A new, biocompatible hyaluronic acid (HA)–silk hydrogel composite was fabricated and tested for use as a securable drug delivery vehicle. The composite consisted of a hydrogel formed by cross-linking thiol–modified HA with poly(ethylene glycol)-diacrylate, within which was embedded a reinforcing mat composed of electrospun silk fibroin protein. Both HA and silk are biocompatible, selectively degradable biomaterials with independently controllable material properties. Mechanical characterization showed the composite tensile strength as fabricated to be 4.43 ± 2.87 kPa, two orders of magnitude above estimated tensions found around potential target organs. In the presence of hyaluronidase (HAse) in vitro, the rate of gel degradation increased with enzyme concentration although the reinforcing silk mesh was not digested. Composite gels demonstrated the ability to store and sustainably deliver therapeutic agents. Time constants for in vitro release of selected representative antibacterial and anti-inflammatory drugs varied from 46.7 min for cortisone to 418 min for hydrocortisone. This biocomposite showed promising mechanical characteristics for direct fastening to tissue and organs, as well as controllable degradation properties suitable for storage and release of therapeutically relevant drugs.
ManuskiattiWMaibachHI. Hyaluronic acid and skin: wound healing and aging. Int J Dermatol1996; 35: 539–544.
2.
PakuSPaweletzN. First steps of tumor-related angiogenesis. Lab Invest1991; 65: 334–346.
3.
PrestwichGDKuoJ-W. Chemically-modified HA for therapy and regenerative medicine. Curr Pharm Biotech2008; 9: 242–245.
4.
KuoJW. Practical aspects of hyaluronan-based medical products, Boca Raton, FL: CRC Taylor & Francis, 2006.
5.
HuMSabelmanEELaiSTimekEKZhangFHentzVR. Polypeptide resurfacing method improves fibroblast’s adhesion to hyaluronan strands. J Biomed Mater Res1999; 47: 79–84.
6.
PrestwichGD. Engineering a clinically-useful matrix for cell therapy. Organogenesis2008; 4: 42–47.
7.
PrestwichGD. Evaluating drug toxicity and efficacy in three dimensions: using synthetic extracellular matrices in drug discovery. Acc Chem Res2008; 41: 139–148.
8.
Gluzman-PoltorakZCohenTHerzogYNeufeldG. Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165. J Biol Chem2000; 275: 18040–18045.
9.
HosackLWFirpoMAScottJAPrestwichGDPeattieRA. Microvascular maturity elicited in tissue treated with cytokine-loaded hyaluronan-based hydrogels. Biomaterials2008; 29: 2336–2347.
10.
EliaRFuegyPWVanDeldenAFirpoMAPrestwichGDPeattieRA. Stimulation of in vivo angiogenesis byin situ crosslinked, dual growth factor-loaded, glycosaminoglycan hydrogels. Biomaterials2010; 31(17): 4630–4638.
11.
MorraM. Engineering of biomaterials surfaces by hyaluronan. Biomacromolecules2005; 6: 1205–1223.
12.
ShuXZLiuYPalumboFSLuoYPrestwichGD. In situ crosslinkable hyaluronan hydrogels for tissue engineering. Biomaterials2004; 25: 1339–1348.
KaplanDLAdamsWWFarmerBVineyC. Silk: biology, structure, properties and genetics. In: Kaplan D, Adams WW, Farmer B and Viney C (ed.) Silk polymers: materials science and biotechnology, ACS Symposium Series 544. Washington, DC: American Chemical Society, 19942–2.
19.
Perez-RigueiroJVineyCLlorcaJElicesM. Mechanical properties of silkworm silk in liquid media. Polymer2000; 41: 8433–8439.
20.
WangXKlugeJLeiskGGKaplanDL. sonication-induced gelation of silk fibroin for cell encapsulation. Biomaterials2008; 29: 1054–1064.
21.
HoranRLAntleKColletteALWangYHuangJMoreauJE. In vitro degradation of silk fibroin. Biomaterials2005; 26: 3385–3393.
22.
WangYRudymDDWalshAAbrahamsenLKimHKimHS. In vivo degradation of three-dimensional silk fibroin scaffolds. Biomaterials2008; 29: 3415–3428.
23.
ZhangXBaughmanCBKaplanDL. In vitro evaluation of electrospun silk fibroin scaffolds for vascular cell growth. Biomaterials2008; 29: 2217–2227.
24.
LiCVepariCJinHKimHJKaplanDL. Electrospun silk-BMP-2 scaffolds for bone tissue engineering. Biomaterials2006; 27: 3115–3124.
25.
MinBMJeongbLNamYSKimJMKimJYParkWH. Formation of silk fibroin matrices with different texture and its cellular response to normal human keratinocytes. Int J BiolMacromol2004; 34: 281–288.
