Incorporating Hyaluronic Acid into Anti-Wrinkle Cosmetic Formulations

1. Introduction?

A naturally occurring glycosaminoglycan found in both human and animal beings, hyaluronic acid aids in a variety of biological functions, such as wound healing, cell hydration, and joint lubrication.

The skin, eyes, and cartilage all contain significant amounts of this special molecule, which is very prevalent in connective tissues and the extracellular matrix of both humans and animals.

Because of its remarkable capacity to hold water—up to 1,000 times its weight—hyaluronic acid has found use as a source material in pharmaceutical, medicinal, and cosmetic applications to supply its hydrating and regenerating qualities. [1-6].?

The repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine serve as the building blocks of hyaluronic acid, making it a linear polymer.

These monomers are connected by β-1,4 and β-1,3 glycosidic linkage alternations. Hyaluronic acid is a long-sugar derivative that is made up of two components: D-glucuronic acid and N-acetyl-D-glucosamine.

There is a pattern formed by these blocks using two different kinds of connections: β-1,4 and β-1,3 glycosidic links. Hyaluronic acid has an amazing ability to bind water through its carboxyl and hydroxyl groups because of its hydrophilic and highly polar characteristics.

Hyaluronic acid has the ideal hydration feature due to its capacity to absorb and retain water. Furthermore, hyaluronic acid's carboxyl groups provide it with a negative charge that enables it to combine with cations to form viscoelastic gels, which are essential for joint lubrication and skin elasticity.

Hyaluronic acid's molecular weight, which fluctuates over a very large range, influences its biological function: High-molecular-weight hyaluronic acid is antiangiogenic and immunosuppressive anti-inflammatory and protective, whereas low-molecular-weight distress signals and potent inducers of inflammation and angiogenesis. [4, 7, 8]?

Hyaluronic acid was historically obtained from animal sources since it is found in large quantities in rooster combs.

This method mechanically extracts and purifies the substance to create high-quality hyaluronic acid suitable for medical purposes. Animal-derived hyaluronic acid does have several drawbacks, though, including the potential for allergic reactions, contamination from animal-borne illnesses, and ethical quandaries surrounding the rearing and harvesting of animals.

The process can also be more costly and less sustainable because there are fewer animal resources available. [9-11]?

As technology has advanced, microbial fermentation processes have been created as an alternative to animal sources. In these operations, bacteria such as Streptococcus zooepidemicus, which naturally produces hyaluronic acid, are commonly employed. While fermenting in nutrient-rich environments, these bacterial strains create hyaluronic acid as part of their extracellular matrix.

Subsequently, the hyaluronic acid is extracted, purified, and made ready for various applications. This microbial approach has several advantages over animal extraction, including lower allergenic potential, greater safety, and enhanced sustainability and scalability.

More control over the molecular weight and purity of hyaluronic acid is also provided, making it suitable for a range of applications, such as injectable dermal fillers, cosmetics, and even joint health supplements. [12-15]?

Recombinant DNA technology, which includes introducing the genes necessary for the manufacture of hyaluronic acid into non-pathogenic bacteria such as Escherichia coli, that are naturally present in the human gut. is another cutting-edge technique.

Because of the more moral and controlled manufacturing process, hyaluronic acid can be customized to meet individual requirements, which is very useful in pharmaceuticals and luxury cosmetics.

Sustainability can be further enhanced by recombinant hyaluronic acid synthesis, which reduces dependency on animal resources and the environmental effect of traditional processes. [16-20]?

In an effort to provide vegan and cruelty-free alternatives, plant-based and synthetic hyaluronic acid substitutes have also surfaced in recent years.

Despite the fact plants do not naturally produce hyaluronic acid, they do use botanical sources to create modified polysaccharides that have comparable viscoelastic and moisturizing qualities. [21]

On the other hand, synthetic approaches create molecules that mimic natural hyaluronic acid by chemically synthesizing or structurally altering other biopolymers. [21, 22]? ?

In the end, the shift away from hyaluronic acid sourced from animals to microbial, recombinant, and plant-based substitutes reflects rising customer desire for ingredients made in a way that is safe, ethical, and sustainable.

In addition to upholding moral principles, this development in hyaluronic acid manufacturing is in line with biotechnology advancements and the expanding demand for flexible, biocompatible materials in the pharmaceutical, medical, and cosmetics sectors.?

The hydrating, lubricating, and biocompatible qualities of hyaluronic acid make it useful in a wide range of industrial, medicinal, and cosmetic applications.

Here’s an overview of its main applications:?

