Acta Biomaterialia
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2025
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IF 9.6
Junqi Dai,Li Ni,Chenyang Jin,Xin Tian,Yujie Shen,Yan Miao,Yong Xu,Fan He,Huilin Yang
Cell transplantation for nucleus pulposus (NP) regeneration represents a promising strategy for intervertebral disc degeneration (IVDD). Nonetheless, the hostile microenvironment within the degenerated intervertebral discs, characterized by redox imbalance and elevated mechanical pressure, poses risks of low cell survival and inadequate cell colonization for efficient NP regeneration. To address these challenges, we developed a biomimetic, esterase-responsive composite hydrogel microsphere (GHKM) for cell delivery, consisting of gelatin methacrylate (GelMA) mixed with HAMA-KGN, a conjugate of hyaluronic acid methacrylate (HAMA) and the small heterocyclic molecule kartogenin (KGN) via ester bonds. GHKM mimic the NP extracellular matrix (ECM), providing essential adhesion and mechanical support for cell proliferation, while facilitating cellular adaptation to the adverse microenvironment through the esterase-responsive release of KGN. Furthermore, GHKM exhibit favorable biocompatibility and promote or protect ECM synthesis by nucleus pulposus cells (NPCs) under both normal and inflammatory conditions. Transcriptomic sequencing analysis indicates a correlation between enhanced ECM synthesis and enrichment of antioxidant-related pathways. Subsequent cellular biological studies reveal that GHKM can also reduce reactive oxygen species production within the inflammatory milieu. The underlying mechanism of its protective effect on matrix metabolism may involve the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the upregulation of downstream antioxidant enzymes. In vivo implantation of NPCs-laden GHKM into rat tail nuclectomy models for 4 and 8 weeks preserved disc height, structure, and biological function, with histological analysis confirming NP regeneration. These findings present GHKM as a promising, synergistic transplantation strategy for NP regeneration in IVDD. Statement of significance This study introduces an esterase-responsive gelatin methacrylate/hyaluronic acid methacrylate-kartogenin composite hydrogel microsphere (GHKM) system, aimed at mimicing the extracellular matrix (ECM) of the nucleus pulposus (NP) to address the pressing challenge of intervertebral disc degeneration (IVDD). These microspheres offer an innovative solution for cell transplantation therapy by simultaneously addressing two critical barriers: the harsh microenvironment of the degenerated disc and the need for sustained therapeutic effects. GHKM provide mechanical support, enhance cell survival, and adapt dynamically to adverse conditions through esterase-responsive release of kartogenin (KGN), a multifunctional molecule with chondrogenic, anti-inflammatory, and antioxidative properties. This study will not only interest researchers focused on regenerative medicine and biomaterials but also inspire new directions for tackling complex degenerative diseases.
研究领域:
再生医学
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生物材料学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Qian Han,Jiahui He,Lang Bai,Ying Huang,Baojun Chen,Zhenlong Li,Meiguang Xu,Qiaonan Liu,Shuai Wang,Nuanyang Wen,Jing Zhang,Baolin Guo,Zhanhai Yin
Partial-thickness cartilage defect (PTCD) is a common and formidable clinical challenge without effective therapeutic approaches. The inherent anti-adhesive characteristics of the extracellular matrix within cartilage pose a significant impediment to the integration of cells or biomaterials with the native cartilage during cartilage repair. Here, an injectable photocrosslinked bioadhesive hydrogel, consisting of gelatin methacryloyl (GM), acryloyl-6-aminocaproic acid- g -N-hydroxysuccinimide (AN), and poly(lactic- co -glycolic acid) microspheres loaded with kartogenin (KGN) (abbreviated as GM/AN/KGN hydrogel), is designed to enhance interfacial integration and repair of PTCD. After injected in situ at the irregular defect, a stable and robust hydrogel network is rapidly formed by ultraviolet irradiation, and it can be quickly and tightly adhered to native cartilage through amide bonds. The hydrogel exhibits good adhesion strength up to 27.25 ± 1.22 kPa by lap shear strength experiments. The GM/AN/KGN hydrogel demonstrates good adhesion, low swelling, resistance to fatigue, biocompatibility, and chondrogenesis properties in vitro. A rat model with PTCD exhibits restoration of a smoother surface, stable seamless integration, and abundant aggrecan and type II collagen production. The injectable stable adhesive hydrogel with long-term chondrogenic differentiation capacity shows great potential to facilitate repair of PTCD.