26.
SchneiderAWangXYKaplanDLGarlickJAEglesC. Biofunctionalized electrospun silk mats as a topical bioactive dressing for accelerated wound healing. Acta Biomater2009; 5: 2570–2578.
27.
JinHFridrikhSVRutledgeGCKaplanDL. Electrospinning Bombyx mori silk with poly(ethylene oxide). Biomacromolecules2002; 3: 1233–1239.
28.
JinHChenJKarageorgiouVAltmanGHKaplanDL. Human bone marrow stromal cell responses on electrospun silk fibroin mats. Biomaterials2004; 25: 1039–1047.
29.
WilsonDValluzziRKaplanDL. Conformational transitions in model silk peptides. Biophys J2000; 78: 2690–2701.
30.
Band PA. Chemistry and clinical applications. In: Laurent TC (ed.) The chemistry, biology and medical applications of hyaluronan and its derivatives. London, UK: Portland Press Ltd., 1998, pp. 33–42.
31.
FraserJRELaurentTCLaurentUBG. Hyaluronan: its nature, distribution, function and turnover. J Intern Med1997; 242: 27–33.
32.
LuoYKirkerKRPrestwichGD. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. J Control Rel2000; 69: 169–184.
33.
PikeDBCaiSPomraningKRFirpoMAFisherRJShuXZ. Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. Biomaterials2006; 27: 5242–5251.
34.
LimSTForbesBBerryDJMartinGPBrownMB. In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits. Int J Pharm2002; 231: 73–82.
35.
NaKKimSWooDGSunBKYangHNChungHM. Combination material delivery of dexamethasone and growth factor in hydrogel blended with hyaluronic acid constructs for neocartilage formation. J Biomed Mat Res A2007; 83: 779–786.
36.
HahnSKKimJSShimoboujiT. Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin. J Biomed Mater Res2007; 80A: 916–924.
37.
Prestwich GD. Hyaluronic acid-based clinical biomaterials for cell and molecule delivery in regenerative medicine. J Control Rel 2011; doi:10.1016/j.jconrel.2011.04.007.
38.
PeattieRNayateAFirpoMShelbyJFisherRPrestwichGD. Stimulation of in vivo angiogenesis by cytokine-loaded hyaluronic acid hydrogel implants. Biomaterials2004; 25: 2789–2798.
39.
AllisonDGrande-AllenK. Hyaluronan: a powerfultissue engineering tool. Tissue Eng2006; 12(8): 2131–2140.
40.
LuQZhangBLiMZuoBKaplanDLHuangY. Degradation mechanism and control of silk fibroin. Biomacromolecules2011; 12: 1080–1086.
41.
JinHJParkJKarageorgiouVKimUJValluzziRKaplanDL. Water-stable silk films with reduced β-sheet content. Adv Funct Mater2005; 15: 1241–1247.
BeekMVJonesLSheardownH. Hyaluronic acid containing hydrogels for the reduction of protein adsorption. Biomaterials2008; 29: 780–789.
44.
XiaoHKaplanDCebeP. Effect of water on the thermal properties of silk fibroin. Thermochim Acta2007; 461: 137–144.
45.
DaveVTamagnoMFocherB. Hyaluronic acid – (hydroxyproppyl)cellulose blends: a solution and solid state study. Macromolecules1995; 28: 3531–3539.
46.
CloydJMMalhotraNRWengLChenWMauckRLElliottDM. Material properties in unconfined compression of human nucleus pulposus, injectable hyaluronic acid-based hydrogels and tissue engineering scaffolds. Eur Spine J2007; 16: 1892–1898.
47.
ZhangXZWuDQChuCC. Synthesis, characterization and controlled drug release of thermosensitive IPN–PNIPAAm hydrogels. Biomaterials2004; 25: 3793–3805.
48.
Niederer SA, Buist ML, Pullan AJ and Smith NP. Calculating work in the ischemic heart. In: Proceedings of the 26th Annual IEEE Engineering and Medicine in Biology Society Conference, San Francisco, USA, September 1–5, 2004, pp. 3646–3649.
49.
PeattieRAYuBCaiSFirpoMAPikeDBFisherRJ. Heparin regulation of cytokine release from hyaluronan-based hydrogels. Drug Deliv2008; 15: 363–371.
50.
MakaiMCsányiENémethZPálinkásJErosI. Structure and drug release of lamellar liquid crystals containing glycerol. Int J Pharm2003; 256: 95–107.
51.
CaiSLiuYShuXPrestwichGD. Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor. Biomaterials2005; 26(30): 6054–6067.
52.
WissinkMJBBeerninkRPootAAEngbersGHMBeugelingTvan AkenWG. Improved endothelialization of vascular grafts by local release of growth factor from heparinized collagen matrices. J Control Rel2000; 64: 103–114.
