Technical Review Article | Open Access | Published 7th October 2024
Wonders of Hydrogel: Bringing in a new era of excellent wound healing
Roohi Yusufi, Akanksha Dwivedi*, Sumeet Dwivedi, G.N. Darwhekar | EJPPS | 293 (2024) | Click to download pdf
Abstract
This thorough review clarifies the novel function of hydrogels in the healing of wounds, with an emphasis on the various hydrogel formulations and their results. Because of their special physicochemical qualities, hydrogels are at the forefront of medical innovation, revolutionizing the way wounds are treated. This review examines the specific uses of several hydrogel types in wound healing in addition to their basic characteristics. Hydrogel films containing gentamicin, L-arginine, and glycerol for high-definition wound coverage; hydrogel dressings with high antimicrobial qualities and advantageous rheological characteristics; naringenin and gentamicin co-loaded in-situ spray hydrogels for easy application and prolonged medication retention; injectable hydrogels with thiolate polyethylene glycol and silver nitrate for antibacterial and angiogenic properties; hydrogels infused with aloe vera for collagen promotion and improved wound healing; and a variety of in situ forming hydrogels containing collagen, poly-d-lysine, chondroitin sulphate, alginate/silk fibroin, benzaldehyde-terminated PEG, dodecyl-modified chitosan, and crosslinked polymeric materials for a variety of wound healing applications.
Additionally, the abstract provides a thorough synthesis of scientific evidence by incorporating recent studies and references that highlight the therapeutic outcomes linked with each type of hydrogel. This comprehensive investigation offers a state-of-the-art understanding of hydrogel research today, but it also looks ahead to a time when these adaptable materials will continue to redefine excellence in healthcare, opening up new possibilities for better patient outcomes and overall healthcare efficacy.
Keywords: Wound, Hydrogel, Wound dressing
Introduction
A three-dimensional (3D) network of hydrophilic polymers makes up hydrogel (Lim et al,.2010). The network gives the polymeric system an insoluble characteristic and permits the hydrogels to absorb water up to thousands of times their equivalent weight in water, with a range of 10–20% (an arbitrary lower limit) until the process achieves an equilibrium state (Gupta et al., 2010). Because of their jelly-like texture and non-toxicity, hydrogel dressings are frequently used on wounds with odd forms and edges. They are primarily applied to granulating wounds, dry to moderately draining wounds, and necrotic wounds to promote autolytic debridement.
Hydrogels that are fully swelled are pliable, soft, and have little interfacial tension. a number of physical characteristics shared by living tissues. The hydrogel's elastic qualities can lessen the surrounding tissues' stimulation. A low interfacial tension between the bodily fluid and the hydrogel surface can maximize the reduction of cell adhesion and protein absorption, lessening the likelihood of an adverse immunological response (Hamidi et al., 2008). Many polymer hydrogels, including polyethylene glycol (PEG), polyvinyl alcohol (PVA), and polyacrylate acid (PAA), can lengthen the drug's retention period and boost the tissue's permeability (Amsden et al., 2015). In the process of tissue regeneration, the hydrogel not only provides support for the cells but also carries a therapeutic payload because of its composition and mechanical characteristics that resemble those of the natural extracellular matrix (ECM) (Tessmar et al, 2007).
Chen et al., (2018) proposed a benzaldehyde-terminated PEG and dodecyl-modified chitosan hybrid hydrogel system, loading, and controlling the release of VEGF. In an in-vivo diabetic animal study, this hydrogel product sped up the formation of granulation of tissue and collagen remodeling, ultimately encouraging the re-epithelialization and complete skin regeneration of chronic wounds.
Wang et al., (2019) created an injectable polypeptide-based hydrogel and loaded it with exosomes of mesenchymal stem cells obtained from adipose tissue. The hydrogel product considerably enhanced HUVEC cell migration and proliferation. This hydrogel product sped up the formation of collagen remodeling and granulated tissue, ultimately promoting the re-epithelialization and full skin regeneration of chronic wounds in an in-vivo diabetic animal research investigation.
