In Situ Deposition of Drug and Gene Nanoparticles on a Patterned Supramolecular Hydrogel to Construct a Directionally Osteochondral Plug
Corresponding Author: Yiying Qi
Nano-Micro Letters,
Vol. 16 (2024), Article Number: 18
Abstract
The integrated repair of bone and cartilage boasts advantages for osteochondral restoration such as a long-term repair effect and less deterioration compared to repairing cartilage alone. Constructing multifactorial, spatially oriented scaffolds to stimulate osteochondral regeneration, has immense significance. Herein, targeted drugs, namely kartogenin@polydopamine (KGN@PDA) nanoparticles for cartilage repair and miRNA@calcium phosphate (miRNA@CaP) NPs for bone regeneration, were in situ deposited on a patterned supramolecular-assembled 2-ureido-4 [lH]-pyrimidinone (UPy) modified gelation hydrogel film, facilitated by the dynamic and responsive coordination and complexation of metal ions and their ligands. This hydrogel film can be rolled into a cylindrical plug, mimicking the Haversian canal structure of natural bone. The resultant hydrogel demonstrates stable mechanical properties, a self-healing ability, a high capability for reactive oxygen species capture, and controlled release of KGN and miR-26a. In vitro, KGN@PDA and miRNA@CaP promote chondrogenic and osteogenic differentiation of mesenchymal stem cells via the JNK/RUNX1 and GSK-3β/β-catenin pathways, respectively. In vivo, the osteochondral plug exhibits optimal subchondral bone and cartilage regeneration, evidenced by a significant increase in glycosaminoglycan and collagen accumulation in specific zones, along with the successful integration of neocartilage with subchondral bone. This biomaterial delivery approach represents a significant toward improved osteochondral repair.
Highlights:
1 A multifactorial and oriented scaffolds was constructed to stimulate osteochondral regeneration.
2 This is the first demonstration that both drug and gene nanoparticles were spatially deposited on a patterned film through metal-ligand interactions.
3 For the first time, film-rolling approach was employed to construct osteochondral plug to mimick the Haversian canal structure of natural bone.
Keywords
Download Citation
Endnote/Zotero/Mendeley (RIS)BibTeX
- C.G. Pfeifer, M.B. Fisher, V. Saxena, M. Kim, E.A. Henning et al., Age-dependent subchondral bone remodeling and cartilage repair in a minipig defect model. Tissue Eng. C Methods 23(11), 745–753 (2017). https://doi.org/10.1089/ten.TEC.2017.0109
- M. Tamaddon, H. Gilja, L. Wang, J.M. Oliveira, X. Sun et al., Osteochondral scaffolds for early treatment of cartilage defects in osteoarthritic joints: from bench to clinic. Biomater. Transl. 1(1), 3–17 (2020). https://doi.org/10.3877/cma.j.issn.2096-112X.2020.01.002
- A.M. Yousefi, M.E. Hoque, R.G. Prasad, N. Uth, Current strategies in multiphasic scaffold design for osteochondral tissue engineering: a review. J. Biomed. Mater. Res. A 103(7), 2460–2481 (2015). https://doi.org/10.1002/jbm.a.35356
- X. Niu, N. Li, Z. Du, X. Li, Integrated gradient tissue-engineered osteochondral scaffolds: challenges, current efforts and future perspectives. Bioact. Mater. 20, 574–597 (2023). https://doi.org/10.1016/j.bioactmat.2022.06.011
- W. Wei, W. Liu, H. Kang, X. Zhang, R. Yu et al., A one-stone-two-birds strategy for osteochondral regeneration based on a 3d printable biomimetic scaffold with kartogenin biochemical stimuli gradient. Adv. Healthc. Mater. 12(15), e2300108 (2023). https://doi.org/10.1002/adhm.202300108
- S. Hu, Z. Li, D. Shen, D. Zhu, K. Huang et al., Exosome-eluting stents for vascular healing after ischaemic injury. Nat. Biomed. Eng. 5(10), 1174–1188 (2021). https://doi.org/10.1038/s41551-021-00705-0
