via oral administration to dogs confirmed the versatile potential of the TPU platform as intermediate-strong and low-intermediate sustained characteristics were obtained for the IM tablets and HME mini-matrices, respectively.

Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells

A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells.

Verapamil eluting stents as a possible treatment for vasospasm after subarachnoid hemorrhage

ObjectiveThe only pharmacologic prophylaxis for cerebral vasospasm after subarachnoid hemorrhage is oral nimodipine. A novel way to mitigate this risk may be to design a drug eluting stent that elutes...

Poly (vinyl alcohol)/chitosan cryogels as PH responsive ciprofloxacin carriers

The pH responsiveness of swelling behavior and the release of ciprofloxacin hydrochloride from poly (vinyl alcohol)/chitosan cryogels of various compositions were investigated. All cryogels swelled and reached equilibrium within 100 min, indicating that the cryogels swell relatively fast. Increasing the chitosan content in the poly (vinyl alcohol) cryogels increased the swelling capacity of the cryogels. The poly (vinyl alcohol)/chitosan cryogels exhibited a sudden change in swelling characteristics at a certain pH value of the swelling medium as critical pH of 6.37–6.68 which depends on chitosan content. Ciprofloxacin hydrochloride was loaded into poly (vinyl alcohol)/chitosan cryogels to study its in-vitro release. Drug release behavior was found to be pH-dependent. The release mechanism changes with pH of the medium and mainly at critical pH. The release rate is high in acidic medium (pH 4.5 and 5.5) as compared with basic one (pH 7.4), in the last pH medium the drug being delivered in a prolonged period and with a slow release rate. The pH responsiveness indicates that these systems are interesting drug carriers for the oral formulations or as wound dressing materials.

Improving Pharmaceutical Characteristics of Curcumin by Alginate/Pectin Microparticles

This study was aimed at the preparation of curcumin-loaded alginate/pectin microparticles (beads) in order to enhance the pharmaceutical effect of curcumin as a drug for colon related diseases. For this purpose, three types of curcumin-loaded beads were prepared with different alginate/pectin ratios (100/0, 75/25 and 50/50) and studied in various experiments including the release of curcumin from beads and swelling of beads in buffer solutions of simulated gastric, intestinal, and colon fluids. The results of curcumin releasing experiments under conditions mimicking stomach to colon transit showed that the beads with higher content of pectin exhibit stronger curcumin entrapment, slower release rate, and lower swelling. Thus, 50/50 alginate/pectin composition has minimum release in the upper parts of gastrointestinal tract (stomach and intestine). However, when these beads reached colonic buffer medium, the curcumin release suddenly increased. Therefore, beads with 50/50 alginate/pectin compositions could be useful as a suitable carrier for curcumin delivery to colon. Moreover, the stability and chemical protection of curcumin encapsulated in these beads was confirmed by high performance liquid chromatography measurements after a period of six months.

Hypoglycemic activity and stability enhancement of human insulin–tat mixture loaded in elastic anionic niosomes

This study aimed to investigate the synergistic effect of trans-activator of transcription (Tat) and niosomes for the improvement of hypoglycemic activity of orally delivered human insulin. The elastic anionic niosomes composing of Tween 61/cholesterol/dicetyl phosphate/sodium cholate at 1:1:0.05:0.02 molar ratio loaded with insulin–Tat mixture (1:3 molar ratio) was prepared. Deformability of the elastic anionic niosomes decreased after loaded with the mixture of 1.35 times. For the in vitro release, the insulin (T10 = 4 h) loaded in the elastic anionic niosomes indicated the slower release rate than insulin in the mixture (T10 = 3 h) loaded in niosomes. At room temperature (30 ± 2 °C), the mixture loaded in elastic anionic niosomes was more chemical stable than the free mixture of 1.3, 1.4 and 1.7 times after stored for 4, 8 and 12 weeks, respectively. Oral administration in the alloxan-induced diabetic mice of the mixture loaded in elastic anionic niosomes with the insulin doses at 25, 50 and 100 IU/kg body weight indicated significant hypoglycemic activity with the percentage fasting blood glucose reduction of 1.95, 2.10 and 2.10 folds of the subcutaneous insulin injection at 12 h, respectively. This study has demonstrated the synergistic benefits of Tat and elastic anionic niosomes for improving the hypoglycemic activity of the orally delivered human insulin as well as the stability enhancement of human insulin when stored at high temperature. The results from this study can be further developed as an effective oral insulin delivery.

