Characterizing individual differences in functional connectivity using dual-regression and seed-based approaches

A central challenge for neuroscience lies in relating inter-individual variability to the functional properties of specific brain regions. Yet, considerable variability exists in the connectivity patterns between different brain areas, potentially producing reliable group differences. Using sex differences as a motivating example, we examined two separate resting-state datasets comprising a total of 188 human participants. Both datasets were decomposed into resting-state networks (RSNs) using a probabilistic spatial independent component analysis (ICA). We estimated voxel-wise functional connectivity with these networks using a dual-regression analysis, which characterizes the participant-level spatiotemporal dynamics of each network while controlling for (via multiple regression) the influence of other networks and sources of variability. We found that males and females exhibit distinct patterns of connectivity with multiple RSNs, including both visual and auditory networks and the right frontal–parietal network. These results replicated across both datasets and were not explained by differences in head motion, data quality, brain volume, cortisol levels, or testosterone levels. Importantly, we also demonstrate that dual-regression functional connectivity is better at detecting inter-individual variability than traditional seed-based functional connectivity approaches. Our findings characterize robust—yet frequently ignored—neural differences between males and females, pointing to the necessity of controlling for sex in neuroscience studies of individual differences. Moreover, our results highlight the importance of employing network-based models to study variability in functional connectivity

3D-Printing of Drug-Eluting Implants: An Overview of the Current Developments Described in the Literature

The usage of 3D-printing for drug-eluting implants combines the advantages of a targeted local drug therapy over longer periods of time at the precise location of the disease with a manufacturing technique that easily allows modifications of the implant shape to comply with the individual needs of each patient. Research until now has been focused on several aspects of this topic such as 3D-printing with different materials or printing techniques to achieve implants with different shapes, mechanical properties or release profiles. This review is intended to provide an overview of the developments currently described in the literature. The topic is very multifaceted and several of the investigated aspects are not related to just one type of application. Consequently, this overview deals with the topic of 3D-printed drug-eluting implants in the application fields of stents and catheters, gynecological devices, devices for bone treatment and surgical screws, antitumoral devices and surgical meshes, as well as other devices with either simple or complex geometry. Overall, the current findings highlight the great potential of the manufacturing of drug-eluting implants via 3D-printing technology for advanced individualized medicine despite remaining challenges such as the regulatory approval of individualized implants

Glycerol gelatin for 3D-printing of implants using a paste extrusion technique

Fused deposition modeling as an additive manufacturing technique has gained great popularity for the fabrication of medical devices as well as pharmaceutical dosage forms over the last years. Particularly the variety of geometries that can be printed determines the attractiveness of this technique enabling a shape adaption of e.g. implants. In the presented work the soft hydrogel material glycerol gelatin was investigated towards its applicability in 3D-printing as an alternative to the commonly applied and mostly rigid polyesters. Model implants loaded with the model drug quinine and with the shape of a hollow cylinder were printed via an extrusion based technique utilizing the piston feed in a hydrogel filled heatable syringe. Glycerol gelatin hydrogels need to be crosslinked to avoid gel-sol-transition at body temperature. For this purpose three different crosslinking methods (insertion, dipping, spraying) with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) were evaluated regarding their crosslinking efficiency and drug losses during the crosslinking process. Dipping of the implant into an aqueous solution with at least 50 mM EDC and 10 mM NHS was found to be the most efficient crosslinking technique in conjunction with a smaller drug loss during processing compared to inserting. However, the use of hydrogels also causes problems as an intense and highly variable swelling of the printed structures during crosslinking (120.7 % ± 11.9 % for 10 times dipping in 50mM EDC/10 mM NHS) and a great dependency of the volume on storage conditions complicate the preparation of tailor-made implants. The release of the model drug quinine from printed and crosslinked implants was fast and nearly completed within 6 hours

Influence of Siluron® insertion on model drug distribution in the simulated vitreous body

Biorelevant in vitro test systems may be helpful to understand the in vivo behaviour of modern intravitreal dosage forms such as implants and injections. The already presented Vitreous Model (VM) in combination with the Eye Movement System (EyeMoS) was used to simulate the situation after a vitrectomy in combination with Siluron® silicone oil (SO) insertion in vitro and to investigate the distribution of the model drug fluorescein sodium (FS) within the modified VM. The state after a vitrectomy was simulated in vitro by replacing half the volume of the gelled vitreous substitute by SO. Under consideration of simulated eye movements the position of SO towards the simulated vitreous body was examined. Furthermore, the influence of two different injection techniques was studied. On the one hand, FS was injected directly into the gel and on the other hand the injection was set through the gel in order to directly reach the SO. Independent of the injection technique, it was shown that the model drug distributed almost exclusively into the gel and not into the SO. This can be explained with the backflow of FS into the gel and the lack of solubility in the SO. Using the modified VM and EyeMoS, the in vitro characterization of drug release and distribution behaviour of intravitreal injections can be performed under consideration of a simulated vitrectomy

