Design and Chemical Engineering of Polymeric Biomaterials: Functionalization, Crosslinking, and Characterization Strategies for Advanced 3D Bioprinting

Authors

  • Fatemeh Khan Jani * Department of Chemistry, To.C., Islamic Azad University, Tonekabon, Iran.

https://doi.org/10.48313/bic.vi.42

Abstract

Three-Dimensional (3D) bioprinting of polymeric biomaterials has emerged as a transformative platform in tissue engineering, enabling the fabrication of patient-specific scaffolds with precise spatial control. The performance of these constructs is fundamentally governed by the chemical architecture of the constituent polymers and the mechanisms of crosslinking that dictate their rheological behavior, mechanical integrity, and degradation kinetics, which collectively determine print fidelity and biological functionality. This review synthesizes current advances in natural and chemically modified synthetic polymers, elucidates the physicochemical principles underlying physical, ionic, and covalent crosslinking modalities, and highlights the intricate structure-property relationships that shape the behavior of printable bioinks. Moreover, contemporary characterization methodologies, recent material innovations, persistent challenges, and emerging directions aimed at enhancing biocompatibility and functional maturation are critically examined. Collectively, this work provides a rigorous framework to guide the rational design, optimization, and translational development of polymer-based biomaterials for next-generation regenerative medicine.

Keywords:

Three-dimensional bioprinting, Polymeric biomaterials, Bioinks, Hydrogels, Tissue engineering

References

  1. [1] Gentile, P., Chiono, V., Carmagnola, I., & Hatton, P. V. (2014). An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. International journal of molecular sciences, 15(3), 3640–3659. https://doi.org/10.3390/ijms15033640

  2. [2] Cui, X., Breitenkamp, K., Finn, M. G., Lotz, M., & D’Lima, D. D. (2012). Direct human cartilage repair using three-dimensional bioprinting technology. Tissue engineering part a, 18(11–12), 1304–1312. https://doi.org/10.1089/ten.tea.2011.0543

  3. [3] Yue, K., Trujillo-de Santiago, G., Alvarez, M. M., Tamayol, A., Annabi, N., & Khademhosseini, A. (2015). Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials, 73, 254–271. https://doi.org/10.1016/j.biomaterials.2015.08.045

  4. [4] Chimene, D., Kaunas, R., & Gaharwar, A. K. (2020). Hydrogel bioink reinforcement for additive manufacturing: A focused review of emerging strategies. Advanced materials, 32(1), 1902026. https://doi.org/10.1002/adma.201902026

  5. [5] Ouyang, L., Armstrong, J. P. K., Lin, Y., Wojciechowski, J. P., Lee-Reeves, C., Hachim, D., … ., & Stevens, M. M. (2020). Expanding and optimizing 3D bioprinting capabilities using complementary network bioinks. Science advances, 6(38), eabc5529. https://doi.org/10.1126/sciadv.abc5529

  6. [6] Lin, C. C., Raza, A., & Shih, H. (2011). PEG hydrogels formed by thiol-ene photo-click chemistry and their effect on the formation and recovery of insulin-secreting cell spheroids. Biomaterials, 32(36), 9685–9695. https://doi.org/10.1016/j.biomaterials.2011.08.083

  7. [7] Petta, D., Armiento, A. R., Grijpma, D., Alini, M., Eglin, D., & D’este, M. (2018). 3D bioprinting of a hyaluronan bioink through enzymatic-and visible light-crosslinking. Biofabrication, 10(4), 44104. https://doi.org/10.1088/1758-5090/aadf58

  8. [8] Wang, L. L., Highley, C. B., Yeh, Y. C., Galarraga, J. H., Uman, S., & Burdick, J. A. (2018). Three-dimensional extrusion bioprinting of single-and double-network hydrogels containing dynamic covalent crosslinks. Journal of biomedical materials research part a, 106(4), 865–875. https://doi.org/10.1002/jbm.a.36323

  9. [9] Faramarzi, N., Yazdi, I. K., Nabavinia, M., Gemma, A., Fanelli, A., Caizzone, A., ... ., & Tamayol, A. (2018). Patient-specific bioinks for 3D bioprinting of tissue engineering scaffolds. Advanced healthcare materials, 7(11), 1701347. https://doi.org/10.1002/adhm.201701347