2. Applications?

2.1 Medicine??

• Ophthalmology: Hyaluronic acid is used in eye surgeries including corneal transplants and cataract surgery to maintain eye structure, shield delicate eye tissues, and encourage healing. [23-27]?

• Orthopedics: Intra-articular injections of hyaluronic acid assist with treating osteoarthritis by lubricating joints, reducing discomfort, and improving joint function. [28, 29]?

• Wound Healing: Hyaluronic acid-based dressings and lotions speed up the healing process by maintaining a moist environment and promoting cell migration and angiogenesis. [30-34]?

• Drug Delivery: Hyaluronic acid is a biocompatible substance that can be used as a drug delivery carrier because it can produce hydrogels that provide controlled release. [35-38]?

• Anti-adhesion Therapy: Hyaluronic acid gels are used in surgery to prevent tissue adhesion while it heals, especially in abdominal and gynecological procedures. [39, 40]?

2.2 Cosmetic and Dermatology Applications?

• A key ingredient in moisturizers and serums, hyaluronic acid can significantly hydrate, improve skin suppleness, and reduce wrinkles. [41-43]?

• Dermal Fillers: Dermal Fillers: Injectable hyaluronic acid fillers are commonly used to contour the face, minimize wrinkles, and add volume to areas like the lips and cheeks. [44, 45] However, there are reports of various adverse effects of this application of hyaluronic acid. [46, 47]?

• Anti-aging Treatments: Hyaluronic acid's hydrating properties help to keep wrinkles from showing and give the skin a more youthful appearance. [48-50]?

• Shampoos and conditioners contain hyaluronic acid to enhance hair structure, reduce frizz, and keep the scalp hydrated. [51]?

2.3 Aesthetic and Dental Applications?

• A non-surgical technique for lip and facial enhancement, hyaluronic acid injections help to volumize and shape lips and other facial features. [52, 53]?

• Dental Applications: Hyaluronic acid is used in periodontology and oral surgery due to its anti-inflammatory and wound-healing properties. [54, 55]?

2.4 Nutraceuticals and Dietary Supplements?

• Hyaluronic acid-containing supplements help to maintain the skin's health and hydration. [43, 56] These dietary supplements address diseases like osteoarthritis and promote joint health. [57, 58]?

2.5 Tissue Engineering and Regenerative Medicine?

• Because hyaluronic acid-based scaffolds are so biocompatible and encourage tissue growth and cell adhesion, they are utilized in tissue engineering. [59] They are frequently used with other substances to promote the healing of bone and cartilage. [60, 61]?

2.6 Veterinary Medicine?

• Dogs and horses with osteoarthritis can benefit from injectable hyaluronic acid, which improves joint function and comfort. [62, 63]??

2.7. Food Industry?

• Because of its moisturizing qualities, hyaluronic acid is sometimes added as a functional ingredient to foods and drinks. [64-66]?

The following are some possible advantages of multifunctional hyaluronic acid, with a focus on use in cosmetics:?

3. Role in Personal Care?

3.1. Skin Hydration?

Hyaluronic acid is capable of attracting and retaining moisture due to its hygroscopic nature, which allows it to draw water from the surrounding environment and maintain it on the skin's surface. Hyaluronic acid is one of the best moisturizing agents available; it can bind up to 1,000 times its weight in water.

Applying hyaluronic acid to the skin produces a thin, imperceptible film that attracts water molecules and keeps the skin moisturized throughout the day. In addition to plumps the skin, this action smoothens out any dryness or roughness.

By increasing moisture levels and leaving the skin feeling smooth, elastic, and renewed, products that contain hyaluronic acid can significantly improve the condition of people with dry or dehydrated skin. [41, 67, 68]?

3.2. Anti-Aging Effects?

Hyaluronic acid is a powerful ingredient in anti-aging products because of its plumping effects. By attracting water into the outer layers of the skin, hyaluronic acid smoothens out wrinkles and fine lines, creating the appearance of youthful radiance.

This temporary "filling" process softens expression lines and crow's feet while promoting a generally dewy, glowing complexion.

Additionally, as people age, their skin's natural hyaluronic acid levels decrease, which results in dryness and a loss of firmness. By raising hyaluronic acid levels, skincare procedures can eventually undo these effects and make the skin appear tighter and more elastic.

Lower molecular weights of hyaluronic acid also penetrate deeper at a structural level, promoting the synthesis of collagen and reducing the visible signs of aging. [41-43, 69]?

3.3. Skin Barrier Support?

The skin barrier serves as the body's primary defense against chemicals, environmental stressors, and moisture loss.

Hyaluronic acid helps to reinforce this barrier by preventing transepidermal water loss (TEWL) and forming a breathable, protective layer on the skin's surface. This action reduces the likelihood of irritation, dryness, and inflammation while maintaining optimal hydration.

