Journal of Angiology & Vascular Surgery Category: Medical Type: Review Article

Hyaluronic Acid: An Old Molecule with New Perspectives

G Abatangelo1, P Brun2, G P Avruscio3 and V Vindigni4*
1 Department Of Medicine, University Of Padova, Padova, Italy
2 Department Of Molecular Medicine, Histology Unit, University Of Padova, Padova, Italy
3 Department Of Cardiac, Thoracic And Vascular Sciences, Angiology Unit, University Of Padova, Padova, Italy
4 Department Of Neurosciences, Clinic Of Plastic And Reconstructive Surgery, University Of Padova, Padova, Italy

*Corresponding Author(s):
V Vindigni
Department Of Neurosciences, Clinic Of Plastic And Reconstructive Surgery, University Of Padova, Padova, Italy
Tel:+39 0498212715,

Received Date: Mar 15, 2022
Accepted Date: Mar 17, 2022
Published Date: Mar 24, 2022


Hyaluronic acid or hyaluronan was discovered 88 years ago and many scientist all over the world have investigated this interesting and multifaceted molecule. This article provides a short overview in the fields of wound healing, angiogenesis, drug delivery, tissue engineering, biomedical application in ophthalmology, eye pathology/surgery, osteorthrosis/cartilage repair, cancer therapy. Due to its exceptional rheological, hygroscopic and viscoelastic properties for decades HA was considered only a structural component of many tissues. The biosynthesis of this polysaccharide that occurs at the surface of cell membrane, the discovery of several specific cell receptors, the properties of small HA oligosaccharides to stimulate angiogenesis, the capacity of HA to initiate signal transduction in certain cell types changed dramatically the view of the role of this molecule. Furthermore the clinical use of HA is continually expanding in several fields such as skin repair, joints and eye pathologies, cancer therapy. This great potential in medicine stimulated the research on chemical modifications of this molecule with the aim to obtain new products and derivatives. Minor chemical modifications of the molecule, such as its esterification, have made possible the production of highly biocompatible materials in the form of gels, gauzes, nonwoven meshes, membranes and tubes. These biomaterials can be used as antiadhesive wound coverage and as scaffolds for in vitro and in vivo tissue engineering such as skin, cartilage, blood  vessels. Also the association of HA with other substances such as collagen, elastin, lactose-modifies-chitosan, PLGA and poly-L-lysine allows the formulation of new compounds and scaffolds for several clinical applications.


In 1934 Karl Meyer and John Palmer isolated hyaluronic acid from the vitreous humor of the bovine eye [1]. After35 years it was possible to know its structure thanks to the work of Laurent in 1970 [2]. Hyaluronic Acid (HA) is a long, unbranched polysaccharide composed of repeating disaccharides of D-glucuronic and N-acetyl-D-glucosamine with Molecular Weight (MW) ranging from 0,1 x 106 up to 2 x 107Da. It reaches a great concentration in the vitreous body of the eye and in the umbilical cord [3]. In this embryonic district the MW of this molecule reaches the highest value as compared with other organs and tissues.  Since at physiological pH, the carboxyl groups of the molecule are dissociated and can attract cations, such as Na+, Balazs proposed the name “hyaluronan” as an alternative to “hyaluronic acid” [4]. The molecule is widely distributed in nature and it is present in many living organisms from bacteria to all vertebrates. It plays an important role in the Extracellular Matrix (ECM) of adult soft connective tissues where regulates hydration, tissue homeostasis and resistance to forces of compression such as in articular cartilage. In this tissue HA interacts with many proteoglycans giving rise to large molecule composites which in turn are responsible for the stabilization of ECM structure. High MW HA plays an important role as lubricant in the joints cavity. In addition to these mechanical properties, HA can play a more complex role forming a pericellular coat around most of the cells where behaves as a signaling molecule and regulates cell adhesion, migration and proliferation. It is present also inside the cells in various cytoplasmic structures [5]. By considering all these biological and structural properties HA plays a key role in many physiological and pathological conditions. 

The biocompatibility, viscoelastic properties, and physiological activity of HA make it an ideal substance for several clinical applications, such as in ophthalmology, rheumatology, and dermatology. In addition esterification with benzyl alcohol of HA yields biocompatible and biodegradable HA-based biomaterials in the form of membranes, non-woven tissues [6,7], tubes and gauzes widely used for wound covering and for in vitro reconstruction of human tissues such as, dermis, epidermis, vascularized skin and cartilage.

Synthesis and degradation of HA

In1997 Weigel, et al. demonstrated that unlike others glycosaminoglycans HA is not synthesized  in the Golgi apparatus but on the inner side of the cell membranes by three different synthetases [8], namely synthetase 1 (HAS 1), syntethase 2 (HAS 2) and synthetase 3 (HAS 3) [9]. After the synthesis the HA chain is then translocated to the extracellular space. During morphogenesis and in some pathological conditions the three enzymes are differently expressed and generate HA with different MW [10,11].

The degradation time of HA varies ranging from 10-25 hours in the skin to a few minutes in the blood stream by means of macrophages present in the lymph nodes and in the liver [12]. Six different hyaluronidases are present either inside and on the surface of the human cells while in tissues the degradation occurs during inflammatory process by Reactive Oxygen Species (ROS), superoxide, nitric oxide [13]. 

The amount and the molecular weight of the molecule depends on the equilibrium between HA synthesis and degradation. The resulting different molecular sizes can determine different and sometimes opposing biological actions [14]. While high MW HA exerts anti-inflammatory effects, the low MW molecules are pro-inflammatory and in addition promote angiogenesis and tissue repair in wound healing process [15,16]. Even though the mechanism of action remains largely unclear, high MW-HA, differently from low MW, inhibit tumor progression by slowing down cell motility [17].

