Incorporating Connective Tissue Growth Factor into Regenerative and Personalised Medicine for Tendon and Ligament Regeneration: A Systematic Review

Main Article Content

Quan Fu Gan Ker Woon Choy Chai Nien Foo Zhang Li Pooi Pooi Leong Soon Keng Cheong

Abstract

Background: Tendon and ligament disorders particularly those of the weight bearing joints are associated with decreased physical activities affecting the quality of life. Current management includes conservative and surgical approaches requires a relatively long recovery time, in addition to the post-operative complications such as infection of the wound site and joint stiffness if managed surgically. Connective tissue growth factor is a type of growth factor expressed during second phase of the healing process and is responsible for tissue healing by stimulating the release of extracellular matrix responsible for tissue healing. Hence, the objective of this review is to identify available studies relating to the used of connective tissue growth factor in tissue culture for tendon and ligament healing.


Methods: Studies were identified from PubMed Central, BioMed Central, ScienceDirect, and Wiley Online Library with the keywords: Connective Tissue Growth Factor ‘OR’ CTGF ‘OR’ CCN ‘AND’ Regeneration ‘AND’ Healing from the year 2019 to present, 2024. All literatures were reviewed in three phases by two reviewers.


Results and Conclusion: There were only three articles which met our inclusion criteria. In general, connective tissue growth factor had been reported to be beneficial for ligament and tendon regeneration. However, the effective connective tissue growth factor dose for optimal ligament and tendon regeneration healing could not be determined due to the different cell source and delivery methods utilised among the identified articles.

Article Details

How to Cite
GAN, Quan Fu et al. Incorporating Connective Tissue Growth Factor into Regenerative and Personalised Medicine for Tendon and Ligament Regeneration: A Systematic Review. Medical Research Archives, [S.l.], v. 12, n. 7, july 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5522>. Date accessed: 08 dec. 2024. doi: https://doi.org/10.18103/mra.v12i7.5522.
Section
Review Articles

