Advanced Stem Cell Therapy: 3D‐Bioprinted Brain‐Like Transplants for Alzheimer's Disease‐Like Dementia

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder that lacks effective treatments and urgently requires innovative therapeutic strategies. Although stem cell therapy has demonstrated efficacy in preclinical and clinical studies, it faces challenges such as low cell survival (<5%) and uncontrolled glial differentiation. This study aims to develop a 3D‐bioprinted neural patch to enhance stem cell therapy for AD. The hypothesis is that a supportive bioengineered microenvironment would improve cell integration and neuronal differentiation, leading to functional recovery. A tri‐component bioink (gelatin/alginate/fibrinogen) is created with tunable printability, biocompatibility, and biodegradation, establishing functional transplantation microenvironments for a 3D‐printed human induced pluripotent stem cell (hiPSC)‐derived neural progenitor cell (NPC) construct as a hippocampal patch. The system (TTBT) maintains NPC survival and promotes neuronal differentiation, neurite development, and calcium signaling in vitro. In AD‐like rats, these constructs improved cell retention (3.41‐fold over suspensions), enhanced neuron (79.21 ± 6.67% vs 65.08 ± 7.14%) and GABAergic neuron (29.85 ± 7.69% vs 15.93 ± 10.33%) differentiation, and restored long‐term potentiation (LTP) to 97.89% ± 19.84% of healthy control levels. Behavioral tests also show memory improvement, particularly in the Morris water maze. This 3D‐printed therapy not only holds potential for enhancing stem cell treatments but also addresses other 3D brain defects.