The Laryngoscope Lippincott Williams & Wilkins, Inc. © 2004 The American Laryngological, Rhinological and Otological Society, Inc. Chondroitin Sulfate Hydrogel and Wound Healing in Rabbit Maxillary Sinus Mucosa M. Erik Gilbert, MD; Kelly R. Kirker, PhD; Steven D. Gray, MD; P. Daniel Ward, MD; Juliana G. Szakacs, MD; Glenn D. Prestwich, PhD; Richard R. Orlandi, MD Objectives/Hypothesis: Chondroitin sulfate (CS) is a glycosaminoglycan in the extracellular matrix of all vertebrates. A biocompatible, nonimmunogenic, pli- able hydrogel preparation of CS has recently been produced and has shown benefit in wound healing in murine and porcine epidermis. The objective of the current experiment is to compare the wound healing properties of CS hydrogel versus no treatment in wounds of the maxillary sinus mucosa. Study Design: Prospective investigation in an animal model. Meth- ods: A 6 mm wound was created in bilateral maxillary sinuses of 17 New Zealand white rabbits. CS hydrogel (case) and no dressing (control) were randomly as- signed to one side each as wound treatment. Wounds were examined ex vivo at 2, 4, 6, 10, and 14 day postin- jury intervals. Wound diameter was measured micro- scopically by a blinded investigator. Representative specimens were examined histologically. Results: The CS disc was partially integrated into the wounds at the 4-day interval and completely integrated by the 6-day interval. The average wound diameters for the case versus control side were similar at 2 days (3.75 mm vs. 4.42 mm) but differed significantly at 4 days (2.86 mm. vs. 3.80 mm., P  .035). At 6 days, the wounds could not be discerned on either the case or control sides. However, histologic analysis revealed acceler- ated healing with the CS treatment. The treated wounds displayed respiratory epithelium as opposed to the squamous epithelium exhibited on the un- treated sides. Conclusions: Despite some limitations, the New Zealand white rabbit is an effective model for the study of sinonasal wound healing. CS hydrogel accelerates wound healing in sinonasal mucosa at a 4-day endpoint. We propose that the CS hydrogel acts as a surrogate extracellular matrix, serving as a re- pository for cytokines and growth factors produced by the regenerating mucosa. It may also provide a structural framework for fibroblasts and epithelial regeneration. Further study is necessary to establish this relationship. Laryngoscope, 114:1406 –1409, 2004 INTRODUCTION Chondroitin sulfate (CS) is a naturally occurring lin- ear polysaccharide comprised of -1,3 linked glucuronic acid and (-1,4)N-acetyl-galactosamine (GlaNAc) sulfated on either the 4 or 6 position of the GlaNAc residues. Along with hyaluronan (HA), CS is one of several glycosamino- glycans (GAGs) in the extracellular matrix (ECM) of all vertebrates. CS is most frequently found as a proteoglycan in which CS is covalently bound to the core protein by way of 10 to 100 xylolose-modified Ser residues. CS proteogly- cans (e.g., aggrecan, versican, and decorin) have various biologic functions, including collagen fibril assembly, 1 intra- cellular signaling, cell recognition, connection of ECM con- stituents to cell surface glycoproteins, 2 and cell orientation during axon generation. 3 HYAFF-11, a chemically esterified form of HA, a nonsulfated GAG, is currently marketed com- mercially in a gel preparation as a postoperative wound healing adjuvant and adhesiolytic after endoscopic sinus surgery in humans. 4 However, as a recent review by Watelet et al. 5 points out, little is known about wound healing of the paranasal sinus mucosa, particularly with respect to the role of the ECM constituents, including HA and CS. Recently, an experimental, biocompatible, nonimmu- nogenic, pliable CS hydrogel was produced. 6 This CS hy- drogel was beneficial in healing full-thickness cutaneous wounds in a mouse model and was a superior treatment than the HA hydrogel and the controls in that setting. 6 Similarly, CS was superior to a HA hydrogel and to con- trols in a partial-thickness wound in a pig model. 7 It was theorized that improved wound healing could be demon- strated in the sinonasal mucosa as well. This experiment assesses the effect of the CS gel on wound healing in the mucosa of the maxillary sinus in a rabbit model. MATERIALS AND METHODS CS gels were prepared as previously described. 6 CS was modified under carbodiimide condensation conditions using adi- From the Division of Otolaryngology–Head and Neck Surgery (M.E.G., S.D.G., P.D.W., R.R.O.), University of Utah Medical Center, School of Medicine, Salt Lake City, UT; the Department of Bioengineering (K.R.K., G.D.P.), University of Utah, Salt Lake City, UT; the Department of Pathol- ogy (J.G.S.), University of Utah, University Hospital, Salt Lake City; and the Department of Medicinal Chemistry (G.D.P.), University of Utah, Salt Lake City, UT, U.S.A. We thank the University of Utah and the National Institutes of Health (DC 04336 to GDP and the late SDG) for financial support of this research. Conflict of interest: Dr. Orlandi and Dr. Prestwich are co-founders of Sentrx Surgical, Inc. Editor’s Note: This Manuscript was accepted for publication Febru- ary 12, 2004. Send Correspondence to Dr. Richard R Orlandi, Division of Otolaryn- gology–Head and Neck Surgery, University of Utah Medical Center, 3C-120 School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132, U.S.A. Laryngoscope 114: August 2004 Gilbert et al.: Chondroitin Sulfate Hydrogel and Wound Healing 1406