Tyrosol-Derived Biodegradable Inks with Tunable Properties for 3D Printing

Three-dimensional (3D) printing has emerged as a valuable tool in medicine over the past few decades. With a growing number of applications using this advanced processing technique, new polymer libraries with varied properties are required. Herein, they investigate tyrosol-based poly(ester-arylate)s as biodegradable inks in fused deposition modeling (FDM). Tyrosol-based polycarbonates and polyesters have proven to be useful biomaterials due to their excellent tunability, nonacidic degradation components, and the ability to be functionalized. Polymers are synthesized by polycondensation between a custom diphenol and commercially available diacids. Thermal properties, degradation rates, and mechanical properties are all tunable based on the diphenol and diacid chosen. Evaluation of material print as it relates to chemical structure, molecular weight, and thermal properties was explored. Higher-molecular-weight polymers greater than 50 kDa exhibit thermal degradation during printing and at some points are too viscous to print. It was determined that polymers with lower processing temperatures and molecular weights were printable regardless of the structure. An exception to this was pHTy6 that was printed at 65 kDa with minimal degradation. This is most likely due to its low melting temperature and, as a result, lower printing temperatures. Additionally, chemical improvements were made to incorporate thiol–alkene click chemistry as a means for postprint curing. Low-molecular-weight pHTy6 was end-capped with alkene functionality. This material was then formulated with either a dithiol for chain extension or tetrathiol for cross-linking. Scaffolds were cured after printing for 5, 15, 30 and 60 min intervals where longer cure times resulted in a tougher material. This design builds on the library of biologically active materials previously explored and aims to bring new biomaterials to the field of 3D-printed personal medicine.

Three-dimensional (3D) printing is an increasingly attractive tool in biomaterials research due to its ability to tailor medical products to patient-specific needs.Tissue engineering,dentistry,and drug delivery have benefited from the ability to design scaffolds and models with complex architectures. Comparatively, traditional methods for fabrication such as solvent-casting, braiding, and compression molding often require additional surgical steps to fit the device at an implant site. Imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) can be translated into print specifications using computer-assisted design software. This allows complex architectures that are patient-specific to be printed using instrumentation already available in clinical facilities. One major hurdle that has been identified recently is the limited availability of biodegradable 3D-printable ink libraries.Biodegradable materials have been the focus of medical devices as they eliminate the need for future surgical procedures that carry the potential for infection and complications.Polymer micelles, hydrogels, supramolecularly cross-linked systems, and dynamically cross-linked systems have been successfully employed in direct ink writing (DIW) and fused deposition modeling (FDM) but many traditional biodegradable thermoplastic polymers have been limited by melt properties and susceptibility to degradation during printing. Current materials used in additive manufacturing include poly(lactic acid) (PLA) and polycaprolactone (PCL). Both polymers are available commercially in their filament form and have been used extensively in fused deposition modeling (FDM) printing. PLA and PCL are limited by their late-stage degradation byproducts causing local tissue acidosis and slow degradability, respectively, leading to the need for new printable material libraries.

Visual representation of process from base polymer selection through postprint curing.

Kohn et al. have focused their research on identifying new polymer libraries that can address these known challenges. Amino acid-based polymers have the benefit of increased inherent biocompatibility, chemical stability, and tunability. Specifically, tyrosine-derived polymers have been successfully commercialized, seeing use in drug-eluting polymeric coatings for hernia meshes and pacemaker pouches as well as cardiac stents. Unfortunately, the presence of amide functionality and pendant carbon chains results in amorphous materials with high processing temperatures, making FDM challenging to apply.Semicrystalline materials, on the other hand, exhibit melt properties favorable for printing. These materials often have the ability to flow in the melt form followed by rapid transition back to a solid after leaving the printhead.Recently, the Kohn lab has identified tyrosol-derived poly(ester-arylate)s as a new library of biocompatible, tunable polymers with semicrystalline properties. These polymers have been further characterized and their structure–property relationships were identified with the ability to modulate thermal, mechanical, and degradative properties.

Printability of the polymers and respective printing parameters

Guvendiren and Kohn et al. published a study evaluating a copolymer of tyrosyl 4-hydroxyphenylacetate (HTy) and phenylenediacetic acid. This polymer was chosen for its additional intermolecular interactions through π–π stacking in both the diphenol and diacid. Proof-of-concept printing was illustrated, and additional studies focusing on the functionalization of the material to incorporate bioactivity to the polymer were reported. While the biological function of a material plays a crucial role in developing new biomaterials, equally important is the ability for new materials to match the mechanical properties and degradation rates of application-specific regenerative processes and environments. Through a structure–property relationship approach, variables in polymer design including chemical structure, molecular weight, and polymer properties can be explored to expedite lead material discovery and optimal printing parameters.

Mechanical properties of printed formulations containing HDT (left) or PETMP (right) with varied curing times and thiol/alkene ratios.

Herein, they investigate the impact of the chemical structure and molecular weight on print parameters. Changes to polymer repeat unit chain length and mobility can help determine the correlation between chemical structure and resulting printability. Additionally, since these polymers are biodegradable, it is crucial that the material does not significantly change through temperature-induced degradation during printing.Polymers with higher molecular weights require higher processing temperatures to compensate for increases in melt viscosity. As a result, lower-molecular-weight polymers are typically used, resulting in weaker mechanical properties due to lower degrees of chain entanglement.One method to overcome limitations of low molecular weights is through interpenetrating network formation. Reports of using double network formation through ionic cross-linking paired with photo-cross-linking have led to improved chain entanglement and thus superior mechanical properties. Forming these networks often require complex processes, and concerns over mixing and potential phase separation are introduced. A more streamlined approach is to chemically modify a material to increase molecular weight and thus improve mechanical properties post printing using click chemistry. Through similar approaches to the chemical modifications explained in Guvendiren and Kohn’s work, thiol–ene click chemistry can be applied to cause chain extension or cross-linking with ultraviolet (UV) curing post printing. These changes combine the printability of low-molecular-weight polymers at lower temperatures, preventing degradation, with the robust mechanical properties of higher-molecular-weight polymers. Overall, their results indicate the versatility of tyrosol-derived poly(ester-arylate)s in 3D printing and chemical modifications, which allow for improved mechanical properties through cross-linking or chain extension.

  1. Tyrosol-Derived Biodegradable Inks with Tunable Properties for 3D Printing Jarrod Cohen, Cemile Kilic Bektas, Andrew Mullaghy, M. Mario Perera, Adam J. Gormley, and Joachim Kohn ACS Biomaterials Science & Engineering Article ASAP DOI: 10.1021/acsbiomaterials.1c00464