Research progress on bone repair biomaterials with the function of recruiting endogenous mesenchymal stem cells_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHAO Junjie ^1,2 , ZHAO Yuhao ^1,2 , PU Yanchuan ^1,3 , WANG Xiyu ^1,2 , HUANG Pengfei ^1,2 , ZHANG Zhaokun ^1,2 ,  ZHAO Haiyan ^1,2

1. The First School of Clinical Medicine, Lanzhou University, Lanzhou Gansu, 730000, P. R. China;
2. Department of Orthopaedics, the First Hospital of Lanzhou University, Lanzhou Gansu, 730000, P. R. China;
3. Department of Orthopaedics, Wuwei People’s Hosptial, Wuwei Gansu, 733000, P. R. China;

Corresponding author：

ZHAO Haiyan, Email: zhaohaiyan8606@163.com

Keywords：

Bone tissue engineering; mesenchymal stem cells; bone defect; bone repair; biomaterial

DOI：

10.7507/1002-1892.202407101

Video：

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Objective To review the research progress on bone repair biomaterials with the function of recruiting endogenous mesenchymal stem cells (MSCs). Methods An extensive review of the relevant literature on bone repair biomaterials, particularly those designed to recruit endogenous MSCs, was conducted, encompassing both domestic and international studies from recent years. The construction methods and optimization strategies for these biomaterials were summarized. Additionally, future research directions and focal points concerning this material were proposed. Results With the advancement of tissue engineering technology, bone repair biomaterials have increasingly emerged as an ideal solution for addressing bone defects. MSCs serve as the most critical “seed cells” in bone tissue engineering. Historically, both MSCs and their derived exosomes have been utilized in bone repair biomaterials; however, challenges such as limited sources of MSCs and exosomes, low survival rates, and various other issues have persisted. To address these challenges, researchers are combining growth factors, bioactive peptides, specific aptamers, and other substances with biomaterials to develop constructs that facilitate stem cell recruitment. By optimizing mechanical properties, promoting vascular regeneration, and regulating the microenvironment, it is possible to create effective bone repair biomaterials that enhance stem cell recruitment. Conclusion In comparison to cytokines, phages, and metal ions, bioactive peptides and aptamers obtained through screening exhibit more specific and targeted recruitment functions. Future development directions for bone repair biomaterials will involve the modification of peptides and aptamers with targeted recruitment capabilities in biological materials, as well as the optimization of the mechanical properties of these materials to enhance vascular regeneration and adjust the microenvironment.

