Bioactive small-molecule gas delivery for enhanced bone regeneration: modulation of cellular signaling and remodeling of the regenerative microenvironment.
- 1Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
- 2Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China.
- 3Department of Orthopaedics, The Fifth People's Hospital of Sichuan Province, Chengdu, China.
Abstract
Complex bone defects are characterized not only by structural loss but also by persistent inflammation, insufficient vascularization, oxidative stress, impaired cell recruitment, and disrupted bone remodeling, which collectively limit endogenous repair. Bioactive small-molecule gases have emerged as versatile regulators of bone regeneration because of their rapid diffusion, low-dose activity, and ability to modulate multiple cellular and microenvironmental processes. This mini-review summarizes the biological roles and biomaterial-based delivery strategies of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S), oxygen (O₂), and hydrogen (H₂) in bone repair. NO primarily promotes angiogenesis and osteogenic-angiogenic coupling, whereas CO contributes mainly to anti-inflammatory, antioxidant, and cytoprotective regulation. H₂S exhibits broader effects by coordinating redox homeostasis, macrophage polarization, vascularization, mitochondrial function, and osteogenic differentiation. O₂ and H₂ provide complementary benefits by alleviating hypoxia, reducing oxidative damage, and remodeling senescence-associated microenvironments. To overcome the rapid diffusion, short half-life, limited local retention, and narrow therapeutic windows of free gases, diverse delivery platforms have been developed, including nanoscale gas-generating systems, stimuli-responsive materials, injectable hydrogels, biomimetic scaffolds, and living gas-producing biomaterials. These systems enable localized, sustained, or on-demand gas release and can integrate immunomodulation, reactive oxygen species scavenging, angiogenic stimulation, bioelectric cues, and mechanical support. Representative studies demonstrate promising outcomes in critical-sized, osteoporotic, diabetic, inflammatory, and aging-related bone defects. Nevertheless, clinical translation remains constrained by challenges in dose control, release kinetics, material degradation, biosafety, long-term metabolism, and stage-specific therapeutic adaptation. Future research should focus on precisely matching gas release profiles to the temporal phases of bone healing and on developing multifunctional platforms that combine gaseous signaling with other regenerative cues.
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BibTeX
@article{zhong2026bioactive,
title = {{Bioactive small-molecule gas delivery for enhanced bone regeneration: modulation of cellular signaling and remodeling of the regenerative microenvironment.}},
author = {Zhou Zhong and Biao Cao and Xin Duan},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1992564},
url = {https://europepmc.org/article/MED/42928943},
note = {CC BY},
}
RIS
TY - JOUR
TI - Bioactive small-molecule gas delivery for enhanced bone regeneration: modulation of cellular signaling and remodeling of the regenerative microenvironment.
AU - Zhou Zhong
AU - Biao Cao
AU - Xin Duan
PY - 2026
DA - 2026/10/12
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1992564
UR - https://europepmc.org/article/MED/42928943
AB - Complex bone defects are characterized not only by structural loss but also by persistent inflammation, insufficient vascularization, oxidative stress, impaired cell recruitment, and disrupted bone remodeling, which collectively limit endogenous repair. Bioactive small-molecule gases have emerged as versatile regulators of bone regeneration because of their rapid diffusion, low-dose activity, and ability to modulate multiple cellular and microenvironmental processes. This mini-review summarizes the biological roles and biomaterial-based delivery strategies of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S), oxygen (O₂), and hydrogen (H₂) in bone repair. NO primarily promotes angiogenesis and osteogenic-angiogenic coupling, whereas CO contributes mainly to anti-inflammatory, antioxidant, and cytoprotective regulation. H₂S exhibits broader effects by coordinating redox homeostasis, macrophage polarization, vascularization, mitochondrial function, and osteogenic differentiation. O₂ and H₂ provide complementary benefits by alleviating hypoxia, reducing oxidative damage, and remodeling senescence-associated microenvironments. To overcome the rapid diffusion, short half-life, limited local retention, and narrow therapeutic windows of free gases, diverse delivery platforms have been developed, including nanoscale gas-generating systems, stimuli-responsive materials, injectable hydrogels, biomimetic scaffolds, and living gas-producing biomaterials. These systems enable localized, sustained, or on-demand gas release and can integrate immunomodulation, reactive oxygen species scavenging, angiogenic stimulation, bioelectric cues, and mechanical support. Representative studies demonstrate promising outcomes in critical-sized, osteoporotic, diabetic, inflammatory, and aging-related bone defects. Nevertheless, clinical translation remains constrained by challenges in dose control, release kinetics, material degradation, biosafety, long-term metabolism, and stage-specific therapeutic adaptation. Future research should focus on precisely matching gas release profiles to the temporal phases of bone healing and on developing multifunctional platforms that combine gaseous signaling with other regenerative cues.
SN - 2296-634X
ER -