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Oxygen generating biomaterial

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An oxygen generating biomaterial (OGB) is a material designed to produce, store and release oxygen within biological environments. These materials are investigated for various applications in the biomedical field, including tissue engineering, regenerative medicine and implants.[1][2]

Oxygen plays a key role inside human body and it is essential for cellular metabolism and functionality.[3] In physiological conditions it is delivered to all tissues and organs through the circulatory system.[4] If the oxygen availability is insufficient, a condition known as hypoxia develops and may result in cellular dysfunction.[3] Limited oxygen availability may ultimately lead to cell death via apoptosis and necrosis.[5] In this context, oxygen generating biomaterials can provide localized oxygen supply and compensation for low oxygen availability. Currently, several approaches have been investigated to achieve these goals, including oxygen-releasing and oxygen-carrying materials.[1][2]

Oxygen supply mechanisms

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Oxygen generating approaches can supply oxygen following different mechanisms. These mechanisms include oxygen-releasing compounds, such as inorganic peroxides and hydrogen peroxide-based systems, as well as oxygen-carrying materials, such as perfluorocarbons and hemoglobin-based carriers.[2][6]

Oxygen-releasing materials

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The oxygen-releasing materials include solid inorganic peroxide and hydrogen peroxide-based systems, which release oxygen rather than simply delivering it.[1][7]

Solid inorganic peroxides

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Solid inorganic peroxides are a family of compounds which include calcium peroxide (), magnesium peroxide () and sodium percarbonate (). In aqueous environments these materials undergo hydrolytic dissolution.[1][2]

An initial dissociation leads to the formation of hydrogen peroxide:

This reaction is followed by the decomposition of hydrogen peroxide into oxygen:

Solid inorganic peroxides present different solubility in water:[8]

Solid peroxide Solubility in water
Calcium peroxide 1.65 g/L at 20°C
Magnesium peroxide 0.086 g/L at 18°C
Sodium percarbonate 120 g/L at 20°C
Mortar and pestle with white powder
Calcium peroxide powder

The different inorganic peroxides exhibit distinct solubility and decomposition characteristics, which influence their oxygen release profiles.[8]

Sodium percarbonate is highly soluble in water and facilitates the immediate release of oxygen, whereas calcium peroxide and magnesium peroxide are less soluble. Among these materials, calcium peroxide is frequently investigated in oxygen-generating biomaterials because it releases oxygen through hydrogen peroxide formation and has been incorporated into different biomaterial systems.[1][8]

Hydrogen peroxide-based systems

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Hydrogen peroxide-based systems use hydrogen peroxide () as a direct source of oxygen. In aqueous environments, decomposes into water and molecular oxygen according to the following reaction:[2]

This process can occur spontaneously or it can be accelerated by catalysts and enzymes (e.g. catalase).[9] Hydrogen peroxide-based approaches have been investigated to provide a localised oxygen supply in biomedical applications.[10]

Oxygen-carrying materials

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Perfluorocarbons

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Perfluorocarbons (PFCs) are organic compounds in which all the hydrogen atoms are replaced with fluorine.[11] PFCs are chemically inert and have low polarizability.[12] PFCs are capable of storing and releasing oxygen according to the oxygen partial pressure gradient between the PFCs and the surrounding environment. Oxygen molecules are stored by physical dissolution mediated by van der Waals forces.[13]

Hemoglobin-based oxygen carriers

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Hemoglobin-based oxygen carriers are investigated because hemoglobin is the primary natural carrier in the human body. However, it cannot be used independently due to its tendency to fragment into dimers and monomers outside of red blood cells (RBCs), leading to toxicity. To address this issue, a variety of synthetic alternatives to RBCs, mimicking the natural oxygen delivery of RBCs, have been introduced.[14][15]

Challenges and limitations

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In biological environments, if oxygen availability is insufficient, optimal cellular survival and functionality cannot be achieved.[5] In this context, oxygen-generating biomaterials can supply oxygen, addressing hypoxia-related issues and supporting cell viability, metabolism, and function. A major challenge reported for the development of oxygen-generating biomaterials is achieving controlled oxygen release in these biological environments.[16] In fact, several studies report that an initial burst release of can be harmful to cells:[1][5] if a large amount of oxygen is released abruptly and too quickly, it can lead to local oxidative stress and may ultimately cause cytotoxicity.[1][16] Consequently, the amount and release rate of oxygen are crucial factors for a safe and effective use. For this reason, various biomaterial platforms are being investigated in order to control and modulate oxygen release in biomedical applications.[1][7][6]

