3D-printed scaffold-based strategies for enthesis regeneration: a systematic review of the literature

Abstract

Background The enthesis is a specialized transitional tissue that enables load transfer between tendon and bone through a graded tendon–fibrocartilage–bone interface. Following injury or surgical repair, regeneration of the native enthesis remains challenging, often resulting in mechanically inferior fibrous scar tissue. Additively manufactured three-dimensional (3D) scaffolds have emerged as a promising strategy to recreate the structural and biological complexity of the tendon–bone interface. This systematic review evaluated the current preclinical evidence on 3D scaffold-based approaches for enthesis regeneration. Methods This systematic review was conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420261388606). PubMed, Embase, and Web of Science were searched from inception to 13 February 2026. Original preclinical studies investigating additively manufactured 3D scaffold-based strategies for tendon–bone interface or enthesis regeneration were included. Data regarding scaffold design, biological augmentation, and in vitro, in vivo, and biomechanical outcomes were qualitatively synthesized. Methodological quality was assessed using SYRCLE’s Risk of Bias tool. Results Nine preclinical animal studies published between 2019 and 2025 met the inclusion criteria. Most studies used rabbit rotator cuff repair models. Polymer-based scaffolds, particularly polycaprolactone and poly (lactic-co-glycolic acid), were the most frequently used materials. Advanced architectures included gradient, multiphasic, bioprinted, and coaxial constructs, often combined with mesenchymal stem cells, growth factors, or controlled-release systems. Across studies, scaffold-based strategies consistently promoted enhanced lineage-specific differentiation, fibrocartilage formation, collagen organization, and interface maturation compared with controls. Biomechanical testing demonstrated improved ultimate load, stiffness, tensile strength, or energy absorption in all experimental groups. Constructs combining biomimetic architecture with biological augmentation generally achieved good outcomes, although regenerated interfaces remained inferior to native tissue. Risk-of-bias assessment showed overall unclear methodological quality due to insufficient reporting. Conclusion Additively manufactured 3D scaffold-based strategies show promise for improving enthesis regeneration in preclinical models. Constructs integrating spatially organized architecture with controlled biological signaling demonstrated the most favorable structural and biomechanical outcomes. However, current evidence is limited to heterogeneous short-term animal studies, and complete restoration of native enthesis structure and function has not yet been achieved.