By supporting the skin's natural lipid barrier, hyaluronic acid helps build a stronger, more resilient complexion that is better able to withstand external stressors.

People with sensitive or damaged skin will particularly benefit from hyaluronic acid's ability to lessen irritation and encourage the skin's natural healing processes. [70, 71]?

4. Compatibility with Other Ingredients?

One of the most remarkable characteristics of hyaluronic acid is its compatibility with a wide range of active ingredients, including vitamins (such vitamin C), antioxidants, peptides, and even exfoliating acids. [72-74]

Because it is gentle and non-comedogenic, hyaluronic acid makes an ideal base ingredient, boosting formulation effectiveness without causing sensitivity or irritation. For instance, peptides can cooperate with hyaluronic acid to promote collagen synthesis and skin suppleness, while hyaluronic acid can enhance its brightening effects when combined with vitamin C. [72, 75]

Hyaluronic acid's compatibility with other hydrators, such glycerin and ceramides, further improves its capacity to retain moisture, creating well-rounded, highly effective skincare solutions suitable for all skin types.?

Due to its ability to address hydration, anti-aging, skin barrier protection, and compatibility with other substances, hyaluronic acid has become a crucial ingredient in skincare products. It is natural, flexible, and well-tolerated, and it offers some advantages.?

5. Efficacy and stability of Hyaluronic acid in cosmetic formulation?

Anti-wrinkle therapies use hyaluronic acid with varying molecular weights to target different layers of the skin. High-molecular-weight hyaluronic acid's primary function is surface hydration; it forms a thin layer that calms the skin and reduces trans-epidermal water loss, temporarily plumping the skin and minimizing tiny wrinkles.

Conversely, low-molecular-weight hyaluronic acid can more profoundly hydrate the skin's dermal layers, resulting in longer-lasting improvements in the skin's suppleness and resilience.

The multi-layer strategy used by hyaluronic acid-based skincare products, which allows them to provide both immediate and long-term anti-aging benefits, is responsible for their popularity. [4, 76-78]?

One important factor in hyaluronic acid's effectiveness in anti-wrinkle treatments is the formulation's stability. [79] Hyaluronic acid is highly susceptible to environmental factors including UV radiation in its natural condition, [80] temperature changes, and pH variations.

Therefore, maintaining the efficacy and integrity of hyaluronic acid in skincare products requires the use of stability-enhancing procedures. Manufacturers commonly cross-link hyaluronic acid's chemical chains to stabilize it, creating a network of interconnected hyaluronic acid molecules. [81-86]

This cross-linked form of hyaluronic acid not only increases stability but also provides a controlled release mechanism that helps the skin hold onto moisture for longer.

Cross-linked hyaluronic acid's sustained-release properties allow it to provide long-lasting hydration, which over time can improve skin texture and reduce the visibility of wrinkles. [70, 87, 88]??

Additionally, encapsulation techniques are frequently used to improve the stability of hyaluronic acid in skincare products.

By enclosing hyaluronic acid in lipid or polymer-based carriers, which reduce its exposure to environmental stressors, the danger of premature breakdown is reduced.

Furthermore, these carriers ensure that hyaluronic acid reaches certain skin layers for maximum efficacy by enabling tailored delivery. This strategy is highly beneficial in anti-aging formulations, where stability and controlled dispersion are necessary to achieve dependable and long-lasting results. [89, 90]?

In conclusion, the effectiveness of hyaluronic acid in anti-wrinkle skincare products is based on its remarkable hydrating qualities, which allow it to plump the skin, encourage suppleness, and lessen the appearance of wrinkles.

Maintaining its efficacy over time depends on its stability, which is achieved by encapsulation, cross-linking, and the combination of components that complement one another.

Because of its scientifically demonstrated ability to enhance skin texture, hydration, and resilience both instantly and over time, hyaluronic acid is still a common ingredient in anti-aging skincare products.?

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References:?

