Engineering of Biomaterials for Additive Manufacturing in Precision Medicine

Abstract

In current clinical practice, implants are often produced with standardized sizes and functionalities to address specific subgroups of the population. From a clinical and patient perspective, these strategies can provide sub-optimal clinical outcomes, such as delayed recovery, higher recurrence of certain diseases, and long-term complications. In the last decades, the healthcare sector is shifting towards more personalized approaches with the goal of customizing therapies based on patient’s genetic, molecular, and anatomical signature. To accelerate the transition into precision medicine, new technologies, advanced biomaterials design, and efficient personalization strategies are needed. Additive manufacturing (AM) is an enabling technology for personalized medicine that provides freedom of design, multimaterial components, and tailored functionalities that are not feasible with conventional manufacturing. Early examples of AM in the medical and pharmaceutical sector, such as patient specific 3D-printed airway splint or high dosage load orodispersible tables have shown tremendous benefits. Effective fabrication via AM requires advanced biomaterials design. The engineered inks need to satisfy specific physical constraints defined by the AM technology and to ensure biofunctionality based on the targeted application. To address these needs, we developed a universal nanocarrier ink (UNI) platform for direct ink writing based on engineered polymer–nanoparticle (PNP) assembly. Different ink formulations were prepared specifically for tissue engineering and drug delivery. The understanding of the molecular interaction between the components of PNP hydrogels is of fundamental importance to efficiently design inks. We observed that nanoparticle properties, such as size and surface poly(ethylene glycol) (PEG) density, played a fundamental role on the viscoelasticity of PNP hydrogels. To describe their rheology, we combined a fractional viscoelastic model with hydrodynamic reinforcement. We demonstrated that small NPs are more effective than large NPs in slowing polymer chain mobility as they provided a larger total surface area available for interactions, increasing the mechanical properties. Moreover, we investigated the softness of NPs and the effect on PNP interactions. Softer NPs were more effective than harder NPs in decreasing polymer chain mobility and increasing overall PNP viscoelastic properties. Each AM technology provides its own advantages and limitations. Deposition-based AM approaches enables the fabrication of multimaterial constructs; however, a current limitation is the resolution of fabricated objects, as this is usually dictated by the nozzle diameter. Stimulus-triggered AM approaches allow for biofabrication with micron-scale resolution; however, only a limited number of cytocompatible resins are currently available. To overcome these limitations, we introduced a photopatterning-enhanced direct ink writing approach to fabricate hierarchical biomaterials with controlled properties at micro and macro-scale. Direct ink writing fabricated multimaterial scaffolds, while digital light processing cured the deposited biomaterial and tailored the local mechanics of the printed construct. Our UNI platform was leveraged to formulate dual bioinks compatible with both AM technologies. The fabricated hierarchical biomaterials had tunable mechanical reinforcement and demonstrated cytocompatible environments for biofabrication. PNP hydrogels have shown great utility in different applications. To further extend the accessible ranges of functionalities, the mechanical properties, and the dynamicity of this class of materials we leveraged polypseudorotoxane-based supramolecular design. The inclusion of α-cyclodextrin (αCD) with PEGylated NPs of PNP hydrogels reinforced and expanded the modularity PNP hydrogel platform. CD–PNP hydrogels were formulated for high-fidelity 3D printing and tissue engineering as well as for engineering conductive or magnetic materials. Current pharmaceutical manufacturing technologies are effective in mass producing drugs; however, they have substantial limitations in formulating drugs that are tailored to each individual needs. New approaches are needed to provide more flexible formulations and capabilities. We leveraged the freedom of design ensured by AM to engineer advanced functionalities, such as multimodal drug formulations and unconventional release kinetics. Different biomaterial ink formulations were used to print drug delivery system containing model drugs. The release profile was engineered by adjusting specific parameters, such as the formulation of the ink and the composition of the drug delivery system. This approach could facilitate and accelerate the fabrication of personalized medications requiring advanced drug delivery systems. A current limitation of deposition-based AM techniques is the high shear forces generated within the nozzle during ink extrusion. This can be harmful to cells and active ingredients. To overcome this challenge, we used computational fluid dynamic simulations to investigate and characterize flow properties of PNP and CD–PNP hydrogels. Further, a few new nozzle designs were proposed to reduce the maximum shear stress experienced in the ink during extrusion. These nozzle designs could be beneficial to increase cell viability during manufacturing and to improve shape fidelity of printed construct. Overall, in the field of medical and pharmaceutical sciences there is a clear interest to provide better and more personalized treatments. The field of precision biomaterials is constantly evolving as are AM technologies. Combined together they can provide disruptive solutions with tremendous benefits for the healthcare sector. Our proposed strategy to use PNP and CD–PNP hydrogels with direct ink writing and photopatterning-enhanced direct ink writing could serve the scope of precision medicine and enable personalized treatments.