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REVIEW
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Spatiotemporal application of small molecules in fracture healing

Hairu Sui1,2# ,  Zhonglin Wu3# ,  Ziqi Xiong1,2 ,  Hui Zhang1,2,4 ,  Boon Chin Heng5 ,  Jing Zhou1,2,6*
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1 Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
2 Dr. Li Dak Sum Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
3 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
4 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou, Zhejiang, China
5 Department of Dental Materials Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, China
6 China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, Zhejiang, China
BMT, 00087 https://doi.org/10.12336/bmt.24.00087
Submitted: 10 December 2024 | Revised: 19 February 2025 | Accepted: 11 March 2025 | Published: 30 April 2025
Copyright © 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
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Abstract

Skeletal injuries and disorders are major causes of physical disability worldwide, posing an intractable clinical challenge. Within the field of regenerative medicine, researchers are continuously developing new therapeutic strategies to promote bone regeneration. Small molecules, defined as bioactive compounds with a molecular weight of <1,000 Da, have emerged as promising agents capable of precisely regulating intracellular signaling pathways to enhance bone regeneration. Their cost-effectiveness, superior membrane permeability, and minimal immunogenicity have positioned them at the forefront of both fundamental research and clinical applications. In recent years, advancements in artificial intelligence have accelerated the development and screening of small-molecule drugs, broadening their potential therapeutic applications. Furthermore, innovations in dynamic drug delivery systems have advanced the concept of spatial precision, enabling the controlled release of drug doses over time and achieving the spatiotemporal application of small molecules. These systems release specific small molecules in a sequence, synchronizing therapeutic interventions with the dynamic process of bone healing. Spatiotemporal delivery strategies, which effectively replicate the complex and highly ordered processes of bone healing, have the potential to reduce drug side effects and enhance healing efficacy. However, clinical translation remains hindered by insufficient spatiotemporal control and limited pharmacokinetic precision, challenges that this review explores in depth. We systematically examine stage-specific molecular targets of signaling pathways and their corresponding small molecule modulators. In addition, we discuss current approaches to spatiotemporal delivery strategies, such as stimuli-responsive delivery systems. Finally, we explore the status of clinical applications, the challenges encountered, and potential solutions regarding the spatiotemporal release strategy. We hope this review will contribute to the development of future spatiotemporal delivery strategies, ultimately improving outcomes for patients with impaired fracture healing.

Keywords
Bone regeneration
Fracture healing
Sequential application
Signaling pathways
Small molecules
Spatiotemporal strategy
Funding
This work was supported by the National Key Research and Development Program of China (2023YFB3813000), the National Natural Science Foundation of China (T2121004, 92268203), the Key R&D Program of Zhejiang (2024SSYS0027), and the Zhejiang Provincial Natural Science Foundation of China (No. LTGY23H060009).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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