1.	Shi W, Jiang Y, Wu T, et al. Advancements in drug-loaded hydrogel systems for bone defect repair. Regen Ther, 2023, 25: 174-185.
2.	Stahl A, Yang YP. Regenerative approaches for the treatment of large bone defects. Tissue Eng Part B Rev, 2021, 27(6): 539-547.
3.	Tang G, Liu Z, Liu Y, et al. Recent trends in the development of bone regenerative biomaterials. Front Cell Dev Biol, 2021, 9: 665813. doi: 10.3389/fcell.2021.665813.
4.	Bunpetch V, Zhang ZY, Zhang X, et al. Strategies for MSC expansion and MSC-based microtissue for bone regeneration. Biomaterials, 2019, 196: 67-79.
5.	Ai Y, Dai F, Li W, et al. Photo-crosslinked bioactive BG/BMSCs^@GelMA hydrogels for bone-defect repairs. Mater Today Bio, 2023, 23: 100882. doi: 10.1016/j.mtbio.2023.100882.
6.	Lei Y, Wang Y, Shen J, et al. Stem cell-recruiting injectable microgels for repairing osteoarthritis. Advanced Functional Material, 2021, 31(48): 2105084. doi: 10.1002/adfm.202105084.
7.	Kim KD, Lee S, Kim M, et al. Exosome-coated silk fibroin 3D-scaffold for inducing osteogenic differentiation of bone marrow derived mesenchymal stem cells. Chemical Engineering Journal, 2021, 406: 127080. doi: 10.1016/j.cej.2020.127080.
8.	Julien A, Kanagalingam A, Martínez-Sarrà E, et al. Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat Commun, 2021, 12(1): 2860. doi: 10.1038/s41467-021-22842-5.
9.	Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nature biotechnology, 2014, 32(3): 252-260.
10.	Cao S, Zhao Y, Hu Y, et al. New perspectives: In-situ tissue engineering for bone repair scaffold. Composites Part B: Engineering, 2020, 202: 108445. doi: 10.1016/j.compositesb.2020.108445.
11.	Wu C, Yan J, Ge C, et al. Macrophage membrane-reversibly camouflaged nanotherapeutics accelerate fracture healing by fostering MSCs recruitment and osteogenic differentiation. J Nanobiotechnology, 2024, 22(1): 411. doi: 10.1186/s12951-024-02679-y.
12.	Eissa S, Zourob M. Aptamer-based label-free electrochemical biosensor array for the detection of total and glycated hemoglobin in human whole blood. Sci Rep, 2017, 7(1): 1016. doi: 10.1038/s41598-017-01226-0.
13.	Xu Z, Wu J, Gong P, et al. Accelerate wound healing by microscale gel array patch encapsulating defined SDF-1α gradient. J Control Release, 2023, 358: 1-12.
14.	Wang H, Chang X, Ma Q, et al. Bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration. Bioact Mater, 2022, 21: 324-339.
15.	Chen L, Yu C, Xiong Y, et al. Multifunctional hydrogel enhances bone regeneration through sustained release of stromal cell-derived factor-1α and exosomes. Bioact Mater, 2022, 25: 460-471.
16.	Gong JS, Zhu GQ, Zhang Y, et al. Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells. Mater Today Bio, 2023, 23: 100854. doi: 10.1016/j.mtbio.2023.100854.
17.	Meng L, Zhao Y, Bu W, et al. Bone mesenchymal stem cells are recruited via CXCL8-CXCR2 and promote EMT through TGF-β signal pathways in oral squamous carcinoma. Cell Prolif, 2020, 53(8): e12859. doi: 10.1111/cpr.12859.
18.	Zeng J, Xiong S, Zhou J, et al. Hollow hydroxyapatite microspheres loaded with rhCXCL13 to recruit BMSC for osteogenesis and synergetic angiogenesis to promote bone regeneration in bone defects. Int J Nanomedicine, 2023, 18: 3509-3534.
19.	Liu S, Liu Y, Jiang L, et al. Recombinant human BMP-2 accelerates the migration of bone marrow mesenchymal stem cells via the CDC42/PAK1/LIMK1 pathway in vitro and in vivo. Biomater Sci, 2018, 7(1): 362-372.
20.	Wu J, Cao L, Liu Y, et al. Functionalization of silk fibroin electrospun scaffolds via bmsc affinity peptide grafting through oxidative self-polymerization of dopamine for bone regeneration. ACS Appl Mater Interfaces, 2019, 11(9): 8878-8895.
21.	Zhang W, Zhang Y, Li X, et al. Multifunctional polyphenol-based silk hydrogel alleviates oxidative stress and enhances endogenous regeneration of osteochondral defects. Mater Today Bio, 2022, 14: 100251. doi: 10.1016/j.mtbio.2022.100251.
22.	Bai J, Ge G, Wang Q, et al. Engineering stem cell recruitment and osteoinduction via bioadhesive molecular mimics to improve osteoporotic bone-implant integration. Research (Wash D C), 2022, 2022: 9823784. doi: 10.34133/2022/9823784.
23.	Zhang W, Sun T, Zhang J, et al. Construction of artificial periosteum with methacrylamide gelatin hydrogel-wharton’s jelly based on stem cell recruitment and its application in bone tissue engineering. Mater Today Bio, 2022, 18: 100528. doi: 10.1016/j.mtbio.2022.100528.
