Materials
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2022
·Vol. 15
·期 17
·5962
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IF 3.748
Bo Chen,Yu Liang,Yunjia Song,Yunkai Liang,Jian Jiao,Hong Bai,Ying Li
Host immune response has gradually been accepted as a critical factor in achieving successful implant osseointegration. The aim of this study is to create a favorable immune microenvironment by the dominant release of IL-4 during the initial few days after implant insertion to mitigate early inflammatory reactions and facilitate osseointegration. Herein, the B-TNT/PDA/IL-4 substrate was established by immobilizing an interleukin-4 (IL-4)/polydopamine (PDA) coating on a black TiO2nanotube (B-TNT) surface, achieving on-demand IL-4 release under near infrared (NIR) irradiation. Gene Ontology (GO) enrichment analyses based on high-throughput DNA microarray data revealed that IL-4 addition inhibited osteoclast differentiation and function. Animal experiment results suggested that the B-TNT/PDA/IL-4+Laser substrate induced the least inflammatory, tartrate-resistant acid phosphatase, inducible nitric oxide synthase and the most CD163 positive cells, compared to the Ti group at 7 days post-implantation. In addition, 28 days post-implantation, micro-computed tomography results showed the highest bone volume/total volume, trabecular thickness, trabecular number and the lowest trabecular separation, while Hematoxylin-eosin and Masson-trichrome staining revealed the largest amount of new bone formation for the B-TNT/PDA/IL-4+Laser group. This study revealed the osteoimmunoregulatory function of the novel B-TNT/PDA/IL-4 surface by photothermal release of IL-4 at an early period post-implantation, thus paving a new way for dental implant surface modification.Keywords:photothermal;controlled release;IL-4;PDA;TiO2nanotubes;osseointegration;near-infrared laser;titanium
研究领域:
生物材料
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免疫学
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组织工程
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牙科种植学
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产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2025
·
IF 7.9
Lifang Xie,Tianxiang Yuan,Su Hu,Chenmin Zhao,WenLi Huang,Wei Ding,Ye Zhang,Xianwen Hu
Chronic diabetic wounds exhibit impaired healing due to a complex interplay of pathological mechanisms, including persistent hyperglycemia, excessive matrix metalloproteinase-9 (MMP9) activity, and chronic inflammation, which disrupt tissue repair and regeneration. A central driver of this dysregulated healing is macrophage polarization imbalance, with excessive pro-inflammatory M1 and insufficient reparative M2 macrophages, prolonging inflammation and delaying tissue remodeling. To address these challenges, we developed a dual-responsive hydrogel composed of phenylboronic acid-functionalized polyethyleneimine (PEI-PBA), polyvinyl alcohol (PVA), and Benzaldehyde-PEG-Benzaldehyde (DF-PEG-DF) for controlled co-delivery of interleukin-4 (IL-4) and salvianolic acid A (SalA). This dynamically crosslinked hydrogel responds to the diabetic wound microenvironment, enabling pH- and glucose-triggered release. IL-4 promotes M2 macrophage repolarization, resolving inflammation and enhancing tissue repair, while SalA scavenges reactive oxygen species (ROS) and inhibits MMP9 activity, preserving extracellular matrix (ECM) integrity and supporting regeneration. In vivo, the hydrogel significantly accelerated wound closure in diabetic mice by promoting M2 polarization and reducing MMP9-mediated matrix degradation. This coordinated modulation of the inflammatory and proteolytic microenvironment attenuated inflammation, enhanced angiogenesis, and increased collagen deposition, collectively facilitating tissue regeneration. These findings suggest this intelligent hydrogel is a promising therapeutic strategy for chronic diabetic wound healing with translational potential.