Biomaterial platforms and applications

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The delivery of oxygen-releasing and oxygen-carrying materials can be achieved through different strategies.[17][18] The selection of the biomaterials and approaches to incorporate them has a significant influence on the oxygen release kinetics and consequently on the functionality. Overall, the application of oxygen generating biomaterials is dependent on the chosen platform and its oxygen release profile, which affect their suitability for specific biomedical challenges.[2][6]

Hydrogels

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A white blob of gel on a petri dish held by a gloved hand
A sample of hydrogel based on cellulose

Hydrogels are three-dimensional networks with high water content and soft structure.[19] Due to their structural characteristics and tunable properties, they represent suitable candidates to encapsulate therapeutic agents, such as oxygen generating materials.[20] Hydrogels comprise both natural (e.g. alginate, gelatin, collagen, hyaluronic acid) and synthetic (e.g. polyethylene glycol) materials.[19] Their minimally invasive administration and ability to mimic the extracellular matrix have contributed to their use in biomedical applications.[19] Hydrogels are used as matrices for the incorporation of oxygen-releasing compounds and oxygen carriers. The high water content and permeability of these materials facilitate nutrients transport within the material.[21] Oxygen generating hydrogels have been investigated for applications in wound healing, tissue engineering and also to facilitate angiogenesis.[22][23]

Scaffolds

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Scaffolds are three-dimensional structures specifically designed to provide structural and mechanical support for cell adhesion, proliferation and growth, with the aim of mimicking the properties of the extracellular matrix.[24] They are typically fabricated from different biomaterials, including polymers, ceramics or composite systems, using various techniques such as electrospinning, freeze-drying, solvent casting and particulate leaching and 3D printing.[24] The interconnected porosity of these structures is a fundamental characteristic that facilitates the diffusion of nutrients, waste products and signalling molecules.[24] Scaffolds can thus incorporate oxygen generating materials to supply oxygen and maintain local oxygen availability in order to enhance cell viability, support angiogenesis and reduce hypoxic conditions. As a result, they are widely explored in tissue engineering and regenerative medicine applications, particularly for bone, cartilage and skin repair.[25][26][27][28]

Films

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Microscope image of a film with dark circles near the bottom
Microscope image of oxygen bubbles generated from a film

Films are thin biomaterial structures typically made from polymers, both natural, such as chitosan or collagen, and synthetic, such as polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA).[29] They are widely used for a variety of biomedical applications because, according to their properties, composition and design, they can achieve different functions.[29] Films can incorporate oxygen generating materials within their matrix. Oxygen generating films have been explored for various biomedical applications, including wound dressings, tissue preservation, and implantable devices.[30][31]

Microspheres and nanoparticles

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Microspheres and nanoparticles are particulate biomaterials ranging in size from the micrometer to nanometer scale, respectively.[32][33] They are designed to embed specific agents, enabling their controlled release to the target area. They can be synthesized using different materials, such as biodegradable polymers, lipids or inorganic compounds.[34] Due to their high surface-area-to-volume ratio and tunable reactivity, these systems are particularly effective for encapsulation of oxygen generating materials, allowing for controlled release kinetics and a targeted delivery.[35] Micro/nano scale particulate oxygen-releasing materials also possess the advantage of being injectable or incorporated within larger structures, such as hydrogels, scaffolds or films and these systems are being investigated due to their ability to provide oxygen supply, reduce hypoxia and improve tissue regeneration.[36][37][38]

Composite systems

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Composite systems refer to the combination of two or more biomaterial platforms within a single construct. These hybrid oxygen generating systems are created to combine the properties and advantages of different biomaterials. They can thus integrate combinations of hydrogels, scaffolds, films, microspheres, and nanoparticles to achieve multiple functions together with oxygen supply. Examples of such materials include peroxide-loaded hydrogels, microsphere-reinforced scaffolds and multilayer oxygen-generating films.[39][40][41]