  10. [10] Ghosh, K., Shu, X. Z., Mou, R., Lombardi, J., Prestwich, G. D., Rafailovich, M. H., & Clark, R. A. F. (2005). Rheological characterization of in situ cross-linkable hyaluronan hydrogels. Biomacromolecules, 6(5), 2857–2865. https://doi.org/10.1021/bm050361c

  11. [11] Soltan, N., Ning, L., Mohabatpour, F., Papagerakis, P., & Chen, X. (2019). Printability and cell viability in bioprinting alginate dialdehyde-gelatin scaffolds. ACS biomaterials science & engineering, 5(6), 2976–2987. https://doi.org/10.1021/acsbiomaterials.9b00167

  12. [12] Heo, D. N., Alioglu, M. A., Wu, Y., Ozbolat, V., Ayan, B., Dey, M., … ., & Ozbolat, I. T. (2020). 3D Bioprinting of carbohydrazide-modified gelatin into microparticle-suspended oxidized alginate for the fabrication of complex-shaped tissue constructs. ACS applied materials & interfaces, 12(18), 20295–20306. https://doi.org/10.1021/acsami.0c05096

  13. [13] Tabriz, A. G., Hermida, M. A., Leslie, N. R., & Shu, W. (2015). Three-dimensional bioprinting of complex cell laden alginate hydrogel structures. Biofabrication, 7(4), 45012. https://doi.org/10.1088/1758-5090/7/4/045012

  14. [14] Chen, Q., Tian, X., Fan, J., Tong, H., Ao, Q., & Wang, X. (2020). An Interpenetrating alginate/gelatin network for three-dimensional (3D) cell cultures and organ bioprinting. Molecules, 25(3), 1–20. https://doi.org/10.3390/molecules25030756

  15. [15] Ning, L., Mehta, R., Cao, C., Theus, A., Tomov, M., Zhu, N., … ., & Serpooshan, V. (2020). Embedded 3D bioprinting of gelatin methacryloyl-based constructs with highly tunable structural fidelity. ACS applied materials & interfaces, 12(40), 44563–44577. https://doi.org/10.1021/acsami.0c15078

  16. [16] Lim, K. S., Schon, B. S., Mekhileri, N. V, Brown, G. C. J., Chia, C. M., Prabakar, S., … ., & Woodfield, T. B. F. (2016). New visible-light photoinitiating system for improved print fidelity in gelatin-based bioinks. ACS biomaterials science & engineering, 2(10), 1752–1762. https://doi.org/10.1021/acsbiomaterials.6b00149

  17. [17] Poldervaart, M. T., Goversen, B., De Ruijter, M., Abbadessa, A., Melchels, F. P. W., Öner, F. C., … ., & Alblas, J. (2017). 3D bioprinting of methacrylated hyaluronic acid (MeHA) hydrogel with intrinsic osteogenicity. PloS one, 12(6), e0177628. https://doi.org/10.1371/journal.pone.0177628

  18. [18] Kim, H. S., Kim, C., & Lee, K. Y. (2022). Three-dimensional bioprinting of polysaccharide-based self-healing hydrogels with dual cross-linking. Journal of biomedical materials research part a, 110(4), 761–772. https://doi.org/10.1002/jbm.a.37325

  19. [19] Makadia, H. K., & Siegel, S. J. (2011). Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers, 3(3), 1377–1397. https://doi.org/10.3390/polym3031377

  20. [20] Stichler, S., Böck, T., Paxton, N., Bertlein, S., Levato, R., Schill, V., ... ., & Groll, J. (2017). Double printing of hyaluronic acid/poly (glycidol) hybrid hydrogels with poly (ε-caprolactone) for MSC chondrogenesis. Biofabrication, 9(4), 44108. https://doi.org/10.1088/1758-5090/aa8cb7

  21. [21] Wu, D., Wang, W., Diaz-Dussan, D., Peng, Y. Y., Chen, Y., Narain, R., & Hall, D. G. (2019). In situ forming, dual-crosslink network, self-healing hydrogel enabled by a bioorthogonal nopoldiol–benzoxaborolate click reaction with a wide pH range. Chemistry of materials, 31(11), 4092–4102. https://doi.org/10.1021/acs.chemmater.9b00769

