Background: Hyaluronan (HA) is present in extracellular spaces and interstitia of many tissue types. As it is capable of binding high amounts of water, HA provides ideal conditions for cell migration and proliferation. Under conditions of cellular crowding, it also permits lineage-specific differentiation and thus promotes many aspects of healing and tissue remodeling. Methods: The simplicity of its structure makes it amenable to chemical modifications and/or combined formulations with other bioactive substances. Thus a wide variety of clinical applications have been proposed, several of which are currently being implemented in advanced therapies. Results: Known features of HA biology, in particular regarding synthesis and processes related to signaling and control, have been adopted to elaborate specific products in order to support progress in regenerative medicine. Purified HA, HA-based hydrogels or special HA composites have been formulated together with other well-characterized biomaterials and bioactive factors. HA is currently employed in a variety of therapeutic applications both in its pure form and in a biofunctionalized form. Conclusions: HA plays an essential role in regenerative processes. Owing to the growing scientific knowledge in this field, medicinal products based on HA have been devised and are being routinely applied in ophthalmology or in trauma and transplantation surgery. Further areas of application are contemplated, such as the use of HA composite scaffold material in tissue engineering, or refined HA hydrogels enabling controlled release of medication.

Keywords:
Extracellular matrix, Regeneration, Wound healing, Mesenchymal stem cells, Biomaterial
1.
Jiang D, Liang J, Noble PW: Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007;23:435–461.
2.
Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, Simon JC: Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 2000;165:1863–1870.
3.
Bollyky PL, Lord JD, Masewicz SA, Evanko SP, Buckner JH, Wight TN, Nepom GT: Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J Immunol 2007;179:744–747.
4.
Tammi RH, Tammi MI: Hyaluronan accumulation in wounded epidermis: a mediator of keratinocyte activation. J Invest Dermatol 2009;129:1858–1860.
5.
Labat-Robert J, Robert AM, Robert L: Aging of the extracellular matrix. Méd Longévité 2012;4:3–32.
6.
Weigel PH, DeAngelis PL: Hyaluronan synthases: a decade-plus of novel glycosyltransferases. J Biol Chem 2007;282:36777–36781.
7.
Chao H, Spicer AP: Natural antisense mRNAs to hyaluronan synthase 2 inhibit hyaluronan biosynthesis and cell proliferation. J Biol Chem 2005;280:27513–27522.
8.
Jokela TA, Jauhiainen M, Auriola S, Kauhanen M, Tiihonen R, Tammi MI, Tammi RH: Mannose inhibits hyaluronan synthesis by down-regulation of the cellular pool of UDP-N-acetylhexosamines. J Biol Chem 2008;283:7666–7673.
9.
Kultti A, Pasonen-Seppanen S, Jauhiainen M, Rilla KJ, Karna R, Pyoria E, Tammi RH, Tammi MI: 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 2009;315:1914–1923.
10.
Vigetti D, Clerici M, Deleonibus S, Karousou E, Viola M, Moretto P, Heldin P, Hascall VC, De Luca G, Passi A: Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells. J Biol Chem 2011;286:7917–7924.
11.
Turley EA, Naor D: RHAMM and CD44 peptides – analytic tools and potential drugs. Front Biosci 2012;17:1775–1794.
12.
Prestwich GD: Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J Control Release 2011;155:193–199.
13.
Ballios BG, Cooke MJ, van der Kooy D, Shoichet MS: A hydrogel-based stem cell delivery system to treat retinal degenerative diseases. Biomaterials 2010;31:2555–2564.
14.
Su WY, Chen KH, Chen YC, Lee YH, Tseng CL, Lin FH: An injectable oxidated hyaluronic acid/adipic acid dihydrazide hydrogel as a vitreous substitute. J Biomater Sci Polym Ed 2011;22:1777–1797.
15.
Itakura H, Kishi S, Kotajima N, Murakami M: Decreased vitreal hyaluronan levels with aging. Ophthalmologica2009;223:32–35.
16.
Burdick JA, Prestwich GD: Hyaluronic acid hydrogels for biomedical applications. Adv Mater 2011;23:H41–H56.
17.
Vanderhooft JL, Alcoutlabi M, Magda JJ, Prestwich GD: Rheological properties of cross-linked hyaluronan-gelatin hydrogels for tissue engineering. Macromol Biosci 2009;9:20–28.
18.
Darr A, Calabro A: Synthesis and characterization of tyramine-based hyaluronan hydrogels. J Mater Sci Mater Med 2009;20:33–44.
19.
