4D Printable Salicylic Acid Photopolymers for Sustained Drug Releasing, Shape Memory, Soft Tissue Scaffolds

Abstract

3D printing of pharmaceuticals offers a unique opportunity for long-term, sustained drug release profiles for an array of treatment options. Unfortunately, this approach is often limited by physical compounding or processing limitations. Modification of the active drug into a prodrug compound allows for seamless incorporation with advanced manufacturing methods that open the door to production of complex tissue scaffold drug depots. Here we demonstrate this concept using salicylic acids with varied prodrug structures for control of physical and chemical properties. The role of different salicylic acid derivatives (salicylic acid, bromosalicylic allyl ester, iodosalicylic allyl ester) and linker species (allyl salicylate, allyl 2-(allyloxy)benzoate, allyl 2-(((allyloxy)carbonyl)oxy)benzoate) were investigated using thiol–ene cross-linking in digital light processing (DLP) 3D printing to produce porous prodrug tissue scaffolds containing more than 50% salicylic acid by mass. Salicylic acid photopolymer resins were all found to be highly reactive (solidification within 5 s of irradiation at λ = 405 nm), while the cross-linked solids display tunable thermomechanical behaviors with low glass transition temperatures (T gs) and elastomeric behaviors, with the carbonate species displaying an elastic modulus matching that of adipose tissue (approximately 65 kPa). Drug release profiles were found to be zero order, sustained release based upon hydrolytic degradation of multilayered scaffolds incorporating fluorescent modeling compounds, with release rates tuned through selection of the linker species. Cytocompatibility in 2D and 3D was further demonstrated for all species compared to polycarbonate controls, as well as salicylic acid-containing composites (physical incorporation), over a 2-week period using murine fibroblasts. The use of drugs as the matrix material for solid prodrug tissue scaffolds opens the door to novel therapeutic strategies, longer sustained release profiles, and even reduced complications for advanced medicine.

Advanced Biomaterials for 3D Printing via a Synergistic Dual-Photopolymer Design

“…For example, machine learning − can be used to predict which materials will work best for 3D-printed, biodegradable objects for certain applications, based on the database integrating the viscosities, mechanical properties, and degradability of cross-linking networks corresponding to existing photopolymers with different structures and chain lengths. On the other hand, a high-throughput process could be integrated into the material screening and function characterization to accelerate their biomedical applications, such as drug delivery. − Additionally, multiple-photopolymer formulations could also be considered to reach more complex polymer networks beyond the dual-photopolymer design. Different types of polymers and multifunctional junctions can be combined to manipulate the properties of the heterogeneous polymer networks …”

ABA Block Copolyester Thiol–Ene Resin From Triethylborane-Assisted Ring-Opening Copolymerization

“…Particularly, thiol-norbornene click chemistry is biorthogonal, making possible a wide range of bioinks that incorporate living cells in the resin. , But their difficult synthesis and purification, and the resultant high cost, limit their potential for commercial success. 4Degra by 4D Biomaterials is the first commercialized thiol-norbornene resin. , It comprises polycarbonate with pendant allyl and norbornene groups, synthesized via base-catalyzed ring-opening polymerization of respective cyclic carbonate monomers. 4Degra, therefore, has properties that many acrylate-based materials lack: shape memory, biodegradability, and tunable elasticity.…”