AccScience Publishing / IJB / Online First / DOI: 10.36922/ijb.2632
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RESEARCH ARTICLE

Hydrogel bioink formulation for 3D bioprinting: Sustained delivery of PDGF-BB and VEGF in biomimetic scaffolds for tendon partial rupture repair

Sandra Ruiz-Alonso1,2,3 ,  Jorge Ordoyo-Pascual1,2,3 ,  Markel Lafuente-Merchan1,2,3 ,  Fátima García-Villén1,2,3 ,  Myriam Sainz-Ramos1,2,3 ,  Idoia Gallego1,2,3 ,  Laura Saenz- Del-Burgo1,2,3* ,  Jose L. Pedraz1,2,3*
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1 NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
2 Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
3 Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
IJB, 2632 https://doi.org/10.36922/ijb.2632
Submitted: 4 January 2024 | Accepted: 20 February 2024 | Published: 1 April 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

In the evolving field of tissue engineering, the power of three-dimensional (3D) bioprinting technology can be harnessed by innovative methodologies to address the complex challenges of treating partial tendon injuries. In order to engineer a solution for this type of musculoskeletal injuries, a biomimetic bioink and a scaffold developed using 3D bioprinting technology and capable of delivering cells and growth factors were investigated. For the development of the bioink, a hydrogel type structure was selected based on a strategic combination of alginate, hyaluronic acid, gelatin, and fibrinogen. This tailored combination exhibited favorable rheological behavior and impeccable printability. The bioink, demonstrating promising characteristics, was then employed to fabricate both acellular scaffolds and tissue constructs. The structures possessed mechanical properties suitable and adequate for addressing partial tendon injuries and achieved a microenvironment that allowed good metabolic activity of tenocytes, maintenance of their phenotype, and overexpression of genes related to macromolecules of tendon extracellular matrix. Regarding growth factors delivery, vascular endothelial growth factor (VEGF165) and platelet-derived growth factor (PDGF-BB) were successfully incorporated into the bioink. Their release profile was thoroughly studied, and their activity once released was demonstrated. Together, these results suggest that the developed bioink and the resulting 3D structures can have an important impact on tendon partial injury therapies. The multifaceted capabilities of the bioink and the developed tissue constructs position them as crucial contributors to the advancement of tendon injury therapies, marking a significant stride toward enhanced patient outcomes and regenerative medicine practices.

Keywords
Regenerative medicine
Growth factors delivery
Biomimetic bioink
Rheological behavior
Hydrogel
Natural materials
Partial tendon injuries
Funding
This project was supported by the Basque Country Government (Consolidated Groups, IT1448-22) and by the TriAnkle European project (Horizon 2020 TriAnkle 952981-2). This research was also supported by CIBER-Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación.
References
  1. Cieza A, Causey K, Kamenov K, Hanson SW, Chatterji S, Vos T. Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2021;396(10267):2006-2017. doi: 10.1016/S0140-6736(20)32340-0
  2. Liu S, Wang B, Fan S, Wang Y, Zhan Y, Ye D. Global burden of musculoskeletal disorders and attributable factors in 204 countries and territories: a secondary analysis of the Global Burden of Disease 2019 study. BMJ Open. 2022;12(6):e062183-062183. doi: 10.1136/bmjopen-2022-062183
  3. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Committee on Identifying Disabling Medical Conditions Likely to Improve with Treatment. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: National Academies Press; 2020.