Monitoring Physiological Changes in Haloarchaeal Cell during Virus Release.

The slow rate of adsorption and non-synchronous release of some archaeal viruses have hindered more thorough analyses of the mechanisms of archaeal virus release. To address this deficit, we utilized four viruses that infect Haloarcula hispanica that represent the four virion morphotypes currently known for halophilic euryarchaeal viruses: (1) icosahedral internal membrane-containing SH1; (2) icosahedral tailed HHTV-1; (3) spindle-shaped His1; and (4) pleomorphic His2. To discern the events occurring as the progeny viruses exit, we monitored culture turbidity, as well as viable cell and progeny virus counts of infected and uninfected cultures. In addition to these traditional metrics, we measured three parameters associated with membrane integrity: the binding of the lipophilic anion phenyldicarbaundecaborane, oxygen consumption, and both intra- and extra-cellular ATP levels.

Investigation of self-sustained beating oscillations in a Rijke burner

Thermoacoustic oscillations occur in a Rijke burner with a porous plug stabilized premixed flame. In addition to regular limit cycle oscillations, the thermoacoustic system also presents self-sustained periodic amplitude modulations, or beating oscillations, near the flame equivalence ratio limits of thermoacoustic instability. The beating oscillations exhibit approximately 1Hz or even lower frequency amplitude modulations for the acoustic pressure and the heat release rate. It is also found that low frequency flame pulsations arise with the amplitude modulations. The different characteristics of the beating oscillations near the upper and lower equivalence ratio limits are distinguished and explained by the coupling between the low frequency flame pulsations and the thermoacoustic instability. To simulate the beating oscillations, this paper proposes a flame model that incorporates the flame dynamics at the amplitude modulation time scale (∼s) and the acoustic time scale (∼ms). The simulation results of the thermoacoustic system suggest that this flame model can qualitatively predict the amplitude modulation caused by the slow pulsating flame temperature and heat release rate. Flame heat loss plays an important role in low frequency flame pulsations, and its effects on beating oscillations are discussed. Several simulation cases at different equivalence ratios are performed to retrieve the amplitude modulations near the upper and lower equivalence ratio limits. The results are in keeping with the experimental observations.

Tuning core hydrophobicity of spherical polymeric nanoconstructs for docetaxel delivery

AbstractThe reformulation of nanoparticles of chemotherapeutic molecules is often required to enhance their bioavailability, increase blood longevity and eventually improve the outcome of the pharmacological intervention. Docetaxel (DTXL), a potent anti‐cancer drug daily used for the treatment of different neoplastic diseases, is one of such molecules. Here, spherical polymeric nanoconstructs (SPNs) with a characteristic size of 200 nm are designed for the delivery of DTXL. SPNs comprise a hydrophobic polymeric core where the drug is entrapped and are externally stabilized by a lipid monolayer decorated with polyethylene glycol chains. Two different polymers are used for the core formation, namely poly(d,l‐lactide‐co‐glycolic) acid (PLGA), which has been extensively used for similar biomedical applications, and poly(3‐hydroxybutyrate) (P(3HB)), which is a natural polymer produced by a wide variety of bacterial species under nutrient limiting conditions. The two nanoformulations of DTXL are compared in terms of loading, release and cytotoxic drug potential. Consistent with the higher hydrophobicity of P(3HB) over PLGA, the former polymer allows for a higher loading efficiency (almost double that of PLGA) and slower release rates. No significant difference is observed in terms of internalization rate and cytotoxicity potential. This work demonstrates that P(3HB) could be a valid alternative to the more conventional PLGA for the delivery and controlled release of hydrophobic therapeutic molecules. © 2016 Society of Chemical Industry