研究领域:
生物材料
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药物递送
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糖尿病创面修复
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免疫调控
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再生医学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Xianzhen Yin,Yiting Li,Congling Yang,Jie Weng,Jianxin Wang,Jie Zhou,Bo Feng
Macrophage phenotype conversion is crucial for improving post-traumatic angiogenesis and tissue repair. Biomaterials with the ability of skewing macrophage phenotype have attracted widespread attention in the field of tissue engineering. The aim of this study was to transform macrophage phenotype by a three-step process; anodizing, drug loading and coating with polyelectrolyte multilayer (PEM) films. Interleukin (IL)-4, an anti-inflammatory cytokine, was loaded into titania nanotubes (TNTs) on the titanium surface. Subsequently, sodium alginate (ALG) and chitosan (CS) were alternately assembled onto IL-4-loaded TNTs and cross-linked with genipin/calcium chloride, finally forming cross-linked PEM films. The IL-4 release profile and cellular immune response of the modified surface was investigated. In the simulated biological solution, only 20% of IL-4 were detected in the first 3 days, with a sustained release of approximately 5 ng over 10 days. The results of gene expression and protein secretion in macrophages indicated that IL-4-loaded PEM films significantly attenuated the inflammatory activity of macrophages at the later stage through down-regulating the mRNA and protein levels of inflammatory markers. In summary, IL-4 was controlled released from the cross-linked PEM films deposited on the nanotubes, leading to the temporal conversion of macrophage phenotype.
研究领域:
生物材料
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组织工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xiao Jiang,Yutao Jian,Yuan Zhang,Juan Zhong,Qiulan Li,Xiaodong Wang,Xiaoshi Jia,Xiangnan Wu,Ke Zhao,Yitong Yao
The successful filling of bone defects remains challenging due to the incongruity between bone graft materials and the dynamic process of bone healing. Developing multifunctional materials matching the dynamic process of bone healing offers a viable solution to the current dilemma. Lines of evidence have shown that engineering osteoimmunomodulatory biomaterials can modulate the function of immune cells and thus promote bone regeneration. Herein, we utilized silk fibroin (SF) and polyglycolic acid (PGA) to create a PGA-SF core–shell fibrous scaffold, incorporating interleukin-4 (IL-4) and tricalcium phosphate (TCP) as a codelivery system (PGA/TCP-SF/IL-4), aiming to achieve an initial rapid release of IL-4 and sustained release of TCP. The PGA/TCP-SF/IL-4 scaffold mimicked the native bone structure and showed superior tenacity in the wetting regime. In vitro studies demonstrated that the PGA/TCP-SF/IL-4 scaffold significantly reduced the inflammatory response by upregulating the M2 macrophages, created a favorable microenvironment for osteogenesis, and facilitated osteogenic differentiation and mineralization. Implantation of the PGA/TCP-SF/IL-4 scaffold into the rat skull defect model notably increased the formation of new bones. IL-4 and TCP acted synergistically in attenuating inflammation and enhancing osteogenic differentiation. Overall, this multifunctional scaffold comprehensively considers the various demands in the bone defect region, which might have a significant potential for application in bone reconstruction.
研究领域:
生物材料
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组织工程
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骨愈合
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免疫学
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再生医学
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DOI
PubMed
高影响因子
Nano Research
·
2024
·
IF 9.5
Zhu Shengjie,Huang Danqing,Luan Qichen,Li Yang,Gan Jingjing,Zhao Yuanjin,Sun Lingyun
Macrophages play a pivotal role in systemic lupus erythematosus (SLE) therapy. Efforts have been made to develop multifunctional drug delivery systems capable of directing macrophage polarization. Here, we present a novel hyaluronic acid methacrylate (HAMA) hydrogel microparticle encapsulating multiple cytokines for SLE remission though enhancing macrophage functions. The HAMA microparticles loaded with monocyte chemotactic protein-1 (MCP-1) and interleukin-4 (IL-4) were fabricated by using a microfluidic technology. The released MCP-1 facilitates the aggregation of inflammatory macrophages, after which IL-4 induces the macrophage phenotype shift from inflammatory M1 to immune-protective M2, thus restoring immune balance. We have demonstrated in MRL/lpr mice that the hydrogel microparticles could improve their efficacy of intraperitoneal drug delivery, modulate immune function, and attenuate the disease symptoms. These results suggest that our proposed microparticles delivery platform has potential clinical value for treating autoimmune diseases.