References

1. Logerstedt DS, Ebert JR, MacLeod TD, Heiderscheit BC, Gabbett TJ, Eckenrode BJ. Effects of and Response to Mechanical Loading on the Knee. Sports Medicine 2021 52:2. 2021;52(2):201-235. Doi:10.1007/S40279-021-01579-7
2. Abdelbasset WK, Sulieman A. An Overview on Low Back Pain and Functional Disability: Associated Risk Factors and Management. Journal of Disability Research. 2022;1(1):19-22. Doi:10.57197/JDR-2022-0004
3. Runer A, Csapo R, Hepperger C, Herbort M, Hoser C, Fink C. Anterior Cruciate Ligament Reconstructions With Quadriceps Tendon Autograft Result in Lower Graft Rupture Rates but Similar Patient-Reported Outcomes as Compared With Hamstring Tendon Autograft: A Comparison of 875 Patients. https://doi.org/101177/0363546520931829. 2020;48(9):2195-2204. Doi:10.1177/0363546520931829
4. Slagers AJ, Dams OC, van Zalinge SD, et al. Psychological Factors Change During the Rehabilitation of an Achilles Tendon Rupture: A Multicenter Prospective Cohort Study. Phys Ther. 2021;101(12):1-10. Doi:10.1093/PTJ/PZAB226
5. Gan QF, Foo CN, Leong PP, Cheong SK. Regenerative Medicine as a Potential and Future Intervention for Ankle Sprain. Malaysian Journal of Medicine and Health Sciences. 2020;16(2):290-299. Accessed May 1, 2020. https://www.medic.upm.edu.my/upload/dokumen/2020042010413441_MJMHS_0235.pdf
6. Gan QF, Foo CN, Leong PP, Cheong SK. Incorporating regenerative medicine into rehabilitation programmes: A potential treatment for ankle sprain. Int J Ther Rehabil. 2021;28(2). Doi:10.12968/ijtr.2019.0119
7. Gnanasegaran N, Govindasamy V, Simon C, et al. Effect of dental pulp stem cells in MPTP-induced old-aged mice model. Eur J Clin Invest. 2017;47(6):403-414. Doi:10.1111/eci.12753
8. Simon C, Gan Q, Kathivaloo P, et al. Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice. Int J Mol Sci. 2019;20(3):568. Doi:10.3390/ijms20030568
9. Gan QF, Choy KW, Foo CN, Leong PP, Cheong SK. Incorporating insulin growth Factor-1 into regenerative and personalised medicine for musculoskeletal disorders: A systematic review. J Tissue Eng Regen Med. 2021;15(5):419-441. Doi:10.1002/TERM.3192
10. Teixeira F, Salgado A. Mesenchymal stem cells secretome: current trends and future challenges. Neural Regen Res. 2020;15(1):75. Doi:10.4103/1673-5374.264455
11. Swanson WB, Omi M, Zhang Z, et al. Macropore design of tissue engineering scaffolds regulates mesenchymal stem cell differentiation fate. Biomaterials. 2021;272:120769. Doi:10.1016/J.BIOMATERIALS.2021.120769
12. Iijima K, Otsuka H. Cell Scaffolds for Bone Tissue Engineering. Bioengineering 2020, Vol 7, Page 119. 2020;7(4):119. Doi:10.3390/BIOENGINEERING7040119
13. Nour-Eldeen G, Abdel-Rasheed M, EL-Rafei AM, Azmy O, El-Bassyouni GT. Adipose tissue-derived mesenchymal stem cells and chitosan/poly (vinyl alcohol) nanofibrous scaffolds for cartilage tissue engineering. Cell Regeneration. 2020;9(1):1-12. Doi:10.1186/S13619-020-00045-5/FIGURES/10
14. Gan QF, Lim YT, Foo CN, et al. Incorporating Insulin Growth Factor-1 into Regenerative and Personalized Medicine for Cardiovascular Disease: A Systematic Review. Curr Stem Cell Res Ther. 2022;17. Doi:10.2174/1574888X17666220407085901
15. Quan Fu G, Ker Woon C, Chai Nien F, et al. Understanding the Role of IGF-1 in Regenerative Medicine for Skin Regeneration, the Future of Wound Healing: A Systematic Review. Review of International Geographical Education Online. 2021;11(7):1166-1189. Accessed June 8, 2022. https://rigeo.org/submit-a-menuscript/index.php/submission/article/view/2091/
16. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol. 1991;114(6):1285-1294. Doi:10.1083/JCB.114.6.1285
17. Moussad EEDA, Brigstock DR. Connective Tissue Growth Factor: What’s in a Name? Mol Genet Metab. 2000;71(1-2):276-292. Doi:10.1006/MGME.2000.3059