See also

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References

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  1. 1 2 3 4 5 6 7 8 Zhao, Jiayi; Zhou, Chao; Xiao, Yang; Zhang, Kunyan; Zhang, Qiang; Xia, Linying; Jiang, Bo; Jiang, Chanyi; Ming, Wenyi; Zhang, Hengjian; Long, Hengguo; Liang, Wenqing (12 January 2024). "Oxygen generating biomaterials at the forefront of regenerative medicine: advances in bone regeneration". Frontiers in Bioengineering and Biotechnology. 12 1292171. doi:10.3389/fbioe.2024.1292171. PMC 10811251. PMID 38282892.
  2. 1 2 3 4 5 6 Gholipourmalekabadi, Mazaher; Zhao, Susan; Harrison, Benjamin S.; Mozafari, Masoud; Seifalian, Alexander M. (December 2016). "Oxygen-Generating Biomaterials: A New, Viable Paradigm for Tissue Engineering?". Trends in Biotechnology. 34 (12): 1010–1021. doi:10.1016/j.tibtech.2016.05.012. PMID 27325423.
  3. 1 2 Meletis, Chris D.; Wilkesa, Kimberly (15 February 2019). "The Crucial Role of Oxygen for Health". Journal of Restorative Medicine. 8 (1). doi:10.14200/jrm.2019.0106.
  4. ↑ Peate, Ian (2020-12-02). "The circulatory system". British Journal of Healthcare Assistants. 14 (11): 548–553. doi:10.12968/bjha.2020.14.11.548. ISSN 1753-1586.
  5. 1 2 3 Willemen, Niels G.A.; Hassan, Shabir; Gurian, Melvin; Li, Jinghang; Allijn, Iris E.; Shin, Su Ryon; Leijten, Jeroen (November 2021). "Oxygen-Releasing Biomaterials: Current Challenges and Future Applications". Trends in Biotechnology. 39 (11): 1144–1159. Bibcode:2021Tbiot..39.1144W. doi:10.1016/j.tibtech.2021.01.007. PMC 9078202. PMID 33602609.
  6. 1 2 3 Hosseini, Fatemeh S.; Abedini, Amir Abbas; Chen, Feiyang; Whitfield, Taraje; Ude, Chinedu C.; Laurencin, Cato T. (8 November 2023). "Oxygen-Generating Biomaterials for Translational Bone Regenerative Engineering". ACS Applied Materials & Interfaces. 15 (44): 50721–50741. Bibcode:2023AAMI...1550721H. doi:10.1021/acsami.2c20715. PMID 36988393.
  7. 1 2 Ashammakhi, Nureddin; Darabi, Mohammad Ali; Kehr, Nermin Seda; Erdem, Ahmet; Hu, Shu-kai; Dokmeci, Mehmet R.; Nasr, Ali S.; Khademhosseini, Ali (2020-01-13). "Advances in Controlled Oxygen Generating Biomaterials for Tissue Engineering and Regenerative Therapy". Biomacromolecules. 21 (1): 56–72. doi:10.1021/acs.biomac.9b00546. ISSN 1525-7797.
  8. 1 2 3 Waite, Andrew James; Bonner, James S.; Autenrieth, Robin (May 1999). "Kinetics and Stoichiometry of Oxygen Release from Solid Peroxides". Environmental Engineering Science. 16 (3): 187–199. Bibcode:1999EEngS..16..187W. doi:10.1089/ees.1999.16.187.
  9. ↑ Suvarnapathaki, Sanika; Nguyen, Michelle A.; Goulopoulos, Anastasia A.; Lantigua, Darlin; Camci-Unal, Gulden (2021). "Engineering calcium peroxide based oxygen generating scaffolds for tissue survival". Biomaterials Science. 9 (7): 2519–2532. doi:10.1039/d0bm02048f. PMC 11442008. PMID 33565527.
  10. ↑ Abdi, Syed Izhar Haider; Ng, Sing Muk; Lim, Jeong Ok (May 2011). "An enzyme-modulated oxygen-producing micro-system for regenerative therapeutics". International Journal of Pharmaceutics. 409 (1–2): 203–205. doi:10.1016/j.ijpharm.2011.02.041. PMID 21356297.
