Evaluation of Hydroxyethyl Cellulose Grades as the Main Matrix Former to Produce 3D-Printed Controlled-Release Dosage Forms.

Diclofenac sodium tablets were successfully prepared via hot-melt extrusion (HME) and fused deposition modeling (FDM), using different molecular-weight (Mw) grades of hydroxyethyl cellulose (HEC) as the main excipient. Hydroxypropyl cellulose (HPC) was added to facilitate HME and to produce drug-loaded, uniform filaments. The effect of the HEC grades (90-1000 kDa) on the processability of HME and FDM was assessed. Mechanical properties of the filaments were evaluated using the three-point bend (3PB) test. Breaking stress and distance were set in relation to the filament feedability to identify printer-specific thresholds that enable proper feeding. The study demonstrated that despite the HEC grade used, all formulations were at least printable. However, only the HEC L formulation was feedable, showing the highest breaking stress (29.40 ± 1.52 MPa) and distance (1.54 ± 0.08 mm). Tablet drug release showed that the release was Mw dependent up to a certain HEC Mw limit (720 kDa). Overall, the release was driven by anomalous transport due to drug diffusion and polymer erosion. The results indicate that despite being underused in FDM, HEC is a suitable main excipient for 3D-printed dosage forms. More research on underutilized polymers in FDM should be encouraged to increase the limited availability.

Calculation of Mass Transfer and Cell-Specific Consumption Rates to Improve Cell Viability in Bioink Tissue Constructs.

Biofabrication methods such as extrusion-based bioprinting allow the manufacture of cell-laden structures for cell therapy, but it is important to provide a sufficient number of embedded cells for the replacement of lost functional tissues. To address this issue, we investigated mass transfer rates across a bioink hydrogel for the essential nutrients glucose and glutamine, their metabolites lactate and ammonia, the electron acceptor oxygen, and the model protein bovine serum albumin. Diffusion coefficients were calculated for these substances at two temperatures. We could confirm that diffusion depends on the molecular volume of the substances if the bioink has a high content of polymers. The analysis of pancreatic 1.1B4 ß-cells revealed that the nitrogen source glutamine is a limiting nutrient for homeostasis during cultivation. Taking the consumption rates of 1.1B4 ß-cells into account during cultivation, we were able to calculate the cell numbers that can be adequately supplied by the cell culture medium and nutrients in the blood using a model tissue construct. For blood-like conditions, a maximum of ~106 cells·mL-1 was suitable for the cell-laden construct, as a function of the diffused substrate and cell consumption rate for a given geometry. We found that oxygen and glutamine were the limiting nutrients in our model.

A targeted rheological bioink development guideline and its systematic correlation with printing behavior.

Bioprinting for tissue or disease models is a promising but complex process involving biofabrication, cell culture and a carrier material known as bioink. The native extracellular matrix (ECM), which forms the scaffold for cellsin vivo, consists of several components including collagen as a gelling agent to confer mechanical stiffness and provide a substrate for cell attachment. Bioprinting therefore needs an artificial ECM that fulfills the same functions as its natural counterpart during and after the printing process. The combination of bioink materials determines the immune response of the host, cell compatibility and adhesion. Here we evaluate multi-material blending with four pre-selected components using a design of experiments approach. Our exemplary designed hydrogel is highly reproducible for the development of artificial ECM and can be expanded to incorporate additional requirements. The bioink displays shear-thinning behavior and a high zero-shear viscosity, which is essential for the printing process. We assessed the printing behavior of our bioink over a wide range of the key process parameters for extrusion-based bioprinting (temperature, pressure, feed rate, and nozzle geometry). Several processing temperatures were linked by rheological measurements directly to the 3D printing process. The printing results were evaluated using a self-developed categoric strand screening process, varying the feed rate and pressure with a fixed nozzle. Accordingly, nozzles differing in size and shape were evaluated and the interactions between printing pressure and feed rate were characterized separately by applying a modified O-R-O test. We tested the short-term cultivation stability of our bioink to mimic the hypothermic and hyperthermic conditions of the human body. As result we present an expandable concept for bioink development and a highly reproducible and well-characterized procedure for printing with the newly developed hydrogel. We provide detailed insights into the relationship between printing parameters, rheological parameters and short-term cultivation stability.