Smart Biomaterials for Bone Regeneration: From Microenvironmental Modulation to Personalized Therapy

Summary

This review summarizes smart biomaterial strategies for bone regeneration, focusing on microenvironmental modulation, stimulus responsiveness, immunoengineering, 3D/4D printing, artificial intelligence-assisted design, and translational challenges in personalized bone repair.

Abstract

The rapid evolution of smart biomaterials has opened new therapeutic avenues for complex bone defects, non-union fractures, and post-tumor resection reconstruction. Conventional bone substitutes often suffer from insufficient bioactivity, mechanical mismatch, and a lack of capacity to modulate the healing microenvironment. In contrast, smart biomaterials can dynamically adjust their physicochemical properties in response to external stimuli (light, electricity, magnetic fields, or mechanical forces) or internal cues (ROS, pH, or enzyme activity), enabling precise control over cellular behaviors and local microenvironmental dynamics. Recent advances in immuno-engineered materials, particularly those designed to polarize macrophages toward a pro-regenerative M2 phenotype, have shown promise in attenuating inflammation and accelerating osteogenesis. Concurrently, 3D/4D printing technologies enable programmable control of scaffold architecture, degradation profiles, and the spatial distribution of bioactive factors, thereby supporting personalized therapeutic strategies. Artificial-intelligence-driven material discovery and structural optimization further expand the design space for next-generation, high-performance bone repair biomaterials. This review provides a comprehensive synthesis of recent progress in smart biomaterials for bone regeneration, with emphasis on stimulus-responsive mechanisms, immune-modulatory strategies, advanced manufacturing technologies, and AI-enabled design, and highlights the key barriers and future directions for their clinical translation. In this review, smart biomaterial is used as an umbrella term; stimulus-responsive biomaterial denotes the subclass that responds to an external trigger (light, magnetic, electrical, mechanical, pH, ROS, or enzyme); and intelligent biomaterial is treated as synonymous with smart biomaterial. These terms are not used interchangeably.

Introduction

Large bone defects, fracture non-unions, and post-tumor resection reconstruction remain among the most formidable challenges in orthopedics, imposing substantial morbidity and disability worldwide^1,2. Although traditional therapeutic approaches—including autografts, allografts, metal implants, and conventional bioceramics—have improved clinical outcomes to some extent, they are still constrained by donor-site scarcity, immune rejection, infection risk, insufficient bioactivity, and limited capacity to modulate the complex regenerative microenvironment^3,