Annabi et al., (2017) reported on a sprayable hydrogel with broad-spectrum antimicrobial activity to treat chronic wounds. Through visible light-induced crosslinking, this hydrogel was created with gelatine methacrylic and methacryloyl-substituted recombinant human trophoblastic. According to the results, this hydrogel product was significantly better than store-bought tissue adhesives and caused less inflammation in a model of a murine animal,
suggesting that it might be used as a substitute suture to aid in the healing of chronic wounds and stave off further infections.
Any disturbance or injury to living tissue, including skin, mucous membranes, or organs, is referred to as a wound (Bordoni et al., 2023). Injuries can arise abruptly from mechanical, thermal, or chemical assault, or they can develop gradually over time as a result of underlying medical conditions such diabetes mellitus, venous or arterial insufficiency, or immunologic disorders (Michelsen et al., 2008). Among other parameters, wound location, damage method, depth of injury, timing of onset (acute vs. chronic), and wound sterility can all significantly affect wound appearance (Bordoni et al., 2023).
Figure 1- Classification of Wounds (Maqsood et al.,2016).
Figure 2-Factors Influencing the Healing of Wounds
Healing Process of Wounds
To comprehend the mechanism of tissue healing, wound healing is a continuous process that occurs in all damaged tissue and is divided into four phases (Richardson et al.,2004). Four overlapping phases in healing occur: remodelling, proliferation, inflammation, and haemostasis. The infiltration of particular cell types into the wound site characterises each phase are shown in figure 3 (Diegelmann et al., 2004). Table I depicts phases in the healing of wounds.
Figure 3 –Different Phases in the Healing of Wounds
Table I-Different Stages of Wound Healing
Wound healing is the process by which a live organism replaces damaged or lost tissue with newly generated tissue and this epidermis, which is the skin's surface epithelial layer, and dermis, which is the skin's deeper connective layer, work together to create a barrier that shields healthy skin from the elements. A controlled series of biochemical processes are triggered when the barrier is breached in order to heal the harm (GR et al.,1998). The classification of specific wounds is described in table II.
Table II- Classification of Specific Wounds
Hydrogels as Wound Dressings
Since the early 1980s, researchers have gradually examined and used the intrinsic qualities of membranes as wound dressings to promote skin healing and shield the skin defect zone from infection (Sood et al, 2014). The following mechanism by which hydrogels function as wound dressings is described in figure 6. Hydrogels have the ability to absorb and hold onto wound exudates, which encourages fibroblast growth and keratinocyte migration. The latter two procedures are critical for full epithelialization and wound healing (Rimmer et al., 2010).
Table III- Type of Hydrogels in Wound Healing
Furthermore, the hydrogel structure's tight mesh size guards against infection by keeping germs and other microorganisms from getting to the injured area. Nonetheless, the structure of hydrogels enables the delivery of medicinal and other bioactive substances, such as antibiotics, to the wound centre. These molecules have the potential to get enmeshed in hydrogel networks during the gelling process, and they can also be transferred by absorbing wound exudates during the sustained release phase following hydrogel contact with the wound surface. Hydrogels' substantial water content, which resembles tissue, gives them the flexibility and elasticity required to adapt to wounds in various body locations.
Figure 4 - Types of Hydrogels for Healing Wounds
Hydrogels with Functions as Wound Dressings to Promote Wound Healing
The potential for hydrogel multifunctional capabilities is quite high. Hydrogels with chronic wound healing can contain a variety of functional features, including pro-angiogenic, antibacterial, and anti-inflammatory qualities, as well as adhesiveness, biocompatibility, biodegradability, and vascularization potential are shown in figure 5. In order to present an appropriate matrix during chronic wound healing without causing harm to the surrounding tissue, a hydrogel must be biocompatible.
Other crucial factors include the hydrogels' biodegradability and pace of biodegradation, which act as a transient template for the growth of fibroblasts, the re-epithelialization and neovascularization of wounds, and the remodelling of chronic wounds. Additionally, bio adhesivity is crucial for maintaining the hydrogel dressings surrounding the wound region throughout time, enhancing homeostasis, preserving the wound's moisture content and collecting exudates from the healing tissue. Since the prolonged healing of chronic wounds may increase the likelihood of infection, which negatively impacts the healing process, antimicrobial hydrogels can be useful in preventing infections. The primary cause of chronic wound healing delays is the inflammatory phase. Anti-inflammatory hydrogels shorten the healing period of wounds by promoting the change from the inflammatory to the proliferative stage, as described in figure 8.