  22. [22] Lee, M., Bae, K., Guillon, P., Chang, J., Arlov, Ø., & Zenobi-Wong, M. (2018). Exploitation of cationic silica nanoparticles for bioprinting of large-scale constructs with high printing fidelity. ACS applied materials & interfaces, 10(44), 37820–37828. https://doi.org/10.1021/acsami.8b13166

  23. [23] Lai, J., Chen, X., Lu, H. H., & Wang, M. (2024). 3D bioprinting of graphene oxide-incorporated hydrogels for neural tissue regeneration. 3D printing and additive manufacturing, 11(6), e2022–e2032. https://doi.org/10.1089/3dp.2023.0150

  24. [24] Olate-Moya, F., Rubí-Sans, G., Engel, E., Mateos-Timoneda, M. Á., & Palza, H. (2024). 3D bioprinting of biomimetic alginate/gelatin/chondroitin sulfate hydrogel nanocomposites for intrinsically chondrogenic differentiation of human mesenchymal stem cells. Biomacromolecules, 25(6), 3312–3324. https://doi.org/10.1021/acs.biomac.3c01444

  25. [25] Rizwana, N., Maslekar, N., Chatterjee, K., Yao, Y., Agarwal, V., & Nune, M. (2024). Dual crosslinked antioxidant mixture of Poly(vinyl alcohol) and cerium oxide nanoparticles as a bioink for 3D bioprinting. ACS applied nano materials, 7(16), 18177–18188. https://doi.org/10.1021/acsanm.3c02962

  26. [26] Ouyang, L., Highley, C. B., Sun, W., & Burdick, J. A. (2017). A generalizable strategy for the 3D bioprinting of hydrogels from nonviscous photo-crosslinkable inks. Advanced materials, 29(8), 1604983. https://doi.org/10.1002/adma.201604983

  27. [27] De Melo, B. A. G., Jodat, Y. A., Mehrotra, S., Calabrese, M. A., Kamperman, T., Mandal, B. B., … ., & Shin, S. R. (2019). 3D printed cartilage-like tissue constructs with spatially controlled mechanical properties. Advanced functional materials, 29(51), 1906330. https://doi.org/10.1002/adfm.201906330

  28. [28] Darabi, M. A., Khosrozadeh, A., Wang, Y., Ashammakhi, N., Alem, H., Erdem, A., ... ., & Xing, M. (2020). An alkaline based method for generating crystalline, strong, and shape memory polyvinyl alcohol biomaterials. Advanced science, 7(21), 1902740. https://doi.org/10.1002/advs.201902740

  29. [29] Zhu, J., He, Y., Wang, Y., & Cai, L. H. (2024). Voxelated bioprinting of modular double-network bio-ink droplets. Nature communications, 15(1), 5902. https://doi.org/10.1038/s41467-024-49705-z

  30. [30] Huh, J., Moon, Y.-W., Park, J., Atala, A., Yoo, J. J., & Lee, S. J. (2021). Combinations of photoinitiator and UV absorber for cell-based digital light processing (DLP) bioprinting. Biofabrication, 13(3), 34103. https://doi.org/10.1088/1758-5090/abfd7a

  31. [31] Greene, T., & Lin, C.-C. (2015). Modular cross-linking of gelatin-based thiol–norbornene hydrogels for in vitro 3d culture of hepatocellular carcinoma cells. ACS biomaterials science & engineering, 1(12), 1314–1323. https://doi.org/10.1021/acsbiomaterials.5b00436

  32. [32] Mihajlovic, M., Rikkers, M., Mihajlovic, M., Viola, M., Schuiringa, G., Ilochonwu, B. C., … ., & Vermonden, T. (2022). Viscoelastic chondroitin sulfate and hyaluronic acid double-network hydrogels with reversible cross-links. Biomacromolecules, 23(3), 1350–1365. https://doi.org/10.1021/acs.biomac.1c01583

  33. [33] Barreiro Carpio, M., Gonzalez Martinez, E., Dabaghi, M., Ungureanu, J., Arizpe Tafoya, A. V., Gonzalez Martinez, D. A., … ., & Moran-Mirabal, J. M. (2023). High-fidelity extrusion bioprinting of low-printability polymers using carbopol as a rheology modifier. ACS applied materials & interfaces, 15(47), 54234–54248. https://doi.org/10.1021/acsami.3c10092