研究领域:
生物医学工程
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组织工程
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再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Bionic Engineering
·
2025
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IF 5.8
Liu Hengyu,Huang Bingzhe,Zhang Hanyang,Zhong Zhuan,Jia Guoliang,Zhang Jiaxin,Gao Xiaofan,Qiao Hongqing,Li Rudong,Mei Nan,Wang Jincheng,Chang Fei,Liu He
Osteochondral defects involving both articular cartilage and subchondral bone remain challenging in clinical treatment. Inspired by the zonal organization of native osteochondral tissue and the sophisticated architecture of articular cavity, we designed a biomimetic bilayer scaffold system using 3D printing technology. The scaffold recreates the natural structural and mechanical gradients of the osteochondral interface, featuring a gradient transition from cartilage to bone phase. To enhance the bio-functionality of this biomimetic design, we incorporated the small molecule Kartogenin (KGN), which has shown promising potential in cartilage regeneration by promoting chondrogenic differentiation and inhibiting cartilage degeneration. However, the reparative efficacy of KGN is highly concentration-dependent, and the optimal concentration within complex three-dimensional scaffold environments remains unclear. Through both in vitro and in vivo evaluations of this bio-inspired scaffold system loaded with varying KGN concentrations, we identified that 5 µM KGN (SCS@K5) achieved optimal outcomes. At 12 weeks, the SCS@K5 treatment resulted in better organized osteochondral tissue with improved interface integration relative to other groups. This biomimetic gradient design incorporating KGN release offers a viable approach for osteochondral defect repair.
研究领域:
生物医学工程
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组织工程
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再生医学
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药物递送系统
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生物制造
✓ 已验证
产品关联
DOI
高影响因子
Materials Today Bio
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2025
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IF 10.2
Hengyu Liu,Hongqing Qiao,Rudong Li,Wenbo Yang,Xingchen Guo,Yuhang Wang,Nan Mei,Jincheng Wang,Fei Chang
Osteochondral defects represent a formidable clinical challenge due to their distinctive stratified architecture and limited intrinsic healing capacity. However, conventional tissue engineering scaffolds exhibit significant limitations in replicating the gradient properties of native osteochondral tissue while maintaining chondrogenic phenotypes. This study presents a novel bio-customized gradient scaffold CSK@G inspired by natural osteochondral architecture, developed through strategic material composition control and graduated porosity design techniques, for integrated repair of osteochondral defects. Through precise biomimetic design, the scaffold successfully recapitulates the spatial heterogeneity of native tissue by accurately mimicking five anatomically distinct layers—superficial cartilage, middle cartilage, deep cartilage, calcified cartilage, and subchondral bone. Additionally, Kartogenin (KGN)-loaded Chitosan (CS) hydrogels are strategically incorporated within cartilaginous zones to facilitate stem cell homing and create optimal cellular microenvironments that provide region-specific biochemical cues for enhanced chondrogenic differentiation. Comprehensive experimental results, both in vitro and in vivo , demonstrate that this bio-customized gradient scaffold significantly facilitates integrated osteochondral repair while effectively maintaining chondrogenic phenotypes. This work proposes a novel bio-customized strategy for osteochondral tissue engineering, resulting in a bio-customized scaffold that closely mimics the hierarchical properties of natural osteochondral tissue.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2024
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IF 8.3
Lujie Zong,Qing Wang,Houyi Sun,Qian Wu,Yaozeng Xu,Huilin Yang,Shujun Lv,Liang Zhang,Dechun Geng
Osteoarthritis (OA) is a common joint disease characterized by progressive cartilage degeneration. Unfortunately, currently available clinical drugs are mainly analgesics and cannot alleviate the development of OA. Kartogenin (KGN) has been found to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes for the treatment of cartilage damage in early OA. However, KGN, as a small hydrophobic molecule, is rapidly cleared from the synovial fluid after intra-articular injection. This study synthesized a KGN-loaded nanocarrier based on PLGA/polydopamine core/shell structure to treat OA. The fluorescence signal of KGN@PLGA/PDA-PEG-E7 nanoparticles lasted for 4 weeks, ensuring long-term sustained release of KGN from a single intra-articular injection. In addition, the polyphenolic structure of PDA enables it to effectively scavenge reactive oxygen species, and the BMSC-targeting peptide E7 (EPLQLKM) endows KGN@PLGA/PDA-PEG-E7 NPs with an effective affinity for BMSCs. As a result, the KGN@PLGA/PDA-PEG-E7 nanoparticles could effectively induce cartilage in vitro and protect the cartilage and subchondral bone in a rat ACLT model. This therapeutic strategy could also be extended to the delivery of other drugs, targeting other tissues to treat joint diseases.