  11. ↑ Miller, Margeaux A.; Sletten, Ellen M. (2020-12-11). "Perfluorocarbons in Chemical Biology". ChemBioChem. 21 (24): 3451–3462. doi:10.1002/cbic.202000297. ISSN 1439-4227. PMC 7736518. PMID 32628804.
  12. ↑ Riess, Jean G. (January 2005). "Understanding the Fundamentals of Perfluorocarbons and Perfluorocarbon Emulsions Relevant to In Vivo Oxygen Delivery". Artificial Cells, Blood Substitutes, and Biotechnology. 33 (1): 47–63. doi:10.1081/BIO-200046659. PMID 15768565.
  13. ↑ Jägers, Johannes; Wrobeln, Anna; Ferenz, Katja B. (February 2021). "Perfluorocarbon-based oxygen carriers: from physics to physiology". Pflügers Archiv - European Journal of Physiology. 473 (2): 139–150. doi:10.1007/s00424-020-02482-2. PMC 7607370. PMID 33141239.
  14. ↑ Hu, Jilin; Wang, Quan; Wang, Ying; You, Guoxing; Li, Penglong; Zhao, Lian; Zhou, Hong (July 2020). "Polydopamine-based surface modification of hemoglobin particles for stability enhancement of oxygen carriers". Journal of Colloid and Interface Science. 571: 326–336. Bibcode:2020JCIS..571..326H. doi:10.1016/j.jcis.2020.03.046. PMID 32208203.
  15. ↑ Paciello, Antonio; Amalfitano, Giuseppe; Garziano, Alessandro; Urciuolo, Francesco; Netti, Paolo A. (October 2016). "Hemoglobin-Conjugated Gelatin Microsphere as a Smart Oxygen Releasing Biomaterial". Advanced Healthcare Materials. 5 (20): 2655–2666. doi:10.1002/adhm.201600559. PMID 27594116.
  16. 1 2 Suvarnapathaki, Sanika; Wu, Xinchen; Lantigua, Darlin; Nguyen, Michelle A.; Camci-Unal, Gulden (December 2019). "Breathing life into engineered tissues using oxygen-releasing biomaterials". NPG Asia Materials. 11 (1) 65. Bibcode:2019npjAM..11...65S. doi:10.1038/s41427-019-0166-2. ISSN 1884-4049.
  17. ↑ Sun, Xin; Yao, Fanglian; Zhang, Hong; Li, Junjie (May 2022). "Oxygen-generating materials and their biomedical applications: a review". Journal of Materials Science. 57 (20): 9077–9103. doi:10.1007/s10853-022-07229-1. ISSN 0022-2461.
  18. ↑ Nikolopoulos, Vasilios K.; Augustine, Robin; Camci-Unal, Gulden (2023). "Harnessing the potential of oxygen-generating materials and their utilization in organ-specific delivery of oxygen". Biomaterials Science. 11 (5): 1567–1588. doi:10.1039/D2BM01329K. ISSN 2047-4830. PMC 10015602. PMID 36688522.
  19. 1 2 3 Ho, Tzu-Chuan; Chang, Chin-Chuan; Chan, Hung-Pin; Chung, Tze-Wen; Shu, Chih-Wen; Chuang, Kuo-Pin; Duh, Tsai-Hui; Yang, Ming-Hui; Tyan, Yu-Chang (2 May 2022). "Hydrogels: Properties and Applications in Biomedicine". Molecules. 27 (9): 2902. Bibcode:2022Molec..27.2902H. doi:10.3390/molecules27092902. PMC 9104731. PMID 35566251.
  20. ↑ Jacob, Shery; Nair, Anroop B.; Shah, Jigar; Sreeharsha, Nagaraja; Gupta, Sumeet; Shinu, Pottathil (2021-03-08). "Emerging Role of Hydrogels in Drug Delivery Systems, Tissue Engineering and Wound Management". Pharmaceutics. 13 (3): 357. doi:10.3390/pharmaceutics13030357. ISSN 1999-4923. PMC 7999964. PMID 33800402.
  21. ↑ de Sousa Araújo, Erlane; Domingues Stocco, Thiago; Fernandes de Sousa, Gustavo; Afewerki, Samson; Marciano, Fernanda Roberta; Alexandre Finzi Corat, Marcus; Michelle Machado de Paula, Mirian; Ferreira Cândido Lima Verde, Thiago; Cristina Moreira Silva, Mayara; Oliveira Lobo, Anderson (September 2021). "Oxygen-generating microparticles in chondrocytes-laden hydrogels by facile and versatile click chemistry strategy". Colloids and Surfaces B: Biointerfaces. 205 111850. doi:10.1016/j.colsurfb.2021.111850. PMID 34015729.
