Reinstating Niche Failure in Diabetic Cranial Defects via Chronotaxic Signal-Amplifying Fluidic Biomimetic Hydrogel

Sep 29, 2026

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Stem cell niches (SCNs) are scarce and hypoactive, and chronic inflammation in diabetes further causes niche failure and regenerative deficits after injury. The work develops an in situ moldable fluidic biomimetic niche (GelSSO/PDA@SDF) as a chronotaxic signal amplifier to restore autonomous cranial regeneration. The hydrogel releases nanoparticles for early SDF-1/CXCR4 recruitment, AKT-dependent angiogenesis, and M1 macrophage suppression, followed by SSO-driven osteogenic niche activation and diabetic vascularized bone repair.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Stem cell niches in health and disease

Biomimetic niche strategies

Conclusion

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Reinstating Niche Failure in Diabetic Cranial Defects via Chronotaxic Signal-Amplifying Fluidic Biomimetic Hydrogel Yingji Mao, Yu Chen, Runlin Fan, Pengzhen Zhuang, Hongbo Zhang,* and Pinghui Zhou* Cranial stem cell niches (SCNs) are intrinsically scarce and hypoactive, and, exacerbated by chronic inﬂammation in diabetes, lead to niche failure and regenerative deﬁcit after injury. Herein, an in situ moldable ﬂuidic biomimetic niche (GelSSO/PDA@SDF) is developed as a chronotaxic signal ampliﬁer to enhance SCN abundance and activity, aiming to restore autonomous regeneration. This biomimetic niche integrates PDA@SDF nanoparticles and a GelSSO hydrogel precursor, synthesized via dopamine self-polymerization/protein coupling and sequential methacrylation/sequencespeciﬁc oligodeoxynucleotide (SSO) grafting, respectively. Photocrosslinked GelSSO/PDA@SDF can preferentially and sustainably release PDA@SDF nanoparticles to trigger early-phase signal ampliﬁcation, characterized by SDF- 1􀀂/CXCR4-mediated recruitment of endothelial and mesenchymal progenitors, vascular niche activation driving AKT-dependent angiogenesis, and suppressed M1 macrophage dominance. Progressive hydrogel degradation initiates the secondary signal ampliﬁcation phase, in which prolonged SSO release creates a transcriptionally active osteogenic niche for MAPK/ERK-induced osteogenesis. In vivo, the in situ structured GelSSO/PDA@SDF conformed to defect geometry, promoting the early establishment of an immunologically favorable, progenitor-enriched niche through local immunomodulation and endogenous cell homing, followed by successive activation of vascular and osteogenic niches, ultimately achieving diabetic cranial vascularized bone regeneration. Thus, this chronotaxic signal-amplifying biomimetic niche oﬀers a versatile strategy for restoring autonomous regeneration in the diabetic cranium and other poorly regenerative tissues. 1. Introduction Stem cell niches (SCNs) are specialized microenvironments that integrate multidimensional signals to preserve stemness, direct diﬀerentiation, and coordinate repair, thereby determining the regenerability of tissues. [1–3] This capacity varies hierarchically across tissues and anatomy owing to the spatial heterogeneity of SCNs. From atissue perspective, the skin and liver harbor numerous, broadly distributed, and highly injury-responsive SCNs that enable rapid restoration of structure and function. In contrast, the myocardium and central nervous system, characterized by SCN scarcity and hypoactivity, are poorly regenerative, leading to functionally limited scarring. [4,5] Anatomically, marrow-rich endosteal and periosteal SCNs in the femur support structural and mechanical healing, while the cranium, lacking such supportive SCNs, struggles to bridge defects. [6,7] Beyond these baseline constraints, pathological conditions such as diabetes further deplete SCN abundance and activity via chronic inﬂammation, exacerbating the regenerative deﬁcit, especially in tissues where SCNs are already scarce. [8,9] Thus, enhancing SCN abundance and activity in intrinsically and pathologically disadvantaged Y. Mao, R. Fan, P. Zhou Department of Orthopedics Anhui Province Key Laboratory of Tissue Transplantation The First Aﬃliated Hospital of Bengbu Medical University Bengbu 233004, China E-mail: [phzhou@bbmu.edu.cn](phzhou@bbmu.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202516398](https://doi.org/10.1002/advs.202516398)[ ](https://doi.org/10.1002/advs.202516398)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202516398 Y. Mao

FAQs

What problem does this study address in diabetic cranial injuries?

Diabetes-related chronic inflammation depletes and hypoactivates stem cell niches, leading to niche failure and impaired regeneration after cranial defects.

How does GelSSO/PDA@SDF function as a chronotaxic signal amplifier?

It provides sequential signal phases by sustainably releasing PDA@SDF nanoparticles first for recruitment and vascular activation, then degrading to enable prolonged SSO release that drives osteogenic niche formation.

Which biological pathways are highlighted for early vascular and later bone regeneration?

Early phase recruitment is mediated by SDF-1/CXCR4 and angiogenesis proceeds via AKT-dependent mechanisms, while the secondary osteogenic phase involves MAPK/ERK-induced osteogenesis.

Sep 29, 2026

Uploaded by Fahsai

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