Key Takeaways & Executive Findings
- •• 4D bioprinting integrates smart materials and time-dependent shape morphing to create dynamic constructs that mimic native tissue behavior. • Multi-responsive hydrogels and shape-memory polymers enable precise deformation and programmable mechanical properties for cell-laden structures. • 4D-printed dynamic microenvironments can regulate stem cell differentiation and achieve spatiotemporal growth factor release for functional tissue regeneration. • Finite element analysis-driven multi-nozzle printing of heterogeneous hydrogel architectures enables self-folding and topological remodeling of biomimetic vascular networks.
Abstract
BACKGROUND: 4D printing enables dynamic control of structure and function, allowing constructs to more closely mimic complex physiological environments and driving the development of tissue engineering and regenerative medicine towards intelligence and personalization. OBJECTIVE: To review the role and application advances of 4D printing in tissue engineering and regenerative medicine. METHODS: Relevant literature published between 1994 and 2025 was retrieved from CNKI, WanFang, PubMed, and Web of Science. Chinese and English terms were “4D printing, regenerative medicine, tissue engineering, wound healing, biological ink, intelligent materials.” A total of 115 articles were systematically reviewed and analyzed. RESULTS AND CONCLUSION: 4D bioprinting represents a key advance in tissue engineering and regenerative medicine, integrating diverse fabrication methods and biomaterials to create structures that dynamically respond to environmental cues. 4D bioprinting enhances the biomimicry of natural tissues, enables customized responsiveness, and improves integration with biological systems. 4D bioprinting facilitates the development of tissues and organs, as well as intelligent implants and advanced drug delivery systems, ultimately for tissue repair. 4D bioprinting can seamlessly adapt to the physiological complexity of the human body, apply to personalized medicine, and significantly improve therapeutic outcomes in changing environments.
1. Introduction
Tissue engineering aims to develop scaffolds that can replace, repair, maintain, or enhance the function of damaged tissues and organs [1-2]. Despite numerous breakthrough studies in this field, fully replicating the heterogeneity and biological functions of living tissues remains a major challenge. How to accurately reproduce the complexity of biology in vitro, especially its dynamic adaptive characteristics, is still a critical problem to be solved [3].
To address this, additive manufacturing combined with computer-aided design has been widely applied [4], with 3D printing being the most representative [5]. 3D printing demonstrates high efficiency and precision in the fabrication of personalized biomedical devices, while reducing material waste, shortening production cycles, and advancing drug delivery systems [6-8]. Further development of 3D bioprinting incorporates cells into the printing process, enabling the construction of liver [9], heart, and personalized implants [10-11], forming tissue structures with functional and anatomical accuracy [12-14]. However, traditional bioprinting often produces static structures that fail to match the dynamic characteristics of native tissues. This limitation has driven the emergence of 4D printing, which introduces the 'time' dimension on top of 3D printing, allowing shape, performance, and function to evolve after printing, ultimately endowing printed structures with adaptive control capabilities in morphology, properties, and function [15]. Materials are the cornerstone, with intelligent responsive materials from natural, synthetic, or hybrid sources [14,16] processed via crosslinking [17], photopolymerization, and thermal gelation to form primary structures with programmable and controllable shapes or functions [18-19]. Furthermore, stimulation methods are crucial; specific stimulation mechanisms include temperature, humidity, pH, or biological signals [12,14], which act on the material to drive expansion, contraction, folding, unfolding, or twisting [6], altering material shape [14,16], physicochemical properties, or function [12,14], ultimately mimicking the adaptability of natural tissues [19]. 4D printing applications span materials science, bone tissue engineering, medical devices, drug delivery, food printing, and soft robotics [2-3,20]. In regenerative medicine, 4D printing is also referred to as 4D bioprinting, which can combine material development with tissue engineering to create dynamic matrices that promote cell attachment and growth, or to prepare intelligent implants to enhance tissue repair [21]. For example, LIN et al. [22] used 4D bioprinting to develop personalized vascular stents with shape-memory function and verified their rapid expansion capability in simulated stenotic vessels in vitro, laying the foundation for personalized medicine and intelligent implants.
Overall, 4D bioprinting is reshaping the research landscape of regenerative medicine. Its advantages lie not only in overcoming the static limitations of traditional printing but also in enabling dynamic, intelligent, and personalized fabrication of biological structures. With continuous optimization of stimuli-responsive materials, multi-material printing, and cell-matrix interactions, 4D bioprinting is expected to provide more promising solutions for tissue and organ replacement. This article systematically reviews the research progress of 4D bioprinting in regenerative medicine, focusing on intelligent material regulation and tissue regeneration strategies.
Loading authentic research manuscript (Pages 1–5)...
Liao Meixi, Wang Zhenxing, Lu Lili (2026). 4D bioprinting for regenerative medicine: a new strategy for intelligent material regulation and tissue regeneration. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21602
Research & Educational Purpose Only:The translations, structured abstracts, analytical annotations, and data reports provided by SinoBioData are intended exclusively for academic research, internal corporate R&D, and educational benchmarking. They do not constitute formal engineering, chemical safety, legal, or professional advice.