  22. ↑ Han, Min Ji; An, Jeong Ah; Kim, Jeong Min; Heo, Dong Nyoung; Kwon, Il Keun; Park, Kyung Min (April 2023). "Calcium peroxide-mediated bioactive hydrogels for enhanced angiogenic paracrine effect and osteoblast proliferation". Journal of Industrial and Engineering Chemistry. 120: 121–130. doi:10.1016/j.jiec.2022.12.017.
  23. ↑ Tran Vo, Tu Minh; Sanghong, Patthadon; Pongwisuthiruchte, Aphiwat; Aonbangkhen, Chanat; Chen, Xiaogang; Potiyaraj, Pranut (2025). "Self-oxygenating, autonomous self-healing dual-physical crosslinked PVA/chitosan/hydrolysed collagen hydrogels for advanced wound management". Journal of Materials Chemistry B. 13 (35): 11020–11031. doi:10.1039/d5tb00919g. PMID 40827478.
  24. 1 2 3 Eltom, Abdalla; Zhong, Gaoyan; Muhammad, Ameen (7 March 2019). "Scaffold Techniques and Designs in Tissue Engineering Functions and Purposes: A Review". Advances in Materials Science and Engineering. 2019: 1–13. doi:10.1155/2019/3429527.
  25. ↑ Mollajavadi, Mohammad Yasin; Saadatmand, Maryam; Ghobadi, Faezeh (May 2023). "Effect of calcium peroxide particles as oxygen-releasing materials on cell growth and mechanical properties of scaffolds for tissue engineering". Iranian Polymer Journal. 32 (5): 599–608. doi:10.1007/s13726-023-01147-y.
  26. ↑ Suvarnapathaki, Sanika; Wu, Xinchen; Zhang, Tengfei; Nguyen, Michelle A.; Goulopoulos, Anastasia A.; Wu, Bin; Camci-Unal, Gulden (July 2022). "Oxygen generating scaffolds regenerate critical size bone defects". Bioactive Materials. 13: 64–81. doi:10.1016/j.bioactmat.2021.11.002. PMC 8843972. PMID 35224292.
  27. ↑ Sarkar, Naboneeta; Zhao, Jingtong; Zhang, Nicholas Y.; Horenberg, Allison L; Grayson, Warren L. (September 2024). "3D printed O2-generating scaffolds enhance osteoprogenitor- and type H vessel recruitment during bone healing". Acta Biomaterialia. 185: 126–143. doi:10.1016/j.actbio.2024.07.011. PMC 11405102. PMID 39009209.
  28. ↑ Soheili, Shima; Dolatyar, Banafsheh; Adabi, Mohammad Reza; Lotfollahi, Darya; Shahrousvand, Mohsen; Zahedi, Payam; Seyedjafari, Ehsan; Mohammadi-Rovshandeh, Jamshid (2024). "Fabrication of fiber-particle structures by electrospinning/electrospray combination as an intrinsic antioxidant and oxygen-releasing wound dressing". Journal of Materials Chemistry B. 12 (36): 9074–9097. doi:10.1039/d4tb00270a. PMID 39171375.
  29. 1 2 Nathanael, A. Joseph; Oh, Tae Hwan (2020-12-21). "Biopolymer Coatings for Biomedical Applications". Polymers. 12 (12): 3061. doi:10.3390/polym12123061. ISSN 2073-4360. PMC 7767366. PMID 33371349.
  30. ↑ Akhavan-Kharazian, Neda; Izadi-Vasafi, Hossein (July 2019). "Preparation and characterization of chitosan/gelatin/nanocrystalline cellulose/calcium peroxide films for potential wound dressing applications". International Journal of Biological Macromolecules. 133: 881–891. doi:10.1016/j.ijbiomac.2019.04.159. PMID 31028810.
