Researchers Experiment with 3D Printed Microreservoir Devices for Better Drug Delivery

In ‘Additive Manufacturing of Microreservoir Devices for Oral Drug Delivery Using an Acculas BA-30 Micro-Stereolithography Instrument: A Feasibility Study,’ researchers continue to explore the potential for 3D printed drug delivery systems. Here, the authors are testing micro-reservoir geometries for oral drug delivery hoping to further strides in absorption efficiency for drugs critical to so many patients today, like diabetics.

The pharmaceutical industry has an obvious interest in seeing improvements in oral drug delivery, but so do many other research entities as further progress could not only change lives but perhaps save them. The authors point out too that better drug delivery systems lead to improved compliance on the part of the patient.

“In case of inefficient oral drug delivery, the restrictions are set by the nature of the gastrointestinal system. The presence of hydrochloric acid associated with a harsh decline in pH down to 1.5, proteolytic and other digestive enzymes and finally a tightly arranged mucus-secreting epithelial cell layer prove to be very efficient barriers against the delivery and absorption of functional molecules,” state the authors.

A functional carrier system is meant to protect the digestive system against harmful enzymes and pH-gradients, offering the following:

• Stable, biocompatible environment
• Permeability
• Prolonged release pattern
• Non-toxic profile

The researchers point out that along with larger industrial practices for both prototyping and printing of parts, 3D printing and additive manufacturing offer great promise for both micro- and nano-technology too, leading to studies like this one as researchers hope to make further breakthroughs in both medicine and pharmaceutically-related fields.

“Microfabricated reservoir devices, intended for the oral delivery of drugs, have the advantage of an asymmetric design, which in turn allows for a unidirectional release of the loaded drug, potentially promoting increased release toward the intestinal mucosa,” state the researchers.

In this study, the researchers used Materialise Magics software to create 3D files, then printed on a D-MEC Acculas BA-30 micro-stereolithography system. Post processing consisted of soaking the samples in isopropanol for 5 minutes and then drying them with pressurized air.

They began by creating a microcontainer made up of a system of pillars, from micro-pillars to smaller pillars branching out. Microscopy indicated that the shape ‘not fully defined,’ with the structure deviating from the initial design plan.

3D printed simple microcontainers at small scale. SEM images of 3D printed microcontainers (b, c) and STL-file (a) images of the corresponding microcontainer design made with OpenSCAD software. The outer diameter of the container design (a) was 500 μm, the inner diameter 300 μm. The micro-pillars had a bottom diameter of 100 μm, a top diameter of 80 μm, a height of 100 μm and a pitch of 80 μm. The image (c) was taken from a 35° tilted angle.

“The measurements of the tips of the pillars in comparison to the theoretical measurements in the design suggest that approximately only 80% of the pillars, up to a diameter of approximately 80 μm, were fabricated,” stated the researchers. “Since in the design the pillars are directed outwards from the object, the unfinished pillars could also be an explanation for the smaller outer diameter of the object. Finally, another remarkable finding is that the reservoir of the container is not clearly recognizable and seems to be filled. This circumstance could have resulted from improper removal of excess uncured resin residue.”

3D printing of complex topology-optimized microcontainers. SEM images of 3D printed (micro-stereolithography) microcontainers (c, d, e, f, h) and STL-file (a, b, g, i) images of the corresponding complex microcontainer design with everting micro-pillars which were generated using a topology optimization algorithm. The outer diameter of the container design excluding the pillars (a, b) was 2200 μm, including the pillars 2980 μm. The inner diameter was 1800 μm and the height 1000 μm. Observed sizes are depicted in the SEM images and theoretical measurements of the micro-pillars in the STL-file are illustrated in (i). Images (d, e, f, h) were recorded at a tilted angle of 35°.

The team developed a more basic sample for 3D printing, increasing the minimum size to 80 μm, with the overall size reduced to 500 μm, but it was unsuitable as well, with no lithographic layers to be seen:

“The gained findings suggest that the dimensions used in this design, especially the minimum feature sizes were too small to obtain acceptable results with the used instrument,” stated the researchers.

“As a consequence of this fact, the print resin was not fully cured and ultimately the structures of the object did not emerge. Contrary to this, in the second test, the laser power was obviously too high so that more resin was cured than it was supposed to and then the reservoir, as well as the interspace between the micro-pillars, was closed. Since the 3D printer was appropriately calibrated before these tests, it was decided to use the previous laser parameters and not to focus on optimizing laser power any further. Also, in this case, no lithographic layers were visible.”

The team continued to work on print quality, increasing dimensions and adding an overhang, leaving them to discover some similarities with previous samples, but with less deviation.

“While the problem of 3D printing “cups” in stereolithography is a known issue, the post processing of 3D printed structures should accommodate for the removal of excess uncured print resin,” concluded the researchers.  “Under the premise that the post-treatment/cleaning protocol will necessarily need to be the subject of a thorough optimization work, this research demonstrates the feasibility of using SLA 3D printing to fabricate microcontainers for oral drug delivery since millimeter-sized devices could be realized with this micro manufacturing technology.

“From an application point of view a further problem remains. All microcontainers were additively manufactured on a likewise 3D printed grid which irreversibly connected them. However, the working principle of microcontainers for oral drug delivery relies on individually acting containers that attach to the intestinal mucosa. With the current 3D printing method, the release of individual microcontainers is not possible. Therefore, the implementation of 3D printing on a sacrificial release layer as done in micromachining is suggested.”

3D printing has already made countless impacts in the medical realm, but also in the area of medications—where researchers have had more luck in 3D printing pills, developing technology to accelerate dosage, and even automated pill dispensers.

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Resolution assay 5: increasing microcontainer overall size. STL-file models (a1-f1) and SEM images (a2-f2, a3-f3) of microcontainers with differently sized micro-pillars placed on overhang. In contrast to the other figures, all STL-models featured an overall diameter of 1500 μm in the bottom and 2000 μm including overhang. Excluding the pillars, all microcontainers had a height of 600 μm. The dimensions of the micro-pillar top- and bottom diameters were: (a1) 30 μm-80 μm, (b1) 60 μm-100 μm, (c1) 80 μm-130 μm, (d1) 100 μm-170 μm, (e1) 120 μm-200 μm and (f1) 90 μm-200 μm. The height of the micro-pillars was set to be 200 μm. SEM images (A-F3) were recorded from a 35° tilted angle.