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The field of biomedical design and manufacturing has been rapidly evolving, with implants and grafts featuring complex 3D design constraints and materials distributions. By combining a new coding‐based design and modeling approach with high‐throughput volumetric printing, a new approach is demonstrated to transform the way complex shapes are designed and fabricated for biomedical applications. Here, an algorithmic voxel‐based approach is used that can rapidly generate a large design library of porous structures, auxetic meshes and cylinders, or perfusable constructs. By deploying finite cell modeling within the algorithmic design framework, large arrays of selected auxetic designs can be computationally modeled. Finally, the design schemes are used in conjunction with new approaches for multi‐material volumetric printing based on thiol‐ene photoclick chemistry to rapidly fabricate complex heterogeneous shapes. Collectively, the new design, modeling and fabrication techniques can be used toward a wide spectrum of products such as actuators, biomedical implants and grafts, or tissue and disease models.

Docetaxel (DTX) has been widely used for treatment of many types of cancer. However, DTX is poor water soluble and commercial DTX is formulated in nonionic surfactant polysorbate 80 and...

Purpose Most chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed. Methods A bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry ( 1 H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models. Results The dextran–docosahexaenoic acid (DHA)– docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran–DHA–DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice. Conclusion These dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

perfusable channels. In the past decades, microfluidic technology has mostly relied on photolithography and soft lithography applied to materials like glass and elastomers (i.e., PDMS), and has been largely limited to 2D devices. [3,6] In recent years, 3D printing has emerged as a powerful tool to generate highly complex, freeform structures with enhanced functionalities, leading to great advances in various fields from photonic crystals to tissue scaffolds. [7][8][9][10][11][12] While two-photon stereolithography has represented the method of choice for the fabrication in the nm to µm scale, [8,9] for constructs with channels in the millimeter to centimeter scale various printing methods have been explored, such as direct ink writing, [13,14] embedded printing with fugitive inks (FRESH, SWIFT), [15][16][17][18] laser-sintering of sacrificial carbohydrate templates, [19] and digital light processing (DLP). [20][21][22] These technologies have particularly contributed to the tremendous progress in the design of increasingly complex vasculature networks for biomedical applications. [18,[23][24][25] More recently, a novel light-based fabrication method termed volumetric printing (VP) has emerged as a promising technology for such applications, enabling the printing of complex centimeter-sized models within seconds. [26,27] Recent studies have demonstrated the possibility to create hollow, perfusable structures, using materials from glass to biopolymers and possibly targeting mesoscale vasculature. [28][29][30][31] However, as all the methods described above, also VP falls short in covering resolution range from µm/sub-µm up to cm, thus currently limiting its application to microfluidic constructs with features >100-200 µm.Another light-based method named two-photon ablation (2PA) instead offers complementary capabilities, being limited in printing time and construct size, but reaching the highest resolution of any biofabrication method (≤1 µm). [8] 2PA is based on multiphoton ionization induced by high-intensity pulsed lasers, [32,33,34] and has been explored for a variety of applications, from "nanosurgery" to form cell-instructive microchannels. [35][36][37][38][39][40][41] Here, we show for the first time the hybrid/combined use of VP and 2PA printing technology to reproduce a multiscale Multiscale printing of 3D perfusable geometries holds great potential for a range of applications, from microfluidic systems to organ-on-a-chip. However, the generation of freeform designs spanning from centimeter to micrometer features represents an unmet challenge for a single fabrication method and thus may require the convergence of two or more modalities. Leveraging the great advances in light-based printing, herein a hybrid strategy is introduced to tackle this challenge. By combining volumetric printing (VP) and high-resolution two-photon ablation (2PA), the possibility to create multiscale models with features ranging from mesoscale (VP) to microscale (2PA) is demonstrated. To successfully combine these two methods, micro...

The vascular tree spans length scales from centimeter to micrometer. Engineering multiscale vasculature, in particular from millimeter vessels to micrometer-size capillaries, represents an unmet challenge and may require the convergence of two or more printing modalities. Leveraging the great advances in light-based biofabrication, we herein introduce a hybrid strategy to tackle this challenge. By combining volumetric printing (VP) and high-resolution two-photon ablation (2PA), we demonstrate the possibility to create complex multiscale organotypic perfusable models with features ranging from mesoscale (VP) to microscale (2PA). To successfully combine these two methods, we first eliminated micrometer-size defects generated during VP process. Due to optical modulation instability of the laser source and self-focusing phenomenon that occurs when the light triggers the photoresin crosslinking, VP printed constructs feature micrometer-size filaments and channels. By optical tuning the refractive index of the photoresin, we demonstrate defect-free VP that can then be combined with 2PA. To facilitate the 2PA process and meet VP requirements, we introduce a purely protein-based photoclick photoresin combining gelatin-norbornene and gelatin-thiol. By optimizing defect-free VP and 2PA processes, we finally demonstrate the possibility to generate complex 3D vasculature-like constructs with features ranging from ~400 μm of VP to ~2 μm of 2PA. This hybrid strategy opens new possibilities to better recapitulate microtissues vasculature and complex architectures, with particular potential for microfluidics and organ/tissue-on-a-chip technologies.

Accelerating the designing and manufacturing of complex shapes has been a driving factor of modern industrialization. This has led to numerous advances in computational design and modeling and novel additive manufacturing (AM) techniques that can generate and fabricate complex shapes for bespoke applications. By combining new new coding-based design approach with advanced AM techniques for high-throughput fabrication, we envision a new approach to transform the way we design and fabricate complex shapes. Here, we demonstrate an algorithmic voxel-based approach, which can rapidly generate and analyze porous structures, auxetic meshes and cylinders, or perfusable constructs. We use this design scheme in conjunction with new approaches for multi-material volumetric printing based on thiol-ene photoclick chemistry to rapidly fabricate complex heterogeneous structures. Collectively, the new design and fabrication technique we demonstrate can be used across a wide-spectrum of products such as actuators, biomedical implants and grafts, or tissue and disease models.