Abstract
They have several potential biomedical uses, including in cell encapsulation, tissue engineering, the controlled release of therapeutic proteins and drugs and a host of other procedures. Injectable hydrogels are more effective because of their quick sol-gel transition at the injection site. They may change shape to fit any cavity and conceal themselves invisibly between the hydrogel and the tissue. To control the rate and quantity of drug release, hydrogels with a temperature-sensitive consistency are commonly used. Injectable hydrogels are effective for releasing drugs that are unstable at room temperature, in the presence of particular ions, or at a specific pH. Additionally, the key hurdle that must be conquered to enable efficient cell encapsulation therapy is the selection of biomaterial as a membrane for encapsulating cells.
1. Introduction
Hydrogels are three-dimensional polymeric networks that can stay together, even though they have a lot of water in them. Hydrogels are a promising material for use in a wide range of bio-medical procedures, such as substrate in cell culture tissue generation scaffolds, encapsulation of cells, excellent for protein and drug delivery and used in biomedical devices as bio-sealants and bio-adhesives. (Guvendiren et al. 2012)
Hydrogels have a wide range of applications, owing to their ability to simulate the environmental conditions similar to those of tissues such as biocompatibility. They are highly sensitive towards various environmental factors such as temperature, pH and ionic concentration and can maintain the functional and chemical properties of nanoparticle. One of the most vital injectable qualities of hydrogels for minimally invasive surgical procedures is particularly in tissue-engineered and medicine administration applications (Aswathy et al. 2020). The rapid sol-gel transition at the injection site increases the usefulness of injectable hydrogels. They can adapt to any change and can fit between tissue and hydrogel (Li et al. 2020). The incorporation of medicinal compounds and cells prior to injection is facilitated by simple mixing. The two main types of injectable hydrogel are physical cross-linking and chemical cross-linking. Physical cross-linked hydrogels are created by self-assemble under influence of e ternal parameters such as temperature, pH and redox potential, whereas chemical cross-linking is developed via redox-initiated, photo-initiated Michael type addition polymerization, hydrophobic interaction and ionic concentration, which do not depend on the formation of covalent bond. (Rebers et al. 2021)
1.1. Classification of conventional hydrogels
Hydrogels, for example, can be broken down into “natural” and “synthetic” subsets, depending on their origin.
1.1.1 Natural Polymers
Natural polymer-based hydrogels are those hydrogels that consist of the natural substance. These are the natural polymers comprising of collagens, chitosan, gelatin alginates, etc. Deacetylation of chitin yields chitosan, a positively charged polymer made of D-glucosamine and N-acetyl D-glucosamine that is found in abundance in the shells of crustaceans (Croisier and Jérôme, 2013). The Schiff base cross-linking reaction was previously used to create chitosan hydrogels with hyaluronic acid. Hydrogels generated in this way have a better biological response, making them a good candidate for use in abdominal tissue engineering. (Deng et al. 2017)
The natural polymer is suitable for preparing bio inks, because of its simple gelation phenomena and good compatibility. With the help of sodium alginate, collagen or agarose, Yang et al. (2017) created a cell-encapsulated bio ink with impressive mechanical strength and bioactivity (Yang et al. 2018). These natural polymers are most suitable for preparing bio inks, due its low cytotoxicity and biocompatibility along with better water retention capacity. A natural extracellular protein called collagen promotes strong ligand adherence.
1.1.2 Synthetic Polymers
Synthetic polymers are suitable for various biomedical applications, due to its better mechanical and physiochemical properties that are also reproducible and tenable. To a large extent, synthetic polymers’ shortcomings might be attributed to the fact that only a small number of polymers are considered biocompatible. Polyethylene glycol, polyacrylic acid, polyethylene oxide, polyvinyl alcohol, etc., are the most popular synthetic biopolymers utilized in the production of hydrogels. (Lee and Mooney, 2001)
Physical cross-linking was used to create an injectable PNIPAAm-polyethylene glycol hydrogel. The prepared hydrogel showed enhanced cellular response growth of axonal and also helped maintain the sensory mortar function. These hydrogels are ideal candidates for the axons regeneration (Bonnet et al. 2020). Polyethylene glycol synthetic polymer shows properties like natural biopolymer being biocompatible, biodegradable and an ideal candidate for injury of spinal cord by generating nerve fibre and repair nerve (Kong et al. 2017). Additionally, hydrogel prepared using polyvinyl alcohol-polyacrylic acid is suitable for identifying vascular, which decrease the adhesion of platelet (Mannarino et al. 2020). Semi-synthetic polymers, such as cellulose derivatives, gelatin, methacrylate, etc., share characteristics with both synthetic and natural polymers. The hydrogel prepared using synthetic polymers with proteins shows better biological and mechanical properties (Utech and Boccaccini, 2016). The cells of the dorsal root ganglia were previously encapsulated in a hydrogel made of polyethylene and proteins by Berkovitch et al. (2017).
