3D printing biomimetic periosteum: from structural substitution to functional integration

doi:10.3969/j.issn.1674-8115.2026.09.002

Abstract

Abstract:

The periosteum, as the central regulatory barrier for bone regeneration, directs bone repair by supplying osteogenic progenitor cells and diverse bioactive factors; its functional loss is a key reason for the failure of bone defect repair. Conventional periosteal reconstruction methods are markedly limited in clinical practice because they cannot precisely recapitulate the periosteum′s refined hierarchical architecture and multifaceted biological functions. Leveraging its unique strengths in patient-specific high-fidelity shaping, tightly controlled multiscale microarchitectures, and spatiotemporally ordered delivery of bioactive components, 3D printing offers a transformative solution for constructing biomimetic periosteum. Both mainstream clinical bone repair therapies and traditional periosteum fabrication techniques have inherent drawbacks and fail to address the clinical challenge of large bone defect repair effectively. With the advancement of precision regenerative medicine, the developmental philosophy of biomimetic periosteum has shifted from simple structural substitution based on simple defect filling to a new stage of functional integration, characterized by multidimensional physiological simulation and dynamic modulation of the repair microenvironment. This review systematically outlines the periosteum′s core biological functions and clinical needs, focuses on key construction strategies and multi-technology integration pathways for 3D-printed biomimetic periosteum, provides an in-depth analysis of current technical bottlenecks, and envisions an artificial intelligence-driven shift of periosteal reconstruction toward a paradigm of personalized, precision repair. The goal is to provide a theoretical basis and practical reference for the clinical translation of therapies for large bone defects and the development of precision medicine.

Key words: biomimetic periosteum, osseous reconstruction, 3D printing technology, 4D bioprinting, multi-technology integration

CLC Number:

R684.3

Yu Meixuan, Sun Lin, Fu Jingke, Hao Yongqiang, Dai Kerong. 3D printing biomimetic periosteum: from structural substitution to functional integration[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(9): 1169-1178.

Figures/Tables 3

TrendMD

References 58

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Manufacturing	Model	Biomaterial in bioinks	OFC in bioinks	Main effect	Reference
EBP	Rat cranial defect	Fibrous layer: SFHGMA, SA Formation layer: SFP, SA, MCol	Mg²⁺	Simulation of natural periosteal double-layer structure; promotion of cell proliferation and differentiation, angiogenesis, and PC12 cell growth	[29]
EBP	Regeneration of critical-sized bone defects in long bones	GelMA	G-MBGN, VEGF-loaded liposomes	Simulation of periosteum, endosteum, and intermediate bone matrix; significant promotion of angiogenesis	[39]
EBP	Critical-sized bone defect	Formation layer: GelMA, GelMA-H-nHA Fibrous layer: P(ACG-GelMA-L)-Mg²⁺	Ca²⁺, Mg²⁺, nHA	Simulation of natural periosteal double-layer structure, with Mg²⁺-mediated immunomodulation and angiogenesis	[30]
EBP	Bone defect	PLLA/HA, GelMA	rabBMSCs, rabPDSCs	Excellent cell encapsulation and bioactivity; co-culture of BMSCs and PDSCs	[31]
EBP	Bone defect	GelMA, SilMA, GelDA	GO nanosheets, BMSCs	Excellent thermosensitivity and printability; high cell viability and adhesion	[40]
MEW	Critical-sized segmental rat femoral defect	MEW core: PCL FDM Shell: PCL Coating: nnHA	BMP2	High rigidity, structural integrity, sustained BMP2 release, and significant angiogenesis enhancement	[32]
MEW	Large bone defect	PCL membrane, PCL sheet	rhBMP-2, PLGA-PEG-COOH microparticles	Controlled rhBMP-2 release and significant enhancement of in vivo bone regeneration	[35]
SLA	Bone defect	Fibrous layer: PEGDA, TCP Formation layer: GelMA, PEGDA	Mo, Chitosan	Fibrous layer resistance to muscle traction and soft tissue invasion; promotion of osteogenic differentiation by the formation layer	[33]

Manufacturing	Model	Biomaterial in bioinks	OFC in bioinks	Main effect	Reference
EBP	Rat cranial defect	Fibrous layer: SFHGMA, SA Formation layer: SFP, SA, MCol	Mg²⁺	Simulation of natural periosteal double-layer structure; promotion of cell proliferation and differentiation, angiogenesis, and PC12 cell growth	[29]
EBP	Regeneration of critical-sized bone defects in long bones	GelMA	G-MBGN, VEGF-loaded liposomes	Simulation of periosteum, endosteum, and intermediate bone matrix; significant promotion of angiogenesis	[39]
EBP	Critical-sized bone defect	Formation layer: GelMA, GelMA-H-nHA Fibrous layer: P(ACG-GelMA-L)-Mg²⁺	Ca²⁺, Mg²⁺, nHA	Simulation of natural periosteal double-layer structure, with Mg²⁺-mediated immunomodulation and angiogenesis	[30]
EBP	Bone defect	PLLA/HA, GelMA	rabBMSCs, rabPDSCs	Excellent cell encapsulation and bioactivity; co-culture of BMSCs and PDSCs	[31]
EBP	Bone defect	GelMA, SilMA, GelDA	GO nanosheets, BMSCs	Excellent thermosensitivity and printability; high cell viability and adhesion	[40]
MEW	Critical-sized segmental rat femoral defect	MEW core: PCL FDM Shell: PCL Coating: nnHA	BMP2	High rigidity, structural integrity, sustained BMP2 release, and significant angiogenesis enhancement	[32]
MEW	Large bone defect	PCL membrane, PCL sheet	rhBMP-2, PLGA-PEG-COOH microparticles	Controlled rhBMP-2 release and significant enhancement of in vivo bone regeneration	[35]
SLA	Bone defect	Fibrous layer: PEGDA, TCP Formation layer: GelMA, PEGDA	Mo, Chitosan	Fibrous layer resistance to muscle traction and soft tissue invasion; promotion of osteogenic differentiation by the formation layer	[33]

Multi-technology integration	Biomaterial in ink	Bioactive substance in ink	Highlight	Reference
Electrospinning+3D printing	Electrospun collagen-dense scaffold, IMCS	BMSCs	Upper-layer blockade of fibrous tissue invasion; lower-layer promotion of BMSC osteogenic differentiation	[49]
IMT+3D printing	mPCL-TCP	ABG, rhBMP-2, Cerament G^®, Cerament V^®	Excellent clinical adaptability, superior surgical manoeuvrability, and enhanced angiogenesis and osteogenesis	[50]
IMT+3D printing	PLA scaffold, dECM	Bone marrow cells, BMP-2	High-dose, sustained release of BMP-2; reduced fibrosis and macrophage infiltration; optimized BMP-2 loading capacity	[51]

Multi-technology integration	Biomaterial in ink	Bioactive substance in ink	Highlight	Reference
Electrospinning+3D printing	Electrospun collagen-dense scaffold, IMCS	BMSCs	Upper-layer blockade of fibrous tissue invasion; lower-layer promotion of BMSC osteogenic differentiation	[49]
IMT+3D printing	mPCL-TCP	ABG, rhBMP-2, Cerament G^®, Cerament V^®	Excellent clinical adaptability, superior surgical manoeuvrability, and enhanced angiogenesis and osteogenesis	[50]
IMT+3D printing	PLA scaffold, dECM	Bone marrow cells, BMP-2	High-dose, sustained release of BMP-2; reduced fibrosis and macrophage infiltration; optimized BMP-2 loading capacity	[51]