- S. Torii, H. Jinnouchi, A. Sakamoto, M. Kutyna, A. Cornelissen et al., Drug-eluting coronary stents: Insights from preclinical and pathology studies. Nat. Rev. Cardiol.Cardiol. 17(1), 37–51 (2020). https://doi.org/10.1038/s41569-019-0234-x
- M.K. Nguyen, E. Alsberg, Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine. Prog. Polym. Sci.. Polym. Sci. 39(7), 1236–1265 (2014). https://doi.org/10.1016/j.progpolymsci.2013.12.001
- C. Husteden, Y.A. Brito Barrera, S. Tegtmeyer, J. Borges, J. Giselbrecht et al., Lipoplex-functionalized thin-film surface coating based on extracellular matrix components as local gene delivery system to control osteogenic stem cell differentiation. Adv. Healthc. Mater. 12(5), e2201978 (2023). https://doi.org/10.1002/adhm.202201978
- Y. Yang, P. Gao, J. Wang, Q. Tu, L. Bai et al., Endothelium-mimicking multifunctional coating modified cardiovascular stents via a stepwise metal-catechol-(amine) surface engineering strategy. Research 2020, 9203906 (2020). https://doi.org/10.34133/2020/9203906
- X. Li, B. Dai, J. Guo, L. Zheng, Q. Guo et al., Nanop-cartilage interaction: pathology-based intra-articular drug delivery for osteoarthritis therapy. Nano-Micro Lett. 13(1), 149 (2021). https://doi.org/10.1007/s40820-021-00670-y
- K. Johnson, S. Zhu, M.S. Tremblay, J.N. Payette, J. Wang et al., A stem cell-based approach to cartilage repair. Science 336(6082), 717–721 (2012). https://doi.org/10.1126/science.1215157
- M.L. Kang, J.Y. Ko, J.E. Kim, G.I. Im, Intra-articular delivery of kartogenin-conjugated chitosan nano/microps for cartilage regeneration. Biomaterials 35(37), 9984–9994 (2014). https://doi.org/10.1016/j.biomaterials.2014.08.042
- S.S. Lee, G.E. Choi, H.J. Lee, Y. Kim, J.H. Choy et al., Layered double hydroxide and polypeptide thermogel nanocomposite system for chondrogenic differentiation of stem cells. ACS Appl. Mater. Interfaces 9(49), 42668–42675 (2017). https://doi.org/10.1021/acsami.7b17173
- D. Shi, X. Xu, Y. Ye, K. Song, Y. Cheng et al., Photo-cross-linked scaffold with kartogenin-encapsulated nanops for cartilage regeneration. ACS Nano 10(1), 1292–1299 (2016). https://doi.org/10.1021/acsnano.5b06663
- G. Mohan, S. Magnitsky, G. Melkus, K. Subburaj, G. Kazakia et al., Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: a pilot study. J. Orthop. Res.Orthop. Res. 34(10), 1780–1789 (2016). https://doi.org/10.1002/jor.23197
- J. Zhang, J.H. Wang, Kartogenin induces cartilage-like tissue formation in tendon-bone junction. Bone Res. 2, 14008 (2014). https://doi.org/10.1038/boneres.2014.8
- J. Wang, J. Zhou, N. Zhang, X. Zhang, Q. Li, A heterocyclic molecule kartogenin induces collagen synthesis of human dermal fibroblasts by activating the smad4/smad5 pathway. Biochem. Biophys. Res. Commun.. Biophys. Res. Commun. 450(1), 568–574 (2014). https://doi.org/10.1016/j.bbrc.2014.06.016
- R.S. Decker, E. Koyama, M. Enomoto-Iwamoto, P. Maye, D. Rowe et al., Mouse limb skeletal growth and synovial joint development are coordinately enhanced by kartogenin. Dev. Biol. 395(2), 255–267 (2014). https://doi.org/10.1016/j.ydbio.2014.09.011
- X. Su, L. Liao, Y. Shuai, H. Jing, S. Liu et al., miR-26a functions oppositely in osteogenic differentiation of BMSCS and ADSCS depending on distinct activation and roles of WNT and bmp signaling pathway. Cell Death Dis. 6(8), e1851 (2015). https://doi.org/10.1038/cddis.2015.221
- Y. Li, L. Fan, S. Liu, W. Liu, H. Zhang et al., The promotion of bone regeneration through positive regulation of angiogenic-osteogenic coupling using microrna-26a. Biomaterials 34(21), 5048–5058 (2013). https://doi.org/10.1016/j.biomaterials.2013.03.052