1. Antoszewska M, Sokolewicz EM, Barańska-Rybak W. Wide Use of Hyaluronic Acid in the Process of Wound Healing—A Rapid Review. Sci Pharm. 2024;92(2):23. doi:10.3390/scipharm92020023.?
2. Iaconisi GN, Lunetti P, Gallo N, et al. Hyaluronic Acid: A Powerful Biomolecule with Wide-Ranging Applications—A Comprehensive Review. Int J Mol Sci. 2023;24(12):10296. doi:10.3390/ijms241210296.?
3. Sprott H, Fleck C. Hyaluronic Acid in Rheumatology. Pharmaceutics. 2023;15(9):2247. doi:10.3390/pharmaceutics15092247.?
4. Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: A key molecule in skin aging. Dermatoendocrinol. 2012;4(3):253-258. doi:10.4161/derm.21923. PMID: 23467280; PMCID: PMC3583886.?
5. Ding HY, Xie YN, Dong Q, et al. Roles of hyaluronan in cardiovascular and nervous system disorders. J Zhejiang Univ Sci B. 2019;20(5):428-436. doi:10.1631/jzus.B1900155. PMID: 31090268; PMCID: PMC6568231.?
6. Parnigoni A, Viola M, Karousou E, et al. Hyaluronan in pathophysiology of vascular diseases: specific roles in smooth muscle cells, endothelial cells, and macrophages. Am J Physiol Cell Physiol. 2022;323(2):C505-C519. doi:10.1152/ajpcell.00061.2022. PMID: 35759431.?
7. Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): a review. Vet Med-Czech. 2008;53(8):397-411. doi:10.17221/1930-VETMED.?
8. Valachová K, Hassan ME, ?oltés L. Hyaluronan: Sources, Structure, Features and Applications. Molecules. 2024;29(3):739. doi:10.3390/molecules29030739. PMID: 38338483; PMCID: PMC10856924.?
9. Rigo D, et al. Hyaluronic Acid – from Production to Application: A Review. Biointer Res Appl Chem. 2022;13(3):211. doi:10.33263/briac133.211.?
10. Balazs EA, Watson D, Duff IF, Roseman S. Hyaluronic acid in synovial fluid. I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids. Arthritis Rheum. 1967;10(4):357-376. doi:10.1002/art.1780100407. PMID: 6046018.?
11. Kulkarni SS, Patil SD, Chavan DG. Extraction, purification and characterization of hyaluronic acid from Rooster comb. J Appl Nat Sci. 2018;10(1):313-315. doi:10.31018/jans.v10i1.1623.?
12. Liu L, Wang M, Du G, Chen J. Enhanced hyaluronic acid production of Streptococcus zooepidemicus by an intermittent alkaline-stress strategy. Lett Appl Microbiol. 2008;46(3):383-388. doi:10.1111/j.1472-765X.2008.02325.x. Epub 2008 Jan 23. PMID: 18221275.?
13. Liu L, Liu Y, Li J, et al. Microbial production of hyaluronic acid: current state, challenges, and perspectives. Microb Cell Fact. 2011;10:99. doi:10.1186/1475-2859-10-99.?
14. Rangaswamy V, Jain D. An efficient process for production and purification of hyaluronic acid from Streptococcus equi subsp. zooepidemicus. Biotechnol Lett. 2008;30(3):493-496. doi:10.1007/s10529-007-9562-8. Epub 2007 Oct 24. PMID: 17957340.?
15. Ucm R, Aem M, Lhb Z, Kumar V, Taherzadeh MJ, Garlapati VK, Chandel AK. Comprehensive review on biotechnological production of hyaluronic acid: status, innovation, market and applications. Bioengineered. 2022;13(4):9645-9661. doi:10.1080/21655979.2022.2057760. PMID: 35436410; PMCID: PMC9161949.?
16. Lai ZW. Fermentation strategies for production of hyaluronic acid through biosynthesis by Streptococcus zooepidemicus and recombinant Escherichia coli using stirred tank bioreactor. PhD thesis, Universiti Putra Malaysia; 2013.?
17. Lai ZW, Abdul Rahim R, Ariff AB, Mohamad R. Comparison of hyaluronic acid biosynthesis by the recombinant Escherichia coli strains in different mode of bioreactor operation. J Microbiol Biotechnol Food Sci. 2016;6(3):905-910. doi:10.15414/jmbfs.2016/17.6.3.905-910.??
18. Woo JE, Seong HJ, Lee SY, Jang YS. Metabolic engineering of Escherichia coli for the production of hyaluronic acid from glucose and galactose. Front Bioeng Biotechnol. 2019;7:351. doi:10.3389/fbioe.2019.00351. PMID: 31824939; PMCID: PMC6881274.??
19. de Oliveira JD, Carvalho LS, Gomes AMV, et al. Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms. Microb Cell Fact. 2016;15:119. doi:10.1186/s12934-016-0517-4.?