  4. Longo UG, Denaro V. Textbook of Musculoskeletal Disorders. 1st ed. Switzerland AG: Springer Cham; 2023. doi: 10.1007/978-3-031-20987-1
  5. Mahler F, Fritschy D. Partial and complete ruptures of the Achilles tendon and local corticosteroid injections. Br J Sports Med. 1992;26(1):7-14. doi: 10.1136/bjsm.26.1.7
  6. Gatz M, Spang C, Alfredson H. Partial Achilles tendon rupture-a neglected entity: a narrative literature review on diagnostics and treatment options. J Clin Med. 2020;9(10):3380. doi: 10.3390/jcm9103380
  7. Riggin CN, Morris TR, Soslowsky LJ. Tendinopathy II: etiology, pathology, and healing of tendon injury and disease. In: Gomes ME, Reis RL, Rodrigues MT, eds. Tendon Regeneration. Academic Press; 2015:149-183. doi: 10.1016/B978-0-12-801590-2.00005-3
  8. Andarawis-Puri N, Flatow EL, Soslowsky LJ. Tendon basic science: development, repair, regeneration, and healing. J Orthop Res. 2015;33(6):780-784. doi: 10.1002/jor.22869
  9. Kwan TD, El Haj AJ. Multifactorial tendon tissue engineering strategies. In: Gomes ME, Reis RL, Rodrigues MT, eds. Tendon Regeneration. Cambridge, Massachusetts, US: Academic Press; 2015:281-320. doi: 10.1016/B978-0-12-801590-2.00011-9
  10. Engebretson B, Mussett Z, Williams C, Simmons A, Sikavitsas V. Tendon tissue engineering: combined tissue engineering approach for the regeneration of tendons. In: Gomes ME, Reis RL, Rodrigues MT, eds. Tendon Regeneration. Cambridge, Massachusetts, US: Academic Press; 2015:281-320. doi: 10.1016/B978-0-12-801590-2.00011-9
  11. Bianchi E, Ruggeri M, Rossi S, et al. Innovative strategies in tendon tissue engineering. Pharmaceutics. 2021;13(1):89. doi: 10.3390/pharmaceutics13010089
  12. Matai I, Kaur G, Seyedsalehi A, McClinton A, Laurencin CT. Progress in 3D bioprinting technology for tissue/organ regenerative engineering. Biomaterials. 2020;226:119536. doi: 10.1016/j.biomaterials.2019.119536
  13. Ruiz-Alonso S, Lafuente-Merchan M, Ciriza J, Saenz-Del- Burgo L, Pedraz JL. Tendon tissue engineering: cells, growth factors, scaffolds and production techniques. J Control Release. 2021;333:448-486. doi: 10.1016/j.jconrel.2021.03.040
  14. Chen XB, Anvari-Yazdi AF, Duan X, et al. Biomaterials / bioinks and extrusion bioprinting. Bioact Mater. 2023;28:511-536. doi: 10.1016/j.bioactmat.2023.06.006
  15. ASTM International. ISO/ASTM 52900 2021(E). Additive Manufacturing—General Principles—Fundamentals and Vocabulary. Geneva: ASTM International; 2021:1–5.
  16. Hospodiuk M, Moncal KK, Dey M, Ozbolat IT. Extrusion-based biofabrication in tissue engineering and regenerative medicine. In Ovsianikov A, Yoo J, Mironov V, eds. 3D Printing and Biofabrication. New York City, New York, US: Springer International Publishing; 2016:1-27. doi: 10.1007/978-3-319-40498-1_10-1 
  17. Kaliaraj GS, Shanmugam DK, Dasan A, Mosas KK. Hydrogels—a promising materials for 3D printing technology. Gels. 2023;9(3). doi: 10.3390/gels9030260
  18. Li X, Sun Q, Li Q, Kawazoe N, Chen G. Functional hydrogels with tunable structures and properties for tissue engineering applications. Front Chem. 2018;6. doi: 10.3389/fchem.2018.00499
  19. Thang NH, Chien TB, Cuong DX. Polymer-based hydrogels applied in drug delivery: an overview. Gels. 2023; 9(7):523. doi: 10.3390/gels9070523
  20. Schwab A, Levato R, D’Este M, Piluso S, Eglin D, Malda J. Printability and shape fidelity of bioinks in 3D bioprinting. Chem Rev. 2020;120(19):11028-11055. doi: 10.1021/acs.chemrev.0c00084
  21. Lin X, Zhao X, Xu C, Wang L, Xia Y. Progress in the mechanical enhancement of hydrogels: fabrication strategies and underlying mechanisms. J Polym Sci. 2022;60(17):2525-2542. doi: 10.1002/pol.20220154
  22. Hu J, Liu S, Fan C. Applications of functionally-adapted hydrogels in tendon repair. Front Bioeng Biotechnol. 2023;11:1135090. doi: 10.3389/fbioe.2023.1135090
  23. Tabata Y. Tissue regeneration based on growth factor release. Tissue Eng. 2003;9:5-15. doi: 10.1089/10763270360696941
