TPMS-Gyroid Scaffold-Mediated Up-Regulation of ITGB1 for Enhanced Cell Adhesion and Immune-Modulatory Osteogenesis

Jing Wang, Zenan Huang, Zhenzhong Han, Jing Luan, Zihan Li, Xutong Guo, Dongxu Yang, Yazhou Cui, Jinxiang Han, Duo Xu

Full text link: https://pubmed.ncbi.nlm.nih.gov/39853929/ 

TPMS-Gyroid Scaffold-Mediated Up-Regulation of ITGB1 for Enhanced Cell Adhesion and Immune-Modulatory Osteogenesis

1. Scientific Reference

• Study Title: TPMS-Gyroid Scaffold-Mediated Up-Regulation of ITGB1 for Enhanced Cell Adhesion and Immune-Modulatory Osteogenesis
• Authors: Jing Wang, Zenan Huang, Zhenzhong Han, Jing Luan, Zihan Li, Xutong Guo, Dongxu Yang, Yazhou Cui, Jinxiang Han, Duo Xu
• Journal: Advanced Healthcare Materials
• Year of Publication: 2025
• DOI: 10.1002/adhm.202404768

2. Scientific Background

The development of advanced porous biomaterials remains a major focus in bone tissue engineering and regenerative medicine. One of the key challenges in skeletal reconstruction is achieving rapid and durable osseointegration while maintaining mechanical compatibility with surrounding bone tissue. Conventional solid implants may create stiffness mismatches that contribute to stress shielding and compromise long-term biological performance.

Triply Periodic Minimal Surface (TPMS) architectures, particularly Gyroid structures, have attracted considerable attention because of their interconnected porous networks, high surface area, and favorable load distribution characteristics. These features make them attractive candidates for orthopedic and craniofacial reconstruction applications, including future implant design.

Although numerous studies have investigated the effects of porosity on scaffold performance, the biological implications of unit cell size have received comparatively less attention. Understanding how subtle geometric modifications influence cellular behavior, immune responses, and bone regeneration could provide valuable insights for the design of next-generation additively manufactured implants.

3. Study Objective

The primary objective of this study was to investigate how different unit cell sizes within TPMS-Gyroid titanium scaffolds influence mechanical performance, cellular responses, immune modulation, and osseointegration.

The authors specifically sought to determine whether scaffold geometry could regulate Integrin β1 (ITGB1) expression and thereby influence cell adhesion, macrophage polarization, osteogenic differentiation, angiogenesis, and bone regeneration.

4. Methodology

This was a preclinical study combining in vitro and in vivo investigations. Four TPMS-Gyroid titanium scaffolds were manufactured using Selective Laser Melting (SLM), with a fixed porosity of 70% and unit cell sizes of 1.5 mm (TG15), 2 mm (TG20), 2.5 mm (TG25), and 3 mm (TG30).

The researchers evaluated:

• Mechanical properties, including elastic modulus and compressive strength.
• Human bone marrow mesenchymal stem cell (hBMSC) adhesion and proliferation.
• Osteogenic differentiation.
• Macrophage behavior and polarization.
• Angiogenic activity.
• Bone regeneration in an animal model.

Experimental analyses included scanning electron microscopy (SEM), RT-qPCR, immunofluorescence staining, Western blotting, ELISA assays, micro-computed tomography (micro-CT), and histological assessments.

The exact number of animals included in the study is not specified in the provided excerpts.

5. Main Results

Mechanical testing demonstrated that TG15 and TG20 exhibited the highest compressive strength, whereas increasing unit cell size was associated with a progressive reduction in mechanical resistance.

Among all groups, TG20 consistently demonstrated the most favorable biological performance. Human mesenchymal stem cells cultured on TG20 displayed enhanced spreading morphology, increased focal adhesion formation, and higher expression of adhesion-related genes, including ITGB1, PTK2, and VCL.

Improved cellular attachment was accompanied by increased proliferation and stronger osteogenic differentiation. Markers associated with bone formation, including RUNX2, OCN, and BSP, were expressed at higher levels in the TG20 group.

Macrophages cultured on TG20 also exhibited elevated ITGB1 expression and preferential polarization toward the anti-inflammatory M2 phenotype. This was associated with increased expression of regenerative cytokines and reduced inflammatory signaling.

In vivo analyses confirmed superior bone ingrowth and osseointegration around TG20 implants. Micro-CT and histological examinations demonstrated greater new bone formation and improved scaffold-bone contact compared with the other scaffold configurations.