研究领域:
药理学
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免疫学
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生物医学工程
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药物递送系统
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自身免疫疾病
✓ 已验证
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Jiaji Yue,Yuhao Deng,Weichao Sun,Shenglong Li,Mengni Zhu,Fangyue Cheng,Zhen Dai,Hongxi Shang,Jinling Zhang,Jianfei Tang
An IL-4-loaded allomelanin nanoparticle (IL-4@AMNPs) is developed. • IL-4@AMNPs scavenge ROS and reprogram macrophages toward M2 phenotype. • The nanoplatform shows sustained intra-articular retention over 144 h. • IL-4@AMNPs alleviate cartilage degradation and inflammation in OA rats. • A synergistic redox-immune modulation strategy for disease-modifying OA therapy. Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by chronic synovitis and progressive cartilage destruction, in which excessive reactive oxygen species (ROS) play a central pathogenic role. Herein, we reported the design of allomelanin-like nanoparticles loaded with interleukin-4 (IL-4@AMNPs) as a multifunctional nanoplatform. Benefiting from the intrinsic antioxidant activity of AMNPs, the system efficiently scavenges excessive ROS, while the incorporated IL-4 exerts anti-inflammatory and M2-polarizing effects. In a rat model of OA, intra-articular administration of IL-4@AMNPs markedly attenuated cartilage erosion, reduced ROS accumulation, and downregulated matrix metalloproteinase-3 (MMP-3) expression. Furthermore, IL-4@AMNPs suppressed the expression of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), restored the anti-inflammatory cytokine IL-10, and reprogrammed macrophages from the M1 toward the M2 phenotype, thereby reshaping the joint immune microenvironment. Both in vitro and in vivo safety assessments confirmed the excellent biocompatibility and systemic safety of IL-4@AMNPs. Collectively, this study demonstrated that IL-4@AMNPs disrupt the pathological interplay between oxidative stress and inflammation, achieving synergistic chondroprotection via dual ROS scavenging and IL-4-mediated macrophage reprogramming and offering a promising disease-modifying nanotherapeutic strategy for OA treatment. Download: Download high-res image (121KB) Download: Download full-size image
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DOI
高影响因子
iScience
·
2026
·Vol. 29
·期 10
·117739
·
IF 4.5
Lingxi Meng,Rongpu Liu,Siyi Wang,Junyi Wang,Ilya A. Vinnikov,Rong Yang,Xinyu Song,Hongming Zhang,Jiajia Wang,Wenjie Zhang
Apoptosis at bone defects drives an anti-osteogenic oxidative stress environment • IL-4 drives a pro-reparative macrophage phenotype and upregulates the Arg1 pathway • Exogenous Arg fuels efferocytosis and secretion of pro-regenerative factors • Co-delivery of IL-4 and Arg via injectable hydrogel accelerates bone regeneration Summary Host bone microenvironment is a critical factor for successful bone regeneration during implantation. In this work, we identified a spatiotemporal mismatch at drilling-induced injury sites where initial apoptosis outpaces macrophage recruitment, leading to apoptotic cell accumulation and oxidative stress that impairs osteogenic differentiation. To mitigate this phenomenon, we developed a synergistic strategy co-delivering interleukin 4 (IL-4) and arginine (Arg) to reprogram the microenvironment. Mechanistically, IL-4 recruits and polarizes macrophages toward a pro-reparative M2 phenotype, while Arg fuels the arginase-1 metabolic pathway to sustain continual efferocytosis and secretion of pro-regenerative cytokines. In a mouse bone injury model, transcriptomic and histological analyses confirmed that this strategy accelerates apoptotic clearance and establishes an M2-dominant environment, significantly enhancing early bone regeneration. Altogether, this work proposes a novel therapeutic paradigm targeting macrophage efferocytosis to resolve early microenvironmental imbalances, providing a promising therapeutic approach to promote bone defect healing and offering novel insights into optimizing host microenvironments for osseointegration following implantation. Download: Download high-res image (245KB) Download: Download full-size image