Figure –5 Functions of Hydrogel in Wound Dressing (Liang et al.,2021).
It goes without saying that no hydrogel sample could possibly meet every one of the aforementioned requirements at the same time. In actuality, the artificial elements required to maximize the functionality of some of these qualities will cause the inefficiency of the others. In order to attain the optimum balance between the qualities, it is necessary to optimize the production reaction variables in practice. For instance, hydrogels used in drug administration must be porous and responsive to pH or temperature, and sanitary products must have the maximum absorption rate, the lowest rewetting, and the lowest residual monomer (Ahmed et al., 2015).
Figure –6 Mechanism of Hydrogel in Wound Healing (Firlar et al., 2022).
Figure 7- Various Tissue Injury Indications for Hydrogel Wound Adhesives
(Zhang et al., 2022)
Figure - 8 Schematic Representation of the role of Hydrogel Membrane Materials for Enhancing and Accelerating the Wound Healing Phases.
Table IV- Research Data Related to Hydrogels on Wound Healing
Hydrogel
Hydrogels are three-dimensional polymer networks that are insoluble in water and can absorb significant volumes of bodily fluids (Radhakrishnanet al., 2014). The hydrophilic functional groups included in the primary hydrogel polymer chain include amine (NH2), carboxyl
(COOH-), sulphate (SO3H-), and hydroxyl groups (OH-) (Park et al., 2018).
Figure 9 - Structure of Hydrogel at Molecular Level (Cascone et al., 2019)
Physical crosslinking, chemical crosslinking, or a mix of the two can create polymeric hydrogels (Payne et al.,2016). There are several ways to create hydrogels, including using a natural or synthetic polymer as the hydrogel's major source, homopolymer, copolymer, and permeable networks. Anionic and cationic cross-links are created that are both physically and chemically stable, hydrogen gel loading biostable and biodegradable. Recently, hydrogels that react to biological circumstances have drawn increased attention from researchers (Azami et al., 2017).
One characteristic of polymeric materials that enables hydrogels to store enormous amounts of biological fluids and water in their three-dimensional network is their hydrophilic structure. Interesting biomimetic characteristics of hydrogels include their exceptional softness, flexibility, and superior absorption capacity when swollen. They also feature non-toxic, biocompatible, biodegradable, and programmable mechanical qualities (Khutoryanskiy et al., 2015).
For a range of medical applications, such as tissue engineering and the release of therapeutic agents (genes, proteins, or medications), hydrogels are particularly appealing. These characteristics include minimal protein adsorption because of low surface tension, water absorption, soft structure, biocompatibility, and structural resemblance to the extracellular matrix (Park et al.,2018).
Figure -10 Chemical and Physical Aspects for the Classification of Polymeric Hydrogels
Figure 11 :Functional Features of an ideal Hydrogel (Zohuriaan-Mehret al .,2006).
Hydrogel Preparation Methods
Hydrogels are networks of polymers that exhibit hydrophilic properties. Hydrophobic monomers are also occasionally used in the production of hydrogels, even though hydrophilic monomers are usually used. In general, hydrogels can be made from synthetic or natural polymers. Synthetic polymers are naturally hydrophobic and tougher chemically than natural polymers. Although their mechanical strength slows down the pace of degradation, it also contributes to their durability. These two diametrically opposite features should be matched by perfect design. Furthermore, hydrogels based on natural polymers can be created if they have been functionalized with radically polymerizable groups or include suitable functional groups. The polymerization techniques depicted in Figure 12 and Table IV are described as follows:
Figure 12 Methods of Preparation of Hydrogel
Figure 13 Various Advantages & Disadvantages of Hydrogel
Hydrogels in Biomedical Applications
Hydrogels are versatile materials with a wide range of uses because of their unique designs and adaptability to various situations. Hydrogels are sufficiently flexible due to their water content to be used in a variety of biological and industrial applications. Some examples of the biomedical applications are shown in Figure 14.