- F. Jiang, Y. Zong, X. Ma, C. Jiang, H. Shan et al., miR-26a attenuated bone-specific insulin resistance and bone quality in diabetic mice. Mol. Ther. Nucleic Acids 20, 459–467 (2020). https://doi.org/10.1016/j.omtn.2020.03.010
- T. Yu, P. Wang, Y. Wu, J. Zhong, Q. Chen et al., miR-26a reduces inflammatory responses via inhibition of pge2 production by targeting COX-2. Inflammation 45(4), 1484–1495 (2022). https://doi.org/10.1007/s10753-022-01631-2
- R. Zuo, L. Kong, M. Wang, W. Wang, J. Xu et al., Exosomes derived from human cd34(+) stem cells transfected with mir-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis. Stem Cell Res. Ther.Ther. 10(1), 321 (2019). https://doi.org/10.1186/s13287-019-1426-3
- X. Xing, S. Guo, G. Zhang, Y. Liu, S. Bi et al., miR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3k/AKT signaling pathway. Braz. J. Med. Biol. Res. 53(2), e9106 (2020). https://doi.org/10.1590/1414-431X20199106
- W. Wang, J. Chen, M. Li, H. Jia, X. Han et al., Rebuilding postinfarcted cardiac functions by injecting Tiia@PdA nanop-cross-linked ros-sensitive hydrogels. ACS Appl. Mater. Interfaces 11(3), 2880–2890 (2019). https://doi.org/10.1021/acsami.8b20158
- M.J. Shen, C.Y. Wang, D.X. Hao, J.X. Hao, Y.F. Zhu et al., Multifunctional nanomachinery for enhancement of bone healing. Adv. Mater. 34(9), e2107924 (2022). https://doi.org/10.1002/adma.202107924
- P.Y. Dankers, E.N. van Leeuwen, G.M. van Gemert, A.J. Spiering, M.C. Harmsen et al., Chemical and biological properties of supramolecular polymer systems based on oligocaprolactones. Biomaterials 27(32), 5490–5501 (2006). https://doi.org/10.1016/j.biomaterials.2006.07.011
- H. Sun, J. Xu, Y. Wang, S. Shen, X. Xu et al., Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair. Bioact. Mater. 24, 477–496 (2023). https://doi.org/10.1016/j.bioactmat.2022.12.021
- Q. Zeng, Q. Peng, F. Wang, G. Shi, H. Haick et al., Tailoring food biopolymers into biogels for regenerative wound healing and versatile skin bioelectronics. Nano-Micro Lett. 15(1), 153 (2023). https://doi.org/10.1007/s40820-023-01099-1
- L. Yang, Y. Liu, L. Sun, C. Zhao, G. Chen et al., Biomass microcapsules with stem cell encapsulation for bone repair. Nano-Micro Lett. 14, 4 (2022). https://doi.org/10.1007/s40820-021-00747-8
- Q. Zhang, G. Kuang, W. Li, J. Wang, H. Ren et al., Stimuli-responsive gene delivery nanocarriers for cancer therapy. Nano-Micro Lett. 15(1), 44 (2023). https://doi.org/10.1007/s40820-023-01018-4
- Y. Han, B. Jia, M. Lian, B. Sun, Q. Wu et al., High-precision, gelatin-based, hybrid, bilayer scaffolds using melt electro-writing to repair cartilage injury. Bioact. Mater. 6(7), 2173–2186 (2021). https://doi.org/10.1016/j.bioactmat.2020.12.018
- Z. Qiao, M. Lian, Y. Han, B. Sun, X. Zhang et al., Bioinspired stratified electrowritten fiber-reinforced hydrogel constructs with layer-specific induction capacity for functional osteochondral regeneration. Biomaterials 266, 120385 (2021). https://doi.org/10.1016/j.biomaterials.2020.120385
- C.Y. Xu, R. Inai, M. Kotaki, S. Ramakrishna, Aligned biodegradable nanofibrous structure: a potential scaffold for blood vessel engineering. Biomaterials 25(5), 877–886 (2004). https://doi.org/10.1016/s0142-9612(03)00593-3
- L. Koepsell, L. Zhang, D. Neufeld, H. Fong, Y. Deng, Electrospun nanofibrous polycaprolactone scaffolds for tissue engineering of annulus fibrosus. Macromol. Biosci.. Biosci. 11(3), 391–399 (2011). https://doi.org/10.1002/mabi.201000352
- Y. Zhang, F. Yang, K. Liu, H. Shen, Y. Zhu et al., The impact of PLGA scaffold orientation on in vitro cartilage regeneration. Biomaterials 33(10), 2926–2935 (2012). https://doi.org/10.1016/j.biomaterials.2012.01.006