  31. ↑ Forget, Aurelien; Staehly, Camille; Ninan, Neethu; Harding, Frances J.; Vasilev, Krasimir; Voelcker, Nicolas H.; Blencowe, Anton (9 October 2017). "Oxygen-Releasing Coatings for Improved Tissue Preservation". ACS Biomaterials Science & Engineering. 3 (10): 2384–2390. doi:10.1021/acsbiomaterials.7b00297. PMID 33445296.
  32. ↑ Saralidze, Ketie; Koole, Leo H.; Knetsch, Menno L.W. (2010-06-07). "Polymeric Microspheres for Medical Applications". Materials. 3 (6): 3537–3564. Bibcode:2010Mate....3.3537S. doi:10.3390/ma3063537. ISSN 1996-1944. PMC 5521755.
  33. ↑ McNamara, Karrina; Tofail, Syed A. M. (2017-01-02). "Nanoparticles in biomedical applications". Advances in Physics: X. 2 (1): 54–88. Bibcode:2017AdPhX...2...54M. doi:10.1080/23746149.2016.1254570. ISSN 2374-6149.
  34. ↑ Altammar, Khadijah A. (2023-04-17). "A review on nanoparticles: characteristics, synthesis, applications, and challenges". Frontiers in Microbiology. 14 1155622. doi:10.3389/fmicb.2023.1155622. ISSN 1664-302X. PMC 10168541. PMID 37180257.
  35. ↑ Pereira, Beatriz; Santos, Catarina (9 April 2026). "Oxygen-Releasing Calcium Peroxide Nanoparticles for Biomedical Applications: From Synthesis to Clinical Relevance". Applied Sciences. 16 (8): 3678. doi:10.3390/app16083678.
  36. ↑ Zhang, Mengen; Kiratiwongwan, Tawan; Shen, Wei (April 2020). "Oxygen-releasing polycaprolactone/calcium peroxide composite microspheres". Journal of Biomedical Materials Research Part B: Applied Biomaterials. 108 (3): 1097–1106. doi:10.1002/jbm.b.34461. PMID 31393674.
  37. ↑ Tomioka, Daisuke; Fujita, Satoshi; Groll, Jürgen; Matsusaki, Michiya (25 July 2023). "Hydroxyapatite Nanocoating on Calcium Peroxide Microparticles for Sustained Oxygen Release". Chemistry of Materials. 35 (14): 5378–5391. doi:10.1021/acs.chemmater.3c00601.
  38. ↑ Ícaro Sousa Morais, Alan; Wang, Xichi; Vieira, Ewerton; Viana, Bartolomeu; Silva-Filho, Edson; Furtini, Josy; Afewerki, Samson; Corat, Marcus; Silva, Heurison; Marciano, Fernanda; Ruiz-Esparza, Guillermo; Domingues Stocco, Thiago; De-Paula, Mirian; Lobo, Anderson (February 2020). "Electrospraying Oxygen-Generating Microparticles for Tissue Engineering Applications". International Journal of Nanomedicine. 15: 1173–1186. doi:10.2147/IJN.S237334. PMC 7037066. PMID 32110015.
  39. ↑ Zou, Ting; Liang, Ye; Kang, Jun; Liu, Junqing; Kang, Wenyan; Jiang, Shan; Zhang, Chengfei (April 2024). "Oxygen enrichment mediated by calcium peroxide loaded gelatin methacrylate hydrogel eradicates periodontal biofilms". International Journal of Biological Macromolecules. 265 (Pt 1) 130868. doi:10.1016/j.ijbiomac.2024.130868. PMID 38492687.
  40. ↑ Daneshmandi, Leila; Laurencin, Cato T. (May 2020). "Regenerative engineered vascularized bone mediated by calcium peroxide". Journal of Biomedical Materials Research Part A. 108 (5): 1045–1057. doi:10.1002/jbm.a.36879. PMID 31925886.
  41. ↑ Touri, Maria; Moztarzadeh, Fathollah; Osman, Noor Azuan Abu; Dehghan, Mohammad Mehdi; Mozafari, Masoud (March 2018). "3D–printed biphasic calcium phosphate scaffolds coated with an oxygen generating system for enhancing engineered tissue survival". Materials Science and Engineering: C. 84: 236–242. doi:10.1016/j.msec.2017.11.037. PMID 29519434.
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