Silica nano-carrier as a sustained delivery system of GDF5 for intervertebral disc regenerative medicine

Event Abstract Back to Event Silica nano-carrier as a sustained delivery system of GDF5 for intervertebral disc regenerative medicine Nina Henry1, 2, 3, Johann Clouet1, 3, 4, 5, Pauline Colombier1, 3, Eric Gautron2, Bernard Humbert2, Jean Le Bideau2, Catherine Le Visage1, 3 and Jérôme Guicheux1, 3, 6 1 INSERM, UMRS 791, Center for OsteoArticular and Dental Tissue Engineering (LIOAD), France 2 CNRS, UMR 6502, Institute of Materials Jean Rouxel (IMN), France 3 Université de Nantes, UFR Odontologie, France 4 CHU Nantes, PHU 11 Pharmacie, Pharmacie Centrale, France 5 Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, France 6 CHU Nantes, PHU 4 OTONN, France Introduction: Intervertebral disc (IVD) degeneration is one of the major causes of low back pain[1]. The sustained delivery of therapeutic factors able to promote IVD regenerative processes in situ is contemplated and biomaterials-based delivery systems are widely studied[2]. Among all biomaterials, mesoporous silicas are of interest with respect to their properties and lack of cytotoxicity[3],[4]. In this context, we studied mesoporous silica nanofibers (MSNFs)[5] as a drug delivery system. The loading and release capacity of MSNFs and the protein-silica interactions were explored using a model protein (lysozyme). MNSFs were then characterized as a bioactive carrier for Growth Differentiation Factor 5 (GDF5), a nucleopulpogenic factor[6]. Methods: Lysozyme was incubated with MSNFs (50x500nm) in different conditions of pH, time and concentrations. Analyses of protein-silica interactions were performed with transmission electron microscopy (TEM), attenuated total reflectance infrared (ATR/IR) and zeta potential (ZP). Release was performed in PBS, pH 7.2 at 37°C for 20 days. Lysozyme concentration and biological activity were measured with BCA method and enzymatic assay, respectively.GDF5 was incubated with MSNFs at pH 7 for 48h at concentrations from 1-4µg/mL. Release was performed in PBS, pH 7.2 at 37°C for 48h. GDF5 concentration and bioactivity were measured with ELISA and by testing the Smad 1/5/8 pathway activation in human adipose stromal cell (hASC) by western blot, respectively. Nucleopulpogenic commitment of hASC by released GDF5 was finally assessed using RT qPCR (aggrecan, type II collagen, OVOS2, PAX1, CD24) and immunohistology (alcian blue, type II collagen, aggrecan, OVOS2, PAX1, CD24). Results and Discussion: Lysozyme was successfully adsorbed on MSNFs and the highest amount of adsorbed lysozyme was obtained at pH 10, concentration of 200 mg/mL and 48h of incubation. Different lysozyme morphologies were observed by TEM. The ATR/IR study, which compared amides, Si-O-Si, Si-OH and water bonds between lysozyme, MSNFs and MSNFs/lysozyme, combined with ZP results, suggest that protein-silica interactions must be mostly driven by hydrogen bonds involving the amide II of the protein. Release experiments showed a burst within the 1st hour followed by a slower release rate, leading to a sustained release for up to 20 days. The biological activity of the released protein was maintained at all time points. We also demonstrated that GDF5 could be adsorbed and released onto MSNFs. GDF5 bioactivity, evaluated by Smad 1/5/8 phosphorylation, was evidenced for higher GDF5-loaded concentrations onto MSNFs and cells commitment was assessed. Conclusion: MSNFs are promising nano-carriers for therapeutic factors delivery. Moreover, protein-silica interactions were extensively described and revealed hydrogen bond-mediated interactions. Further experiments will focus on the association of GDF5-loaded MSNFs with hASC with an adapted scaffold for in vivo proof of concept. The authors would like to thank Nicolas Stephant, Paul Pilet and Françoise Lary for their contributions.; Financial support : FARMA "Etude ET3-683", Région Pays de la Loire "Projet LMA", ANR "REMEDIV" and FRM Projet DBS20131128442.