- Y. Qi, W. Zhang, G. Li, L. Niu, Y. Zhang et al., An oriented-collagen scaffold including wnt5a promotes osteochondral regeneration and cartilage interface integration in a rabbit model. FASEB J. 34(8), 11115–11132 (2020). https://doi.org/10.1096/fj.202000280R
- X. Xu, D. Shi, Y. Shen, Z. Xu, J. Dai et al., Full-thickness cartilage defects are repaired via a microfracture technique and intraarticular injection of the small-molecule compound kartogenin. Arthritis Res. Ther.Ther. 17(1), 20 (2015). https://doi.org/10.1186/s13075-015-0537-1
- H. Jing, X. Zhang, M. Gao, K. Luo, W. Fu et al., Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating jnk and beta-catenin-related pathways. FASEB J. 33(4), 5641–5653 (2019). https://doi.org/10.1096/fj.201802137RRR
- A. Baharlou Houreh, E. Masaeli, M.H. Nasr-Esfahani, Chitosan/polycaprolactone multilayer hydrogel: a sustained kartogenin delivery model for cartilage regeneration. Int. J. Biol. Macromol.Macromol. 177, 589–600 (2021). https://doi.org/10.1016/j.ijbiomac.2021.02.122
- M. Hou, Y. Zhang, X. Zhou, T. Liu, H. Yang et al., Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis. Cell Death Dis. 12(5), 483 (2021). https://doi.org/10.1038/s41419-021-03765-x
- S. Yang, S. Guo, S. Tong, X. Sun, Promoting osteogenic differentiation of human adipose-derived stem cells by altering the expression of exosomal mirna. Stem Cells Int. 2019, 1351860 (2019). https://doi.org/10.1155/2019/1351860
- W.M. Hodges, F. O’Brien, S. Fulzele, M.W. Hamrick, Function of micrornas in the osteogenic differentiation and therapeutic application of adipose-derived stem cells (ASCS). Int. J. Mol. Sci. 18(12), 2597 (2017). https://doi.org/10.3390/ijms18122597
- J. Yin, S. Pan, X. Guo, Y. Gao, D. Zhu et al., Nb(2)C MXene-functionalized scaffolds enables osteosarcoma phototherapy and angiogenesis/osteogenesis of bone defects. Nano-Micro Lett. 13(1), 30 (2021). https://doi.org/10.1007/s40820-020-00547-6
- R. Li, H. Wang, J.V. John, H. Song, M.J. Teusink et al., 3d hybrid nanofiber aerogels combining with nanops made of a biocleavable and targeting polycation and miR-26a for bone repair. Adv. Funct. Mater.Funct. Mater. 30(49), 2005531 (2020). https://doi.org/10.1002/adfm.202005531
- Y. Xiong, F. Cao, L. Hu, C. Yan, L. Chen et al., miRNA-26a-5p accelerates healing via downregulation of PTEN in fracture patients with traumatic brain injury. Mol. Ther. Nucleic Acids 17, 223–234 (2019). https://doi.org/10.1016/j.omtn.2019.06.001
- M. Gan, Q. Zhou, J. Ge, J. Zhao, Y. Wang et al., Precise in-situ release of microrna from an injectable hydrogel induces bone regeneration. Acta Biomater. Biomater. 135, 289–303 (2021). https://doi.org/10.1016/j.actbio.2021.08.041
- X. Zhang, Y. Li, Y.E. Chen, J. Chen, P.X. Ma, Cell-free 3d scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun.Commun. 7, 10376 (2016). https://doi.org/10.1038/ncomms10376
- T. Vacik, J.L. Stubbs, G. Lemke, A novel mechanism for the transcriptional regulation of wnt signaling in development. Genes Dev. 25(17), 1783–1795 (2011). https://doi.org/10.1101/gad.17227011
- L. Jiang, S. Cao, Role of microRNA-26a in cartilage injury and chondrocyte proliferation and apoptosis in rheumatoid arthritis rats by regulating expression of CTGF. J. Cell. Physiol. 235(2), 979–992 (2020). https://doi.org/10.1002/jcp.29013
- X. Shao, Z. Hu, Y. Zhan, W. Ma, L. Quan et al., mir-26a-tetrahedral framework nucleic acids mediated osteogenesis of adipose-derived mesenchymal stem cells. Cell Prolif.Prolif. 55(7), e13272 (2022). https://doi.org/10.1111/cpr.13272
- Y. Li, L. Fan, J. Hu, L. Zhang, L. Liao et al., mir-26a rescues bone regeneration deficiency of mesenchymal stem cells derived from osteoporotic mice. Mol. Ther.Ther. 23(8), 1349–1357 (2015). https://doi.org/10.1038/mt.2015.101