6. Clinical Analysis

One of the most important contributions of this study is its demonstration that scaffold architecture influences biological performance beyond simple porosity considerations. The findings suggest that unit cell size can directly affect how cells perceive and interact with implant surfaces.

The proposed mechanism centers on the regulation of ITGB1 expression. Increased ITGB1 activity appears to enhance cellular adhesion while simultaneously influencing macrophage behavior. This dual effect is particularly relevant because successful bone regeneration depends not only on osteogenic cells but also on the early immune response occurring at the implant interface.

The concept of osteoimmunomodulation has gained increasing interest in regenerative medicine. Rather than viewing inflammation solely as a challenge to be controlled, researchers are exploring ways to guide immune responses toward regenerative pathways. In this study, the TG20 architecture appeared to favor M2 macrophage polarization, creating a microenvironment that supported both osteogenesis and angiogenesis.

From a translational perspective, these findings may have implications for the future design of porous implants used in orthopedic reconstruction, maxillofacial surgery, and potentially implant dentistry. Nevertheless, caution is warranted because the data originate from preclinical models. Clinical effectiveness, long-term performance, and patient-related outcomes remain to be established through human studies.

7. Clinical Applications

Although direct clinical recommendations cannot be derived from this preclinical investigation, the findings may be relevant to several areas of bone regeneration and implant development, including:

• Bone tissue engineering.
• Large bone defect reconstruction.
• Orthopedic implant design.
• Craniofacial and maxillofacial reconstruction.
• Additive manufacturing of patient-specific implants.
• Development of porous titanium biomaterials.
• Future implantology and osseointegration-focused device design.

The study highlights the importance of geometric optimization as a design strategy for improving biological integration of implantable biomaterials.

8. Level of Evidence, Limitations, and Transparency

This publication represents a preclinical experimental study combining laboratory and animal investigations.

Consequently, the level of evidence is lower than that provided by clinical trials, prospective cohort studies, or systematic reviews. The findings should therefore be interpreted as mechanistic and exploratory rather than definitive clinical evidence.

The authors acknowledge several limitations. While the study identifies ITGB1 as a potential mediator of scaffold-induced biological responses, the precise molecular pathways linking physical scaffold architecture to integrin regulation remain incompletely understood. They also note that bone growth direction was not extensively analyzed and suggest that future studies should investigate underlying molecular mechanisms in greater depth.

No specific conflicts of interest are reported in the information provided.

9. Key Study Points

• Study Type: Preclinical in vitro and in vivo investigation
• Level of Evidence: Preclinical
• Population or Sample: Cell culture models and animal experiments
• Number of Patients or Implants: Not specified in the provided information
• Follow-up Duration: Up to 10 weeks in vivo
• Primary Outcome: Influence of TPMS-Gyroid unit cell size on osseointegration
• Main Finding: The 2 mm unit cell scaffold (TG20) demonstrated the most favorable biological performance
• Scientific Conclusion: Enhanced ITGB1 expression was associated with improved cell adhesion, osteogenesis, angiogenesis, and M2 macrophage polarization
• Potential Limitations: Preclinical design, limited mechanistic clarification, absence of clinical validation

10. Scientific Impact

This study contributes meaningful evidence to the growing body of research investigating the relationship between scaffold architecture and biological performance. While porosity has traditionally been considered the dominant design parameter for porous implants, the present work highlights the importance of unit cell size as an independent factor influencing cellular and immune responses.

The findings advance current understanding of how physical scaffold geometry may regulate biological processes through integrin-mediated signaling pathways. By linking structural design to osteogenesis, angiogenesis, and immune modulation, the study supports a more comprehensive approach to biomaterial development.

Furthermore, the identification of ITGB1 as a potential mechanistic mediator provides a valuable framework for future investigations aimed at optimizing scaffold design for regenerative applications. These results may help guide the development of next-generation additively manufactured implants that integrate mechanical, biological, and immunological considerations into a single design strategy.

11. Editorial Conclusion

This preclinical study demonstrates that TPMS-Gyroid scaffold architecture can significantly influence cellular adhesion, immune regulation, and bone regeneration. Among the configurations evaluated, the TG20 scaffold exhibited the most favorable balance of mechanical and biological properties, largely through enhanced ITGB1 expression and promotion of a regenerative immune microenvironment. While these findings provide important insights into scaffold design optimization, further translational and clinical research is required before their relevance to human implant therapy can be fully established.