• Hydrogel for Drug Delivery
Controlled drug delivery systems (DDS) have been developed to overcome the limits of regular medicine formulations. DDS are intended to release pharmaceuticals at precise rates over predefined durations of time. Hydrogels are a fantastic material choice for medication delivery applications because of their extraordinary qualities. Hydrogel structures with high porosity can be achieved by regulating the degree of cross-linking in the matrix and the hydrogel's affinity for the aqueous environment where swelling occurs. Pharmaceuticals can be put into and, under the right circumstances, released from hydrogels because of their porous architecture, which make them highly permeable to many types of pharmaceuticals (Bahram et al., 2015).
• Sensing
A broad range of reactions, including deformation and transparency changes, to different stimuli including temperature, pH, magnetic fields, and chemicals are made possible by the diversity of hydrogel chemistry. By coating stimuli-responsive hydrogel on silicon wafer, hydrogel interferometry is created that is responsive to humidity, volatile vapor, copper ions, and glycoprotein through changes in hydrogel thickness. As a result of the interference of light reflected by the hydrogel and silicon wafer surface, different visible structure colours are presented (Sunet al., 2018).
The combination of chemistry, mechanics, and optics led to the development of this sensing system. Salinity can be measured using a fibre Bragg grating (FBG) coated with hydrogel. The hydrogel covering swells to reach various equilibrium states at varying saline concentrations, which causes variations in FBG stretching and alterations in the wavelength of the reflected "Bragg" signal. This sensing device can, in theory, be expanded to detect more chemical species by changing the gel chemistry using the same (Cong et al., 2002).
Figure 14 Hydrogel for Bio-Applications
• Meniscus Tissue Engineering
The ability of meniscal tissue to recover after trauma is restricted. Because injectable hydrogel-based solutions are less intrusive than traditional meniscus treatments, they have offered an option. The meniscus is crucial for preserving the knee joint's homeostasis, and tissue engineering techniques are crucial for repairing and regenerating damaged meniscus tissues in this location (Kim et al., 2018). Certain human tissues, such meniscus and cartilage, have little to no blood flow, which prevents them from mending from injuries. Injecting a hydrogel containing medication or repair cells into the injured area may aid in promoting tissue regeneration.
• Hydrogels for Self-Healing
Hydrogels with self-healing properties are made of dynamic covalent bonds and non-covalent interactions such as hydrophobic, electrostatic, and hydrogen bonding (Liu et al., 2018), Based on their mechanical characteristics, self-healing hydrogels are categorized as soft and robust hydrogels for use in biological applications. Sturdy self-healing hydrogels are employed as soft robots (wearable or implantable biosensors, for example) that have a longer lifespan and improved mechanical performance as a result of fatigue or damage repair. Because they may be injected using tiny needles and remain at the intended locations, soft self-healing hydrogels are utilized in 3D printing and cell/drug delivery. Numerous medical applications, including wound healing (Paulet al., 2014), surface coating, 3D printing (Loebel et al., 2017), and tissue engineering, are covered by self-healing hydrogels (Rodell et al.,2015), and regeneration, drug delivery (Lee et al.,2018).
• Contact lenses
The field of ophthalmology, particularly contact lenses, is a major application for synthetic hydrogels in bio-applications. A tiny optical device called a contact lens is applied directly to the cornea to change its power. Leonardo da Vinci first proposed the idea of wearing contact lenses in 1508; at the time, this involved submerging the eye into a bowl of water. Professor Otto Wichterle created poly (2-hydroxyethyl methacrylate) (PHEMA) lenses at the end of 1960; this innovation marked the pinnacle of contact lens development and the dawn of the era of soft lenses (Michalek et al., 2010).
• Biosensors
Combining chemical and physical sensors results in a biosensor. A biosensor can be described as a tool that converts biochemical data into useful analytical information or as a tool that can identify and report a biophysical property of the system under study. As useful instruments for a broad range of application areas such as environmental monitoring, home diagnostics, and point-of-care testing, biosensors are becoming more and more significant.