HA Cell Surface Receptors

Several cell receptors for HA, the so called hyaladherins, have been identified [18,19], and their number is continuously growing. CD44 (Cluster of Differentiation 44), RHAMM or CD168 (Receptor for Hyaluronan Mediated Motility), LYVE1 (Lymphatic-Vessel Endothelial receptor 1) are specific cell membrane proteins while additional receptors are molecules present in the extracellular matrix, such as aggrecan and several proteoglycans. Binding of HA to hyaladherins promote several cell activities such as proliferation, differentiation and motility. CD44 and RHAMM are the principal cell membrane receptors that can trigger different cell responses [20]. CD44is the most studied receptor present in all human cell types. It is a glycoprotein expressed by a single gene that via alternative splicing gives rise to various isoforms with different functions and properties [21,22]. The HA receptor RHAMM, also known as CD168, promotes cell motility and migration by interacting with cytoskeletal proteins [23], with kinase protein complexes [24,25], mitochondria and microtubules [26,27]. The hyaladherin LYVE1 mediates the entry of leucocytes into lymphatic vessels and the traffic of HA from tissues to lymph [28,29].

Medical Applications of HA and its Derivatives

Osteoarthrosis and cartilage regeneration 

One of the most widespread pathologies affecting senile and middle age population in the word is Osteoarthrosis (OA) that affects knee, hip and several minor body joints. Non Steroidal Drugs (NSAIDs) and corticosteroids are the most used drugs to relieve pain, even though they can cause undesirable side effects. For this reason several studies have been devoted to find alternative therapies and in 1971 Balazs proposed the visco-supplementation with HA for the treatment of osteoarthritis in human and horses [30]. The rationale of HA supplementation was the restoration of the rheological properties of the synovial fluid lost in OA where the MW of this molecule decreases as consequence of the hydrolytic effects of Reactive Oxygen Species (ROS) that in turn give rise to decreased fluid viscosity and cartilage erosion. In the last four decades several HA preparations have been proposed to protect articular cartilage and to relieve pain, such as Synvisc [31,32], Hyalgan [33,34]. Both HA preparations need multiple injections and are effective without side effects. In addition they last longer suggesting that do not restore only the rheological function of the synovial fluid but probably interact with cell membrane receptors.As demonstrated by Brun, et al. Hyalgan is able to protect chondrocytes from ROS damage and restore their survival and proliferation [35]. These effects are mediated by the interaction of HA with CD44 hyaladherin. To avoid repeated intra-articular injections a Hexadecylamide Derivative of HA (HYADD) has been proposed for intra-articular administration [36]. 

Furthermore, to improve the therapeutic effects a new formulation of HA has recently been proposed. Namely the mixture of HA and a lactose-modified chitosan (Chitlac®). This new compound has been tested either in human chondrocyte cultures and in experimentally induced osteoarthrosis in animals with encouraging results to promote clinical trials [37,38]. 

The progression of OA and mechanical injuries are the main causes that give rise to full thickness cartilage defects. The only effective therapy for this pathological condition is represented by the complex surgical procedure of autologous chondrocyte transplantation. An alternative possibility is represented by the use of three dimensional biodegradable scaffolds obtained by the total esterification of HA with benzyl alcohol (Hyaff-11®, Fidia, Italy) in the form of non-woven meshes. Human chondrocytes obtained by a simple biopsy of cartilage are successufully cultured inside these scaffolds and give rise to cartilage tissue [39-40]. This in vitro reconstructed cartilage can be then transplanted into the injured area of the joint and several clinical studies have demonstrated that after implantation the new tissue undergoes a regeneration with the formation of a hyaline cartilage [41-44]. 


For its hygroscopic and visco-elastic properties HA plays an important role in the skin, the largest organ of the body. It is associated with wound repair although the mechanism through which influences the process is not clear [45-47]. Several clinical studies demonstrate the positive effects of HA in promoting wound repair either in animal experimental models and in humans [48-50]. HA plays an important role in proliferative and inflammatory phases of wound repair as already demonstrated [51-53]. Recently many studies have been focused on the use of some HA-based biomaterials (Hyaff-11) for tissue engineering. These products have been demonstrated to be biocompatible, biodegradable and non toxic [54]. These biomaterials can be seeded either with fibroblasts and keratinocytes to obtain in vitro reconstructed skin substitutes. Dermal-like tissue was obtained by seeding non-woven meshes with dermal fibroblasts [55-57]. A Hyaluronic Acid membrane was used as delivery system for cultured keratinocytes either in wound and burns [58-62]. In order to provide the in vitro skin constructs with microvessels Tonello and coworkers obtained endothelialized skin substitutes by seeding fibroblasts and endothelial cells with Hyaff meshes [63,64]. Recently investigations have been conducted on HA based hydrogels and nanofibrous scaffolds synthesized either with chitosan and corn-stark and propolis [65-67]. Other interesting materials have been proposed for wound healing such as methacrilated gelatin and methacrilated hialuronic acid containing adipose derived stem cells [68]. 

Angiogenesis and vascular tissue 

West and Kumar in 1989 demonstrated for the first time that low MW HA stimulated the angiogenesis in embryonic tissue [69]. Moreover HA was shown to be active also in promoting recruitment and activation of neutrophils and macrophages which in turn secrete angiogenic factors [70]. For this role in angiogenesis HA derived biomaterialss (Hyaff-11) in the form of tubules have been utilized as small diameter vascular conduits. These tubular structures were grafted in rat abdominal aorta [71-73], in rat vena cava and in pig carotid artery as temporary absorbable guides to promote complete regeneration of vascular wall [74,75]. The experimental studies demonstrated the feasibility to create a biodegradable vascular guide for in vivo regeneration and reconstruction of small vessels. 