20. Mao Z, Shin HD, Chen R. A recombinant E. coli bioprocess for hyaluronan synthesis. Appl Microbiol Biotechnol. 2009;84(1):63-69. doi:10.1007/s00253-009-1963-2. Epub 2009 Mar 24. PMID: 19308402.?
21. https://en.vivatis.de/greeniuronic-organic-2/ Accessed December 2024.??
22. Putri RR, Nugraha T, Christy S. Extraction of hyaluronic acid from Aloe barbadensis (Aloe Vera). J Funct Food Nutraceutical. 2020;1(2):111-118. doi:10.33555/jffn.v1i2.33.??
23. Verdoliva V, Bedini E, De Luca S. Sustainable chemical modification of natural polysaccharides: mechanochemical, solvent-free conjugation of pectins and hyaluronic acid promoted by microwave radiations. Biomacromolecules. 2024;25(10):6217-6228. doi:10.1021/acs.biomac.4c00844. Epub 2024 Sep 13. PMID: 39269184.?
24. Lapcik L Jr, Lapcik L, De Smedt S, et al. Hyaluronan: preparation, structure, properties, and applications. Chem Rev. 1998;98:2663-2684.??
25. Vogel R, Crockett RS, Oden N, Laliberte TW, Molina L. Sodium hyaluronate ophthalmic solution study, G. Demonstration of efficacy in the treatment of dry eye disease with 0.18% sodium hyaluronate ophthalmic solution (Vismed, Rejena). Am J Ophthalmol. 2010;149:594-601.??
26. Posarelli C, Passani A, Del Re M, et al. Cross-linked hyaluronic acid as tear film substitute. J Ocul Pharmacol Ther. 2019;35(7). doi:10.1089/jop.2018.015.??
27. Hsiao CW, Cheng H, Ghafouri R, Ferko NC, Ayres BD. Corneal outcomes following cataract surgery using ophthalmic viscosurgical devices composed of chondroitin sulfate-hyaluronic acid: a systematic review and meta-analysis. Clin Ophthalmol. 2023;17:2083-2096. doi:10.2147/OPTH.S419863.?
28. Gilat R, Haunschild ED, Knapik DM, Evuarherhe A, Parvaresh KC, Cole BJ. Hyaluronic acid and platelet-rich plasma for the management of knee osteoarthritis. Int Orthop. 2021;45:345-354.?
29. Agostini F, Bressanin E, de Sire A, et al. The effect of intra-articular injections of hyaluronic acid for the treatment of trapezio-metacarpal joint osteoarthritis. J Pers Med. 2024;14(8):806. doi:10.3390/jpm14080806.?
30. Sudhakar K, Ji SM, Kummara MR, Han SS. Recent progress on hyaluronan-based products for wound healing applications. Pharmaceutics. 2022;14(10):2235. doi:10.3390/pharmaceutics14102235.??
31. Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: A systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 2012;20(3):317-331.??
32. Wang T, Zheng Y, Shi Y, Zhao L. pH-responsive calcium alginate hydrogel laden with protamine nanoparticles and hyaluronan oligosaccharide promotes diabetic wound healing by enhancing angiogenesis and antibacterial activity. Drug Deliv Transl Res. 2019;9:227-239.??
33. Séon-Lutz M, Couffin AC, Vignoud S, Schlatter G, Hébraud A. Electrospinning in water and in situ crosslinking of hyaluronic acid/cyclodextrin nanofibers: Towards wound dressing with controlled drug release. Carbohydr Polym. 2019;207:276-287.??
34. Fatehi Hassanabad A, Zarzycki AN, Jeon K, et al. Prevention of post-operative adhesions: A comprehensive review of present and emerging strategies. Biomolecules. 2021;11(7):1027. doi:10.3390/biom11071027.?
35. Larsen NE, Balazs EA. Drug delivery systems using hyaluronan and its derivatives. Adv Drug Deliv Rev. 1991;7(2):279-293.??
36. Xiao B, Han MK, Viennois E, et al. Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy. Nanoscale. 2015;7(42):17745-17755.??
37. Ji P, Wang L, Chen Y, et al. Hyaluronic acid hydrophilic surface rehabilitating curcumin nanocrystals for targeted breast cancer treatment with prolonged biodistribution. Biomater Sci. 2020;8(1):462-472.??
38. Agrawal S, Dwivedi M, Ahmad H, et al. CD44 targeting hyaluronic acid coated lapatinib nanocrystals foster the efficacy against triple-negative breast cancer. Nanomedicine. 2018;14(2):327-337.?