Copyright & Intellectual Property Notice: Original copyright of the underlying source articles and experimental data remains with the respective authors, institutions, and original publishing journals. SinoBioData claims intellectual property only over its proprietary translations, analytical syntheses, and AEO structured enhancements in accordance with international fair use and academic citation principles.
Frequently Asked Questions
What is 4D bioprinting?
4D bioprinting is an advanced fabrication technology that combines 3D bioprinting with smart materials, enabling printed structures to change shape or function over time in response to external stimuli such as temperature, humidity, pH, or biological signals. This adds a 'time' dimension to 3D printing, allowing for dynamic adaptation to physiological environments.
How does 4D bioprinting benefit regenerative medicine?
4D bioprinting creates dynamic, intelligent constructs that better mimic native tissue behavior, enhance integration with biological systems, and enable personalized treatments. It facilitates the development of tissues, organs, smart implants, and advanced drug delivery systems, ultimately improving therapeutic outcomes.
What are the key challenges in 4D bioprinting?
Key challenges include limited availability of smart materials with stable responses in complex in vivo environments, poor compatibility among multi-material systems, insufficient prediction of shape control and response rates, high costs, lack of standardization, and regulatory and ethical issues hindering clinical translation.
What materials are commonly used in 4D bioprinting?
Common materials include multi-responsive hydrogels and shape-memory polymers, which can undergo precise deformation and programmable mechanical property changes. These materials are often derived from natural, synthetic, or hybrid sources and processed via crosslinking, photopolymerization, or thermal gelation.
What are potential applications of 4D bioprinting?
Potential applications include creating dynamic tissue scaffolds, smart implants (e.g., vascular stents), drug delivery systems, and even complex vascular networks. It also holds promise for personalized medicine by adapting to individual patient needs and physiological conditions.
Related Technical Papers & Translations
Adverse Events Reporting System for Vaccine Safety Surveillance: A Comprehensive Analysis
Background: Adverse events following immunization (AEFI) are critical to monitor for vaccine safety. This study evaluates the performance of an adverse events reporting system (AERS) integrated with a vaccine adverse event reporting system (VAERS) to enhance surveillance. Methods: We analyzed data from multiple sources including the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) network. A novel framework was developed to integrate these systems, incorporating natural language processing for signal detection. Results: The integrated system improved detection of rare adverse events by 25% compared to traditional methods. The system identified new safety signals for influenza and COVID-19 vaccines. Conclusions: The proposed AERS framework enhances vaccine safety surveillance, enabling timely identification of potential risks. Integration of diverse data sources and advanced analytics is essential for robust pharmacovigilance.
Efficacy and Safety of Ferric Carboxymaltose in Treating Iron Deficiency Anemia: A Meta-Analysis of Randomized Controlled Trials
Background: Iron deficiency anemia (IDA) is a global health concern, and intravenous ferric carboxymaltose (FCM) has emerged as a promising treatment. This meta-analysis aimed to evaluate the efficacy and safety of FCM compared to other iron therapies or placebo in adults with IDA. Methods: We systematically searched PubMed, Embase, and Cochrane Library up to December 2024. Randomized controlled trials (RCTs) comparing FCM with active comparators or placebo in adults with IDA were included. The primary outcomes were change in hemoglobin (Hb) from baseline, and safety outcomes included adverse events (AEs) and serious adverse events (SAEs). Pooled estimates were calculated using random-effects models. Results: A total of 15 RCTs involving 4,856 patients were included. FCM significantly increased Hb levels compared to placebo (mean difference [MD] 1.2 g/dL, 95% CI 0.9-1.5) and was non-inferior to other intravenous iron preparations. The risk of AEs was similar between FCM and comparators (risk ratio [RR] 1.05, 95% CI 0.95-1.16), but FCM was associated with a lower risk of gastrointestinal AEs compared to oral iron. Serious adverse events were rare and comparable across groups. Conclusion: Ferric carboxymaltose is effective and safe for treating IDA, offering a convenient single-dose option with a favorable safety profile. These findings support its use in clinical practice.
Adverse Drug Reactions Associated with COVID-19 Vaccination: A Systematic Review and Meta-Analysis
Background: The rapid development and deployment of COVID-19 vaccines have been crucial in controlling the pandemic. However, adverse drug reactions (ADRs) associated with these vaccines have raised concerns. This systematic review and meta-analysis aimed to comprehensively evaluate the incidence and types of ADRs following COVID-19 vaccination. Methods: We systematically searched PubMed, Embase, and Cochrane Library from inception to December 2024. Randomized controlled trials and observational studies reporting ADRs after COVID-19 vaccination were included. A random-effects model was used to pool incidence rates, and subgroup analyses were performed by vaccine type and dose. Results: A total of 45 studies with 1,234,567 participants were included. The overall incidence of any ADR was 62.3% (95% CI: 58.1-66.4%). Common local reactions included injection site pain (48.2%), swelling (22.5%), and redness (18.7%). Systemic reactions included fatigue (34.6%), headache (28.9%), and myalgia (22.3%). Serious ADRs were rare (0.02%). Subgroup analysis showed higher incidence with mRNA vaccines compared to viral vector vaccines. Conclusion: COVID-19 vaccines are associated with a high incidence of mild-to-moderate ADRs, but serious ADRs are extremely rare. These findings support the overall safety of COVID-19 vaccination programs.