Histological, immunohistochemical and ultra-structural analyses showed complete endothelialization of the tube's luminal surface, sequential regeneration of vascular wall and the biodegradation of the biomaterial four months after implantation. At this time new vessel remained to connect the artery stumps. In addition to monitor patency of vascular graft in pig carotid artery functional duplex scan studies after 1 and 5 months were performed confirming regular blood flow throughout the prosthesis and the new reconstituted artery tract [75]

Given its high haemocompatibility additional studies have been performed on HA combined with other materials, such as chitosan based films. These composite structures when seeded with mesenchymal stem cells showed good biocompatibility and induced fibroblastic differentiation [76]. Another promising good material to be used as cardiovascular substitute is the expanded polytetrafluoroethylene treated with HA [77]. Also titanium microstrips coated with HA have been used for the co-culture of endothelial cells and smooth muscle cells with satisfactory results [78]. Low MW HA derivatives can be associated to hydrogels for fabricating dense tissues in vitro with a good capacity to promote endothelial cell motility [79]. HA has proven to exerts a potential role for the treatment of ischemia since it can remodel the tissue microenvironment and facilitate stem cell differentiation toward a vascular lineage, thus confirming its possible use for cell-based therapy [80]. 

Cancer therapy 

The coniugation of antitumoral drugs with HA appears to be a potentially successful tool hoping that in the near future some technical difficulties will be resolved. The functions of HA, Hyaluronan Syntetases (HAS) and HA receptors in cancer cells undergo complex interactions [81]. Given the high biocompatibility and biodegradability HA has been suggested as an optimal drug carrier by considering also that cell CD44 receptors are able to internalize either HA and associated nanoparticles or liposomes [82-86]. Additional studies on the role of HAS and Hyaladerins in cancer biology may lead to improvements of their therapeutical usage. Indeed many cancer cells of solid tumors synthesize great quantity of HA with an increased cancer progression and metastasis [87]. It has been demonstrated that over-expression of HAS2 induces both progression of several tumors and chemiotherapy resistance [88-94]. On the other hand in some tumors the inhibition of HAS leads to inhibition of metastasis [95]. Fragmentation of HA due to over expression of hyaluronidases can be responsible of cancer progression [96,97]. However the role of HA, hyaluronidases and Ha syntetases in cancer appears controversial and clinical tests up to now are very few, even though the studies on these molecules can support their potential use in cancer therapy. 


Eye vitreous body was the district from which hyaluronic acid was extracted for the first time by Meyer and Palmer in 1934 [1]. It is present also in conjunctiva, lacrimal gland and in the epithelium of cornea. Since during surgical ophthalmic procedures it necessary to replace the lost vitreous fluid, in 1980 HA was proposed by Balazs for viscosurgical supplementation in order to maintain either enough space for surgical manipulation and to protect from mechanical trauma [98]. In 1982 the first HA derivative commercially available for oftalmic applications was Healon® [99]. This preparation has been widely used as a therapeutic tool in many and different surgical operations performed on the eye. Later on other new cohesive ophthalmic viscosurgical devices were proposed for corneal protection and intraocular pressure [100]. For the treatment of dry eye syndrome, drops of aqueous HA solutions are also used as eye lubricant for the protection of corneal surface [101]. Recently additional HA preparation are available in ophthalmology such as Systane®, OptiveFusion™. Safety and effectiveness of these new products has been shown by several in vivo and in vitro studies [102-105]. Furthermore low MW HA solutions have recently been used to improve hydration of contact lens given its ability to prolong wettability [106,107]. HA has been also used as drug delivery substance for topical administration of ophthalmic drugs such as antibiotics and anti-inflammatory medicines. Indeed HA when combined with medicaments is able to slow down the delivery time and also can modulate the dose [108,109]. The proven properties of HA as drug delivery molecule can offer possibilities for additional investigations of pharmaceutical applications. 

Adipose tissue 

HA-based scaffolds have been investigated by several authors for adipose tissue engineering [110]. There is an important need of in vitro reconstructed fat for the correction of dermis defects in plastic and reconstructive surgery. Several HA materials have been used for adipocyte cultures to be implanted in vivo [111]. Tan, et al. injected thermo responsive HA gel in athymic mouse and showed in situ gel formation [112]. Generally a rapid resorption of HA has been observed after in vivo implantation of cultured adipocytes [113,114]. Instead when HA-based (Hyaff-11®) pre-adipocyte seeded scaffold was grafted in patients the graft survival was longer and lasted for up to 16 weeks [115]. Fan et al. demonstrated that adipocyte growth was stimulated when HA hydrogel was functionalized to obtain release of dexamethasone [116]. Along this line of research magnetic HA nano-sphere were developed in order to release dexamethasone and in vitro studies showed increase viability of adipocytes [117]. Other scaffolds have been developed for adipose tissue in vitro reconstruction. Collagen with cross-linked HA scaffolds seeded with adipocytes were able to induce increased gene expression of adipsin [118]. Furthermore scaffolds made up by the combination of elastin and collagen have been investigated and the results demonstrated a good cell proliferation and adhesion [119]. Engineered constructed made by gelatin-HA scaffolds seeded with Adipose Stem Cells (ASC) were implanted in murine and porcine animal models and compared with acellular gels. Specific gene expression of leptin, a P2, PPAR-g and LPL, were greater in the adipocyte containing gels as compared with a cellular scaffolds [120]. From all the cited works in this section it appears evident that HA has been tested either alone or combined with other materials for adipose tissue reconstruction with the aim to promote fat reconstruction to be used for the correction of skin defects..

Peripheral nerve 

Another interesting field of investigation is represented by the widespread use of HA in peripheral nerve tissue engineering. In particular HA hydrogels showed to be a good material for the survival rate and proliferation of neuronal precursors with the possibility to have a role both in nerve regeneration and in central nervous system therapy [121-126]. Furthermore HA hydrogels are able to promote proliferation and differentiation of nervous cells precursors that could open a new approach for the therapy of neurodegenerative diseases [127-129]. Also the association of chitosan and HA either in the form of conduits [130] and injectable hydrogels were successfully used in peripheral nerve regeneration [131]. Other biodegradable polymers, such as PLGA and poly-L-lysine have been combined with HA to obtain composite materials useful for the controlled delivery of drugs for axonal growth either in vitro and in vivo [132,133]. More complex structures were investigated by Wang in order to decrease inflammatory response in the field of tissue engineering of nervous tissues [134]. The Author developed porous scaffold with HA doped-poly (3,4-ethylenedioxythiophene)/chitosan/gelatin nanoparticles into chitosan-gelatin matrix. The biological property of this construct supported adhesion, proliferation, and synapse growth in nerve tissue regeneration. 

