What question did this study set out to answer?

This review aims to address the challenges of regenerating the tendon-bone interface (TBI) under chronic degenerative conditions.

May 25, 2026Open Access

Immunoengineering in the field of tendon and bone regeneration: immunomodulatory biomaterials, delivery platforms, and preclinical models for chronic diseases

Puntos clave

This review aims to address the challenges of regenerating the tendon-bone interface (TBI) under chronic degenerative conditions.
Systematic review of bone immunoengineering approaches
Analysis of regulatory networks and macrophage polarization dynamics
Overview of innovative biophysical and chemical intervention strategies, including piezoelectric nanohydrogels and microfluidic systems.
Identified core regulatory networks crucial for TBI regeneration
Showed potential of piezoelectric nanohydrogels in improving the regenerative microenvironment
Highlighted importance of advanced preclinical evaluation systems in bridges to clinical applications.

Resumen

The functional and structural reconstruction of the tendon-bone interface (TBI) is a major challenge in orthopedics and sports medicine. Under the influence of chronic degenerative pathologies such as aging, diabetes, and rheumatoid arthritis, the cascading collapse of the local immune-metabolic network disrupts the regenerative microenvironment of the tissue, making the clinical translation of traditional inert physical scaffolds extremely difficult. This review systematically summarizes the latest paradigm shifts in “bone immunoengineering” aimed at overcoming the complex challenges of TBI regeneration. We first decode the core regulatory networks that control interface heterogeneity remodeling, thoroughly analyzing the spatiotemporal polarization dynamics of macrophages, the double-edged effects of the Piezo1-YAP mechanotransduction axis, and the “neuro-immune-skeletal” ternary communication mechanism. Based on this pathological framework, we comprehensively overview next-generation intelligent biophysical and chemical intervention strategies for actively reprogramming extreme microenvironments. These strategies include piezoelectric nanohydrogels for electromechanical-metabolic coupling, Janus asymmetric microfluidic interfaces for multi-ion spatiotemporal rectification, and precise spatial delivery platforms for targeted clearance of senescent cells and engineered exosomes. Furthermore, to overcome the translational barriers between underlying mechanisms and clinical applications, we focus on the cross-scale evolution of preclinical evaluation systems, elaborating on the core value of three-dimensional tendon-bone organoids, microfluidic organ-on-chip systems, and high-resolution spatial transcriptomics. Finally, this review envisions advanced microphysiological systems characterized by closed-loop dynamic adaptive biomaterials, spatiotemporal matching of degradation kinetics, and deep integration with artificial intelligence (AI), highlighting their broad prospects in driving the next-generation of personalized, precise regenerative medicine in orthopedics.

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