  24. Koria P. Delivery of growth factors for tissue regeneration and wound healing. BioDrugs. 2012;26(3):163-175. doi: 10.2165/11631850-000000000-00000
  25. Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med. 2008;42(5):314. doi: 10.1136/bjsm.2007.040071
  26. Kuroda Y, Kawai T, Goto K, Matsuda S. Clinical application of injectable growth factor for bone regeneration: a systematic review. Inflamm Regen. 2019;39(1):20. doi: 10.1186/s41232-019-0109-x
  27. Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J R Soc Interface. 2011;8(55):153-170. doi: 10.1098/rsif.2010.0223
  28. Wang Z, Wang Z, Lu WW, Zhen W, Yang D, Peng S. Novel biomaterial strategies for controlled growth factor delivery for biomedical applications. NPG Asia Mater. 2017;9(10):e435. doi: 10.1038/am.2017.171
  29. Li H, Luo S, Wang H, et al. The mechanisms and functions of TGF-β1 in tendon healing. Injury. 2023;54(11):111052. doi: 10.1016/j.injury.2023.111052
  30. Evrova O, Buschmann J. In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review. Eur Cell Mater. 2017;34:15-39. doi: 10.22203/eCM.v034a02
  31. Wang Y, Li J. Current progress in growth factors and extracellular vesicles in tendon healing. Int Wound J. 2023;20(9):3871-3883. doi: 10.1111/iwj.14261
  32. Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33(5): 381-394. doi: 10.2165/00007256-200333050-00004
  33. Miescher I, Rieber J, Calcagni M, Buschmann J. In vitro and in vivo effects of IGF-1 delivery strategies on tendon healing: a review. Int J Mol Sci. 2023;24(3):2370. doi: 10.3390/ijms24032370
  34. 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):7-12. doi: 10.1002/jor.24475
  35. Hope M, Saxby TS. Tendon healing. Foot Ankle Clin. 2007;12(4):553-567. doi: 10.1016/j.fcl.2007.07.003  
    1. Hee CK, Dines JS, Solchaga LA, Shah VR, Hollinger JO. Regenerative tendon and ligament healing: opportunities with recombinant human platelet-derived growth factor BB-homodimer. Tissue Eng. Part B Rev. 2012;18(3): 225-234. doi: 10.1089/ten.teb.2011.0603
    2. Naderi H, Matin MM, Bahrami AR. Review paper: critical issues in tissue engineering: biomaterials, cell sources, angiogenesis, and drug delivery systems. J Biomater Appl. 2011;26(4):383-417. doi: 10.1177/0885328211408946
    3. Naghieh S, Chen X. Printability–a key issue in extrusion-based bioprinting. J Pharm Anal. 2021;11(5):564-579. doi: 10.1016/j.jpha.2021.02.001
    4. Małkowski P, Ostrowski L, Brodny J. Analysis of Young’s modulus for carboniferous sedimentary rocks and its relationship with uniaxial compressive strength using different methods of modulus determination. J Sustain Min. 2018;17(3):145-157. doi: 10.1016/j.jsm.2018.07.002
    5. Barreto IS, Pierantoni M, Hammerman M, et al. Nanoscale characterization of collagen structural responses to in situ loading in rat Achilles tendons. Matrix Biol. 2023;115:32-47. doi: 10.1016/j.matbio.2022.11.006
    6. Lukin I, Erezuma I, Maeso L, et al. Progress in gelatin as biomaterial for tissue engineering. Pharmaceutics. 2022;14(6):1177. doi: 1110.3390/pharmaceutics14061177
    7. Saravanakumar K, Park S, Santosh SS, et al. Application of hyaluronic acid in tissue engineering, regenerative medicine, and nanomedicine: a review. Int J Biol Macromol. 2022;222:2744-2760. doi: 10.1016/j.ijbiomac.2022.10.055

    43 Farshidfar N, Iravani S, Varma RS. Alginate-based biomaterials in tissue engineering and regenerative medicine. Mar Drugs. 2023;21(3):189. doi: 10.3390/md21030189

    1. Sanz-Horta R, Matesanz A, Gallardo A, et al. Technological advances in fibrin for tissue engineering. J Tissue Eng. 2023;14:20417314231190288. doi: 10.1177/20417314231190288
    2. Bird B, Armstrong RC, Hassager O. Dynamics of Polymeric Liquids. Volume 1 Fluid Mechanics. Hoboken, New Jersey, US: John Wiley & Sons; 1987.
    3. Cooke ME, Rosenzweig DH. The rheology of direct and suspended extrusion bioprinting. APL Bioeng. 2021;5(1):011502. doi: 10.1063/5.0031475
    4. Thompson RL, Sica LUR, de Souza Mendes PR. The yield stress tensor. J Non Newtonian Fluid Mech. 2018;261:211-219. doi: 10.1016/j.jnnfm.2018.09.003