- Y.H. Liao, Y.H. Chang, L.Y. Sung, K.C. Li, C.L. Yeh et al., Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b. Biomaterials 35(18), 4901–4910 (2014). https://doi.org/10.1016/j.biomaterials.2014.02.055
- A.S. Levy, J. Lohnes, S. Sculley, M. LeCroy, W. Garrett, Chondral delamination of the knee in soccer players. Am. J. Sports Med. 24(5), 634–639 (1996). https://doi.org/10.1177/036354659602400512
- C.R. Chu, J.S. Dounchis, M. Yoshioka, R.L. Sah, R.D. Coutts et al., Osteochondral repair using perichondrial cells. A 1-year study in rabbits. Clin. Orthop. Relat. Res.. Orthop. Relat. Res. 340, 220–229 (1997). https://doi.org/10.1097/00003086-199707000-00029
- Q. Meng, S. An, R.A. Damion, Z. Jin, R. Wilcox et al., The effect of collagen fibril orientation on the biphasic mechanics of articular cartilage. J. Mech. Behav. Biomed. Mater.Behav. Biomed. Mater. 65, 439–453 (2017). https://doi.org/10.1016/j.jmbbm.2016.09.001
- W. Yan, X. Xu, Q. Xu, Z. Sun, Z. Lv et al., An injectable hydrogel scaffold with kartogenin-encapsulated nanops for porcine cartilage regeneration: a 12-month follow-up study. Am. J. Sports Med. 48(13), 3233–3244 (2020). https://doi.org/10.1177/0363546520957346
References
C.G. Pfeifer, M.B. Fisher, V. Saxena, M. Kim, E.A. Henning et al., Age-dependent subchondral bone remodeling and cartilage repair in a minipig defect model. Tissue Eng. C Methods 23(11), 745–753 (2017). https://doi.org/10.1089/ten.TEC.2017.0109
M. Tamaddon, H. Gilja, L. Wang, J.M. Oliveira, X. Sun et al., Osteochondral scaffolds for early treatment of cartilage defects in osteoarthritic joints: from bench to clinic. Biomater. Transl. 1(1), 3–17 (2020). https://doi.org/10.3877/cma.j.issn.2096-112X.2020.01.002
A.M. Yousefi, M.E. Hoque, R.G. Prasad, N. Uth, Current strategies in multiphasic scaffold design for osteochondral tissue engineering: a review. J. Biomed. Mater. Res. A 103(7), 2460–2481 (2015). https://doi.org/10.1002/jbm.a.35356
X. Niu, N. Li, Z. Du, X. Li, Integrated gradient tissue-engineered osteochondral scaffolds: challenges, current efforts and future perspectives. Bioact. Mater. 20, 574–597 (2023). https://doi.org/10.1016/j.bioactmat.2022.06.011
W. Wei, W. Liu, H. Kang, X. Zhang, R. Yu et al., A one-stone-two-birds strategy for osteochondral regeneration based on a 3d printable biomimetic scaffold with kartogenin biochemical stimuli gradient. Adv. Healthc. Mater. 12(15), e2300108 (2023). https://doi.org/10.1002/adhm.202300108
S. Hu, Z. Li, D. Shen, D. Zhu, K. Huang et al., Exosome-eluting stents for vascular healing after ischaemic injury. Nat. Biomed. Eng. 5(10), 1174–1188 (2021). https://doi.org/10.1038/s41551-021-00705-0
S. Torii, H. Jinnouchi, A. Sakamoto, M. Kutyna, A. Cornelissen et al., Drug-eluting coronary stents: Insights from preclinical and pathology studies. Nat. Rev. Cardiol.Cardiol. 17(1), 37–51 (2020). https://doi.org/10.1038/s41569-019-0234-x
M.K. Nguyen, E. Alsberg, Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine. Prog. Polym. Sci.. Polym. Sci. 39(7), 1236–1265 (2014). https://doi.org/10.1016/j.progpolymsci.2013.12.001
C. Husteden, Y.A. Brito Barrera, S. Tegtmeyer, J. Borges, J. Giselbrecht et al., Lipoplex-functionalized thin-film surface coating based on extracellular matrix components as local gene delivery system to control osteogenic stem cell differentiation. Adv. Healthc. Mater. 12(5), e2201978 (2023). https://doi.org/10.1002/adhm.202201978
Y. Yang, P. Gao, J. Wang, Q. Tu, L. Bai et al., Endothelium-mimicking multifunctional coating modified cardiovascular stents via a stepwise metal-catechol-(amine) surface engineering strategy. Research 2020, 9203906 (2020). https://doi.org/10.34133/2020/9203906
