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Three-Dimensional Printing Technologies for Drug Delivery Applications
an implant containing both a reservoir system containing drug rhBMP-2 [121] . Implant studies that use 3D printing
rifampicin and a matrix system containing levofloxacin technology are presented in Table 13.
aimed at treating conditions with combined bone infections Seemingly, most drugs are tissue growth factors and
in the same device [106] , demonstrating the ability to print an antibiotics. There are limited works on 3D printing of
implant with multiple drug release systems within a single immunoregulatory drugs, which are needed in the recent
IDDD. Wu et al. also investigated the use of BJ processing development in tissue engineering [124] .
to build columnar-shaped tablets (CST), doughnut-shaped
tablets (DST), and multilayer-shaped tablets (MLST) from 5. Future directions and challenges
PLLA, which contained a barrier layer without drug on 3D printing technology will transform disease treatment,
the upper and lower surfaces of the implant [107] . Dynamic enabling more advanced high-resolution DDDs,
soaking of the implants displayed the MLST to provide with suitable substrates and more controlled release
improved consistency of drug release characteristics due profiles. This technology offers unique advantages in
to smaller fluctuations in surface area of the device. Years terms of product consistency, customization of drug
after, Wu et al. replaced the drugs with levofloxacin and administration, and combinations of different APIs,
tobramycin in the layers to demonstrate its applicability to making the treatment more accurate for the benefit of the
treat osteomyelitis [108] . patient [125] . To this end, challenges to bed addressed in 3D
Extrusion-based printing has been used to print printing technology as well as the efforts to adapt to or
IDDDs, including implant, stents, catheters and hernia benefit from new technologies are inevitable.
meshes. Sandler et al. produced PLA antimicrobial medical In pharmaceutical applications, many variables
devices, whereby HME technique allows 5% loading of regarding processes, printers, compounds, formulations,
the anti-microbial drug to be mixed into the material in type of dosages, post-treatments, and final distribution
the printing process, showing 89.56% reduction of biofilm contribute to the drug delivery success, and compounds
formation [109] . Other studies, which used filament extrusion with the highest quality, accuracy and efficacy as well as
instead, loaded the API by either coating of the polymer safety to patients are paramount. Management and care
pellets with the API [110,111] or mixing before the creation of of all compounds involved represent a critical factor not
the final filament [112,113] . Boetker et al. co-extruded polylactic only when formulations are created, but also when type
acid and either 20 or 40% hydroxypropyl methylcellulose of dosage is selected and the drug is printed. In addition,
(HE) (Metolose ) into disks, and determined an increase even though the printed product complies with all desired
®
in degradation rates associated with higher amount of ME. characteristics, it may also need a post-treatment, a stage
This study shows the potential to customize the degradation that should be carefully monitored to avoid any alteration
rates of materials by altering the flow properties of the to the effect of the drug [126] . Therefore, quality control
polymer blend . and safety are fundamental throughout the fabrication
[55]
Syringe extrusion has predominantly been utilized process. Assuring quality and safety already represents a
to validate the ability to extrude magnetic composite challenge and even more so when it comes to 3D printing
scaffolds and silica nanoparticulate composites and in large-scale manufacturing [127,128] .
hydrogels, which would be unsuitable to print under While it is clear that very strict parameters should
heated conditions seen in filament extrusion and HME. be met to avoid any problem for patients, clear guidance
Unlike heated extrusion techniques, these materials do not and regulations regarding the materials, processes, as
solidify on printing, with the gel-like structure providing well as printers almost do not exist due to the novelty
enough support for the following layers to be printed. of the technology. Even for the post-manufacture quality
Instead, they require post-printing drying processes to assessment of 3D-printed devices, standard guidance has
evaporate any remaining solvents [27,114-119] . not yet been published. Current regulations of traditional
SLM techniques have also been established as a manufacturing are not applicable to the flexibility that 3D
method for 3D printing IDDDs, with prominence in printing techniques would need; 3D printing allows the
producing parts with good structural integrity. For instance, manufacture of personalized and multi-drug medicines,
Maher et al. used SLM to print titanium bone replacement and there is still no standard guidance in this regard [129-131] .
implants enriched with anticancer drugs doxorubicin In 2017, the U.S. FDA published a guidance on 3D printed
(DOX) with particles and tubular arrays on the surface medical devices and prosthetics, which does not apply to
of the implant in order to promote cell attachment [120] . DDDs. Spritam, by Aprecia Pharmaceuticals, is the only
A similar concept was detailed by Parry et al. who used product fabricated by 3D printing that has been approved
SLA to produce poly (propylene fumarate) scaffolds for commercialization [127,130] .
with integrated pores to encourage cell attachment, Regulatory guidance is needed for materials,
whilst the printing of carbonate hydroxyapatite mineral processes and products, and for this, there are different
coatings and polymer microspheres promoted DR of the elements to consider, as detailed in Table 14.

336 International Journal of Bioprinting (2022)–Volume 8, Issue 4