39. Liu H, Xu Y, Yi N, Yi W. Efficacy and safety of hyaluronic acid gel for the prevention of intrauterine adhesion: A meta-analysis of randomized clinical trials. Gynecol Obstet Invest. 2018;83(3):227-233. doi: 10.1159/000486674. Epub 2018 Mar 7. PMID: 29514160.??
40. de Wilde MS, Devassy R, Krentel H, De Wilde RL, Torres-de la Roche LA. Self-cross-linked hyaluronic acid gel for adhesion prophylaxis in laparoscopic deep endometriosis removal: Safety report of a prospective pilot study. J Clin Med. 2024;13(20):6284. doi:10.3390/jcm13206284.?
41. Pavicic T, Gauglitz GG, Lersch P, et al. Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment. J Drugs Dermatol. 2011;10(9):990-1000. PMID: 22052267.??
42. Oe M, Sakai S, Yoshida H, et al. Oral hyaluronan relieves wrinkles: A double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017;10:267-273. doi: 10.2147/CCID.S141845.??
43. Hsu TF, Su ZR, Hsieh YH, Wang MF, Oe M, Matsuoka R, Masuda Y. Oral hyaluronan relieves wrinkles and improves dry skin: A 12-week double-blinded, placebo-controlled study. Nutrients. 2021 Jun 28;13(7):2220. doi: 10.3390/nu13072220. PMID: 34203487; PMCID: PMC8308347.?
44. Molina B, Romano D, Zazzaron M, et al. Full face tailored treatments using hyaluronan dermal fillers: Biophysical characterization for safe and effective approaches. Cosmetics. 2024;11(4):144. doi: 10.3390/cosmetics11040144.??
45. Lipko-Godlewska S, Bolan?a ?, Kalinová L, et al. Whole-face approach with hyaluronic acid fillers. Clin Cosmet Investig Dermatol. 2021;14:169-178. doi: 10.2147/CCID.S292501.?
46. Hirsch P, Infanger M, Kraus A. A case of upper lip necrosis after cosmetic injection of hyaluronic acid soft-tissue filler: Does capillary infarction play a role in the development of vascular compromise, and what are the implications? J Cosmet Dermatol. 2020;19(6):1316-1320. doi:10.1111/jocd.13391.??
47. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, Dhong ES. Vascular complications of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast Reconstr Aesthet Surg. 2011;64(12):1590-1595. doi:10.1016/j.bjps.2011.07.013.?
48. Draelos ZD, Diaz I, Namkoong J, Wu J, Boyd T. Efficacy evaluation of a topical hyaluronic acid serum in facial photoaging. Dermatol Ther (Heidelb). 2021;11(4):1385-1394. doi:10.1007/s13555-021-00566-0.??
49. Lee DH, Oh IY, Koo KT, et al. Improvement in skin wrinkles using a preparation containing human growth factors and hyaluronic acid serum. J Cosmet Laser Ther. 2015;17(1):20-23. doi:10.3109/14764172.2014.968577.??
50. Nobile V, Buonocore D, Michelotti A, Marzatico F. Anti-aging and filling efficacy of six types of hyaluronic acid-based dermo-cosmetic treatment: double-blind, randomized clinical trial of efficacy and safety. J Cosmet Dermatol. 2014;13(4):277-287. doi:10.1111/jocd.12120.?
51. Yorke K, Amin S. High performance conditioning shampoo with hyaluronic acid and sustainable surfactants. Cosmetics. 2021;8(3):71.??
52. Czumbel LM, Farkasdi S, Gede N, et al. Hyaluronic acid is an effective dermal filler for lip augmentation: A meta-analysis. Front Surg. 2021;8:681028. doi:10.3389/fsurg.2021.681028.??
53. Keramidas E, Rodopoulou S, Gavala MI. A safe and effective lip augmentation method: The step-by-step Φ (Phi) technique. Plast Reconstr Surg Glob Open. 2021;9(2):e3332. doi:10.1097/GOX.0000000000003332.?
54. Miglani A, Vishnani R, Reche A, et al. Hyaluronic acid: Exploring its versatile applications in dentistry. Cureus. 2023;15(10):e46349. doi:10.7759/cureus.46349.??
55. Bhati A, Fageeh H, Ibraheem W, et al. Role of hyaluronic acid in periodontal therapy (Review). Biomed Rep. 2022;17:91. doi:10.3892/br.2022.1574.??
56. Kawada C, Yoshida T, Yoshida H, et al. Ingestion of hyaluronans (molecular weights 800 k and 300 k) improves dry skin conditions: A randomized, double-blind, controlled study. J Clin Biochem Nutr. 2015;56(1):66-73. doi:10.3164/jcbn.14-81.?
57. Minoretti P, Santiago Sáez A, Lia?o Riera M, et al. Efficacy and safety of two chondroprotective supplements in patients with knee osteoarthritis: A randomized, single-blind, pilot study. Cureus. 2024;16(4):e57579. doi:10.7759/cureus.57579.??
