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capabilities: (1) spatiotemporal control of therapeutic agent release through shape-

morphing architectures that respond to physiological cues (e.g., pH, enzymes, or
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temperature) , significantly enhancing treatment precision and efficacy; and (2)
fabrication of organ-level constructs with unprecedented biological fidelity -

incorporating vascular networks, heterogeneous cell distributions, and ECM gradients

that more accurately recapitulate in vivo conditions than conventional 3D models 157 .

Despite these promising advances, 5D printing encounters substantial barriers to

clinical adoption. Challenges include scalability, biocompatibility of embedded

synthetic components, faithful recapitulation of human tissue complexity, and

regulatory obstacles associated with multi-component implantable devices. A critical

and balanced assessment of these limitations—including safety, manufacturing

reproducibility, and validation under clinically relevant conditions—is essential to

translate this technology into viable clinical solutions 156 .

The convergence of microfluidics with 5D printing technology is particularly

promising for oncology applications 158 , enabling: (a) tumor-on-a-chip platforms with

physiologically relevant drug response profiles, (b) biomimetic drug delivery systems

that adapt their release kinetics to TME dynamics, and (c) patient-specific tumor models

that evolve post-implantation to match disease progression 159 . Recent studies

demonstrate 5D-printed scaffolds achieving 92% shape fidelity upon environmental

triggering and sustaining 3-week drug release profiles with 89% bioactivity retention

156 . This technological synergy addresses critical limitations in conventional drug

screening by providing dynamic, vascularized tumor models that better predict clinical

outcomes while reducing animal testing requirements (Figure 8).

While 3D-printed microfluidics currently represents an emerging technology still
in its developmental phase, it has already demonstrated transformative potential in

revolutionizing our understanding of tumor biology. These advanced systems enable

researchers to recreate complex TMEs with unprecedented spatial and temporal

precision 157 , facilitating investigations into critical oncological processes such as

angiogenesis, metastasis, and drug resistance mechanisms 160 . Technology’s unique
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