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DOI
高影响因子
Biomed Research International
·
2022
·
IF 3.246
Cheng Shi,Fei Yuan,Zhilong Li,Zhenhua Zheng,Changliang Yuan,Ziyang Huang,Jianping Liu,Xuping Lin,Taoyi Cai,Guofeng Huang,Zhenqi Ding
Background. The microenvironment of bone defects displayed that M2 polarization of macrophagocyte could promote the osteoblast growth and benefit the wound healing. Bone scaffold transplantation is considered to be one of the most promising methods for repairing bone defects. The present research was aimed at constructing a kind of novel bone scaffold nanomaterial of [email protected] for treating bone defects responding to the wound microenvironment of bone defects and elucidating the mechanics of [email protected] treating bone defect via controlling release of IL-4, inducing M2 polarization and active factor release of macrophagocyte, and eventually relieving osteoblast injury. Methods. [email protected] was firstly fabricated and its release of IL-4 was assessed in vitro. Following, the effects of [email protected] nanocomplex on the release of active factors of macrophage were examined using Elisa assay and promoting M2 polarization of the macrophage by immunofluorescence staining. And then, the effects of active factors from macrophage supernatant induced by [email protected] on osteoblast growth were examined by CCK-8, flow cytometry, and western blot assay. Results. The release curve of IL-4 in vitro displayed that there was more than 80% release ratio for 30th day with a sustained manner in pH 5.5. Elisa assay data showed that [email protected] nanocomplex could constantly promote the release of proproliferative cytokine IL-10, SDF-1α, and BMP-2 in macrophagocyte compared to only IL-4 treatment, and immunofluorescent image showed that [email protected] could promote M2 polarization of macrophagocytes via inducing CD206 expression and suppressing CD86 expression. Osteoblast injury data showed that the supernatant from macrophagocyte treated by [email protected] could promote the osteoblast proliferation by MTT assay. Flow cytometry data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the osteoblast apoptosis from 22.1% to 14.6%, and apoptosis-related protein expression data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the expression of Bax, cleaved caspase 3, and cleaved caspase 8. Furthermore, the immunofluorescent image showed that the supernatant from macrophagocyte treated by [email protected] could inhibit nucleus location of p65, and western blot data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the phosphorylation of IKK and induce the expression of IκB. Conclusion. [email protected] could control the sustaining release of IL-4, and it exerts the protective effect on osteoblast injury via inducing M2 polarization and proproliferative cytokine of macrophagocyte and following inhibiting the apoptosis and NF-κB pathway-associated inflammation of osteoblast.
研究领域:
生物医学工程
·
组织工程
·
细胞生物学
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Congling Yang,Qianying Guo,Xinchun Wang,Hongmei Chen,Huan Tan,Bo Feng,Jie Weng
Multi-responsive drug-delivery systems have been widely explored to enable specific delivery to target sites. Here, interleukin-4 (IL-4), an anti-inflammatory cytokine, is first encapsulated in situ inside a zeolitic imidazolate framework (ZIF-8) to form IL-4@ZIF-8, which is subsequently coated with a diselenide block copolymer to obtain IL-4@ZIF-8@Se-Se-polymer. This delivery system enables redox-responsive release of IL-4 by the diselenide copolymer and a pH-triggered release by ZIF-8. Moreover, IL-4 release is precisely controlled stepwise by the stimuli response, with the dissociation of the diselenide copolymer, and breakdown of the ZIF-8 structure. The targeted release property of the IL-4@ZIF-8@Se-Se-polymer endows the materials with efficient macrophage immune regulation, as systematically demonstrated in vitro. This study provides an effective example of the delivery and on-demand release of IL-4, and may find promising applications in tissue engineering for the management of inflammation.