58. Altman RD, Manjoo A, Fierlinger A, et al. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: A systematic review. BMC Musculoskelet Disord. 2015;16:321. doi:10.1186/s12891-015-0775-z.?
59. Chircov C, Grumezescu AM, Bejenaru LE. Hyaluronic acid-based scaffolds for tissue engineering. Rom J Morphol Embryol. 2018;59(1):71-76.?
60. Crevensten G, Walsh AJ, Ananthakrishnan D, et al. Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng. 2004;32(3):430-434. doi:10.1023/b:abme.0000017545.84833.7c.??
61. Cloyd JM, Malhotra NR, Weng L, et al. Material properties in unconfined compression of human nucleus pulposus, injectable hyaluronic acid-based hydrogels, and tissue engineering scaffolds. Eur Spine J. 2007;16(11):1892-1898. doi:10.1007/s00586-007-0443-6.?
62. Carapeba GO, Cavaleti P, Nicácio GM, Brinholi RB, Giuffrida R, Cassu RN. Intra-Articular Hyaluronic Acid Compared to Traditional Conservative Treatment in Dogs with Osteoarthritis Associated with Hip Dysplasia. Evid Based Complement Alternat Med. 2016;2016:2076921. doi:10.1155/2016/2076921. Epub 2016 Oct 26. PMID: 27847523; PMCID: PMC5101385.??
63. Neuenschwander HM, Moreira JJ, Vendruscolo CP, et al. Hyaluronic acid has chondroprotective and joint-preserving effects on LPS-induced synovitis in horses. J Vet Sci. 2019;20(6):e67. doi:10.4142/jvs.2019.20.e67.?
64. Jiang Y, Jiang Y, Li L, et al. High-molecular-weight hyaluronic acid can be used as a food additive to improve the symptoms of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Biology (Basel). 2024;13(5):319. doi:10.3390/biology13050319.??
65. Joshi R, Sutariya SG, Salunke P. Effect of different molecular weight hyaluronic acids on skim milk functional properties. Foods. 2024;13(5):690. doi:10.3390/foods13050690.??
66. Sutariya SG, Salunke P. Effect of hyaluronic acid and kappa-carrageenan on milk properties: Rheology, protein stability, foaming, water-holding, and emulsification properties. Foods. 2023;12(5):913. doi:10.3390/foods12050913.?
67. Keen MA. Hyaluronic acid in dermatology. Skinmed. 2017;15(6):441-448. PMID: 29282181.??
68. Salih ARC, Farooqi HMU, Amin H, et al. Hyaluronic acid: Comprehensive review of a multifunctional biopolymer. Futur J Pharm Sci. 2024;10:63. doi:10.1186/s43094-024-00636-y.?
69. Immediate and long-term effects of a topical serum with five forms of hyaluronic acid on facial wrinkles and intrinsic skin moisture content. J Am Acad Dermatol. 2016;74(5).?
70. Sundaram H, Mackiewicz N, Burton E, Peno-Mazzarino L, Lati E, Meunier S. Pilot comparative study of the topical action of a novel, crosslinked resilient hyaluronic acid on skin hydration and barrier function in a dynamic, three-dimensional human explant model. J Drugs Dermatol. 2016;15(4):434-441. PMID: 27050698.??
71. Nam G, Lee HW, Jang J, Kim CH, Kim KH. Novel conformation of hyaluronic acid with improved cosmetic efficacy. J Cosmet Dermatol. 2023;22(4):1312-1320. doi: 10.1111/jocd.15555. PMID: 36575898.?
72. Juncan AM, Mois? DG, Santini A, et al. Advantages of hyaluronic acid and its combination with other bioactive ingredients in cosmeceuticals. Molecules. 2021;26(15):4429. doi: 10.3390/molecules26154429. PMID: 34361586; PMCID: PMC8347214.??
73. Pyo JS, Cho WJ. Systematic review and meta-analysis of intravesical hyaluronic acid and hyaluronic acid/chondroitin sulfate instillation for interstitial cystitis/painful bladder syndrome. Cell Physiol Biochem. 2016;39(4):1618-1625. doi: 10.1159/000447863. PMID: 27627755.??
74. Ibrahim ZA, Gheida SF, El Maghraby GM, Farag ZE. Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma. J Cosmet Dermatol. 2015;14(2):113-123. doi: 10.1111/jocd.12143. Epub 2015 Apr 6. PMID: 25847063.?
75. Escobar S, Valois A, Nielsen M, Closs B, Kerob D. Effectiveness of a formulation containing peptides and vitamin C in treating signs of facial ageing: three clinical studies. Int J Cosmet Sci. 2021;43(2):131-135.?