2. Applications of Smart Hydrogels
Hydrogels are versatile and can be used in a wide variety of settings, from biological to industrial. Biomedical, dye removal, heavy metal removal, agri-sanitary diapers, pH sensors, biosensors and super capacitors are just a few of the many uses for hydrogels (Figure 2). Wound dressings, cosmetics, drug delivery, contact lenses and tissue engineering are some of the most prevalent biomedical applications. (Bahram et al. 2016)
2.1 ‘On–Off’ Drug Delivery Systems
Hydrogel that can adjust its volume in response to small variations in temperature and humidity is called a “smart hydrogel.” Methods for controlling drug release include modifying crosslinking densities and creating hydrogels with controlled hydrophobicity monomers. The drug delivery at specific site is another challenge in developing the hydrogels, with these smart hydrogels having capability to deliver the drug at specific site. The interaction level between active molecules is very less, especially in case of protein and peptides. The controlled and site-specific release of the drug helps in reducing the unwanted adverse effect and enhances or improves the efficiency of medical treatments. Smart hydrogels are more efficient drug releases, owing to change in their response according to the specific stimuli. Hydrogels that change consistency in response to temperature are widely employed as an on/off mechanism for managing drug release. By including PNIPAAm into temperature-responsive hydrogels, Okan o et al. (1991, 1992) were able to achieve rapid and precise “on-off” control of drug penetration in response to gradual temperature changes.
2.2 Injectable Hydrogels
Injectable hydrogels are a promising method for delivering a medicine slowly over time for increased therapeutic effect. Any necessary medicine can be implanted in body tissue with ease. Injecting a gel-forming biopolymer in situ, where it can form therapeutic implants or vehicles is thus gaining popularity (Nguyen and Lee 2010). A new class of thermally sensitive chitosan/polyol salt combinations was developed by Chenite et al. (2000) and used to develop implants with the properties of a gel when placed in vivo.
These formulations have a physiological pH and may be retained as a liquid below room temperature, allowing them to encapsulate living cells and therapeutic proteins; beyond body temperature, however, they form monolithic gels. After being injected into a living organism, the liquid formulations solidify as gel implants. For in vivo tissue engineering purposes, this technology was successfully used to provide physiologically active growth factors and an encapsulating matrix for living chondrocytes (Chenite et al. 2000). Drugs that are sensitive to heat, certain ions or pH are particularly effective for use in the treatment of eye disease. The eye presents a difficulty in the development of sustained or controlled release systems, due to its sensitivity and effective defensive mechanisms, such as lacrimal secretion and the blinking reflex, which promote fast drainage of bioactive chemicals following topical administration. The advantages of in situ gels outweigh their disadvantages, since they can be injected as a solution into the eye and then transformed into a gel there. Polymers with a thermo-gelling property called poloxamers may be employed to create efficient methods for administering drugs topically (Wei et al. 2002). To successfully administer biologically active growth factors in vivo and to provide an encapsulating matrix for tissue engineering application with living chondrocytes, injectable hydrogels have been employed.
2.3 Tissue engineering
Tissue engineering is a new field that holds great promise for developing responsive, live tissue replacements that mimic the features of natural tissues. In in vitro scaffold-based tissue engineering, the scaffold itself is a crucial component (Hoffman 2012). Scaffolds are structural three-dimensional templates that aid cell adhesion, migration, differentiation and proliferation and direct the formation of new tissues. Among the many potential scaffolding biomaterials, hydrogels stand out as the most preferred.
Hydrogels also provide an aqueous environment that is analogous to what body cells experience. Hydrogel scaffolds, either synthetic or natural, are used in tissue engineering to mend damaged tissues such as cartilage, tendons, ligaments, skin, blood vessels and heart valves (Lee and Mooney 2001). Additionally, attractive substrates for tissue engineering applications are injectable hydrogels due to their high water content similar to that of tissue, capacity to homogeneously encapsulate cells, effective mass transfer, readily modifiable physical properties and less invasive delivery (Drury and Mooney 2003). When injected into a wound site along with growth factors or targeted cells, the hydrogel precursor undergoes a sol-gel transition in response to local physical or chemical stimulation. Besides its use in tissue engineering, smart hydrogels have the potential to be used for cell encapsulation.
Cell technology is a promising method of treatment for diseases such as diabetes, haemophilia, cancer and renal failure (Williams et al. 2005). It is crucial to pick a suitable biomaterial as a membrane for encapsulating cells, which is the main challenge to overcome, in order to enable effective cell encapsulation therapy. Hydrogels were selected for this function, since they are biocompatible, micro-porous and cause minimal surface irritation to the surrounding tissues.
Conclusion
Hydrogels are 3D polymeric networks that can accommodate a considerable amount of water. Hydrogels are useful for protein and drug delivery, cell encapsulation and bio-sealants and bio-adhesives in biomedical purposes. Source-based classification: natural, synthetic and semi-synthetic. Natural polymer-based hydrogels include collagens, chitosan, gelatin alginates, etc. and Synthetic hydrogels are generated by physically cross-linking poly ethylene glycol, poly acrylic acid and poly ethylene oxide.