In vitro simulation of distribution processes following intramuscular injection

There is an urgent need for in vitro dissolution test setups for intramuscularly applied dosage forms. Especially biorelevant methods are needed to predict the in vivo behavior of newly developed dosage forms in a realistic way. There is a lack of knowledge regarding critical in vivo parameters influencing the release and absorption behavior of an intramuscularly applied drug. In the presented work the focus was set on the simulation of blood perfusion and muscle tissue. A solid agarose gel, being incorporated in an open-pored foam, was used to mimic the gel phase of muscle tissue and implemented in a flow through cell. An aqueous solution of fluorescein sodium was injected. Compared to recently obtained in vivo results the distribution of the model substance was very slow. Furthermore an agarose gel of lower viscosity an open-pored foam and phosphate buffer saline pH 7.4 were implemented in a multi-channel-ceramic membrane serving as a holder for the muscle imitating material. Blood simulating release medium was perfused through the ceramic membrane including filling materials. Transport of the dissolved fluorescein sodium was, in case of the gel, not only determined by diffusion but also by convective transport processes. The more realistic the muscle simulating materials were constituted the less reproducible results were obtained with the designed test setups

3D Printing of Paracetamol Suppositories: An Automated Manufacturing Technique for Individualized Therapy

Pharmaceutical compounding using the molding technique is the currently applied method for the on-demand manufacturing of suppositories and pessaries. Potential errors of this method are difficult to detect, and the possibilities of individualization of size and shape of the suppositories are limited. In this study, a syringe-based semi-solid 3D printing technique was developed for the manufacturing of suppositories in three different printing designs with the suppository bases polyethylene glycol (PEG) and hard fat (HF). The 3D printed suppositories were analyzed for their visual appearance, uniformity of mass and content, diametrical dimension, breaking force and release behavior and compared to suppositories of the same composition prepared by a commonly used molding technique. The results showed no adverse properties for the 3D printed suppositories compared to the molded ones. Moreover, the easy adaptation of shape using the 3D printing technique was demonstrated by the printing of different sizes and infill structures. Thus, 3D printing has great potential to complement the available manufacturing methods for compounded suppositories, as it represents an automated system for the individualized manufacturing of suppositories that meet patients’ needs

The EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms

An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release

3D Printing of Mini Tablets for Pediatric Use

In the treatment of pediatric diseases, suitable dosages and dosage forms are often not available for an adequate therapy. The use of innovative additive manufacturing techniques offers the possibility of producing pediatric dosage forms. In this study, the production of mini tablets using fused deposition modeling (FDM)-based 3D printing was investigated. Two pediatric drugs, caffeine and propranolol hydrochloride, were successfully processed into filaments using hyprolose and hypromellose as polymers. Subsequently, mini tablets with diameters between 1.5 and 4.0 mm were printed and characterized using optical and thermal analysis methods. By varying the number of mini tablets applied and by varying the diameter, we were able to achieve different release behaviors. This work highlights the potential value of FDM 3D printing for the on-demand production of patient individualized, small-scale batches of pediatric dosage forms

Molecular Order in Cold Drawn, Strain-Recrystallized Poly(ε-caprolactone)

Biaxial order in free-standing films of poly­(ε-caprolactone) (PCL), induced by plastic deformation and fibrillation, is studied by infrared transition moment orientational analysis (IR-TMOA) and X-ray diffraction (pole figures). This enables one to determine the order parameter tensor for the different molecular moieties with respect to the sample coordinate system. The main chains of the polymers are aligned with the stretching direction (<u><i>x</i></u>), leading to a strong order of the crystallites (Hermans orientation function, <i>S</i>_<i>xx</i> = 0.9 ± 0.1), and less ordered, amorphous regions (<i>S</i>_<i>xx</i> = 0.34 ± 0.1). The microscopic biaxiality of the system, |<i>S</i>_<i>yy</i> – <i>S</i>_<i>zz</i>| ≈ 0.1, is caused by the macroscopically asymmetric deformation perpendicular to the stretching direction. Cold drawing leads to a reduction in crystallinity and distorted crystallites in the fibrils, indicating the absence of “melting and recrystallization” or “fine slip” processes

Pharmacokinetics of 1-methyl-L-tryptophan after single and repeated subcutaneous application in a porcine model

Abstract: Increased activity of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is associated with immunological and neurological disorders, and inhibition of its enzyme activity could be a therapeutic approach for treatment of these disorders. The aim of the present study was to establish a large animal model to study the accumulation of the potential IDO inhibitor 1-methyltryptophan (1-MT) in blood and different organs of domestic pigs (Sus scrofa domestica). Because 1-MT has not been previously evaluated in pigs, the pharmacokinetics of a single subcutaneous 1-MT application was investigated. Based on this kinetic study, a profile for repeated 1-MT applications over a period of five days was simulated and tested. The results show that a single administration of 1-MT increases its concentrations in blood, with the maximum concentration being obtained at 12 h. Repeated daily injections of 1‑MT generated increasing plasma concentrations followed by a steady-state after two days. Twelve hours after the final application, accumulation of 1-MT was observed in the brain and other organs, with a substantial variability among various tissues. The concentrations of 1-MT measured in plasma and tissues were similar to, or even higher, than those of tryptophan. Our data indicate that repeated subcutaneous injections of 1-MT provide a suitable model for accumulation of 1-MT in plasma and tissues of domestic pigs. These findings provide a basis for further research on the immunoregulatory functions of IDO in a large animal model