76. Bravo B, Correia P, Gon?alves Junior JE, Sant'Anna B, Kerob D. Benefits of topical hyaluronic acid for skin quality and signs of skin aging: From literature review to clinical evidence. Dermatol Ther. 2022 Dec;35(12):e15903. doi: 10.1111/dth.15903. Epub 2022 Oct 21. PMID: 36200921; PMCID: PMC10078143.??
77. Bukhari SNA, Roswandi NL, Waqas M, Habib H, Hussain F, Khan S, Sohail M, Ramli NA, Thu HE, Hussain Z. Hyaluronic acid, a promising skin rejuvenating biomedicine: A review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects. Int J Biol Macromol. 2018 Dec;120(Pt B):1682-1695. doi: 10.1016/j.ijbiomac.2018.09.188. Epub 2018 Oct 1. PMID: 30287361.?
78. Dr. Rudhramyna Gnaneshwar, Hyaluronic Acid: A wonder molecule for the cosmetic and pharma industries https://cdn.syngeneintl.com/2021/08/31014839/Hyaluronic-Acid-A-wonder-molecule-for-the-cosmetic-and-pharma-industries.pdf??
79. ?ádníková P, ?ínová R, Pavlík V, ?imek M, ?afránková B, Hermannová M, Ne?porová K, Velebny V. The Degradation of Hyaluronan in the Skin. Biomolecules. 2022 Feb 3;12(2):251. doi: 10.3390/biom12020251. PMID: 35204753; PMCID: PMC8961566.?
80. Dai G, Freudenberger T, Zipper P, Melchior A, et al. Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of down-regulation of hyaluronic acid synthases. Am J Pathol. 2007 Nov;171(5):1451-61. doi: 10.2353/ajpath.2007.070136. PMID: 17982124; PMCID: PMC2043507.?
81. Jeon O, Song SJ, Lee KJ, Park MH, et al. Mechanical properties and degradation behaviors of hyaluronic acid hydrogels cross-linked at various cross-linking densities. Carbohydrate Polymers. 2007;70(3):251-257.??
82. Coleman S, Plastic Surgery Educational Foundation DATA Committee. Cross-linked hyaluronic acid fillers. Plast Reconstr Surg. 2006;117(2):661-665.??
83. Xu X, Jha AK, Harrington DA, Farach-Carson MC, Jia X. Hyaluronic Acid-Based Hydrogels: from a Natural Polysaccharide to Complex Networks. Soft Matter. 2012;8(12):3280-3294. doi: 10.1039/C2SM06463D. PMID: 22419946; PMCID: PMC3299088.??
84. Segura T, Anderson BC, Chung PH, Webber RE, Shull KR, Shea LD. Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern. Biomaterials. 2005 Feb;26(4):359-71. doi: 10.1016/j.biomaterials.2004.02.067. PMID: 15275810.??
85. Kühne U, Esmann J, von Heimburg D, Imhof M, Weissenberger P, Sattler G. Safety and performance of cohesive polydensified matrix hyaluronic acid fillers with lidocaine in the clinical setting - an open-label, multicenter study. Clin Cosmet Investig Dermatol. 2016 Oct 20;9:373-381. doi: 10.2147/CCID.S115256. PMID: 27799807; PMCID: PMC5076541.??
86. Pavicic T. Efficacy and tolerability of a new monophasic, double-crosslinked hyaluronic acid filler for correction of deep lines and wrinkles. J Drugs Dermatol. 2011 Feb;10(2):134-139. PMID: 21283917.?
87. Sundaram H, Mackiewicz N, Burton E, et al. Pilot comparative study of the topical action of a novel, crosslinked resilient hyaluronic acid on skin hydration and barrier function in a dynamic, three-dimensional human explant model. J Drugs Dermatol. 2016;15(4):434-441.??
88. Chen R, Yang W, Sun J, et al. Triple cross-linked hyaluronic acid based on tri-hyal technique has more durable effect on dermal renewal. Clin Cosmet Investig Dermatol. 2022;15:691-701. doi:10.2147/CCID.S362785.??
89. Bayer IS. Hyaluronic acid and controlled release: A review. Molecules. 2020;25(11):2649. doi:10.3390/molecules25112649.?
90. Huerta-ángeles G, Brandejsová M, ?těpán P, et al. Retinoic acid grafted to hyaluronan for skin delivery: Synthesis, stability studies, and biological evaluation. Carbohydr Polym. 2020;231:115733.??
91. Chen M, Gupta V, Anselmo AC, Muraski JA, Mitragotri S. Topical delivery of hyaluronic acid into skin using SPACE-peptide carriers. J Control Release. 2014 Jan 10;173:67-74. doi:10.1016/j.jconrel.2013.10.007. Epub 2013 Oct 12. PMID: 24129342; PMCID: PMC4128962.?