研究领域:
生物医学工程
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药剂学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Ding Wang,Qiang Zhong,Yixin Xu,Jinlang Fu,Jiajun Xie,Rong Chen,Mingyuan Lei,Zinan Tang,Huaming Mai,Hao Li,Zhanjun Shi,Shaowei Zheng,Hao Cheng
Self-repair of articular cartilage defects is a significant challenge that can be addressed using drug-infused hydrogels, which improve injection convenience and provide immediate in situ adhesion. In this study, we developed a hydrogel incorporating Lipo@Kartogenin (KGN) and the cationic functional peptide SKPPGTSS (SKP) linked to aldehyde-based methacrylated hyaluronic acid (AHAMA). The innovative injectable hydrogel responded to visible light, allowing cross-linking under white light (~30 s) and effective adhesion to cartilage tissue. The hydrogel facilitated the sustained release of KGN and SKP over approximately 28 days as it degraded, thereby promoting the homing and differentiation of endogenous bone marrow-derived mesenchymal stem cells (BMSCs). Transcriptome sequencing showed that Smad4 expression and activation of the TGF-β signaling pathway are fundamental to these processes. In vivo studies in Sprague-Dawley (SD) rats showed that this hydrogel supports optimal hyaline cartilage regeneration within 8 weeks. In conclusion, our visible light-responsive adhesive co-delivery hydrogel effectively recruited native BMSCs to cartilage lesion sites and provided an environment conducive to their differentiation into cartilage, thereby facilitating effective cartilage regeneration. This innovation represents a novel approach to the clinical repair of cartilage defects.
研究领域:
生物材料学
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再生医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Xinding Yu,Jian Wang,Shenglai Zhou,Peng Pan,Tiantian Chen,Xi Wang,Wentao Liu
Due to the extreme difficulty of cartilage, we endeavored to fabricate a novel biodegradable scaffold using natural polysaccharide cellulose and poly(lactic- co -glycolic acid) (PLGA) microspheres incorporating controllably released the cartilage inducer kartogenin (KGN) for enhancing regenerative healing in cartilage tissue. Initially, to facilitate the loading of KGN, PLGA/KGN microspheres were fabricated using the solvent volatilization method. These microspheres exhibited high sphericity, with particle sizes diminishing from 12.11 to 3.27 μm as the emulsification rate increased. Demonstrating adequate encapsulation efficiency, the microspheres enabled controlled drug release, positively influencing cell migration and recruitment. Subsequently, a biodegradable cellulose composite scaffold loaded with PLGA/KGN microspheres was prepared using the freeze-drying method. Compared with pure MCC scaffolds, composite scaffolds had a lower degradation rate, and the incorporation of microspheres promoted cell proliferation and significantly elevated expression of cartilage-related specific genes. In a rat cartilage defect model, it was further demonstrated that the composite scaffold combined with stem cell implantation achieved an optimal repair effect, characterized by vigorous extracellular matrix secretion and increased maturity of the regenerated cartilage tissues, suggesting potential clinical application value as a novel articular cartilage repair product in the future.