From all the above mentioned experimental works it is reasonable to assess that HA used in the form of hydrogel or in association with other substances can play an important and promising role also in the nervous tissue engineering.


In this article we reported a short overview on the several aspects of HA starting from its discovery to the last chemical and biological new findings. This molecule is used for several clinical applications such as eye surgery, osteoarthrosis, wound repair. From its chemical modification several new products have been obtained.  Synvisc®, Hyalgan®, Hyadd®, Arty-Duo®, Healon®, Systane®, OptiveFusion™, Hyaff-11®,various Hydrogels associated with HA are the main HA formulations and derivatives widely used for  the treatment of several pathologies and for tissue engineering of skin, cartilage, small caliber vessels, peripheral nerve conduits. However, these new generations of biocompatible and bio-reabsorbable products should be further developed to improve their therapeutical performances. Drug release, cancer therapy, tissue hydration and dermal augmentation are the main candidates for the application of innovative HA based pharmaceutical formulations.


  1. Meyer K, Palmer JW (1934) The polysaccharide of the vitreous humor. J BiolChem 107: 629.
  2. Laurent TC (1970) Structure of hyaluronic acid. In: Balazs EA (ed.). Chemistry and the molecular biology in the intracellular matrix. Academic press, London, UK.
  3. Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242: 27-33.
  4. Balazs EA, Laurent TC, Jeanloz RW (1986) Nomenclature of the hyaluronic acid. Biochem J 235: 903.
  5. Hascall VC, Majors AK, Motte CA, Evanko SP, Wang AM, et al. (2004) Intracellular hyaluronan: a new frontier for inflammation? Biochimica Et BiophysicaActa-General Subjects 1673: 3-12.
  6. Campoccia D, Doherty P, Radice M, Brun P, Abatangelo G, et al. (1998) Semisynthetic resorbable materials from hyaluronan esterification. Biomaterials 23: 2101-2127.
  7. Benedetti L, Cortivo R, Berti T, Berti A, Pea F, et al. (1993) Biocompatibility and biodegradation of different hyaluronan derivatives (Hyaff) implanted in rats. Biomaterials 14: 1154-1160.
  8. Weigel PH, Hascall VC, Tammi M (1997) Hyaluronan synthases. J Biol Chem 272: 13997-14000.
  9. Itano N, Kimata K (2002) Mammalian hyaluronan synthases. IUBMB Life 54: 195-199.
  10. Toole BP (2001) Hyaluronan in morphogenesis. Semin Cell Dev Biol 12: 79-87.
  11. Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, et al. (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274: 25085-250932.
  12. Fraser JT, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J IntMed 242: 27-33.
  13. Stern R, Jedrzejas MJ (2006) The Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev 106: 818-839.
  14. Tavianatou AG,Caon I, Franchi M, Piperigkou Z, Galesso D, et al. (2019) Hyaluronan: Molecular Size-Dependent Signaling and Biological Functions in Inflammation and Cancer. FEBS J 286: 2883-2908.
  15. Stern R, Asari AA, Sugahara KN (2006) Hyaluronan fragments: An information-rich system. Eur J Cell Biol 85: 699-715.
  16. Day AJ, Motte CA (2005) Hyaluronan cross-linking: a protective mechanism in inflammation? Trends in Immunology 26: 637-643.
  17. Tian X, Azpurua J, Hine C, Vaidya A, Rempel MM, et al. (2013) High molecular mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499: 346-349.
  18. Toole BP (1990) Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol 2: 839.
  19. Turley EA, Noble PW, Bourguignon LYW (2002) Signaling properties of hyaluronan receptors. J Biol Chem 277: 4589-4592.
  20. Smith AM, Belch AR, Mant MJ, Turley EA, Pilarski LM (1996) Hyaluronan-dependent motility of B cells and leukemic plasma cells in blood, but not of bone marrow plasma cells, in multiple myeloma: alternate use of receptor for hyaluronan-mediated motility (RHAMM) andCD44. Blood 87: 1891-1899.
  21. Teriete P, Banerji S, Noble M, Blundell CD, Wright AJ, et al. (2004) Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44. Mol Cell 13: 483-496.
  22. Misra S, Hascall VC, Markwald RR, Ghatak S (2015) Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Front Immunol 6: 201.
  23. Crainie M, Belch AR, Mant MJ, Pilarski LM (1999) Over-expression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. Blood 93:1684.
  24. Kouvidi K, Berdiaki A, Nikitovic D, Katonis P, Afratis N, et al. (1999) Role of receptor for hyaluronic acid-mediate motility (RHAMM) in low molecular weight hyaluronan (LMWHA)-mediated fibrosarcoma cell adhesion. J Biol Chem 286: 38509-38520.
  25. Zaman A, Cui Z, Foley JP, Zhao H, Grimm PC, et al. (2005) Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am J Respir Cell Mol Biol 33: 447-454.
  26. Assmann V, Jenkinson D, Marshall JF, Hart IR (1999) The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments J Cell Sci 112: 3943.
  27. Nikitovic D, Kouvidi K, Karamanos NK, Tzanakakis GN (2013) The roles of hyaluronan/RHAMM/CD44 and their respective interactions along the insidious pathways of fibrosarcoma progression. Biomed Res Int 2013:
  28. Jackson DG (2019) Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol 79: 219-235.
  29. Lawrance W, Banerji S, Day AJ, Bhattacharjee S, Jackson DG (2016) Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization. J Biol Chem 291:8014-8030.
  30. Balazs EA (1971) Hyaluronic acid and matrix implantation. Biotrics Inc, Arlington, USA.
  31. Weiss, Balazs EA (1987) Artroscophyviscosurgery. Artoscophy 3: 138-139.
  32. McCain JP, Balzs EA, Rua H (1989) Preliminary studies on the use of a viscoelastic solution in arthroscopy surgery of the temporomandibular joint. J Oral Maxillofac Surg 47: 1161-1168.
  33. Altman RD, Moskowitz R (1998) Hyalgan Study group Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteo-arthritis of the knee: a randomized clinical trial. J Rheum 25: 2203-2212.
  34. Kolrz G, Kotz R, Hocxhmayer I (2003) Long-term benefits and repeated treatment cycles of intra-articular sodium hyaluronate (Hyalgan) in patients with osteoarthritis of the knee. Semin Arthritis Rheum 32: 310-319.
  35. Brun P, Panfilo S, Gordini DD, Cortivo R, Abatangelo G (2003) The effect of hyaluronan on CD44-mediated survival of normal a hydroxyl radical-damaged chondrocytes. Osteoarthritis Cartilage 11: 208-216.
  36. Brun P, Zavan B, Vindigni V, Schiavinato A, Pozzuoli A, et al. (2003) In vitro response of osteoarthritic chondrocytes and fibroblast-like synoviocytes to a 500-730 kDahyaluronan amide derivative. J Biomed Mater Res B Appl Biomater 100: 2073-2081.
  37. Tarricone E, Elia R, Mattiuzzo E, Faggian A, Pozzuoli A, et al. (2003) The Viability and Anti-Inflammatory Effects of Hyaluronic Acid-Chitlac-TracimoloneAcetonide-β-CyclodextrinComplex on Human Chondrocytes. Cartilage 28: 1947603520908658.
  38. Salamanna F, Giavaresi G, Parrilli A, Martini L, NicoliAldini N, et al. (2019) Effects of intra-articular hyaluronic acid associated to Chitlac (arty-duo®) in a rat knee osteoarthritis model. J Orthop Res 37: 867-876.
  39. Brun P, Abatangelo G, Radice M, Zacchi V, Guidolin D, et al. (2019) Chondrocyte aggregation and reorganization into three-dimensional scaffolds. J of Biomed Mat Res 46: 337-346.
  40. Solchaga LA, Dennis JE, Goldberg VM, Caplan AI (1999) Hyaluronic Acid-Based Polymers as Cell Carriers for Tissue-Engineered Repair of Bone and Cartilage. J of Orthopaedic Res 17: 205-213.
  41. Hollander AP, Dickinson SC, Sims T, Brun P, Cortivo R, et al. (1999) Maturation of tissue engineered cartilage implanted in injured and osteoarthritic human knees. Tissue Eng 12: 1787-1798.
  42. Brun P, Dickinson SC, Zavan B, Cortivo R, Hollander AP, et al. (2008) Characteristics of repair tissue in second-look and third-look biopsies frompatients treated with engineered cartilage: relationship to symptomatology and time after implantation. Arthritis Res Ther 10: 132.
  43. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, et al. (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New England Journal of Medicine 331: 889-895.
  44. Marcacci M, Zaffagnini S, Kon E, Visani A, Iacono F, et al. (2002) Arthroscopic autologous chondrocyte transplantation: technical note. Knee Surg Sports Traumatol Arthroscopy 10: 154-159.
  45. Ghatak S, Maytin EV, Mack J A, Hascall V C, Atanelishvili I, et al. (2015) Roles of proteoglycans and glycosaminoglycans in wound healing and fibrosis. Int J Cell Biol 2015:
  46. Brown JA (2015) The role of hyaluronic acid in wound healing's proliferative phase. J Wound Care 13: 48-51.
  47. Abatangelo G, Martelli M, Vecchia P (1983) Healing of Hyaluronic Acid-Enriched Wounds: Histological Observations. J of Surgical Res 35: 410-416. 
  48. Ortonne JP (1996) A controlled study of the activity of hyaluronic acid in the treatment of venous leg ulcers. J of Dermat Treatment 7: 75-81.
  49. Chen WYJ, Abatangelo G (1999) Functions of hyaluronan in wound repair. Wound Repair and Regeneration 7: 79-89.
  50. Navsaria HA (2022) Biological rationale for the application of hyaluronan in wound healing 279-288.
  51. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T (2016) Hyaluronic acid in inflammation and tissue regeneration. Wounds 28: 78-88.
  52. Trabucchi E, Pallotta S, Morini M, Corsi F, Franceschini R, et al. (2002) Low molecular weight hyaluronic acid prevents oxygen free radical damage to granulation tissue during wound healing. Int J Tissue React 24: 65-71.
  53. Price RD, Myers S, Leigh IM, Navsaria HA (2000) The role of hyaluronic acid in wound healing: assessment of clinical evidence. Am J Clin Dermatol 6: 393-402.
  54. Cortivo R, Brun P, Rastrelli A, Abatangelo G (1991) In vitro studies on biocompatibility of hyaluronic acid esters. Biomaterials 12: 727-730.
  55. Davidson JM, Nanney LB, Broadley KN, Whitsett JS, Aquino AM, et al. (1991) Hyaluronate Derivatives and their Application to Wound Healing: Preliminary Observations. Clinical Materials 8: 171-177.
  56. Galassi G, Brun P, Radice M, Cortivo R, Zanon GF, et al. (2000) In vitro reconstructed dermis implanted in human wounds: degradation studies of the HA-based supporting scaffold. Biomaterials 21: 2183-2191.