研究领域:
生物材料学
·
免疫学
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2026
·
IF 12.9
Zeguo Chen,Zhongshi Wu,Can Huang,Qiying Wu,Chao Xie,Sicheng Chen,Liang Yi,Haoyong Yuan,Sixi Liu,Abdulraheem Mustapha,Siyao Chen,Wansong Chen,Ting Lu,Zhenjie Tang,Yuhong Liu
Delayed endothelialization and inadequate matrix remodeling remain major obstacles in the development of small-diameter vascular grafts (SDVGs; <6 mm). To address these challenges, we developed an immunomodulatory tissue-engineered vascular graft (iTEVG) by integrating hollow mesoporous silica nanoparticles (HMSNs) with tailored mesopore sizes as delivery carriers for immunoregulatory factors. VEGF was selectively immobilized on the intimal surface, while the adventitia incorporated a sequential release system for VEGF and IL-4. VEGF exhibited rapid release (64.04 ± 4.44% in 7 days), promoting monocyte recruitment and adventitial neovascularization, while IL-4 showed sustained release (65.94 ± 2.06% over 28 days), driving long-term M2 macrophage polarization. In rats, iTEVGs achieved 88% endothelial coverage and smooth muscle cell infiltration within 1 month, full-thickness cellularization with a complete trilaminar structure by 3 months, and maintained mechanical integrity without aneurysm formation up to 6 months. This spatially partitioned platform, built on an acellular vascular scaffold, enables precise spatiotemporal regulation of the immune microenvironment and offers a design paradigm that synergistically promotes endothelialization and vascular matrix remodeling. The “intima-targeted regeneration and adventitia-sequential-release” strategy provides a promising template for SDVG design that may be extended to other complex organ constructs.
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
·
IF 7.7
Yifang Chen,Qian Zhang,Na Li,Zhaoqi Zhang,Tong Lei,Han Guo,Hezhe Lu,Yong Zhao
Dendritic cells (DCs) are professional antigen-presenting cells that exhibit significant heterogeneity in development and function. This study found that among 17 cytokines screened, only IL-33 could induce DCs to display a Th9-type cytokine profile, including IL-9, IL-4, and IL-13, in vitro . The response of DCs to IL-33 was synergistically enhanced by TGF-β and IL-4, defining a distinct subset termed DC9. Transcriptomic analysis revealed that DC9 possesses a unique gene expression signature, particularly in cytokine/chemokine clusters, compared to conventional DCs. Mechanistically, DC9 polarization depends on the JAK-STAT6-IRF4 signaling pathway. Functionally, DC9 preferentially drives naive CD4 + T cell differentiation toward Th9 cells in vitro . In an ovalbumin-induced allergic airway inflammatory mouse model, DC9 cells were detectable in lungs and adoptive transfer of DC9 exacerbated disease severity, and increased pulmonary Th9 cells. Collectively, we identify DC9 as a novel DC subset induced by IL-33/TGF-β/IL-4 through the JAK-STAT6-IRF4 axis, which promotes Th9 differentiation and aggravates allergic airway inflammation.
✓ 已验证
DOI
PubMed
高影响因子
Bioactive Materials
·
2025
·
IF 20.3
Xindi Yang,Xiao Liang,Binyi Wang,Xing Gao,Wenqiang Yang,Jiajun Li,Huaan Cai,Zan Tong,Yun Chen
Nerve regeneration after peripheral nerve injury (PNI) depends on exogenous and endogenous pro-healing signals in the microenvironment. Maintaining immune system homeostasis and remodeling the regenerative microenvironment are crucial prerequisites for promoting nerve regeneration. Here, a double-layer PSM/Gel-SC(IL-4) nerve guide conduit was fabricated by photocrosslinking poly (ethylene glycol) diacrylate (PEGDA) and methacrylic acid-sodium alginate (SAMA) hydrogel as the outer layer, with GelMA encapsulating IL-4 overexpressing Schwann cells as the inner layer. PSM/Gel-SC(IL-4) conduit enabled the sustained release of IL-4, inducing pro-healing macrophages polarization through JAK1/STAT6 pathway in vitro . The polarized macrophages further triggered the cellular cascade reactions, enhancing the pro-healing characteristics of endothelial cells and Schwann cells. In addition, PSM/Gel-SC(IL-4) conduit significantly promoted functional recovery and nerve regeneration in 12-mm rat sciatic nerve defect model, induced pro-healing macrophage polarization at the early stage and accelerated angiogenesis and myelination at the nerve regeneration stage. This study developed a novel immunomodulatory strategy to remodel the regenerative microenvironment, and explored the underlying cellular and molecular mechanism, demonstrating considerable therapeutic potential for long-distance nerve defect.
研究领域:
生物医学工程
·
神经科学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）