Nano-rods of doxorubicin with poly(l-glutamic acid) as a carrier-free formulation for intratumoral cancer treatment.

In addition to intravenous injections (i.v.), topical dosing of doxorubicin hydrochloride (DOX) has also been the focus of cancer treatment recently, although it normally requires well-designed drug carriers. In this work, we found that DOX could form fibril-shaped DOX aggregates via self-assembly in phosphate buffer (PB) and then co-assemble with poly(l-glutamic acid) (PGA) at a proper polymer-drug ratio, giving a unique nano-rod-shaped microstructure. The release rate of DOX from the PGA/DOX nano-rods was thus easily controlled at a slower release rate without being encapsulated by any classic carrier. In vitro cell culture demonstrated that the PGA/DOX nano-rods were not favorably taken up by cancer cells, which can be attributed to the negatively charged nature and the non-spherical shape of the aggregates. These features suggest great potential for the PGA/DOX assemblies for a sustained delivery through the intratumoral pathway (i.t.) as a carrier-free formulation. In the mouse model it diminished organ damage at a dose level of 30 mg kg-1via i.t. injections compared to the serious cardiotoxicity and renal toxicity via typical multiple i.v. dosage of free drug solution at 5 mg kg-1. As a result, the PGA/DOX formulation showed efficient anti-tumor activity. The survival rate of tumor bearing mice was significantly increased by over 35% compared to the i.v. injections of DOX solutions. Therefore, PGA/DOX nano-rods may provide a new and safe delivery route of the common anti-tumor drug.

3D printing biomimetic nanomaterials for highly efficient vascularized bone development