18. Lee CH, Shah B, Moioli EK, Mao JJ. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J Clin Invest. 2015;125(10):3992-3992. Doi:10.1172/JCI84508
19. Lee CH, Shah B, Moioli EK, Mao JJ. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J Clin Invest. 2010;120(9):3340-3349. Doi:10.1172/JCI43230
20. Shen H, Jayaram R, Yoneda S, et al. The effect of adipose-derived stem cell sheets and CTGF on early flexor tendon healing in a canine model. Sci Rep. 2018;8(1):11078. Doi:10.1038/s41598-018-29474-8
21. Dorn LE, Petrosino JM, Wright P, Accornero F. CTGF/CCN2 is an autocrine regulator of cardiac fibrosis. J Mol Cell Cardiol. 2018;121:205-211. Doi:10.1016/j.yjmcc.2018.07.130
22. Süt N. Study designs in medicine. Balkan Med J. 2014;31(4):273-277. Doi:10.5152/balkanmedj.2014.1408
23. Shen H, Tarafder S, Park G, et al. The use of connective tissue growth factor mimics for flexor tendon repair. J Orthop Res. 2022;40(12):2754. Doi:10.1002/JOR.25301
24. Li X, Pongkitwitoon S, Lu H, Lee C, Gelberman R, Thomopoulos S. CTGF Induces Tenogenic Differentiation and Proliferation of Adipose-Derived Stromal Cells. J Orthop Res. 2019;37(3):574. Doi:10.1002/JOR.24248
25. Rui YF, Chen MH, Li YJ, et al. CTGF Attenuates Tendon-Derived Stem/Progenitor Cell Aging. Stem Cells Int. 2019;2019. Doi:10.1155/2019/6257537
26. Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and Ligament Healing and Current Approaches to Tendon and Ligament Regeneration. J Orthop Res. 2020;38(1):7. Doi:10.1002/JOR.24475
27. Asahara H, Inui M, Lotz MK. Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis. J Bone Miner Res. 2017;32(9):1773. Doi:10.1002/JBMR.3199
28. Rovere G, Stramazzo L, Romeo M, D’arienzo A, Maccauro G, Camarda L. Hamstring Graft Preparation for ACL Reconstruction. Orthop Rev (Pavia). 2022;14(5). Doi:10.52965/001C.38408
29. Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological outcomes. Open Biol. 2020;10(9):341-370. Doi:10.1098/RSOB.200223
30. Schultz GS, Chin GA, Moldawer L, Diegelmann RF. Principles of Wound Healing. Diabetic Foot Problems. Published online January 1, 2011:395-402. Doi:10.1142/9789812791535_0028
31. Fenwick SA, Hazleman BL, Riley GP. The vasculature and its role in the damaged and healing tendon. Arthritis Res. 2002;4(4):252. Doi:10.1186/AR416
32. Chartier C, Elhawary H, Baradaran A, et al. Healing, Inflammation, and Fibrosis: Tendon: Principles of Healing and Repair. Semin Plast Surg. 2021;35(3):211. Doi:10.1055/S-0041-1731632
33. Fu M, Peng D, Lan T, Wei Y, Wei X. Multifunctional regulatory protein connective tissue growth factor (CTGF): A potential therapeutic target for diverse diseases. Acta Pharm Sin B. 2022;12(4):1740. Doi:10.1016/J.APSB.2022.01.007
34. Tripathi S, Soni K, Agrawal P, Gour V, Mondal R, Soni V. Hypertrophic scars and keloids: a review and current treatment modalities. Biomedical Dermatology 2020 4:1. 2020;4(1):1-11. Doi:10.1186/S41702-020-00063-8
35. Khoo YT, Ong CT, Mukhopadhyay A, et al. Upregulation of secretory connective tissue growth factor (CTGF) in keratinocyte-fibroblast coculture contributes to keloid pathogenesis. J Cell Physiol. 2006;208(2):336-343. Doi:10.1002/JCP.20668
36. Bran GM, Goessler UR, Schardt C, Hormann K, Riedel F, Sadick H. Effect of the abrogation of TGF-β1 by antisense oligonucleotides on the expression of TGF-β-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med. 2010;25(6):915-921. Doi:10.3892/ijmm_00000422
37. Luo L, Li J, Liu H, et al. Adiponectin is involved in connective tissue growth factor-induced proliferation, migration and overproduction of the extracellular matrix in keloid fibroblasts. Int J Mol Sci. 2017;18(5). Doi:10.3390/ijms18051044
38. Li MH, Sanchez T, Pappalardo A, Lynch KR, Hla T, Ferrer F. Induction of antiproliferative connective tissue growth factor expression in Wilms’ tumor cells by sphingosine-1-phosphate receptor 2. Molecular Cancer Research. 2008;6(10):1649-1656. Doi:10.1158/1541-7786.MCR-07-2048