研究领域:
组织工程学
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再生医学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2016
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IF 7.145
Xuezhou Li,Jianxun Ding,Zhengzheng Zhang,Modi Yang,Jiakuo Yu,Jincheng Wang,Fei Chang,Xuesi Chen
Recently, cartilage tissue engineering (CTE) attracts increasing attention in cartilage defect repair. In this work, kartogenin (KGN), an emerging chondroinductive nonprotein small molecule, was incorporated into a thermogel of poly(l-lactide-co-glycolide)–poly(ethylene glycol)–poly(l-lactide-co-glycolide) (PLGA–PEG–PLGA) to fabricate an appropriate microenvironment of bone marrow mesenchymal stem cells (BMSCs) for effective cartilage regeneration. More integrative and smoother repaired articular surface, more abundant characteristic glycosaminoglycans (GAGs) and collagen II (COL II), and less degeneration of normal cartilage were obtained in the KGN and BMSCs coloaded thermogel group in vivo. In conclusion, the KGN-loaded PLGA–PEG–PLGA thermogel can be utilized as an alternative support for BMSCs to regenerate damaged cartilage in vivo.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Guanrong Li,Renhao Ni,Zheyuan Shi,Haijiao Mao,Yang Luo,Xu Cao,Chi Zhang,Yuetian Liu,Zhanping Jin,Jun Chen,Jun Fu,Hua Zhang,Yingchun Zhu
Hydrogel-based cartilage tissue engineering (HCTE) offers a promising strategy for the regeneration of articular cartilage. However, the effectiveness of current HCTE is hindered by the low efficiency of stem cell transplantation and insufficient chondrogenic differentiation. Here, we develop a mechanically optimized and biochemically sustained biomaterial system that integrates a dynamic hydrazone/covalent dual-crosslinked hyaluronan (HA) hydrogel with kartogenin (KGN)-loaded poly(lactic- co -glycolic acid) microspheres to facilitate stem cell chondrogenesis and repair articular cartilage. This composite hydrogel features excellent injectability and self-healing behavior, allowing for minimally invasive implantation while protecting cell viability. The tunable viscoelasticity of the hydrogel enhances focal adhesion formation in bone-marrow mesenchymal stem cells (BMSCs), promoting their spreading, proliferation, and aggregation. Furthermore, the combined effects of hydrogel viscoelasticity and sustained KGN release markedly promote the expression of cartilage-specific genes and the secretion of extracellular matrix components through the integrin-mediated Hippo signaling pathway and KGN-mediated TGF-β signaling pathway. This dual-stimuli hydrogel embedded with BMSCs significantly promotes the regeneration of articular cartilage in rabbit models. Overall, the designed KGN composite dynamic HA-based hydrogel enables highly effective transplantation and promotes efficient chondrogenesis of stem cells, providing a promising approach for stem cell therapy and cartilage regeneration.
研究领域:
组织工程学
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再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2022
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IF 6.064
Zhang Hanyuan,Fang Weijun,Zhao Tingting,Zhang Huabing,Gao Liang,Li Jingya,Wang Rujing,Xu Weiping
The cartilage has poor ability to mount a sufficient healing response. Herein, kartogenin (KGN), an emerging stable non-protein compound with the ability to recruit bone marrow mesenchyme stem cells (BMSCs) to promote chondrogenic differentiation, was grafted onto dopamine-Fe(III) chelating nanoparticles, followed by involving a gelatin- and dextran-based injectable hydrogel to mimic the extracellular matrix to promote cartilage repair. The in vitro results demonstrated that KGN underwent long-term sustained release behavior and availably promoted the deep migration of BMSC cells in yielding hydrogels. Furthermore, in vivo New Zealand white rabbits’ cartilage defect model repairing results showed that cartilage defect obtained significant regeneration post operation in the 12th week, and the defect edge almost disappeared compared to adjacent normal cartilage tissue. Meanwhile, the T2-weighted magnetic resonance imaging (MRI) property resulting from dissociative Fe (III) can significantly monitor the degradation degree of the implanted hydrogels in the defect site. This integrated diagnosis and treatment system gives insight into cartilage regeneration.
