3D printing of pharmaceuticals offers long-term, sustained drug release profiles. Unfortunately, this approach is limited by physical compounding and processing limitations. However, modification of the active drug into a prodrug compound allows for seamless incorporation compatible with advanced manufacturing methods for producing complex tissue scaffolds. demonstrated here using salicylic acid with tunable chemistries for control of physical and chemical properties. Here, we leverage salicylic acid derivatives to produce a library of photopolymers for 3D printing pro-drug tissue scaffolds and implantable drug depots. The role of different salicylic acid derivatives and linker species were investigated using photocrosslinking and vat photopolymerization 3D printing to produce porous and solid pro-drug tissue scaffolds containing more than 50% salicylic acid (pro-drug), suitable for further compounding or mixing with synergistic compounds. These resins may be rapidly 3D printed, where physical properties may be tuned to different tissue types (the carbonate species displaying elastic moduli matching that of adipose tissue ~65 kPa) as well as personalized for release rates. The pro-drug scaffolds hydrolyze spontaneously in the body to yield salicylic acid with a nearly zero-order release profile and may further be processed into multi-layered scaffold for synergistic or independent hydrolytic release of multiple drug compounds sequentially. The sustained release is based upon hydrolytic degradation, with release rates tuned through selection of the linker species. Cytocompatibility and biocompatibility are further explored for these materials, as well as the broader applicability of this technique in the field of sustained drug delivery. Important considerations from this work include the high loading potentials that may be achieved, the lack of burst release as seen with non-covalent incorporation of other drug systems, the synergistic loading of multiple compounds simultaneously, and the translational potential of both this platform and the techniques. These 4D scaffolds have excellent potential for green manufacturing biomaterials and pharmaceuticals with an excess of 50% bioderived composition, far exceeding the compositional make-up, physical property performance, and advanced properties of other 3D printing resins while furthering the development of adipose tissue engineering scaffolds and actively sustained drug delivery platforms.

4D printing of pro-drug compounds for sustained and personalized drug release implantable depots

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