<table><caption>**Table 6**
Challenges and opportunities in 4D printing for biomedical applications.</caption><thead><tr><th>Challenge</th><th>Description</th><th>Examples</th><th>Future opportunities</th></tr></thead><tbody><tr><td>Biocompatibility</td><td>Ensuring materials seamlessly integrate with biological systems without adverse effects such as cytotoxicity or inflammatory reactions.</td><td>Chitosan-based hydrogels for antimicrobial properties; PLA blends for reduced protein adsorption.</td><td>Using bioactive coatings, nanostructured surfaces, and AI to design biocompatible materials.</td></tr><tr><td>Degradation Rates</td><td>Achieving controlled degradation rates to match healing processes while ensuring non-toxic by-products.</td><td>PGA sutures with predictable degradation; PLA scaffolds for tissue regeneration.</td><td>Incorporating enzymatically degradable components; using biodegradable nanoparticles for reinforcement.</td></tr><tr><td>Limited availability of responsive polymers</td><td>Limited choice of materials capable of responding to diverse stimuli (temperature, pH, light, etc.) and meeting mechanical requirements.</td><td>PNIPAM for temperature sensitivity; alginate hydrogels for pH responsiveness.</td><td>Exploring biohybrid polymers and renewable biomass sources for responsive materials.</td></tr><tr><td>Precision in complex shapes</td><td>Maintaining geometric fidelity and function when printing intricate, patient-specific geometries with smart materials.</td><td>Shrinkage/warping in SLA-printed hydrogels; uneven thermal history and weak interlayer adhesion in FDM of SMPs.</td><td>Improved exposure/thermal control, better process windows, dual-curing chemistries, and design rules that account for shrinkage and anisotropy.</td></tr><tr><td>Reproducibility</td><td>Ensuring consistent actuation and properties across batches despite material/process variability and post-processing sensitivity.</td><td>Batch-to-batch formulation variation altering shape-memory response; humidity-dependent swelling of hydrogels; uneven resin curing affecting scaffold mechanics.</td><td>In-line monitoring, closed-loop process control, standardized post-processing/sterilization workflows, and predictive models to reduce variability.</td></tr><tr><td>High production costs</td><td>High costs of smart feedstocks and multi-material platforms, plus extra programming/activation steps that slow production.</td><td>Expensive multi-stimuli hydrogels and LCEs; specialized equipment for multi-material control and thermal programming.</td><td>Lower-cost bio-derived/resourced feedstocks, recycling of failed prints, scalable synthesis routes, and faster curing/continuous manufacturing strategies.</td></tr><tr><td>Long-term performance</td><td>Ensuring devices maintain integrity under long-term physiological stress, such as pulsatile blood flow or dehydration effects.</td><td>Nitinol stents for cardiovascular applications; double-network hydrogels for cartilage replacement.</td><td>Using surface treatments and graphene oxide reinforcements to enhance device lifespan.</td></tr><tr><td>Fatigue resistance</td><td>Resistance to repetitive loading cycles and prevention of microcracks or material creep</td><td>SMP composites with carbon nanotubes; alginate-calcium phosphate</td><td>Use of self-healing polymers and hierarchical structures for robust fatigue resistance.</td></tr></tbody></table>

<table><caption>**Table 6 (continued)**</caption><thead><tr><th>Challenge</th><th>Description</th><th>Examples</th><th>Future opportunities</th></tr></thead><tbody><tr><td rowspan="2">Disposal of non-biodegradable components</td><td>under physiological conditions.</td><td>hydrogels for joint replacements.</td><td rowspan="2">Developing cellulose-based hydrogels for temporary use; PLA blends for improved decomposition.</td></tr><tr><td>Addressing environmental risks posed by non-biodegradable materials in single-use devices or temporary implants.</td><td>PLA-based SMPs; cellulose-based hydrogels; chitosan-derived hydrogels for biodegradable solutions.</td></tr><tr><td>Sustainable material sourcing</td><td>Reducing reliance on petroleum-based materials; identifying renewable and waste-derived alternatives.</td><td>Lignin-derived SMPs; PHAs from microbial fermentation; recycled thermoplastics for 4D printing.</td><td>Transition to plant-derived polymers; recycling failed prints to reduce waste. Developing closed-loop systems.</td></tr></tbody></table>

identification and reduction of environmental hotspots [459]. For example, studies evaluating the cradle-to-grave impact of PLA-based SMPs highlighted energy-intensive production stages as key areas for improvement [460]. Biomimetic approaches, such as mimicking the hierarchical structure of natural materials, could further reduce resource use while enhancing material performance.

By prioritizing environmentally conscious practices and sustainable material innovation, 4D printing has the potential to evolve into a technology that aligns with global environmental goals while advancing biomedical applications. The main challenges of 4D printing for biomedical applications are summarized in Table 6.

Comparatively, 3D printing is well-established and finds widespread adoption across various industries, from prototyping to manufacturing of end-use products. It is particularly valued for its ability to create intricate geometries that would be impossible with traditional manufacturing methods. However, 3D printing primarily focuses on producing static objects, which limits its applicability in scenarios that require adaptability and responsiveness. In contrast, 4D printing extends the capabilities of 3D printing by enabling the production of dynamic structures that can change with time. This additional functionality makes 4D printing particularly suited for applications requiring materials that can adapt to their environment or user needs, such as self-folding structures, smart textiles, and responsive medical devices.

Despite its potential, the path to mainstream adoption of 4D printing is fraught with challenges. These include the need for further material innovation, refinement of printing techniques, and cost-effective, scalable manufacturing. For biomedical translation, regulatory and ethical considerations and the lack of standardization are also major barriers. Because 4D-printed devices can change their performance after fabrication or implantation, they require rigorous validation under clinically relevant conditions, along with traceable process control and reliable post-processing and sterilization protocols. Ethical issues are especially important for patient-specific and bioprinted systems, including informed consent, data privacy, and accountability when AI-assisted design is involved. Standardized terminology, reporting, and testing methods for actuation metrics, cyclic durability, aging, and degradation are also needed to improve reproducibility and enable meaningful comparison across studies. Overcoming these challenges will require interdisciplinary collaboration among materials scientists, engineers, clinicians, and regulatory experts to unlock the full potential of 4D printing. As technology continues to evolve, it promises to revolutionize industries by providing new ways to create materials and structures that are not only complex in shape but also dynamic and responsive in function.
CRediT authorship contribution statement

Mohammad Amin Yousefi: Writing – original draft, Visualization, Methodology, Formal analysis, Conceptualization. Davood Rahmatabadi: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Mina Ahmadi: Writing – original draft, Conceptualization. Abbas Bayati: Writing – original draft, Methodology. Majid Baniassadi: Writing – review & editing, Supervision. Abdelghani Laachachi: Writing – review & editing. Vadim V. Silberschmidt: Writing – review & editing. Daniel George: Writing – review & editing. Mostafa Baghani: Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.

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