研究领域:
生物医学工程
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再生医学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2019
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IF 8.063
Shuai Zhang,Peilin Hu,Tao Liu,Zhen Li,Yongcan Huang,Jinqi Liao,Md Rana Hamid,Liru Wen,Ting Wang,Cuiping Mo,Mauro Alini,Sibylle Grad,Tianfu Wang,Di Chen,Guangqian Zhou
Rationale The small molecule Kartogenin (KGN) promotes cartilage regeneration in osteoarthritis (OA) by activating stem cells differentiation, but its pharmacological mode-of-action remains unclear. KGN can be cleaved into 4-aminobiphenyl (4-ABP) and phthalic acid (PA) following enzymolysis of an amide bond. Therefore, this study investigated whether 4-ABP or PA exerted the same action as KGN. Methods KGN, 4-ABP and PA were analyzed in cartilage of mice after oral, intravenous or intra-articular administration of KGN by liquid chromatography-mass spectrometry method. Their effect on proliferation and chondrogenic differentiation of mesenchymal stem cells (MSC) was evaluated in vitro . Furthermore, their effect on cartilage preservation was tested in mice OA model induced by destabilization of medial meniscus. OA severity was quantified using OARSI histological scoring. Transcriptional analysis was used to find the possible targets of the chemicals, which were further validated. Results We demonstrated that while oral or intra-articular KGN delivery effectively ameliorated OA phenotypes in mice, only 4-ABP was detectable in cartilage. 4-ABP could induce chondrogenic differentiation and proliferation of MSC in vitro and promote cartilage repair in OA mouse models mainly by increasing the number of CD44 + /CD105 + stem-cell and prevention of matrix loss. These effect of 4-ABP was stronger than that of KGN. Transcriptional profiling of 4-ABP-stimulated MSC suggested that RPS6KA2 and the PI3K-Akt pathway were 4-ABP targets; 4-ABP could activate the PI3K-Akt pathway to promote MSC proliferation and repair OA injury, which was blocked in RPS6KA2- knockdown MSC or RPS6KA2- deficient mice . Conclusion 4-ABP bio-distribution in cartilage promotes proliferation and chondrogenic differentiation of MSC, and repairs osteoarthritic lesions via PI3K-Akt pathway activation.
研究领域:
药理学
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骨科
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干细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
COMPOSITES PART B-ENGINEERING
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2022
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IF 11.322
Yijian Zhang,Weiling Yin,Yang Liu,Mingzhuang Hou,Qin Shi,Tao Liu,Miao Wang,Huilin Yang,Guoqing Pan,Fan He,Xuesong Zhu
Limited self-renewal potency of cartilage impedes the repair and regeneration at the site of damage. Investigating small-molecule compounds to boost chondrogenesis has yielded the dawn. However, the durability and targeting of current drug delivery and the adaptive integration for cartilage defects are not addressed. Herein, we fabricated a dynamic hydrogel based on the coordination between metal ions and collagen and then supramolecularly enveloped with a chondro-inductive factor kartogenin (KGN) via cyclodextrin (CD). The self-recovery and injectability of dynamic hydrogel enabled minimally invasive and precise treatment of cartilage injury assisted by continuous KGN administration. The hydrogel could significantly promote the expression of cartilage matrix components (type II collagen and aggrecan) in articular chondrocytes without affecting cell proliferation or migration in vitro . Mechanistically, the protective effects depended on enhancing chondrocyte mitochondrial function and intracellular antioxidant properties. In situ hydrogel injection strengthened cartilage regenerative potential and facilitated the reconstruction of subchondral bone following full-thickness defects in vivo . This study revealed that the dynamic chondrogenic hydrogel could benefit cartilage repair via mitochondrial reinforcement, acting as a novel therapeutic strategy for refractory cartilage damage.
研究领域:
生物医学工程
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组织工程
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再生医学
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骨科
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药学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）