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Open research questions in 3D Printing in Biomedical Research

150 unresolved questions extracted from the limitations and future-work sections of 459 3D Printing in Biomedical Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • further investigation of Gd 3+ safety for each individual cell type used, - thorough investigations of the impact of Gd 3+ ions on cellular pathways of interest

    3D Cell Printing and Manipulation with Magnetic Bioinks · 2026 · DOI

  • The paper identifies a gap in the design and preparation of materials with suitable properties for 3D printing and tissue engineering applications. There is a need for materials that can be processed using standard thermoplastic techniques, including 3D printing. The study highlights the importance of thermoresponsive surface behavior and cell culture support in tissue engineering materials.

    Sparse bottlebrush poly (OEGMA-stat-MMA) copolymers for 3D printing and multicellular spheroids harvesting · 2026 · DOI

  • The complexity of liver development and function, which is not well understood. The need to integrate intrinsic and extrinsic cues across model classes. The challenge of applying developmental cues sequentially and adaptively, rather than simultaneously. The requirement to develop predictive models of liver function and disease that can be used for precision medicine and predictive modeling.

    Reverse bioengineering of the liver: developmental principles for next-generation liver-on-a-chip systems · 2026 · DOI

  • 107. Deguchi, S. et al. Usability of polydimethylsiloxane-based microfluidic devices in pharmaceutical research using human hepatocytes. ACS Biomater. Sci. Eng. 7, 3648–3657 (2021). 108. Shinha, K., Nihei, W., Ono, T., Nakazato, R. & Kimura, H. A pharmacokinetic–pharmacodynamic model based on multi-organ- on-a-chip for drug–drug interaction studies. Biomicrofluidics 14, 044108 (2020). 109. Schurdak, M. et al. Applications of the microphysiology systems database for experimental ADME-Tox and disease models. Lab. Chip 20, 1472–1492 (2020). 110. Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018). 111. Skat-Rørdam, J., Lykkesfeldt, J., Gluud, L. L. & Tveden-Nyborg, P. Mechanisms of drug induced liver injury. Cell. Mol. Life Sci. 82, 213 (2025). 112. Moradi, E., Jalili-Firoozinezhad, S. & Solati-Hashjin, M. Microfluidic organ-on-a-chip models of human liver tissue. Acta Biomater. 116, 67–83 (2020). 113. Poloznikov, A. In vitro and in silico liver models: current trends, challenges and opportunities. ALTEX 397–412 https://doi.org/10. 14573/altex.1803221 (2018). 114. Marx, U. et al. Biology-inspired dynamic microphysiological system approaches to revolutionize basic research, healthcare and animal welfare. ALTEX 42, 204–223 (2025). 115. Wang, X. et al. Comparative analysis of cell lineage differentiation during hepatogenesis in humans and mice at the single-cell transcriptome level. Cell Res. 30, 1109–1126 (2020). 116. Mittal, N. et al. Substrate stiffness modulates the maturation of human pluripotent stem-cell-derived hepatocytes. ACS Biomater. Sci. Eng. 2, 1649–1657 (2016). 117. Ardila Riveros, J. C. et al. Automated optimization of endoderm differentiation on chip. Lab. Chip 21, 4685–4695 (2021). 128. Wen, X., Yoshimoto, K., Yamanaka, M., Terada, S. & Kamei, K. In vitro nonalcoholic fatty liver disease model with cyclo-olefin- polymer-based microphysiological systems. Organs-Chip 3, 100010 (2021). 129. Banaeiyan, A. A. et al. Design and fabrication of a scalable liver- lobule-on-a-chip microphysiological platform. Biofabrication 9, 015014 (2017). 130. Tao, T. et al. Microengineered multi-organoid system from hiPSCs to recapitulate human liver-islet axis in normal and type 2 diabetes. Adv. Sci. 9, 2103495 (2022).

    Reverse bioengineering of the liver: developmental principles for next-generation liver-on-a-chip systems · 2026 · DOI

  • insufficient mechanical stability, - poor shape fidelity during printing, - rapid degradation, - batch-to-batch variability, - time-consuming preparation, - limited mechanical robustness, - narrow printability windows

    Bio-inks for skin regeneration: phase-adaptive design, multifunctional platforms, and 4D bioprinting frontiers · 2026 · DOI

  • integrating advanced materials, multi-omics data, and hybrid technologies, - developing smart bio-inks with embedded sensors or stimuli-responsive nanoparticles, - machine learning-guided bioprinting

    Bio-inks for skin regeneration: phase-adaptive design, multifunctional platforms, and 4D bioprinting frontiers · 2026 · DOI

  • Insufficient physiological complexity of current OoC models. Lack of standardization in OoC systems. Poor long-term culture stability of OoC systems.

    Organ-on-a-chip platforms for disease modeling and in vitro diagnostic applications · 2026 · DOI

  • Tissue engineering has advanced significantly, yet multicomponent hydrogels inspired by the compositional complexity of natural extracellular matrices (ECMs) are still underexplored.