A component of biological recognition, the bio element might be in the form of enzymes, antibodies, living cells, or tissues, among other things. It’s important that every bio element be specific to one analyte and doesn't respond to other interferents. Biomolecules can be coupled with sensors via a variety of techniques, such as covalent bonding, physical adsorption, entrapment into a matrix, and entrapment into membranes (Mateescu et al., 2012).
Table IV Examples of Marketed Hydrogels
Conclusion
This detailed review highlights the hydrogels' extraordinary adaptability, covering a wide range of uses from wound healing and medication delivery to tissue engineering. Their crucial function in biomedical developments is revealed via the investigation of their creation methods and distinctive features. Taking stock of the current situation, we can see that the ongoing search for clever hydrogel designs is driving us toward a day when these hydrophilic wonders will completely transform the medical field.
Hydrogels seem to have bright futures ahead of them. Progress in the future could lead to the creation of precisely designed hydrogels for certain medicinal applications, which would increase their therapeutic effectiveness even more. The combination of state-of-the-art technologies, such as stimulus-responsive features and alterations to nanomaterials, may pave the way for novel applications in targeted drug administration and customized medicine.
Furthermore, advances in regenerative medicine may be made possible by our growing understanding of how hydrogels interact with biological systems, resulting in more effective and scar-free healing. Customized treatment approaches may benefit from the incorporation of self-modulating hydrogel formulations as researchers work to overcome the hurdles presented by a variety of wound types.
In a larger sense, the direction that hydrogel technology is taking points to a future in which these artificial biomaterials will be crucial in transforming not just healthcare but also the environment and food industries. Hydrogels have the exciting potential to support varied sectors and sustainable solutions.
Hydrogels' development from basic categories to clever designs essentially reflects a trajectory of ongoing innovation. The upcoming years could see developments that push hydrogels into new fields of use and cement their status as revolutionary materials in the rapidly changing fields of science and medicine.