24.	Nowakowski GS, Dooner MS, Valinski HM, et al. A specific heptapeptide from a phage display peptide library homes to bone marrow and binds to primitive hematopoietic stem cells. Stem Cells, 2004, 22(6): 1030-1038.
25.	Huang B, Li P, Chen M, et al. Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications. J Nanobiotechnology, 2022, 20(1): 25. doi: 10.1186/s12951-021-01230-7.
26.	Vandamme D, Landuyt B, Luyten W, et al. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell Immunol, 2012, 280(1): 22-35.
27.	Zhu Y, Lu F, Zhang G, et al. Overview of signal transduction between LL37 and bone marrow-derived MSCs. J Mol Histol, 2022, 53(2): 149-157.
28.	Ma S, Wang C, Dong Y, et al. Microsphere-gel composite system with mesenchymal stem cell recruitment, antibacterial, and immunomodulatory properties promote bone regeneration via sequential release of LL37 and W9 peptides. ACS Appl Mater Interfaces, 2022, 14(34): 38525-38540.
29.	Chen X, Zhang L, Shao X, et al. Specific clearance of senescent synoviocytes suppresses the development of osteoarthritis based on aptamer-functionalized targeted drug delivery system. Advanced Functional Materials, 2022, 32(17): 2109460. https://doi.org/10.1002/adfm.202109460.
30.	Hou Z, Meyer S, Propson NE, et al. Characterization and target identification of a DNA aptamer that labels pluripotent stem cells. Cell Res, 2015, 25(3): 390-393.
31.	Miao Y, Liu X, Luo J, et al. Double-network dna macroporous hydrogel enables aptamer-directed cell recruitment to accelerate bone healing. Adv Sci (Weinh), 2024, 11(1): e2303637. doi: 10.1002/advs.202303637.
32.	Wang Z, Lao A, Huang X, et al. Apt-19s-functionalized 3D-printed mesoporous bioactive glass scaffold promotes bmsc recruitment in bone regeneration via SDF-1α/CXCR4 axis and MAPK signaling. Advanced Functional Materials, 2024. https://doi.org/10.1002/adfm.202316675.
33.	Zhou C, Xu AT, Wang DD, et al. The effects of Sr-incorporated micro/nano rough titanium surface on rBMSC migration and osteogenic differentiation for rapid osteointegration. Biomater Sci, 2018, 6(7): 1946-1961.
34.	Cao B, Li Y, Yang T, et al. Bacteriophage-based biomaterials for tissue regeneration. Adv Drug Deliv Rev, 2019, 145: 73-95.
35.	Sartorius R, D’Apice L, Prisco A, et al. Arming filamentous bacteriophage, a nature-made nanoparticle, for new vaccine and immunotherapeutic strategies. Pharmaceutics, 2019, 11(9): 437. doi: 10.3390/pharmaceutics11090437.
36.	Wang X, Liang Y, Li J, et al. Artificial periosteum promotes bone regeneration through synergistic immune regulation of aligned fibers and BMSC-recruiting phages. Acta Biomater, 2024, 180: 262-278.
37.	Wang X, Zhu X, Wang D, et al. Identification of a specific phage as growth factor alternative promoting the recruitment and differentiation of MSCs in bone tissue regeneration. ACS Biomater Sci Eng, 2023, 9(5): 2426-2437.
38.	Kong D, Wang Q, Huang J, et al. A biomimetic structural material with adjustable mechanical property for bone tissue engineering. Advanced Functional Materials, 2024, 34(8): 2305412. doi: 10.1002/adfm.202305412.
39.	Chen Z, Lv Y. Uninterrupted dynamic stiffening microenvironment enhances the paracrine function of mesenchymal stem cells for vascularization through chromatin remodeling. Materials & Design, 2022, 224(1): 11328. doi: 10.1016/j.matdes.2022.111328.
40.	Wang J, Li J, Lu Y, et al. Incorporation of stromal cell-derived factor-1α in three-dimensional hydroxyapatite/polyacrylonitrile composite scaffolds for bone regeneration. ACS Biomater Sci Eng, 2019, 5(2): 911-921.
41.	Kuang L, Ma X, Ma Y, et al. Self-assembled injectable nanocomposite hydrogels coordinated by in situ generated cap nanoparticles for bone regeneration. ACS Appl Mater Interfaces, 2019, 11(19): 17234-17246.
42.	Zhang X, Li Q, Li L, et al. Bioinspired mild photothermal effect-reinforced multifunctional fiber scaffolds promote bone regeneration. ACS Nano, 2023, 17(7): 6466-6479.
43.	Mao Y, Chen Y, Li W, et al. Physiology-inspired multilayer nanofibrous membranes modulating endogenous stem cell recruitment and osteo-differentiation for staged bone regeneration. Adv Healthc Mater, 2022, 11(21): e2201457. doi: 10.1002/adhm.202201457.

