Correction: 3D printed and stimulus responsive drug delivery systems based on synthetic polyelectrolyte hydrogels manufactured via digital light processing.

Correction for '3D printed and stimulus responsive drug delivery systems based on synthetic polyelectrolyte hydrogels manufactured via digital light processing' by Sonja Vaupel et al., J. Mater. Chem. B, 2023, DOI: https://doi.org/10.1039/d3tb00285c.

Micro Injection Molding of Drug-Loaded Round Window Niche Implants for an Animal Model Using 3D-Printed Molds.

A novel approach for the long-term medical treatment of the inner ear is the diffusion of drugs through the round window membrane from a patient-individualized, drug-eluting implant, which is inserted in the middle ear. In this study, drug-loaded (10 wt% Dexamethasone) guinea pig round window niche implants (GP-RNIs, ~1.30 mm × 0.95 mm × 0.60 mm) were manufactured with high precision via micro injection molding (µIM, Tmold = 160 °C, crosslinking time of 120 s). Each implant has a handle (~3.00 mm × 1.00 mm × 0.30 mm) that can be used to hold the implant. A medical-grade silicone elastomer was used as implant material. Molds for µIM were 3D printed from a commercially available resin (TG = 84 °C) via a high-resolution DLP process (xy resolution of 32 µm, z resolution of 10 µm, 3D printing time of about 6 h). Drug release, biocompatibility, and bioefficacy of the GP-RNIs were investigated in vitro. GP-RNIs could be successfully produced. The wear of the molds due to thermal stress was observed. However, the molds are suitable for single use in the µIM process. About 10% of the drug load (8.2 ± 0.6 µg) was released after 6 weeks (medium: isotonic saline). The implants showed high biocompatibility over 28 days (lowest cell viability ~80%). Moreover, we found anti-inflammatory effects over 28 days in a TNF-α-reduction test. These results are promising for the development of long-term drug-releasing implants for human inner ear therapy.

3D printed and stimulus responsive drug delivery systems based on synthetic polyelectrolyte hydrogels manufactured via digital light processing.

Hydrogels are three-dimensional hydrophilic polymeric networks absorbing up to and even more than 90 wt% of water. These superabsorbent polymers retain their shape during the swelling process while enlarging their volume and mass. In addition to their swelling behavior, hydrogels can possess other interesting properties, such as biocompatibility, good rheological behavior, or even antimicrobial activity. This versatility qualifies hydrogels for many medical applications, especially drug delivery systems. As recently shown, polyelectrolyte-based hydrogels offer beneficial properties for long-term and stimulus-responsive applications. However, the fabrication of complex structures and shapes can be difficult to achieve with common polymerization methods. This obstacle can be overcome by the use of additive manufacturing. 3D printing technology is gaining more and more attention as a method of producing materials for biomedical applications and medical devices. Photopolymerizing 3D printing methods offer superior resolution and high control of the photopolymerization process, allowing the fabrication of complex and customizable designs while being less wasteful. In this work, novel synthetic hydrogels, consisting of [2-(acryloyloxy) ethyl]trimethylammonium chloride (AETMA) as an electrolyte monomer and poly(ethylene glycol)-diacrylate (PEGDA) as a crosslinker, 3D printed via Digital Light Processing (DLP) using a layer height of 100 µm, are reported. The hydrogels obtained showed a high swelling degree q∞m,t ∼ 12 (24 h in PBS; pH 7; 37 °C) and adjustable mechanical properties with high stretchability (εmax ∼ 300%). Additionally, we embedded the model drug acetylsalicylic acid (ASA) and investigated its stimulus-responsive drug release behaviour in different release media. The stimulus responsiveness of the hydrogels is mirrored in their release behavior and could be exploited in triggered as well as sequential release studies, demonstrating a clear ion exchange behavior. The received 3D-printed drug depots could also be printed in complex hollow geometry, exemplarily demonstrated via an individualized frontal neo-ostium implant prototype. Consequently, a drug-releasing, flexible, and swellable material was obtained, combining the best of both worlds: the properties of hydrogels and the ability to print complex shapes.

Influence of the Volatility of Solvent on the Reproducibility of Droplet Formation in Pharmaceutical Inkjet Printing.

