Alzheimer's disease (AD), a severe neurodegenerative disorder, has long lacked effective curative treatments, imposing a heavy burden on patients and their families.
On November 13, 2025, the Lin Feng-Song Yu team from Tsinghua University published groundbreaking research in Advanced Science, proposing a 3D-bioprinting-based neural stem cell transplantation therapy. This approach successfully restored cognitive function in animal models, opening a new pathway for treating this disease.
Core Challenge: The Bottleneck of Traditional Stem Cell Therapies
Stem cell therapy was once highly anticipated for its potential in neuronal regeneration but faces multiple challenges in clinical application. Studies indicate that traditional stem cell transplantation suffers from issues such as less than 5% cell survival rate, uncontrolled differentiation direction, and difficulty in repairing structural defects in the brain. Furthermore, the pathological microenvironment in the brains of Alzheimer's patients—including abnormal mechanical properties, protein aggregation, and chronic neuroinflammation—further hinders the survival and functional integration of transplanted cells.
While existing 3D brain organoid technologies can provide complex neural structures, they have limitations like uneven cell distribution and difficulties in mass production, making it hard to meet clinical demands. Bioprinting technology, with its advantages of controllability and reproducibility, has become a key breakthrough to address these problems.
Innovative Solution: Design of a 3D-Bioprinted Neural Patch
The research team developed a 3D bioprinting transplantation system named TTBT. Its core is a neural progenitor cell (NPC) construct specifically customized for the pathological features of Alzheimer's disease. The design highlights are reflected in three aspects:
Customized Bioink: A gelatin/alginate/fibrinogen ternary composite system was used. By optimizing the concentration ratio, the material achieves good printability, biocompatibility, and degradation characteristics. Its mechanical properties (1-4 kPa compressive elastic modulus) closely match those of brain tissue, providing a biomimetic microenvironment for stem cells.
Precise Structural Design: Based on the morphology of the rat hippocampus, a flat-bottomed, dot-like structure with a diameter of 1 mm was designed. This maximizes the contact area between the transplant and the host brain tissue while minimizing surgical damage. Spiral path printing ensures structural consistency and implantation feasibility.
Seed Cell Optimization: Human induced pluripotent stem cell-derived neural progenitor cells were selected. After concentration optimization (6.67×10⁶ cells·mL⁻¹), this ensures both cell survival and the rapid formation of mature neural networks.
Experimental Validation: Significant Multi-Dimensional Efficacy
The research team systematically compared the therapeutic effects of transplanting the 3D-bioprinted constructs versus traditional cell suspension injections in an aluminum chloride-induced Alzheimer's disease-like rat model. The results showed:
Advantages in Cell Retention and Differentiation: The cell retention rate in the printed construct group was 3.41 times higher than in the cell suspension group. The neuronal differentiation rate reached 79.21% (significantly higher than 65.08% in the control group), with the GABAergic neuron differentiation rate nearly doubling (29.85% vs. 15.93%). Simultaneously, astrocyte differentiation was suppressed, reducing the risk of glial scar formation.
Neural Function Repair: After transplantation, the integrity of the hippocampal neural network was restored in the model rats, and the expression levels of synapse-related proteins (SYP, PSD-95) approached those of the healthy control group. Long-term potentiation (LTP) function recovered to 97.89% of the healthy level, compared to only 86.99% in the cell suspension group.
Cognitive Behavioral Improvement: The Morris water maze test showed that rats receiving the printed construct transplants had significantly improved spatial learning and memory abilities, employed more efficient search strategies, and performed similarly to healthy rats. Furthermore, levels of neuroinflammatory factors (TNF-α, IL-1β, IL-6) were significantly reduced, and tau protein pathology was alleviated.
Prospects and Outlook
This research, through the deep integration of materials engineering, structural design, and stem cell technology, demonstrates for the first time that 3D-bioprinted neural constructs can multi-dimensionally improve Alzheimer's disease-like pathological features, providing an effective solution to the core bottlenecks of traditional stem cell therapy. The research team stated that this technology is not only applicable to Alzheimer's disease but can also be extended to other brain disorders such as traumatic brain injury.
Currently, the study still has some limitations, such as the animal model not fully replicating the human chronic disease course and the need to scale the constructs for the human brain. Future work will involve optimizing the construct scale through large animal experiments and exploring the integration mechanisms between the transplant and the host neural circuitry to advance the technology toward clinical translation.
The research findings, titled "Advanced Stem Cell Therapy: 3D-Bioprinted Brain-Like Transplants for Alzheimer's Disease-Like Dementia," were published in the November 2025 issue of Advanced Science. The first author of the paper is Ph.D. student Gai Ke from the Department of Mechanical Engineering, and the corresponding authors are Assistant Researcher Song Yu and Professor Lin Feng from the same department. The research was supported by the National Natural Science Foundation of China and the National Key Research and Development Program of China.