39. Astarita C, Arora CL, Trovato L. Tissue regeneration: an overview from stem cells to micrografts. J Int Med Res. 2020;48(6). Doi:10.1177/0300060520914794
40. Resnik SR, Egger A, Abdo Abujamra B, Jozic I. Clinical Implications of Cellular Senescence on Wound Healing. Current Dermatology Reports 2020 9:4. 2020;9(4):286-297. Doi:10.1007/S13671-020-00320-3
41. Vasalou V, Kotidis E, Tatsis D, et al. The Effects of Tissue Healing Factors in Wound Repair Involving Absorbable Meshes: A Narrative Review. Journal of Clinical Medicine 2023, Vol 12, Page 5683. 2023;12(17):5683. Doi:10.3390/JCM12175683
42. Quan Fu G, Pooi Pooi L, Soon Keng C, Chai Nien F. Incorporating stem cells into physical rehabilitation. In: Comprehensive Hematology and Stem Cell Research. Rezaei, Nima. Elsevier; 2024.
43. Lane JG, Amiel D. Ligament histology, composition, anatomy, injury, and healing mechanisms. Bio-orthopaedics: A New Approach. Published online May 26, 2017:291-312. Doi:10.1007/978-3-662-54181-4_23/COVER
44. Wu Q, Liu J, Wang X, et al. Organ-on-a-chip: recent breakthroughs and future prospects. BioMedical Engineering OnLine 2020 19:1. 2020;19(1):1-19. Doi:10.1186/S12938-020-0752-0
45. Padhi A, Nain AS. ECM in Differentiation: A Review of Matrix Structure, Composition and Mechanical Properties. Ann Biomed Eng. 2020;48(3):1071-1089. Doi:10.1007/S10439-019-02337-7/METRICS
46. Short B. A basic guide to stem cell differentiation. J Cell Biol. 2016;215(3):293. Doi:10.1083/JCB.2153IF
47. Runer A, Keeling L, Wagala N, et al. Current trends in graft choice for anterior cruciate ligament reconstruction – part I: anatomy, biomechanics, graft incorporation and fixation. Journal of Experimental Orthopaedics 2023 10:1. 2023;10(1):1-10. Doi:10.1186/S40634-023-00600-4
48. Chamberlain CS, Saether EE, Aktas E, Vanderby R. Mesenchymal Stem Cell Therapy on Tendon/Ligament Healing. J Cytokine Biol. 2017;2(1). Accessed May 4, 2019. http://www.ncbi.nlm.nih.gov/pubmed/28670649
49. Mocchi M, Dotti S, Del Bue M, et al. Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier? Cells. 2020;9(6):1453. Doi:10.3390/cells9061453
50. Rhatomy S, Prasetyo TE, Setyawan R, et al. Prospect of stem cells conditioned medium (secretome) in ligament and tendon healing: A systematic review. Stem Cells Transl Med. 2020;9(8):895-902. Doi:10.1002/sctm.19-0388
51. Woo SLY, Mau JR, Kang H, Liang R, Almarza AJ, Fisher MB. Functional Tissue Engineering of Ligament and Tendon Injuries. Principles of Regenerative Medicine. Published online January 1, 2019:1179-1198. Doi:10.1016/B978-0-12-809880-6.00067-9
52. Kouroupis D, Churchman SM, Giannoudis P V, Jones E. Mesenchymal Stem Cell Applications for Ligament Repair after Joint Trauma. J Clin Exp Pathol. 2014;04(04). Doi:10.4172/2161-0681.1000186
53. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028. Doi:10.1038/NM.2807
54. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature 2020 587:7835. 2020;587(7835):555-566. Doi:10.1038/s41586-020-2938-9
55. Karsdal MA, Nielsen SH, Leeming DJ, et al. The good and the bad collagens of fibrosis – Their role in signaling and organ function. Adv Drug Deliv Rev. 2017;121:43-56. Doi:10.1016/J.ADDR.2017.07.014
56. Antar SA, Ashour NA, Marawan ME, Al-Karmalawy AA. Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation. Int J Mol Sci. 2023;24(4):4004. Doi:10.3390/IJMS24044004
57. Tsai CC, Wu SB, Kau HC, Wei YH. Essential role of connective tissue growth factor (CTGF) in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from Graves’ orbital fibroblasts. Scientific Reports 2018 8:1. 2018;8(1):1-10. Doi:10.1038/s41598-018-25370-3
58. Kuwana M. Strategies for regulating tissue fibrosis and their clinical application. Inflamm Regen. 2020;40(1):1-2. Doi:10.1186/S41232-020-00116-9/METRICS