Drop-on-demand (DOD) inkjet printing enables exact dispensing and positioning of single droplets in the picoliter range. In this study, we investigate the long-term reproducibility of droplet formation of piezoelectric inkjet printed drug solutions using solvents with different volatilities. We found inkjet printability of EtOH/ASA drug solutions is limited, as there is a rapid forming of drug deposits on the nozzle of the printhead because of fast solvent evaporation. Droplet formation of c = 100 g/L EtOH/ASA solution was affected after only a few seconds by little drug deposits, whereas for c = 10 g/L EtOH/ASA solution, a negative affection was observed only after t = 15 min, while prominent drug deposits form at the printhead tip. Due to the creeping effect, the crystallizing structures of ASA spread around the nozzle but do not clog it necessarily. When there is a negative affection, the droplet trajectory is affected the most, while the droplet volume and droplet velocity are influenced less. In contrast, no formation of drug deposits could be observed for highly concentrated, low volatile DMSO-based drug solution of c = 100 g/L even after a dispensing time of t = 30 min. Therefore, low volatile solvents are preferable to highly volatile solvents to ensure a reproducible droplet formation in long-term inkjet printing of highly concentrated drug solutions. Highly volatile solvents require relatively low drug concentrations and frequent printhead cleaning. The findings of this study are especially relevant when high droplet positioning precision is desired, e.g., drug loading of microreservoirs or drug-coating of microneedle devices.

Volumetric mass density measurements of mesenchymal stem cells in suspension using a density meter.

To use regeneratively active cells for cell therapeutic applications, the cells must be isolated from their resident tissues. Different isolation procedures subject these cells to varying degrees of mechanical strain, which can affect the yield of cell number and viability. Knowledge of cell volumetric mass density is important for experimental and numerical optimization of these procedures. Although methods for measuring cell volumetric mass density already exist, they either consume much time and cell material or require a special setup. Therefore, we developed a user-friendly method that is based on the use of readily available instrumentation. The newly developed method is predicated on the linear relationship between the volumetric mass density of the cell suspension and the volumetric mass density, number, and diameter of the cells in the suspension. We used this method to determine the volumetric mass density of mesenchymal stem cells (MSCs) and compared it to results from the established density centrifugation.

Thermal, Mechanical and Biocompatibility Analyses of Photochemically Polymerized PEGDA250 for Photopolymerization-Based Manufacturing Processes.

Novel fabrication techniques based on photopolymerization enable the preparation of complex multi-material constructs for biomedical applications. This requires an understanding of the influence of the used reaction components on the properties of the generated copolymers. The identification of fundamental characteristics of these copolymers is necessary to evaluate their potential for biomaterial applications. Additionally, knowledge of the properties of the starting materials enables subsequent tailoring of the biomaterials to meet individual implantation needs. In our study, we have analyzed the biological, chemical, mechanical and thermal properties of photopolymerized poly(ethyleneglycol) diacrylate (PEGDA) and specific copolymers with different photoinitiator (PI) concentrations before and after applying a post treatment washing process. As comonomers, 1,3-butanediol diacrylate, pentaerythritol triacrylate and pentaerythritol tetraacrylate were used. The in vitro studies confirm the biocompatibility of all investigated copolymers. Uniaxial tensile tests show significantly lower tensile strength (82% decrease) and elongation at break (76% decrease) values for washed samples. Altered tensile strength is also observed for different PI concentrations: on average, 6.2 MPa for 1.25% PI and 3.1 MPa for 0.5% PI. The addition of comonomers lowers elongation at break on average by 45%. Moreover, our observations show glass transition temperatures (Tg) ranging from 27 °C to 56 °C, which significantly increase with higher comonomer content. These results confirm the ability to generate biocompatible PEGDA copolymers with specific thermal and mechanical properties. These can be considered as resins for various additive manufacturing-based applications to obtain personalized medical devices, such as drug delivery systems (DDS). Therefore, our study has advanced the understanding of PEGDA multi-materials and will contribute to the future development of tools ensuring safe and effective individual therapy for patients.

A Novel Hybrid Additive Manufacturing Process for Drug Delivery Systems with Locally Incorporated Drug Depots.

Here, we present a new hybrid additive manufacturing (AM) process to create drug delivery systems (DDSs) with selectively incorporated drug depots. The matrix of a DDS was generated by stereolithography (SLA), whereas the drug depots were loaded using inkjet printing. The novel AM process combining SLA with inkjet printing was successfully implemented in an existing SLA test setup. In the first studies, poly(ethylene glycol) diacrylate-based specimens with integrated depots were generated. As test liquids, blue and pink ink solutions were used. Furthermore, bovine serum albumin labeled with Coomassie blue dye as a model drug was successfully placed in a depot inside a DDS. The new hybrid AM process makes it possible to place several drugs independently of each other within the matrix. This allows adjustment of the release profiles of the drugs depending on the size as well as the position of the depots in the DDS.