Semi-synthetic polymers hold the properties of both synthetic and natural polymers. Hydrogels are being used in biomedicine, dye removal, heavy metal removal, diapers, pH sensors, biosensors and super capacitors. Wound dressings, cosmetics, drug administration, contact lenses and tissue engineering are popular biomedical applications of hydrogel. Most on-off drug release mechanisms involve temperature-responsive hydrogels.
Hydrogel is used for implanting drugs in bodily tissue. Injecting a gel-forming biopolymer in situ is intriguing for creating therapeutic implants and vehicles. Synthetic and natural hydrogels are used to heal cartilage, tendon, ligament, skin, blood vessels and heart valves. Injectable hydrogels are interesting substrates for tissue engineering, owing to their high tissue-like water content, ability to encapsulate cells, efficient mass transfer, readily modifiable physical features and less invasive administration.
References:
1. Aswathy SH, Narendrakumar U, Manjubala I (2020) Commercial hydrogels for biomedical applications. Heliyon 6:. https://doi.org/10.1016/j.heliyon.2020.e03719
2. Bahram M, Mohseni N, Moghtader M (2016) An introduction to hydrogels and some recent applications. In: Emerging concepts in analysis and applications of hydrogels. IntechOpen
3. Berkovitch Y, Seliktar D (2017) Semi-synthetic hydrogel composition and stiffness regulate neuronal morphogenesis. Int J Pharm 523:545–555. https://doi.org/https://doi.org/10.1016/j.ijpharm.2016.11.032
4. Bonnet M, Trimaille T, Brezun J-M, et al (2020) Motor and sensitive recovery after injection of a physically cross-linked PNIPAAm-g-PEG hydrogel in rat hemisectioned spinal cord. Mater Sci Eng C 107:110354. https://doi.org/https://doi.org/10.1016/j.msec.2019.110354
5. Chenite A, Chaput C, Wang D, et al (2000) Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21:2155–2161.
https://doi.org/https://doi.org/10.1016/S0142-9612(00)00116-2
6. Croisier F, Jérôme C (2013) Chitosan-based biomaterials for tissue engineering. Eur Polym J 49:780–792. https://doi.org/https://doi.org/10.1016/j.eurpolymj.2012.12.009
7. Deng Y, Ren J, Chen G, others (2017) Injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for abdominal tissue regeneration. Sci Rep
8. Drury JL, Mooney DJ (2003) Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24:4337–4351. https://doi.org/https://doi.org/10.1016/S0142-9612(03)00340-5
9. Guvendiren M, Lu HD, Burdick JA (2012) Shear-thinning hydrogels for biomedical applications. Soft Matter 8:260–272. https://doi.org/10.1039/c1sm06513k
10. Hoffman AS (2012) Hydrogels for biomedical applications. Adv Drug Deliv Rev 64:18–23.
https://doi.org/10.1016/j.addr.2012.09.010
11. Kong X Bin, Tang QY, Chen XY, et al (2017) Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen Res 12:1003–1008.
https://doi.org/10.4103/1673-5374.208597
12. Lee KY, Mooney DJ (2001) Hydrogels for tissue engineering. Chem Rev 101:1869–1880
13. Li J, Yu F, Chen G, et al (2020) Moist-Retaining, Self-Recoverable, Bioadhesive, and Transparent in Situ Forming Hydrogels to Accelerate Wound Healing. ACS Appl Mater Interfaces 12:2023–2038. https://doi.org/10.1021/acsami.9b17180
14. Mannarino MM, Bassett M, Donahue DT, Biggins JF (2020) Novel high-strength thromboresistant poly (vinyl alcohol)-based hydrogel for vascular access applications. J Biomater Sci Polym Ed 31:601–621
15. Nguyen MK, Lee DS (2010) Injectable biodegradable hydrogels. Macromol Biosci 10:563–579.
https://doi.org/10.1002/mabi.200900402
16. Rebers L, Reichsöllner R, Regett S, et al (2021) Differentiation of physical and chemical cross-linking in gelatin methacryloyl hydrogels. Sci Rep 11:1–12. https://doi.org/10.1038/s41598-021-82393-z
17. Utech S, Boccaccini AR (2016) A review of hydrogel-based composites for biomedical applications: enhancement of hydrogel properties by addition of rigid inorganic fillers. J Mater Sci 51:271–310. https://doi.org/10.1007/s10853-015-9382-5
18. Wei G, Xu H, Ding PT, et al (2002) Thermosetting gels with modulated gelation temperature for ophthalmic use: the rheological and gamma scintigraphic studies. J Control Release 83:65–74. https://doi.org/https://doi.org/10.1016/S0168-3659(02)00175-X
19. Williams CG, Malik AN, Kim TK, et al (2005) Variable cytocompatibility of six cell lines with photoinitiators used for polymerizing hydrogels and cell encapsulation. Biomaterials 26:1211–1218. https://doi.org/https://doi.org/10.1016/j.biomaterials.2004.04.024
20. Yang X, Lu Z, Wu H, et al (2018) Collagen-alginate as bioink for three-dimensional (3D) cell printing based cartilage tissue engineering. Mater Sci Eng C 83:195–201. https://doi.org/https://doi.org/10.1016/j.msec.2017.09.002