  34. [34] Zhang, H., Cong, Y., Osi, A. R., Zhou, Y., Huang, F., Zaccaria, R. P., … ., & Fu, J. (2020). Direct 3D printed biomimetic scaffolds based on hydrogel microparticles for cell spheroid growth. Advanced functional materials, 30(13), 1910573. https://doi.org/10.1002/adfm.201910573

  35. [35] Blaeser, A., Duarte Campos, D. F., Puster, U., Richtering, W., Stevens, M. M., & Fischer, H. (2016). Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity. Advanced healthcare materials, 5(3), 326–333. https://doi.org/10.1002/adhm.201500677

  36. [36] Noh, I., Kim, N., Tran, H. N., Lee, J., & Lee, C. (2019). 3D printable hyaluronic acid-based hydrogel for its potential application as a bioink in tissue engineering. Biomaterials research, 23(1), 1–9. https://doi.org/10.1186/s40824-018-0152-8

  37. [37] Mirani, B., Stefanek, E., Godau, B., Hossein Dabiri, S. M., & Akbari, M. (2021). Microfluidic 3D printing of a photo-cross-linkable bioink using insights from computational modeling. ACS biomaterials science & engineering, 7(7), 3269–3280. https://doi.org/10.1021/acsbiomaterials.1c00084

  38. [38] Kesti, M., Eberhardt, C., Pagliccia, G., Kenkel, D., Grande, D., Boss, A., & Zenobi-Wong, M. (2015). Bioprinting complex cartilaginous structures with clinically compliant biomaterials. Advanced functional materials, 25(48), 7406–7417. https://doi.org/10.1002/adfm.201503423

  39. [39] Stratesteffen, H., Köpf, M., Kreimendahl, F., Blaeser, A., Jockenhoevel, S., & Fischer, H. (2017). GelMA-collagen blends enable drop-on-demand 3D printablility and promote angiogenesis. Biofabrication, 9(4), 45002. https://doi.org/10.1088/1758-5090/aa857c

  40. [40] Taniguchi Nagahara, M. H., Caiado Decarli, M., Inforcatti Neto, P., da Silva, J. V., & Moraes, A. M. (2022). Crosslinked alginate-xanthan gum blends as effective hydrogels for 3D bioprinting of biological tissues. Journal of applied polymer science, 139(28), e52612. https://doi.org/10.1002/app.52612

  41. [41] Niknejad, K., Sharifzadeh Baei, M., & Motallebi Tala Tapeh, S. (2018). Synthesis of metformin hydrochloride nanoliposomes: Evaluation of physicochemical characteristics and release kinetics. International journal of nano dimension, 9(3), 298–313. https://dorl.net/dor/20.1001.1.20088868.2018.9.3.9.7

  42. [42] Mueller, E., Xu, F., & Hoare, T. (2022). FRESH bioprinting of dynamic hydrazone-cross-linked synthetic hydrogels. Biomacromolecules, 23(11), 4883–4895. https://doi.org/10.1021/acs.biomac.2c01046

  43. [43] Wu, J., Sang, L., Kang, R., Li, M., Cheng, C., Liu, A., … ., & Jian, A. (2025). A novel 3D bioprinting crosslinking method based on solenoid valve control. Macromolecular bioscience, 25(8), 2500039. https://doi.org/10.1002/mabi.202500039

  44. [44] Tapeh, S. M. T., Baei, M. S., & Keshel, S. H. (2021). Synthesis of thermogel modified with biomaterials as carrier for hUSSCs differentiation into cardiac cells: Physicomechanical and biological assessment. Materials science and engineering: c, 119, 111517. https://doi.org/10.1016/j.msec.2020.111517

Published

2025-08-20

How to Cite

Khan Jani, F. . (2025). Design and Chemical Engineering of Polymeric Biomaterials: Functionalization, Crosslinking, and Characterization Strategies for Advanced 3D Bioprinting. Biocompounds, 2(3), 151-167. https://doi.org/10.48313/bic.vi.42

Similar Articles

1-10 of 12

You may also start an advanced similarity search for this article.