1. Shi W, Jiang Y, Wu T, et al. Advancements in drug-loaded hydrogel systems for bone defect repair. Regen Ther, 2023, 25: 174-185.
2. Stahl A, Yang YP. Regenerative approaches for the treatment of large bone defects. Tissue Eng Part B Rev, 2021, 27(6): 539-547.
3. Tang G, Liu Z, Liu Y, et al. Recent trends in the development of bone regenerative biomaterials. Front Cell Dev Biol, 2021, 9: 665813. doi: 10.3389/fcell.2021.665813.
4. Bunpetch V, Zhang ZY, Zhang X, et al. Strategies for MSC expansion and MSC-based microtissue for bone regeneration. Biomaterials, 2019, 196: 67-79.
5. Ai Y, Dai F, Li W, et al. Photo-crosslinked bioactive BG/BMSCs^@GelMA hydrogels for bone-defect repairs. Mater Today Bio, 2023, 23: 100882. doi: 10.1016/j.mtbio.2023.100882.
6. Lei Y, Wang Y, Shen J, et al. Stem cell-recruiting injectable microgels for repairing osteoarthritis. Advanced Functional Material, 2021, 31(48): 2105084. doi: 10.1002/adfm.202105084.
7. Kim KD, Lee S, Kim M, et al. Exosome-coated silk fibroin 3D-scaffold for inducing osteogenic differentiation of bone marrow derived mesenchymal stem cells. Chemical Engineering Journal, 2021, 406: 127080. doi: 10.1016/j.cej.2020.127080.
8. Julien A, Kanagalingam A, Martínez-Sarrà E, et al. Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat Commun, 2021, 12(1): 2860. doi: 10.1038/s41467-021-22842-5.
9. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nature biotechnology, 2014, 32(3): 252-260.
10. Cao S, Zhao Y, Hu Y, et al. New perspectives: In-situ tissue engineering for bone repair scaffold. Composites Part B: Engineering, 2020, 202: 108445. doi: 10.1016/j.compositesb.2020.108445.
11. Wu C, Yan J, Ge C, et al. Macrophage membrane-reversibly camouflaged nanotherapeutics accelerate fracture healing by fostering MSCs recruitment and osteogenic differentiation. J Nanobiotechnology, 2024, 22(1): 411. doi: 10.1186/s12951-024-02679-y.
12. Eissa S, Zourob M. Aptamer-based label-free electrochemical biosensor array for the detection of total and glycated hemoglobin in human whole blood. Sci Rep, 2017, 7(1): 1016. doi: 10.1038/s41598-017-01226-0.
13. Xu Z, Wu J, Gong P, et al. Accelerate wound healing by microscale gel array patch encapsulating defined SDF-1α gradient. J Control Release, 2023, 358: 1-12.
14. Wang H, Chang X, Ma Q, et al. Bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration. Bioact Mater, 2022, 21: 324-339.
15. Chen L, Yu C, Xiong Y, et al. Multifunctional hydrogel enhances bone regeneration through sustained release of stromal cell-derived factor-1α and exosomes. Bioact Mater, 2022, 25: 460-471.
16. Gong JS, Zhu GQ, Zhang Y, et al. Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells. Mater Today Bio, 2023, 23: 100854. doi: 10.1016/j.mtbio.2023.100854.
17. Meng L, Zhao Y, Bu W, et al. Bone mesenchymal stem cells are recruited via CXCL8-CXCR2 and promote EMT through TGF-β signal pathways in oral squamous carcinoma. Cell Prolif, 2020, 53(8): e12859. doi: 10.1111/cpr.12859.
18. Zeng J, Xiong S, Zhou J, et al. Hollow hydroxyapatite microspheres loaded with rhCXCL13 to recruit BMSC for osteogenesis and synergetic angiogenesis to promote bone regeneration in bone defects. Int J Nanomedicine, 2023, 18: 3509-3534.
19. Liu S, Liu Y, Jiang L, et al. Recombinant human BMP-2 accelerates the migration of bone marrow mesenchymal stem cells via the CDC42/PAK1/LIMK1 pathway in vitro and in vivo. Biomater Sci, 2018, 7(1): 362-372.
20. Wu J, Cao L, Liu Y, et al. Functionalization of silk fibroin electrospun scaffolds via bmsc affinity peptide grafting through oxidative self-polymerization of dopamine for bone regeneration. ACS Appl Mater Interfaces, 2019, 11(9): 8878-8895.
21. Zhang W, Zhang Y, Li X, et al. Multifunctional polyphenol-based silk hydrogel alleviates oxidative stress and enhances endogenous regeneration of osteochondral defects. Mater Today Bio, 2022, 14: 100251. doi: 10.1016/j.mtbio.2022.100251.
22. Bai J, Ge G, Wang Q, et al. Engineering stem cell recruitment and osteoinduction via bioadhesive molecular mimics to improve osteoporotic bone-implant integration. Research (Wash D C), 2022, 2022: 9823784. doi: 10.34133/2022/9823784.
23. Zhang W, Sun T, Zhang J, et al. Construction of artificial periosteum with methacrylamide gelatin hydrogel-wharton’s jelly based on stem cell recruitment and its application in bone tissue engineering. Mater Today Bio, 2022, 18: 100528. doi: 10.1016/j.mtbio.2022.100528.