X. Li, B. Dai, J. Guo, L. Zheng, Q. Guo et al., Nanop-cartilage interaction: pathology-based intra-articular drug delivery for osteoarthritis therapy. Nano-Micro Lett. 13(1), 149 (2021). https://doi.org/10.1007/s40820-021-00670-y
K. Johnson, S. Zhu, M.S. Tremblay, J.N. Payette, J. Wang et al., A stem cell-based approach to cartilage repair. Science 336(6082), 717–721 (2012). https://doi.org/10.1126/science.1215157
M.L. Kang, J.Y. Ko, J.E. Kim, G.I. Im, Intra-articular delivery of kartogenin-conjugated chitosan nano/microps for cartilage regeneration. Biomaterials 35(37), 9984–9994 (2014). https://doi.org/10.1016/j.biomaterials.2014.08.042
S.S. Lee, G.E. Choi, H.J. Lee, Y. Kim, J.H. Choy et al., Layered double hydroxide and polypeptide thermogel nanocomposite system for chondrogenic differentiation of stem cells. ACS Appl. Mater. Interfaces 9(49), 42668–42675 (2017). https://doi.org/10.1021/acsami.7b17173
D. Shi, X. Xu, Y. Ye, K. Song, Y. Cheng et al., Photo-cross-linked scaffold with kartogenin-encapsulated nanops for cartilage regeneration. ACS Nano 10(1), 1292–1299 (2016). https://doi.org/10.1021/acsnano.5b06663
G. Mohan, S. Magnitsky, G. Melkus, K. Subburaj, G. Kazakia et al., Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: a pilot study. J. Orthop. Res.Orthop. Res. 34(10), 1780–1789 (2016). https://doi.org/10.1002/jor.23197
J. Zhang, J.H. Wang, Kartogenin induces cartilage-like tissue formation in tendon-bone junction. Bone Res. 2, 14008 (2014). https://doi.org/10.1038/boneres.2014.8
J. Wang, J. Zhou, N. Zhang, X. Zhang, Q. Li, A heterocyclic molecule kartogenin induces collagen synthesis of human dermal fibroblasts by activating the smad4/smad5 pathway. Biochem. Biophys. Res. Commun.. Biophys. Res. Commun. 450(1), 568–574 (2014). https://doi.org/10.1016/j.bbrc.2014.06.016
R.S. Decker, E. Koyama, M. Enomoto-Iwamoto, P. Maye, D. Rowe et al., Mouse limb skeletal growth and synovial joint development are coordinately enhanced by kartogenin. Dev. Biol. 395(2), 255–267 (2014). https://doi.org/10.1016/j.ydbio.2014.09.011
X. Su, L. Liao, Y. Shuai, H. Jing, S. Liu et al., miR-26a functions oppositely in osteogenic differentiation of BMSCS and ADSCS depending on distinct activation and roles of WNT and bmp signaling pathway. Cell Death Dis. 6(8), e1851 (2015). https://doi.org/10.1038/cddis.2015.221
Y. Li, L. Fan, S. Liu, W. Liu, H. Zhang et al., The promotion of bone regeneration through positive regulation of angiogenic-osteogenic coupling using microrna-26a. Biomaterials 34(21), 5048–5058 (2013). https://doi.org/10.1016/j.biomaterials.2013.03.052
F. Jiang, Y. Zong, X. Ma, C. Jiang, H. Shan et al., miR-26a attenuated bone-specific insulin resistance and bone quality in diabetic mice. Mol. Ther. Nucleic Acids 20, 459–467 (2020). https://doi.org/10.1016/j.omtn.2020.03.010
T. Yu, P. Wang, Y. Wu, J. Zhong, Q. Chen et al., miR-26a reduces inflammatory responses via inhibition of pge2 production by targeting COX-2. Inflammation 45(4), 1484–1495 (2022). https://doi.org/10.1007/s10753-022-01631-2
R. Zuo, L. Kong, M. Wang, W. Wang, J. Xu et al., Exosomes derived from human cd34(+) stem cells transfected with mir-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis. Stem Cell Res. Ther.Ther. 10(1), 321 (2019). https://doi.org/10.1186/s13287-019-1426-3
X. Xing, S. Guo, G. Zhang, Y. Liu, S. Bi et al., miR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3k/AKT signaling pathway. Braz. J. Med. Biol. Res. 53(2), e9106 (2020). https://doi.org/10.1590/1414-431X20199106
W. Wang, J. Chen, M. Li, H. Jia, X. Han et al., Rebuilding postinfarcted cardiac functions by injecting Tiia@PdA nanop-cross-linked ros-sensitive hydrogels. ACS Appl. Mater. Interfaces 11(3), 2880–2890 (2019). https://doi.org/10.1021/acsami.8b20158