    5. Mezger TG. The Rheology Handbook. 4th ed. Hanover, Germany: Vincentz Network; 2014.
    6. Mortimer S, Ryan AJ, Stanford JL. Rheological behavior and gel-point determination for a model lewis acid-initiated chain growth epoxy resin. Macromolecules. 2001;34(9):2973-2980. doi: 10.1021/ma001835x
    7. Augst AD, Kong HJ, Mooney DJ. Alginate hydrogels as biomaterials. Macromol Biosci. 2006;6(8):623-633. doi: 10.1002/mabi.200600069
    8. Whelihan MF, Kiankhooy A, Brummel-Ziedins K. Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation. J Crit Care. 2014;29(1):24-30. doi: 10.1016/j.jcrc.2013.10.010
    9. Tang JD, Caliari SR, Lampe KJ. Temperature-dependent complex coacervation of engineered elastin-like polypeptide and hyaluronic acid polyelectrolytes. Biomacromolecules. 2018;19(10):3925-3935. doi: 10.1021/acs.biomac.8b00837
    10. Boularaoui S, Al Hussein G, Khan KA, Christoforou N, Stefanini C. An overview of extrusion-based bioprinting with a focus on induced shear stress and its effect on cell viability. Bioprinting. 2020;20:e00093. doi: 10.1016/j.bprint.2020.e00093 
    11. Fakhruddin K, Hamzah MSA, Razak SIA. Effects of extrusion pressure and printing speed of 3D bioprinted construct on the fibroblast cells viability. IOP Conf Ser: Mater Sci Eng. 2018;440(1):012042. doi: 10.1088/1757-899X/440/1/012042
    12. Xu H, Liu J, Zhang Z, Xu C. A review on cell damage, viability, and functionality during 3D bioprinting. Mil Med Res. 2022;9(1):70. doi: 10.1186/s40779-022-00429-5
    13. Wang J, Wei Y, Zhao S, et al. The analysis of viability for mammalian cells treated at different temperatures and its application in cell shipment. PLoS One. 2017;12(4):e0176120. doi: 10.1371/journal.pone.0176120
    14. Murphy CM, O’Brien FJ. Understanding the effect of mean pore size on cell activity in collagen-glycosaminoglycan scaffolds. Cell Adh Migr. 2010;4(3):377-381. doi: 10.4161/cam.4.3.11747
    15. Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. doi: 10.1089/ten.TEB.2012.0437
    16. Voleti PB, Buckley MR, Soslowsky LJ. Tendon healing: repair and regeneration. Annu Rev Biomed Eng. 2012;14(1):47-71. doi: 10.1146/annurev-bioeng-071811-150122
    17. Rolnick KI, Choe JA, Leiferman EM, et al. Periostin modulates extracellular matrix behavior in tendons. Matrix Biol Plus. 2022;16:100124. doi: 10.1016/j.mbplus.2022.100124
    18. Luo T, Tan B, Zhu L, Wang Y, Liao J. A review on the design of hydrogels with different stiffness and their effects on tissue repair. Front Bioeng Biotechnol. 2022;10:817391. doi: 10.3389/fbioe.2022.817391
    19. Abalymov A, Parakhonskiy B, Skirtach AG. Polymer- and hybrid-based biomaterials for interstitial, connective, vascular, nerve, visceral and musculoskeletal tissue engineering. Polymers. 2020;12(3):620. doi: 10.3390/polym12030620
    20. Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4(2):165-178. doi: 10.1242/dmm.004077
    21. Saha K, Pollock JF, Schaffer DV, Healy KE. Designing synthetic materials to control stem cell phenotype. Curr Opin Chem Biol. 2007;11(4):381-387. doi: 10.1016/j.cbpa.2007.05.030
    22. Hwang NS, Varghese S, Elisseeff J. Controlled differentiation of stem cells. Adv Drug Deliv Rev. 2008;60(2):199-214. doi: 10.1016/j.addr.2007.08.036
    23. O’Brien FJ. Biomaterials & scaffolds for tissue engineering. Mater Today. 2011;14(3):88-95. doi: 10.1016/S1369-7021(11)70058-X
    24. Zhang X, Kim T, Thauland TJ, et al. Unraveling the mechanobiology of immune cells. Curr Opin Biotechnol. 2020;66:236-245. doi: 10.1016/j.copbio.2020.09.004
    25. Breuls RGM, Jiya TU, Smit TH. Scaffold stiffness influences cell behavior: opportunities for skeletal tissue engineering. Open Orthop J. 2008;2:103-109. doi: 10.2174/1874325000802010103
    26. Schuurman W, Levett PA, Pot MW, et al. Gelatin-methacrylamide hydrogels as potential biomaterials for fabrication of tissue-engineered cartilage constructs. Macromol Biosci. 2013;13(5):551-561. doi: 10.1002/mabi.201200471
    27. Zhao X, Lang Q, Yildirimer L, et al. Photocrosslinkable gelatin hydrogel for epidermal tissue engineering. Adv Healthc Mater. 2016;5(1):108-118. doi: 10.1002/adhm.201500005
    28. Luo Q, Song G, Song Y, Xu B, Qin J, Shi Y. Indirect co-culture with tenocytes promotes proliferation and mRNA expression of tendon/ligament related genes in rat bone marrow mesenchymal stem cells. Cytotechnology. 2009;61(1-2):1-10. doi: 10.1007/s10616-009-9233-9
    29. Güngörmüş C, Kolankaya D. Gene expression of tendon collagens and tenocyte markers in long-term monolayer and high-density cultures of rat tenocytes. Connect Tissue Res. 2012;53(6):485-491. doi: 10.3109/03008207.2012.694511
Conflict of interest
The authors declare no conflicts of interest.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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