24. Nowakowski GS, Dooner MS, Valinski HM, et al. A specific heptapeptide from a phage display peptide library homes to bone marrow and binds to primitive hematopoietic stem cells. Stem Cells, 2004, 22(6): 1030-1038.
25. Huang B, Li P, Chen M, et al. Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications. J Nanobiotechnology, 2022, 20(1): 25. doi: 10.1186/s12951-021-01230-7.
26. Vandamme D, Landuyt B, Luyten W, et al. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell Immunol, 2012, 280(1): 22-35.
27. Zhu Y, Lu F, Zhang G, et al. Overview of signal transduction between LL37 and bone marrow-derived MSCs. J Mol Histol, 2022, 53(2): 149-157.
28. Ma S, Wang C, Dong Y, et al. Microsphere-gel composite system with mesenchymal stem cell recruitment, antibacterial, and immunomodulatory properties promote bone regeneration via sequential release of LL37 and W9 peptides. ACS Appl Mater Interfaces, 2022, 14(34): 38525-38540.
29. Chen X, Zhang L, Shao X, et al. Specific clearance of senescent synoviocytes suppresses the development of osteoarthritis based on aptamer-functionalized targeted drug delivery system. Advanced Functional Materials, 2022, 32(17): 2109460. https://doi.org/10.1002/adfm.202109460.
30. Hou Z, Meyer S, Propson NE, et al. Characterization and target identification of a DNA aptamer that labels pluripotent stem cells. Cell Res, 2015, 25(3): 390-393.
31. Miao Y, Liu X, Luo J, et al. Double-network dna macroporous hydrogel enables aptamer-directed cell recruitment to accelerate bone healing. Adv Sci (Weinh), 2024, 11(1): e2303637. doi: 10.1002/advs.202303637.
32. Wang Z, Lao A, Huang X, et al. Apt-19s-functionalized 3D-printed mesoporous bioactive glass scaffold promotes bmsc recruitment in bone regeneration via SDF-1α/CXCR4 axis and MAPK signaling. Advanced Functional Materials, 2024. https://doi.org/10.1002/adfm.202316675.
33. Zhou C, Xu AT, Wang DD, et al. The effects of Sr-incorporated micro/nano rough titanium surface on rBMSC migration and osteogenic differentiation for rapid osteointegration. Biomater Sci, 2018, 6(7): 1946-1961.
34. Cao B, Li Y, Yang T, et al. Bacteriophage-based biomaterials for tissue regeneration. Adv Drug Deliv Rev, 2019, 145: 73-95.
35. Sartorius R, D’Apice L, Prisco A, et al. Arming filamentous bacteriophage, a nature-made nanoparticle, for new vaccine and immunotherapeutic strategies. Pharmaceutics, 2019, 11(9): 437. doi: 10.3390/pharmaceutics11090437.
36. Wang X, Liang Y, Li J, et al. Artificial periosteum promotes bone regeneration through synergistic immune regulation of aligned fibers and BMSC-recruiting phages. Acta Biomater, 2024, 180: 262-278.
37. Wang X, Zhu X, Wang D, et al. Identification of a specific phage as growth factor alternative promoting the recruitment and differentiation of MSCs in bone tissue regeneration. ACS Biomater Sci Eng, 2023, 9(5): 2426-2437.
38. Kong D, Wang Q, Huang J, et al. A biomimetic structural material with adjustable mechanical property for bone tissue engineering. Advanced Functional Materials, 2024, 34(8): 2305412. doi: 10.1002/adfm.202305412.
39. Chen Z, Lv Y. Uninterrupted dynamic stiffening microenvironment enhances the paracrine function of mesenchymal stem cells for vascularization through chromatin remodeling. Materials & Design, 2022, 224(1): 11328. doi: 10.1016/j.matdes.2022.111328.
40. Wang J, Li J, Lu Y, et al. Incorporation of stromal cell-derived factor-1α in three-dimensional hydroxyapatite/polyacrylonitrile composite scaffolds for bone regeneration. ACS Biomater Sci Eng, 2019, 5(2): 911-921.
41. Kuang L, Ma X, Ma Y, et al. Self-assembled injectable nanocomposite hydrogels coordinated by in situ generated cap nanoparticles for bone regeneration. ACS Appl Mater Interfaces, 2019, 11(19): 17234-17246.
42. Zhang X, Li Q, Li L, et al. Bioinspired mild photothermal effect-reinforced multifunctional fiber scaffolds promote bone regeneration. ACS Nano, 2023, 17(7): 6466-6479.
43. Mao Y, Chen Y, Li W, et al. Physiology-inspired multilayer nanofibrous membranes modulating endogenous stem cell recruitment and osteo-differentiation for staged bone regeneration. Adv Healthc Mater, 2022, 11(21): e2201457. doi: 10.1002/adhm.202201457.

Chinese Journal of Reparative and Reconstructive Surgery

Latest ArticlesResearch progress on bone repair biomaterials with the function of recruiting endogenous mesenchymal stem cells

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