    3D-Printable and Cytocompatible Hydrogel from Acinetobacter baylyi ADP1 Extracellular Matrix · 2026 · DOI

  • However, their rational design is limited by the lack of quantitative relationships linking design parameters to material properties.

    Data-driven predictive design of engineered living hydrogels · 2026 · DOI

  • Although pre-clinical studies have shown promising results, bringing this research into real-world clinical use remains challenging due to issues like lack of standardisation, difficulties in scaling up, regulatory hurdles, and high costs.

    Cell-laden 3D bioprinted hydrogels for wound healing: cellular mechanism, bioprinting determinants and translational perspectives · 2026 · DOI

  • Despite their potential, the concept of dynamic hydrogels is often used interchangeably, and a systematic review is lacking to clarify this ambiguity.

    Dynamic Hydrogels with Tunable Mechanics for 3D Organoid Derivation · 2025 · DOI

  • Furthermore, the mechanisms through which dynamic mechanical cues regulate organoid formation have not been thoroughly reported.

    Dynamic Hydrogels with Tunable Mechanics for 3D Organoid Derivation · 2025 · DOI

  • While ultrasound has been used for polymer synthesis and mechanochemistry, its application through cavitation for hydrogel synthesis as a constructive force is rare, and the underlying sonochemical mechanisms are poorly understood.

    Ultrasound Cavitation Enables Rapid, Initiator‐Free Fabrication of Tough Anti‐Freezing Hydrogels · 2025 · DOI

  • These biomaterials are mainly bioresorbable or bioinert, with the integration of cells in biomaterials remaining an underexplored area.

    Global trends in clinical trials involving engineered biomaterials · 2024 · DOI

  • Traditional single-use cell-bag bioreactors, limited by their rigid and single-point sensors, struggle with accuracy and scalability for high-quality cell manufacturing.

    Large-scale smart bioreactor with fully integrated wireless multivariate sensors and electronics for long-term in situ monitoring of stem cell culture · 2024 · DOI

  • Existing embedded ink writing approaches are limited by achievable feature sizes ranging from hundreds of microns to tens of millimeters, which hinders their ability to accurately duplicate structures found in various human tissues and organs.

    Multiscale embedded printing of engineered human tissue and organ equivalents · 2024 · DOI

  • However, there are few studies on acoustic cell patterning for fiber production, especially on the radial figure cell arrangements, which mimic many native tissue-like cell arrangements.

    Acoustic Cell Patterning for Structured Cell‐Laden Hydrogel Fibers/Tubules · 2024 · DOI

  • However, its practical advantages in identifying vascular-targeted drug delivery systems (DDS) over traditional in vitro models remain underexplored.

    Organ-on-a-Chip Approach for Accelerating Blood–Brain Barrier Nanoshuttle Discovery · 2024 · DOI

  • Volumetric processing of cryogels functionalized with nanosized units has potential to widen their biomedical applications, however this has remained challenging and relatively underexplored.

    In-Bath 3D Printing of Anisotropic Shape-Memory Cryogels Functionalized with Bone-Bioactive Nanoparticles · 2024 · DOI

  • There are however limited studies on the influence of viscosity on the spreading and migration of cells in 3D bioprinted skin cancer models.

    The influence of viscosity of hydrogels on the spreading and migration of cells in 3D bioprinted skin cancer models · 2024 · DOI

  • The clinical efficacy of MSC-based therapies is significantly limited by the decline in cell viability and functional stability during storage and transportation. There is a need for reliable short-term storage strategies for cellular therapeutics.

    Ambient temperature storage of encapsulated cells in alginate microspheres and core–shell capsules · 2026 · DOI

  • The cell-type-specific nature of FGF effects needs broader investigation beyond MSCs and HeLa cells to establish generalizability across different cell types.

    Ambient temperature storage of encapsulated cells in alginate microspheres and core–shell capsules · 2026 · DOI

  • Conventional calcium ion-based crosslinking methods often result in low bioactivity and poor printing precision. There is a need for the development of composite microfibers with enhanced bioactivity and controlled drug release.

    Fabrication of silicate-based bioactive glass-containing sodium alginate hydrogel microfibers for tissue engineering applications · 2026 · DOI

  • Further development of 3D multicellular bioprinting for personalized immunotherapy assessment and resistance deciphering. Investigation of the mechanisms of immunoresistance and potential strategies for reversal. Clinical translation of 3D bioprinting technology for improved patient outcomes.

    Engineering the tumor microenvironment via 3D multicellular bioprinting for personalized immunotherapy assessment and resistance deciphering · 2026 · DOI

  • Existing preclinical models are neither reliable nor competent to meet actual clinical needs for individualized treatment or further research. The complex tumor microenvironment is a major obstacle to effective immunotherapy.

    Engineering the tumor microenvironment via 3D multicellular bioprinting for personalized immunotherapy assessment and resistance deciphering · 2026 · DOI

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150 open questions have been extracted from the limitations and future-work passages of 459 3D Printing in Biomedical Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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