  57. Brun P, Grosso F, Galassi G, Radice M, Tonello C, et al. (2000) Use of Dermal-like Tissue in the Management of Chronic and Acute Full-Thickness Cutaneous Wounds. Ostomy Wound Management 46: 44-48.
  58. Andreassi L, Casini L, Trabucchi E, Diamantini S, Rastrelli A, et al. (1991) Human Keratinocytes Cultured on Membranes Composed of Benzyl Ester of Hyaluronic Acid Suitable for Grafting. Wounds 3: 116-126.
  59. Myers SR, Grady J, Soranzo C, Sanders R, Green C, et al. (1997) A Hyaluronic Acid Membrane Delivery System for Cultured Keratinocytes: Clinical "Take" Rates in the Porcine Kerato-Dermal Model. J Burn Care Rehabil 18: 214-222.
  60. Hollander DA, Wild M, Konold P, Windolf J (2021) Benzylester hyaluronic acid membranes: a delivery system for autologous keratinocyte cultures in the treatment of complicated chronic and acute wounds. Page no: 303-311.
  61. Zacchi V, Soranzo C, Cortivo R, Radice M, Brun P, et al. (1998) In vitro engeneering of human skin-like tissue. J of Biomed Mat Res 40: 187-194.
  62. Harris PS, di Francesco F, Barisoni D, Leigh IM, Navsaria HA (1999) Use of hyaluronic acid and cultured autologous keratinocytes and fibroblasts in extensive burns. The Lancet, 353: 35-36.
  63. Tonello C, Vindigni V, Zavan B, Abatangelo S, Abatangelo G, et al. (2005) In vitro reconstruction of an endothelialized skin substitute provided with a microcapillary network using biopolymer scaffolds. FASEB J 19: 1546-1548.
  64. Tonello C, Zavan B, Cortivo R, Brun P, Panfilo S, et al. (2003) In vitro reconstruction of human dermal equivalent enriched with endothelial cells. Biomaterials 24: 1205-1211.
  65. Nguyen NT, Nguyen LV, Tran NM, Nguyen DT, Nguyen TN, et al. (2019) The effect of oxidation degree and volume ratio of components on properties and applications of in situ cross-linking hydrogels based on chitosan and hyaluronic acid. Mater SciEng C Mater Biol 103:109-670.
  66. Sandri G, Rossi S, Bonferoni MC, Miele D, Faccendini A, et al. (2019) Chitosan/glycosaminoglycanscaffolds for skinreparation. Carbohydr Polym 220: 219-227.
  67. Eskandarinia A, Kefayat A, Rafienia M, Agheb M, Navid S, et al. (2019) Cornstarch-based wound dressing incorporated with hyaluronic acid and propolis: In vitro and in vivo Carbohydr Polym 216: 25-35.
  68. Eke G, Mangir N, Hasirci N, MacNeil S, Hasirci V (2017) Development of a UV crosslinked biodegradable hydrogel containing adipose derived stem cells to promote vascularization for skin wounds and tissue engineering. Biomaterials 129: 188-198.
  69. West DC, Kumar S (1989) Hyaluronan and angiogenesis.
  70. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964-967.
  71. Lepidi S, Grego F, Vindigni V, Zavan B, Tonello C, et al. (2006) Hyaluronan biodegradable scaffold for small-caliber artery grafting: preliminary results in an animal model. Eur J Vasc Endovasc Surg 32:411-417.
  72. Lepidi S, Abatangelo G, Vindigni V, Deriu GP, Zavan B, et al. (2006) In vivo regeneration of small-diameter (2 mm) arteries using a polymer scaffold. FASEB J 20: 103-105.
  73. Pandis L, Zavan B, Bassetto F, Ferroni L, Iacobellis L, et al. (2011) Hyaluronic acid biodegradable material for reconstruction of vascular wall: a preliminary study in rats. Microsurgery 31:138-145.
  74. Pandis L, Zavan B, Abatangelo G, Lepidi S, Cortivo R, et al. (2010) Hyaluronan-based scaffold for in vivo regeneration of the rat vena cava: Preliminary results in an animal model. J Biomed Mater Res A 93: 1289-1296.
  75. Zavan B, Vindigni V, Lepidi S, Avruscio G, Abatangelo G, et al. (2008) Neoarteries grown in vivo using a tissue-engineered hyaluronan-based scaffold. Faseb J 22: 2853-2861.
  76. Dennaoui H, Chouery E, Rammal H, Abdel-Razzak Z, Harmouch C (2018) Chitosan/hyaluronic acid multilayer films are biocompatible substrate for Wharton's jelly derived stem cells Stem Cell Investig 20: 5-47.
  77. Bui HT, Friederich AR, Li E, Prawel DA, James SP (2018) Hyaluronan enhancement of expanded polytetrafluoroethylene cardiovascular grafts. J Biomater Appl 33: 52-63.
  78. Li J, Zhang K, Wu J, Liao Y, Yang P, et al. (2015) Co-culture of endothelial cells and patterned smooth muscle cells on titanium: construction with high density of endothelial cells and low density of smooth muscle cells. BiochemBiophys Res Commun. 2015; 456: 555-561.
  79. Khanmohammadi M, Sakai S, Taya M (2017) Impact of immobilizing of low molecular weight hyaluronic acid within gelatin-based hydrogel through enzymatic reaction on behavior of enclosed endothelial cells. Int J BiolMacromol 97: 308-316.
  80. Simpson RM, Hong X, Wong M, Karamariti E, Bhaloo SI, et al. (2016). Hyaluronan is crucial for stem cell differentiation into smooth muscle lineage. Stem Cells 34: 1225-1238.
  81. Karbownik MS, Nowak JZ (2013) Hyaluronan: Towards novel anti-cancer therapeutics. Pharmacological Reports 65: 1056-1074.
  82. Mero A, Campisi M (2014) Hyaluronic acid bioconjugates for the delivery of bioactive molecules. Polymers 6: 346-369.