References
01. A. Concheiro, C. Alvarez-Lorenzo., Advanced Drug Delivery Reviews, 65, 9(2013)
02. A.L. Córdoba, L. Deladino, M. Martino., Carbohydrate polymers 95, 1(2013)
03. B. Gorain, M. Pandey, N.H. Leng, et al., International Journal of Pharmaceutics 617, 121617 (2022)
04. C. Asma, E. Meriem, B. Mahmoud and B. Djaafer., Journal of the Chilean Chemical Society 59,1(2014)
05. C.Y. Gong, Q. Wu, Y. Wang, et al., Biomaterials 34, 27(2013)
06. D. Benedec, D. Hanganu, I. Oniga, et al., Pak. J. Pharm. Sci 28, 6(2015)
07. Dai, L.J., Hou, J. and Cai, H.R., Chinese Journal of Integrated Traditional and Western Medicine 24, 2 (2004)
08. D. I. Rudyardjo and S. Wijayanto, Journal of Physics: Conference Series 853, 012042 (2017).
09. E. Chan, Z. Yim, S. Phan, R.F. Mansa, et al., Food and Bioproducts Processing 88, 23(2010)
10. G. Divyashri, R. V. Badhe, B. Sadanandan, et al., Polymers for Advanced Technologies 33, 7(2022)
11. G. Macedo, V.L. Chagas, M. Santos, et al., Biochemical Engineering Journal, 187, 108664(2022)
12. G. Macedo, V. Chagas, M. Santas, et al., Silva, Biochemical Engineering Journal13, 1(2022).
13. J. Patterson, R. Siew, S. W. Herring, A. S. Lin, R. Guldberg, and P. S. Stayton, Biomaterials 31, 6772 (2010).
14. J. Boateng, O. Catanzano., Journal of pharmaceutical sciences 104, 11(2015)
15. J. Chanaj-Kaczmarek, T. Osmałek, M. Paczkowska, J., Pharmaceutics 12, 7(2020)
16. K. C. Preethi, G. Kuttan, and R. Kuttan, Pharmaceutical biology 44, 691 (2006).
17. K.T. Peng, C.F. Chen, I.M. Chu, et al., Biomaterials 31, 19(2010)
18. L.A. Balestrin, J. Bidone, R.C. Bortolin, et al., Journal of Photochemistry and Photobiology B: Biology 163, 269(2016)
19. L. Colobatiu, A. Gavan, A. Mocan, et al., Reactive and Functional Polymers 138, 46(2019)
20. L.Lammoglia-Ordiales, M.E. Vega-Memije, A. Herrera-Arellano, et al., International Wound Journal, 9, 4(2012)
21. M. Annapoorna, S. Kumar, L. R Lakshman, et al., Carbohydrate polymers 92, 2(2013) 22.M.
22. Madaghiele, C. Demitri, A. Sannino, and L. Ambrosio, Burn. Trauma 2, 153 (2014).
23. M Michalak, A zielińska, K Paradowska, Acta Poloniae Pharmaceutica, 78, 2(2021)
24. M Peng, S Xu, , Y Zhang, et al., Journal of Pharmaceutical Sciences, 103, 3(2014)
25. M. Zahid, M Lodhi, A Afzal et al., Gels, 7 3(2021)
26. N. Shafeie, A.T. Naini, H.K. Jahromi., Biomedical and Pharmacology Journal 8, 2(2015)
27. N. K. Olah, G. Osser, R. F. Câmpean, et al., Pakistan journal of pharmaceutical sciences 29, (2016)
28. N.A. Peppas, P. Bures, W. Leobandung, et al., European journal of pharmaceutics and biopharmaceutics 50, 1(2000)
29. P. H. Li, Y.P. Chiu, C.C Shih, et al., Oxidative Medicine and Cellular Longevity, (2016).
30. P. O. Nnamani, F. C. Kenechukwu, C. L. Anugwolu, et al., Tropical Journal of Pharmaceutical Research 13, 9(2014)
31. P. Ranasinghe, S. Pigera, G. S. Premakumara, et al., BMC complementary and alternative medicine 13, 1 (2013).
32. Q. Li, J. Wang, S. Shahani, et al., Biomaterials 27,7(2006)
33. R.G Singh, P.S Negi, C Radha, Journal of functional foods 5, 4(2023)
34. R. Parhi corresponding., Advanced pharmaceutical bulletin 7, 4(2017)
35. S. Anjum, A. Arora, M.S. Alam, B. Gupta., International journal of pharmaceutics 508, 1(2016)
36. S.D. Bhinge, M.A Bhutkar, D.S. Randive, et al., Journal of Research in Pharmacy23, 1(2019)
37. S. Esteghlal, M. Niakousari, S.M.H. Hosseini., International journal of biological macromolecules 114, 1-9(2018)
S.A. Jain, G. Shetty, A, Mullaji, et al., Advanced Science Letters 22, 1(2016)
39. T. Thangarajoo, Y.K. Hsin, M. Pandey, H. Choudhury, et al., Open Chemistry 21, 1(2023)
40. W.F. Lai, A.L Rogach., ACS applied materials & interfaces 9, 13(2017).
41. X. Chen, L. Peng, Y. Shan, et al., International Journal of Pharmaceutics 447, 1-2(2013)
42. Y. Luo, H. Diao, S. Xia, et al., Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials, 94, 1(2010)
43. Y. Luo, H. Diao, S. Xia, et al., The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 94, 1(2010)
44. Y. M. Lim, S. J. An, H. K. Kim, Y. H. Kim, M. H. Youn, H. J. Gwon, J. Shin, and Y. C. Nho, Radiation Physics and Chemistry 78, 441 (2009).
45. Z. Naghizadeh, A.Karkhaneh, A. Khojasteh., Materials Science and Engineering: 89, 256(2018)
Author Information
Corresponding Author: Akanksha Dwivedi*
Email: akd.pharma@gmail.com
Roohi Yusufi, Sumeet Dwivedi, G.N. Darwhekar
Acropolis Institute of Pharmaceutical Education and Research, Indore, (M.P.) - India
Comments