Event Abstract Back to Event 3D printing biomimetic nanomaterials for highly efficient vascularized bone development Benjamin Holmes1*, Michael Plesniak1* and Grace Zhang1, 2, 3 1 The George Washington University, Mechanical and Aerospace Engineering, United States 2 The George Washington University, Department of Biomedical Engineering, United States 3 The George Washington University, Division of Genomic Medicine, Department of Medicine, United States Introduction: Large critical sized bone defects are notoriously hard to regenerate due to the need for such large and complex portions of tissue to have an adequate vascular network. As an emerging tissue fabrication technique, 3D bioprinting offers great precision to control the internal architecture of a scaffold and print complicated structures close in architecture to biological tissue[1]. Thus, the objective of this study is to combine a microvascular 3D printed design with biomimetic nanomaterials (i.e., bone minerals, nanocrystalline hydroxyapatite (nHA) and growth factor loaded nanospheres) for highly efficient fluid perfusion and enhanced vascularized bone regeneration. Materials and Methods: Two types of scaffolds with both large (500 µm radius) and small (250 µm radius) fluid microchannels (Figure 1) were designed and 3D printed via fused deposition molding printing from biocompatible polylactic acid (PLA). Biomimetic osteogenic nHA and angiogenic vascular endothelial growth factor (VEGF) loaded PLGA nanospheres were fabricated and then conjugated onto the 3D printed scaffolds using a multi-step aminolysis process. The scaffolds were characterized via scanning electron microscopy (SEM). The VEGF release from the scaffolds was characterized for 7 days. Both human umbilical vein endothelial cell (HUVECs) and human bone marrow mesenchymal stem cell (hMSCs) functions in the 3D printed scaffolds were investigated in vitro. Figure 1; Computer aided designs (CAD) of large (left) and right (small) microvascular channel bone scaffolds. Results and Discussion: SEM showed that the conjugation of nanomaterials had a noticeable effect on the nano-topography when compared to untreated PLA. 7 day VEGF release study showed a slow release rate after 48 hours on scaffolds with VEGF encapsulated nanospheres, when compared to bare VEGF samples. In addition, the scaffolds with larger microchannels and a smaller PLGA nanosphere concentration both provide a more efficient mechanism for HUVEC cell invasion and proliferation. Figure 2 shows hMSC 3 week differentiation on scaffolds with pre-cultured HUVEC vascular networks. Figure 2; 1, 2 and 3 week calcium deposition of hMSCs cultured on scaffolds which have been pre-cultured with HUVECs for 1 week. Data are ± standard error of the mean, N=3; *p<0.05 when compared to all other groups at weeks 1 and 2, respectively; **p<0.05 when compared to scaffolds with large and small microchannels at week 1; ***p<0.05 when compared to scaffolds with small microchannels at week 3; and #p<0.05 when compared to all other groups at week 3. Excellent calcium deposition was exhibited on scaffolds with both VEGF loaded PLGA nanospheres and nHA. Yet, higher values in calcium were seen on samples with only PLGA nanospheres, when compared to plain PLA controls. A similar trend could be observed for collagen type I synthesis on scaffolds. In both cases, higher amount of bone matrix deposited can be attributed to the presence of nHA, but it can also be inferred that the presence of VEGF and HUVECs induced cell to cell interactions which also lead to faster bone tissue formation. Conclusion: Based on these results, it can be inferred that the use of a drug loaded nanoparticle delivery system, along with nHA, a bioactive conjugation method and highly efficient 3D printed micro designs for cell growth, infiltration and fluid perfusion can yield a highly effective method for the enhanced growth of vascularized bone.

Magnetic Mirtazapine Loaded Poly(propylene glycol)bis(2aminopropylether) (PPG-NH2, MW_2000) Nanocarriers for Controlled Drug Release

Mirtazapine is an antidepressant that was introduced in 1996 for the treatment of moderate and severe depression. Mirtazapine is the only tetracyclic antidepressant that is approved by the Food and Drug Administration to treat depression. Mirtazapine is devoid of most side effects but has antihistamine side effects of drowsiness and weight gain. Its bioavailability is only fifty percent. The low bioavailability and side effects can be improved by altering the pharmokinetic profile of the drug by controlling the release of the drug. The slow release of the drug will reduce the harmful affect it has on the cells decreasing the side effects, as well as the loading of the drug in the nanocarrier will allow for a longer residence time in the body before it is removed by the gastrointestinal tract. In this research paper the pharmokinetic profile of Mirtazapine will be altered by surrounding the drug with a biodegradable polymer called poly(propylene glycol) bis(2-aminopropylether) (PPG-NH2, MW _ 2000) chains. This profile will be done at different polymer concentrations, drug concentrations and solubilizer concentration to see how this will affect the release of the drug. In this research project it was found that using a lower concentration of poly(propylene glycol) bis (2-aminopropylether) (PPG-NH2, MW_2000) chains of 0.5 g/mL led to a slower release in comparison to the other polymer concentrations with an encapsulation of 10 mg of Mirtazapine. When the drug weight was increased but the polymer concentration stayed the same (0.95 g/mL) the release rate increased with drug concentration. Also when the stabilizer concentration was increased, but the polymer concentration and drug concentration remained the same (0.95 g/mL and 10 mg respectively) the release rate increased. Therefore in order to allow for a slower release rate one should use the lower polymer concentration of 0.95 g/mL, with the lower concentration of stabilizer. This will allow for a slower release of the drug Mirtazapine which will lower the side effects and increase the bioavailability percentage.