Jha AK, Hule RA, Jiao T, Teller SS, Clifton RJ, Duncan RL, Pochan DJ, Jia X: Structural analysis and mechanical characterization of hyaluronic acid-based doubly cross-linked networks. Macromolecules 2009;42:537–546.
20.
Crescenzi V, Cornelio L, Di Meo C, Nardecchia S, Lamanna R: Novel hydrogels via click chemistry: synthesis and potential biomedical applications. Biomacromolecules 2007;8:1844–1850.
21.
DeForest CA, Polizzotti BD, Anseth KS: Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat Mater 2009;8:659–664.
22.
Erickson IE, Kestle SR, Zellars KH, Farrell MJ, Kim M, Burdick JA, Mauck RL: High mesenchymal stem cell seeding densities in hyaluronic acid hydrogels produce engineered cartilage with native tissue properties. Acta Biomater 2012;8:3027–3034.
23.
Zhao J, Zhang N, Prestwich GD, Wen X: Recruitment of endogenous stem cells for tissue repair. Macromol Biosci 2008;8:836–842.
24.
Jha AK, Yang W, Kirn-Safran CB, Farach-Carson MC, Jia X: Perlecan domain I-conjugated, hyaluronic acid-based hydrogel particles for enhanced chondrogenic differentiation via BMP-2 release. Biomaterials 2009;30:6964–6975.
25.
Liu Y, Shu XZ, Prestwich GD: Osteochondral defect repair with autologous bone marrow-derived mesenchymal stem cells in an injectable, in situ, cross-linked synthetic extracellular matrix. Tissue Eng 2006;12:3405–3416.
26.
Toh WS, Lee EH, Guo XM, Chan JK, Yeow CH, Choo AB, Cao T: Cartilage repair using hyaluronan hydrogel-encapsulated human embryonic stem cell-derived chondrogenic cells. Biomaterials 2010;31:6968–6980.
27.
Tsai SW, Fang JF, Yang CL, Chen JH, Su LT, Jan SH: Preparation and evaluation of a hyaluronate-collagen film for preventing post-surgical adhesion. J Int Med Res 2005;33:68–76.
28.
Park JS, Cha SJ, Kim BG, Choi YS, Kwon GY, Kang H, An SS: An assessment of the effects of a hyaluronan-based solution on reduction of postsurgical adhesion formation in rats: a comparative study of hyaluronan-based solution and two film barriers. J Surg Res 2011;168:49–55.
29.
Chung YS, Lee KE, Kim HY, Choe J-H, Youn Y-K, Park WS, Koh SH: Anti-adhesive effect and safety of sodium hyaluronate and sodium carboxymethyl cellulose solution in thyroid surgery. Asian J Surg 2010;33:25–30.
30.
Baier Leach J, Bivens KA, Patrick CW Jr, Schmidt CE: Photocrosslinked hyaluronic acid hydrogels: natural, biodegradable tissue engineering scaffolds. Biotechnol Bioeng 2003;82:578–589.
31.
Seidlits SK, Drinnan CT, Petersen RR, Shear JB, Suggs LJ, Schmidt CE: Fibronectin-hyaluronic acid composite hydrogels for three-dimensional endothelial cell culture. Acta Biomater 2011;7:2401–2409.
32.
Xie Y, Upton Z, Richards S, Rizzi SC, Leavesley DI: Hyaluronic acid: evaluation as a potential delivery vehicle for vitronectin: growth factor complexes in wound healing applications. J Control Release 2011;153:225–232.
33.
Rajapaksa S, McIntosh D, Cowin A, Adams D, Wormald P-J: The effect of insulin-like growth factor 1 incorporated into a hyaluronic acid-based nasal pack on nasal mucosal healing in a healthy sheep model and a sheep model of chronic sinusitis. Am J Rhinol 2005;19:251–256.
34.
Matsumoto Y, Kuroyanagi Y: Development of a wound dressing composed of hyaluronic acid sponge containing arginine and epidermal growth factor. J Biomater Sci, Polym Ed 2010;21:715–726.
35.
Johnsson C, Tufveson G: Serum hyaluronan – a potential marker of cardiac allograft rejection? J Heart Lung Transplant 2006;25:544–549.
36.
Tesar BM, Jiang D, Liang J, Palmer SM, Noble PW, Goldstein DR: The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transplant 2006;6:2622–2635.
37.
Shirali AC, Goldstein DR: Activation of the innate immune system by the endogenous ligand hyaluronan. Curr Opin Organ Transplant 2008;13:20–25.
38.
Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma VM: Hyaluronan in human malignancies. Exp Cell Res 2011;317:383–391.
39.
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;20:317–331.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.