M.J. Shen, C.Y. Wang, D.X. Hao, J.X. Hao, Y.F. Zhu et al., Multifunctional nanomachinery for enhancement of bone healing. Adv. Mater. 34(9), e2107924 (2022). https://doi.org/10.1002/adma.202107924
P.Y. Dankers, E.N. van Leeuwen, G.M. van Gemert, A.J. Spiering, M.C. Harmsen et al., Chemical and biological properties of supramolecular polymer systems based on oligocaprolactones. Biomaterials 27(32), 5490–5501 (2006). https://doi.org/10.1016/j.biomaterials.2006.07.011
H. Sun, J. Xu, Y. Wang, S. Shen, X. Xu et al., Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair. Bioact. Mater. 24, 477–496 (2023). https://doi.org/10.1016/j.bioactmat.2022.12.021
Q. Zeng, Q. Peng, F. Wang, G. Shi, H. Haick et al., Tailoring food biopolymers into biogels for regenerative wound healing and versatile skin bioelectronics. Nano-Micro Lett. 15(1), 153 (2023). https://doi.org/10.1007/s40820-023-01099-1
L. Yang, Y. Liu, L. Sun, C. Zhao, G. Chen et al., Biomass microcapsules with stem cell encapsulation for bone repair. Nano-Micro Lett. 14, 4 (2022). https://doi.org/10.1007/s40820-021-00747-8
Q. Zhang, G. Kuang, W. Li, J. Wang, H. Ren et al., Stimuli-responsive gene delivery nanocarriers for cancer therapy. Nano-Micro Lett. 15(1), 44 (2023). https://doi.org/10.1007/s40820-023-01018-4
Y. Han, B. Jia, M. Lian, B. Sun, Q. Wu et al., High-precision, gelatin-based, hybrid, bilayer scaffolds using melt electro-writing to repair cartilage injury. Bioact. Mater. 6(7), 2173–2186 (2021). https://doi.org/10.1016/j.bioactmat.2020.12.018
Z. Qiao, M. Lian, Y. Han, B. Sun, X. Zhang et al., Bioinspired stratified electrowritten fiber-reinforced hydrogel constructs with layer-specific induction capacity for functional osteochondral regeneration. Biomaterials 266, 120385 (2021). https://doi.org/10.1016/j.biomaterials.2020.120385
C.Y. Xu, R. Inai, M. Kotaki, S. Ramakrishna, Aligned biodegradable nanofibrous structure: a potential scaffold for blood vessel engineering. Biomaterials 25(5), 877–886 (2004). https://doi.org/10.1016/s0142-9612(03)00593-3
L. Koepsell, L. Zhang, D. Neufeld, H. Fong, Y. Deng, Electrospun nanofibrous polycaprolactone scaffolds for tissue engineering of annulus fibrosus. Macromol. Biosci.. Biosci. 11(3), 391–399 (2011). https://doi.org/10.1002/mabi.201000352
Y. Zhang, F. Yang, K. Liu, H. Shen, Y. Zhu et al., The impact of PLGA scaffold orientation on in vitro cartilage regeneration. Biomaterials 33(10), 2926–2935 (2012). https://doi.org/10.1016/j.biomaterials.2012.01.006
Y. Qi, W. Zhang, G. Li, L. Niu, Y. Zhang et al., An oriented-collagen scaffold including wnt5a promotes osteochondral regeneration and cartilage interface integration in a rabbit model. FASEB J. 34(8), 11115–11132 (2020). https://doi.org/10.1096/fj.202000280R
X. Xu, D. Shi, Y. Shen, Z. Xu, J. Dai et al., Full-thickness cartilage defects are repaired via a microfracture technique and intraarticular injection of the small-molecule compound kartogenin. Arthritis Res. Ther.Ther. 17(1), 20 (2015). https://doi.org/10.1186/s13075-015-0537-1
H. Jing, X. Zhang, M. Gao, K. Luo, W. Fu et al., Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating jnk and beta-catenin-related pathways. FASEB J. 33(4), 5641–5653 (2019). https://doi.org/10.1096/fj.201802137RRR
A. Baharlou Houreh, E. Masaeli, M.H. Nasr-Esfahani, Chitosan/polycaprolactone multilayer hydrogel: a sustained kartogenin delivery model for cartilage regeneration. Int. J. Biol. Macromol.Macromol. 177, 589–600 (2021). https://doi.org/10.1016/j.ijbiomac.2021.02.122
M. Hou, Y. Zhang, X. Zhou, T. Liu, H. Yang et al., Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis. Cell Death Dis. 12(5), 483 (2021). https://doi.org/10.1038/s41419-021-03765-x