  83. Cho HJ, Yoon HY, Koo H, Ko SH, Shim JS, et al. (2011) Self-assembled nanoparticles based on hyaluronic acid-ceramide (HA-CE) and Pluronic® for tumor-targeted delivery of docetaxel. Biomaterials 32: 7181-7190.
  84. Han NK, Shin DH, Kim JS, Weon KY, Jang CY, et al. (2016) Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells. Int J Nanomed 11: 1413-1425.
  85. Edelman R, Assaraf YG, Levitzky I, Shahar T, Livney YD (2017) Hyaluronic acid-serum albumin conjugate-based nanoparticles for targeted cancer therapy. Oncotarget 8: 24337-24353.
  86. De Stefano I, Battaglia A, Zannoni GF, Prisco MG, Fattorossi A, et al. (2011) Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. Cancer Chemother Pharmacol 68:107-116.
  87. Stern R (2004) Hyaluronan degradation in tumor growth and metastasis. Trends in glycoscience and glycotechnology 16: 171-218
  88. Udabage L, Brownlee GR, Nilsson SK, Brown TJ (2005) The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. Exp Cell Res 310: 205-217.
  89. Lokman NA, Price ZK, Hawkins EK, Macpherson AM, Oehler MK, et al. (2019) 4-methylumbelliferone inhibits cancer stem cell activation and overcomes chemoresistance in ovarian cancer. Cancers 11: 1187.
  90. Anand V, Khandelwal M, Appunni S, Gupta N, Seth A, et al. (2019) CD44 splice variant (CD44v3) promotes progression of urothelial carcinoma of tladder Through Akt/ERK/STAT3 pathways: novel therapeutic approach. Cancer Res Clin Oncol 145: 2649-2661.
  91. Weng CC, Hsieh MJ, Wu CC, Lin YC, Shan YS, et al. (2019) Loss of the transcriptional repressor TGIF1 results in enhanced kras-driven development of pancreatic cancer. Mol Cancer 20: 96.
  92. Kim YH, Lee SB, Shim S, Kim A, Park JH, et al. (2019) Hyaluronic acid synthase 2 promotes malignant phenotypes of colorectal cancer cells through transforming growth factor beta signalling. Cancer Sci 110: 2226-2236.
  93. Sá VK, Rocha TP, Moreira A, Soares FA, Takagaki T, et al. (2015) Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis. Braz J Med Biol Res 48:1039-1047.
  94. Wang SJ, Earle C, Wong G, Bourguignon LY (2013) Role of hyaluronan synthase 2 to promote CD44-dependent oral cavity squamous cell carcinoma progression. Head Neck 35: 511-520.
  95. Chang IW, Liang PI, Li CC, Wu WJ, Huang CN, et al. (2015) HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder. Tumour Biol 36: 5441-5450.
  96. Tan JX, Wang XY, Su XL, Li HY, Shi Y, et al. (2011) Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis. PLoS One 6: 22836.
  97. Novak U, Stylli SS, Kaye AH, Lepperdinger G (1999) Hyaluronidase-2 overexpression accelerates intracerebral but not subcutaneous tumor formation of murine astrocytoma cells. Cancer Res 59: 6246-6250.
  98. Pape LG, Balazs EA (1980) The use of sodium hyaluronate (Healon) in human anterior segment surgery. Ophthalmology 87: 699-705.
  99. Balazs EA (1986) The development of sodium hyaluronate (Healon R) as a viscosirgical material in ophthalmic surgery. In: Eisner G (ed.). Ophthalmic Viscosurgery-a Review of Standards, Techniques and Applications. Bern: Medicopea Page no: 3-19
  100. Neumayer T, Prinz A, Findl O (2008) Effect of a new cohesive ophthalmic viscosurgical device on corneal protection and intraocular pressure in small-incision cataract surgery. J Cataract Refract Surg 34: 1362-1366.
  101. Messmer EM (2015) The pathophysiology, diagnosis, and treatment of dry eye disease, Dtsch Arztebl Int 112: 71-82.
  102. Carracedo G, Villa-Collar C, Martin-Gil A, Serramito M, Santamaría L (2018) Comparison between viscous teardrops and saline solution to fill orthokeratology contact lenses before overnight wear. eye contact lens 44: 307-311
  103. Johnson ME, Murphy PJ, Boulton M (2006) Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefe’s Arch Clin Exp Ophthalmol 244: 109-112.
  104. Christensen MT (2008) Corneal staining reductions observed after treatment with Systane lubricant eye drops. Adv Ther 25: 1191-1199.
  105. Simmons PA, Liu H, Carlisle-Wilcox C, Vehige JG (2015) Efficacy and safety of twonew formulations of artificial tears in subjects with dry eye disease: a 3-month multicenter, active-controlled, randomized trial. Clin Ophthalmol 9: 665-675.
  106. Tarricone E, Mattiuzzo E, Belluzzi E, Elia R, Benetti A, et al. (2020) Impact of a Low Molecular Weight Hyaluronic Acid Derivative on Contact Lens Wettability. Cells 9: 1328.
  107. Yamasaki K, Drolle E, Nakagawa H, Hisamura R, Ngo W, et al. (2021) Impact of a Low Molecular Weight Hyaluronic Acid Derivative on Contact Lens Wettability. Cont Lens Anterior Eye 44: 101334.
  108. Kaur IP, Smitha R (2002) Penetration enhancers and ocular bioadhesives: Two new avenues for ophthalmic drug delivery. Drug DevInd Pharm 28: 353-369.
  109. Awwad S, Abubakre A, Angkawinitwong U, Khaw PT, Brocchini S (2019) In situ antibody-loaded hydrogel for intravitreal delivery. Eur J Pharm Sci 137: 104993.
  110. Casadei A, Epis R, Ferroni L, Tocco I, Gardin C, et al. (2012) Adipose tissue regeneration: a state of the art. J Biomed Biotechnol 2012:
