Spheroid-Hydrogel-Integrated Biomimetic System: A New Frontier in Advanced Three-Dimensional Cell Culture Technology

Abstract

Background: Despite significant advances in three-dimensional (3D) cell culture technologies, creating accurate in vitro models that faithfully recapitulate complex in vivo environments remains a major challenge in biomedical research. Traditional culture methods often fail to simultaneously facilitate critical cell-cell and cell-extracellular matrix (ECM) interactions while providing control over mechanical and biochemical properties.

Summary: This review introduces the spheroid-hydrogel-integrated biomimetic system (SHIBS), a groundbreaking approach that synergistically combines spheroid culture with tailored hydrogel technologies. SHIBS uniquely bridges the gap between traditional culture methods and physiological conditions by offering unprecedented control over both cellular interactions and environmental properties. We explore how SHIBS is revolutionizing fields ranging from drug discovery and disease modeling to regenerative medicine and basic biological research. The review discusses current challenges in SHIBS technology, including reproducibility, scalability, and high-resolution imaging, and outlines ongoing research addressing these issues. Furthermore, we envision the future evolution of SHIBS into more sophisticated organoid-hydrogel-integrated biomimetic systems and its integration with cutting-edge technologies such as microfluidics, 3D bioprinting, and artificial intelligence.

Key messages: SHIBS represents a paradigm shift in 3D cell culture technology, offering a unique solution to recreate complex in vivo environments. Its potential to accelerate the development of personalized therapies across various biomedical fields is significant. While challenges persist, the ongoing advancements in SHIBS technology promise to overcome current limitations, paving the way for more accurate and reliable in vitro models. The future integration of SHIBS with emerging technologies may revolutionize biomimetic modeling, potentially reducing the need for animal testing and expediting drug discovery processes. This comprehensive review provides researchers and clinicians with a holistic understanding of SHIBS technology, its current capabilities, and its future prospects in advancing biomedical research and therapeutic innovations.

Background: Despite significant advances in three-dimensional (3D) cell culture technologies, creating accurate in vitro models that faithfully recapitulate complex in vivo environments remains a major challenge in biomedical research. Traditional culture methods often fail to simultaneously facilitate critical cell-cell and cell-extracellular matrix (ECM) interactions while providing control over mechanical and biochemical properties.

Summary: This review introduces the spheroid-hydrogel-integrated biomimetic system (SHIBS), a groundbreaking approach that synergistically combines spheroid culture with tailored hydrogel technologies. SHIBS uniquely bridges the gap between traditional culture methods and physiological conditions by offering unprecedented control over both cellular interactions and environmental properties. We explore how SHIBS is revolutionizing fields ranging from drug discovery and disease modeling to regenerative medicine and basic biological research. The review discusses current challenges in SHIBS technology, including reproducibility, scalability, and high-resolution imaging, and outlines ongoing research addressing these issues. Furthermore, we envision the future evolution of SHIBS into more sophisticated organoid-hydrogel-integrated biomimetic systems and its integration with cutting-edge technologies such as microfluidics, 3D bioprinting, and artificial intelligence.

Key messages: SHIBS represents a paradigm shift in 3D cell culture technology, offering a unique solution to recreate complex in vivo environments. Its potential to accelerate the development of personalized therapies across various biomedical fields is significant. While challenges persist, the ongoing advancements in SHIBS technology promise to overcome current limitations, paving the way for more accurate and reliable in vitro models. The future integration of SHIBS with emerging technologies may revolutionize biomimetic modeling, potentially reducing the need for animal testing and expediting drug discovery processes. This comprehensive review provides researchers and clinicians with a holistic understanding of SHIBS technology, its current capabilities, and its future prospects in advancing biomedical research and therapeutic innovations.

Keywords: Biomimetic systems; Drug screening; Spheroid-hydrogel interaction; Three-dimensional cell culture; Tissue engineering.

Fig. 1.

Conceptual overview of SHIBS. a Cell spheroid embedded in a hydrogel matrix, showcasing key cell-cell and cell-ECM interactions. b Diverse interactions within SHIBS, including spheroid-spheroid, spheroid-ECM, and multi-cellular spheroid interactions. c Preserved high-density cell-cell interactions with nutrient and waste exchange. The gradient from low to high mechanical properties illustrates the system’s ability to mimic various tissue types, from soft to stiff tissues.

Fig. 2.

Applications of SHIBS in diverse areas of biomedical research. This figure illustrates how SHIBS technology integrates and advances four key areas of biomedical research. Drug discovery and toxicology benefit from more physiologically relevant models, which in turn inform disease modeling approaches. These disease models provide insights that drive regenerative medicine strategies, while all of these applications contribute to and are supported by advances in basic biological research. Together, these interrelated fields demonstrate the versatility of SHIBS in bridging the gap between in vitro and in vivo studies, potentially accelerating therapeutic development and deepening our understanding of complex biological systems.

Fig. 3.

Future directions and integration of SHIBS with emerging technologies. This figure illustrates the projected evolution of SHIBS technology from its current state to the long-term vision. It shows how SHIBS is expected to integrate with advanced technologies such as microfluidics and 3D bioprinting, ultimately evolving into OHIBS. This evolution highlights the potential of SHIBS to create increasingly complex and physiologically relevant models, bridging the gap between in vitro and in vivo research and enabling applications in personalized medicine. OHIBS, organoid-hydrogel-integrated biomimetic system.