Extracellular matrix-inspired 4D SMART biomaterials for bioprinting in tissue engineering

Abstract

Tissue development and regeneration arise from a dynamic interplay among cells, the extracellular matrix (ECM), and surrounding biophysical and biochemical cues. These interactions form the basis for stimuli-responsive materials for advanced regenerative technologies (SMART) that drive innovation in four-dimensional (4D) bioprinting for tissue engineering. This review discusses the biophysical foundations of SMART materials, emphasizing native ECM components, their interactions, and organ-specific properties that inform biomimetic material design. We highlight recent advances in 4D SMART systems, including ionic self-healing, pH-, thermal-, hydration-, and magneto-responsive materials, and their roles in mimicking developmental and regenerative processes. This is followed by a comparative overview of these stimuli-responsive material classes, benchmarked against one another, native ECM performance, and clinical translation requirements, revealing persistent gaps in long-term stability, multi-stimuli integration, and regulatory feasibility. Together, these insights provide an interdisciplinary framework for designing adaptive, responsive biomaterials that guide tissue morphogenesis and advance the future of regenerative medicine.

Keywords

Biomaterials / Extracellular matrix / Four-dimensional bioprinting / Four-dimensional tissue engineering / Regenerative medicine / Stimuli-responsive materials

Funding

This research was supported by the Commonwealth Health Research Board (236-08-21); the National Institutes of Health, under the National Institute of General Medical Sciences grant (P20GM113126); the American Cancer Society (IRG-22-146-07-IRG); National Institutes of Health, under the National Cancer Institute grant (CA036727), the Nexus of Virology, Immunology, and Bioengineering; the Nebraska Tobacco Settlement Biomedical Research Development Funds; the “Regional Innovation System & Education (RISE)” program, through the Gwangju RISE Center, funded by the Ministry of Education and the Gwangju Metropolitan Government, Republic of Korea (2025-RISE-05-011).

Conflict of Interest

Fanben Meng and Daeha Joung serve as the guest editors of this Special Issue, but did not in any way involve in the editorial and peer-review process conducted for this paper, directly or indirectly. Other authors declare they have no competing interests.

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