  111. Vindigni V, Cortivo R, Iacobellis L, Abatangelo G, Zavan B (2009) Hyaluronan benzyl ester as a scaffold for tissue engineering. Int J Mol Sci 10: 2972-2985.
  112. Tan H, Ramirez CM, Miljkovic N, Li H, Rubin J, et al. (2009) Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. Biomaterials 30: 6844-6853.
  113. Hemmrich K, Van de Sijpe K, Rhodes NP, Hunt JA, Di Bartolo C, et al. (2008) Autologous in vivo adipose tissue engineering in hyaluronan-based gels--a pilot study. J Surg Res 144: 82-88.
  114. Okabe K, Yamada Y, Ito K, Kohgo T, Yoshimi R, et al. (2009) Injectable soft-tissue augmentation by tissue engineering and regenerative medicine with human mesenchymal stromal cells, platelet-rich plasm and hyaluronic acid scaffolds. Cytotherapy 11: 307-316.
  115. Stillaert FB, Di Bartolo C, Hunt JA, Rhodes NP, et al. (2008) Human clinical experience with adipose precursor cells seeded on hyaluronic acid-based spongy scaffolds. Biomaterials 29: 3953-3959.
  116. Fan M, Ma Y, Zhang Z, Mao J, Tan Ha, et al. (2015) Biodegradable hyaluronic acid hydrogels to control release of dexamethasone through aqueous Diels-Alder chemistry for adipose tissue engineering. Sci. Eng. C Mater Biol Appl 56: 311-317.
  117. Jia Y, Fan M, Chen HN, Miao YT, Xing L, et al. (2015) Magnetic hyaluronic acid nanospheres via aqueous Diels-Alder chemistry to deliver dexamethasone for adipose tissue engineering. J Colloid Interface Sci 458: 293-299.
  118. Davidenko N, Campbell JJ, Thian ES, Watson CJ, Cameron RE (2010) Collagen-hyaluronic acid scaffolds for adipose tissue engineering. ActaBiomater 6: 3957-3968.
  119. Keck M, Ha luza D, Selig HF, Jahl M, Lumenta DB, et al. (2011) Adipose tissue engineering: three different approaches to seed preadipocytes on a collagen-elastin matrix. Ann Plast Surg 67: 484-488.
  120. Chang KH, Liao HT, Chen JP (2013) Preparation and characterization of gelatin/hyaluronic acid cryogels for adipose tissue engineering: In vitro and in vivo studies. Acta Biomater 9: 9012-9026.
  121. Collins MN, Birkinshaw C (2013) Hyaluronic acid based scaffolds for tissue engineering-A review. Carbohydr Polym 92: 1262-1279.
  122. Zavan B, Abatangelo G, Mazzoleni F, Bassetto F, Cortivo R, et al. (2008) New 3D hyaluronan-based scaffold for in vitro reconstruction of the rat sciatic nerve. Neurol Res. 30: 190-196.
  123. Thomas RC, Vu P, Modi SP, Chung PE, Landis RC, et al. (2017) Schmidt CE. Sacrificial Crystal Templated Hyaluronic Acid Hydrogels As Biomimetic 3D Tissue Scaffolds for Nerve Tissue Regeneration. ACS BiomaterSci Eng 3: 1451-1459.
  124. Horn EM, Beaumont M, Shu XZ, Harvey A, Prestwich GD, et al. (2007) Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury. J Neurosurg 6: 133-140.
  125. Pan L, Ren Y, Cui F, Xu Q (2009) Viability and differentiation of neural precursors on hyaluronic acid hydrogel scaffold. J Neurosci Res 87: 3207-3220.
  126. Liang Y, Walczak P, Bulte JWM (2013) The survival of engrafted neural stem cells within hyaluronic acid hydrogels. Biomaterials 34: 5521-5529.
  127. Yang R, Xu C, Wang T, Wang Y, Wang J, et al. (2017) PTMAc-PEGPTMAc hydrogel modified by RGDC and hyaluronic acid promotes neural stem cells' survival and differentiation in vitro. RSC Adv 7: 41098-41104.
  128. Seidlits SK, Khaing ZZ, Petersen RR, Nickels JD, Vanscoy JE, et al. (2010) The effects of hyaluronic acid hydrogels with tunable mechanical properties on neural progenitor cell differentiation. Biomaterials 31: 3930-3940.
  129. Zhang H, Wei YT, Tsang KS, Sun CR, Li J, et al. (2008) Implantation of neural stem cells embedded in hyaluronic acid and collagen composite conduit promotes regeneration in a rabbit facial nerve injury model. J Transl Med 6:
  130. Wei YT, He Y, Xu CL, Li R, Liu H, et al. (2018) Chitosan conduit combined with hyaluronic acid prevent sciatic nerve scar in a rat model of peripheral nerve crush injury. Mol Med Rep 17: 4360-4368.
  131. Xu H, Zhang L, Bao Y, Yan X, Yin Y, et al. (2011) Preparation and characterization of injectable chitosan–hyaluronic acid hydrogels for nerve growth factor sustained release. J Bioact Compat Pol 32:146-162.
  132. Wang Y, Wei YT, Zu ZH, Ju RK, Guo MY, et al. (2011) Combination of Hyaluronic Acid Hydrogel Scaffold and PLGA Microspheres for Supporting Survival of Neural Stem Cells. Pharm Res 28: 1406-1414.
  133. Wang Y, Wang Y, Liu BF, Wang XM, Sun XD, et al. (2010) Hyaluronic acid hydrogel modified with nogo-66 receptor antibody and poly-L-lysine to promote axon regrowth after spinal cord injury. J Biomed Mater Res part B Appl Biomater 95: 110-117.
  134. Wang S, Guan S, Zhu Z, Li W, Liu T, Ma X (2017) Hyaluronic acid doped-poly(3,4-ethylenedioxythiophene)/chitosan/gelatin (PEDOT-HA/Cs/Gel) porous conductive scaffold for nerve regeneration. Mater Sci Eng C 71: 308-316.

Citation: Abatangelo G, Brun P, Avruscio GP, Vindigni V (2022) Hyaluronic Acid: An Old Molecule with New Perspectives. J Angiol Vasc Surg 7: 085.

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