S. Yang, S. Guo, S. Tong, X. Sun, Promoting osteogenic differentiation of human adipose-derived stem cells by altering the expression of exosomal mirna. Stem Cells Int. 2019, 1351860 (2019). https://doi.org/10.1155/2019/1351860
W.M. Hodges, F. O’Brien, S. Fulzele, M.W. Hamrick, Function of micrornas in the osteogenic differentiation and therapeutic application of adipose-derived stem cells (ASCS). Int. J. Mol. Sci. 18(12), 2597 (2017). https://doi.org/10.3390/ijms18122597
J. Yin, S. Pan, X. Guo, Y. Gao, D. Zhu et al., Nb(2)C MXene-functionalized scaffolds enables osteosarcoma phototherapy and angiogenesis/osteogenesis of bone defects. Nano-Micro Lett. 13(1), 30 (2021). https://doi.org/10.1007/s40820-020-00547-6
R. Li, H. Wang, J.V. John, H. Song, M.J. Teusink et al., 3d hybrid nanofiber aerogels combining with nanops made of a biocleavable and targeting polycation and miR-26a for bone repair. Adv. Funct. Mater.Funct. Mater. 30(49), 2005531 (2020). https://doi.org/10.1002/adfm.202005531
Y. Xiong, F. Cao, L. Hu, C. Yan, L. Chen et al., miRNA-26a-5p accelerates healing via downregulation of PTEN in fracture patients with traumatic brain injury. Mol. Ther. Nucleic Acids 17, 223–234 (2019). https://doi.org/10.1016/j.omtn.2019.06.001
M. Gan, Q. Zhou, J. Ge, J. Zhao, Y. Wang et al., Precise in-situ release of microrna from an injectable hydrogel induces bone regeneration. Acta Biomater. Biomater. 135, 289–303 (2021). https://doi.org/10.1016/j.actbio.2021.08.041
X. Zhang, Y. Li, Y.E. Chen, J. Chen, P.X. Ma, Cell-free 3d scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun.Commun. 7, 10376 (2016). https://doi.org/10.1038/ncomms10376
T. Vacik, J.L. Stubbs, G. Lemke, A novel mechanism for the transcriptional regulation of wnt signaling in development. Genes Dev. 25(17), 1783–1795 (2011). https://doi.org/10.1101/gad.17227011
L. Jiang, S. Cao, Role of microRNA-26a in cartilage injury and chondrocyte proliferation and apoptosis in rheumatoid arthritis rats by regulating expression of CTGF. J. Cell. Physiol. 235(2), 979–992 (2020). https://doi.org/10.1002/jcp.29013
X. Shao, Z. Hu, Y. Zhan, W. Ma, L. Quan et al., mir-26a-tetrahedral framework nucleic acids mediated osteogenesis of adipose-derived mesenchymal stem cells. Cell Prolif.Prolif. 55(7), e13272 (2022). https://doi.org/10.1111/cpr.13272
Y. Li, L. Fan, J. Hu, L. Zhang, L. Liao et al., mir-26a rescues bone regeneration deficiency of mesenchymal stem cells derived from osteoporotic mice. Mol. Ther.Ther. 23(8), 1349–1357 (2015). https://doi.org/10.1038/mt.2015.101
Y.H. Liao, Y.H. Chang, L.Y. Sung, K.C. Li, C.L. Yeh et al., Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b. Biomaterials 35(18), 4901–4910 (2014). https://doi.org/10.1016/j.biomaterials.2014.02.055
A.S. Levy, J. Lohnes, S. Sculley, M. LeCroy, W. Garrett, Chondral delamination of the knee in soccer players. Am. J. Sports Med. 24(5), 634–639 (1996). https://doi.org/10.1177/036354659602400512
C.R. Chu, J.S. Dounchis, M. Yoshioka, R.L. Sah, R.D. Coutts et al., Osteochondral repair using perichondrial cells. A 1-year study in rabbits. Clin. Orthop. Relat. Res.. Orthop. Relat. Res. 340, 220–229 (1997). https://doi.org/10.1097/00003086-199707000-00029
Q. Meng, S. An, R.A. Damion, Z. Jin, R. Wilcox et al., The effect of collagen fibril orientation on the biphasic mechanics of articular cartilage. J. Mech. Behav. Biomed. Mater.Behav. Biomed. Mater. 65, 439–453 (2017). https://doi.org/10.1016/j.jmbbm.2016.09.001
W. Yan, X. Xu, Q. Xu, Z. Sun, Z. Lv et al., An injectable hydrogel scaffold with kartogenin-encapsulated nanops for porcine cartilage regeneration: a 12-month follow-up study. Am. J. Sports Med. 48(13), 3233–3244 (2020). https://doi.org/10.1177/0363546520957346