Magdalena Kucharska, Danuta Ciechańska, Antoni Niekraszewicz, Maria Wiśniewska Wrona, Iwona Kardas

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1 POTENTIAL USE OF CHITOSAN BASED MATERIALE IN MEDICINE Magdalena Kucharska, Danuta Ciechańska, Antoni Niekraszewicz, Maria Wiśniewska Wrona, Iwona Kardas Institute of Biopolymers and Chemicals Fibres, ul. M. Skłodowskiej-Curie 19/27, Lodz, Poland Abstract Polysaccharides are macromolecular polymers that manifest ability toward the forming of fibres, film and coatings. Some of their specific properties like biodegradability and biocompatibility make them suitable for medical application. Chitin, chitosan and alginates are basic polymers mostly used in the preparation of medical biomaterials. In the Institute of Biopolymers and Chemical Fibres (IBWCh) multidirectional investigations are in full swing concerned with the use medical of polysaccharides and their various useful forms. The research includes amongst: multifunctional dressing materials, implants and other polysaccharide biomaterials. Key words: polysaccharides, medicine, biomaterials. Progress on Chemistry and Application of Chitin and Its..., Volume XV,

2 M. Kucharska, D. Ciechańska, A. Niekraszewicz, M. Wiśniewska Wrona, I. Kardas 1. Introduction Polysaccharides are macromolecular polymers that manifest ability toward the forming of fibres, film and coatings. Some of their specific properties like biodegradability and biocompatibility make them suitable for medical application. Chitin, chitosan and alginates are basic polymers mostly used in the preparation of medical biomaterials. Investigations are being conducted in a number of scientific centres concerned with the use of chitin and chitosan in medical dressings. The biological activity of these polymers results from the low-molecular degradation products that are formed under the influence of enzymes which appear in the organism fluids like lysozyme and N-acetylglucosamindase. The degradation products in the form of chito-oligomers manifest the ability to stimulate macrophages; they have also a positive influence upon the deposition of collagen which in turn accelerates the wound healing process [1]. Chitosan, when properly selected for the purpose, exerts a blood-clotting action which provides for its use in haemostatic dressings. Dressing materials based on chitin, chitosan and their derivatives are commercially available. The products are manufactured in only few countries: USA, Japan and some European ones. Eisai Co offers a chitin dressing in the form of a sponge called Chitopack C, and non-woven modified either with chitin (Chitopack P ) or chitosan (Chitopack C P ). Unitika Co (Japan) produces a dressing non-woven made of chitin fibres [2]. 3M (USA) sells its chitosan-based gel Tegasorb and hydrocolloid Tegaderm both designed for the healing of extensive internal wounds [2]. In 2002 the US Army was provided with a haemostatic chitosan dressing for battlefield uses, called HemCon BandageTM [3]. Known are also other chitin/chitosan-based haemostatic materials notably: Syvek patch and RDH (Marine Polymer Technologies), Clo-Sur PAD (Medtronic/Scion), Chito-Seal (Abbott), M-Patch and Trauma DEX (Medafor) [4]. Thanks to specific biological properties, alginates attract many scientists and research hubs. Sodium and calcium alginates in form of fibres, fabrics, knitwear and gel are mainly applied in wound healing. Appropriate dressings do not stick to exudative wounds, are fast hydrophilic, maintain moisture and accelerate the wound healing. Owing to the presence of calcium ions, such dressings are particularly suitable in the controlling of bleeding. In the market of medical devices known are such alginate-based dressings as: Algisite M (Smith&Nephew), Kaltostat (Conva Tec), Melgisorb (Molnlycke), SeaSorb (Coloplast), Tegagen (3M), Sorbalgon (Hartman), Sorbsan (Maersk). In the Institute of Biopolymers and Chemical Fibres (IBWCh) multidirectional investigations are in full swing concerned with the use medical of polysaccharides and their various useful forms. The research includes amongst other: multifunctional dressing materials implants (the modified surgical mesh, vascular prosthesis, prosthesis of peripheral nerve) other polysaccharide biomaterials (surgical glue) 170 Progress on Chemistry and Application of Chitin and Its..., Volume XV, 2010

Chitosan microfibrids and chitosan-alginate microfibrids with the addition of calcium were used to construct of dressing [13, 14].

3 Potential Use of Chitosan Based Materiale in Medicine 2. Multifunctional dressings materials In IBWCh were prepared dressing material, based on the polysaccharides, in the form of sponges to treatment of wounds in all phases of healing. Chitosan microfibrids and chitosan-alginate microfibrids with the addition of calcium were used to construct of dressing [13, 14]. Sponges were prepared using freeze drying metod from mixture of microfibrids chitosan or chitosan-alginate (polymer content wt% ) and glycerol in a weight ratio 1:0.5 (on the dry chitosan). Lyophilization was conducted for about 20 h at -10 C under a pressure reduced to 0.1 mbar (Figure 1). Developed materials were evaluated mechanical properties, sorption capacity and biological - cytotoxicity and haemostatic. The study showed that the sponge meet the basic criteria of the physico-mechanical and biological, which allowing use their as dressings for the treatment of wounds in all phases of healing. Sponges have sufficient strength and a very good sorption properties. Sponges from chitosan-alginate microfibrids absorb about 17-tuple, and sponges from chitosan fibrids 8-tuple the amount of water in relation to its initial mass. Developed dressing materials do not exhibit cytotoxicity, and sponges from chitosan-alginate microfibrids with the addition of calcium in contact in vitro with plasma citrate activate the plasma coagulation system, thereby reducing the time of coagulation of intrinsic and extrinsic pathway. In cooperation with medical company TRICOMED S.A. in Lodz, the dressing to provide first aid treatment of wounds and trauma TROMBOGUARD+ was developed [15]. This is a two-layer dressing consisting of hydrophilic polyurethane sponge with is an absorber layer which is affixed to the biologically active layer containing chitosan, sodium alginate/calcium and silver salts (Figure 2). Figure 1. Surface of sponge with: a) chitosan fibrids, b) chitosan-alginate fibrids with the addition of Ca. Progress on Chemistry and Application of Chitin and Its..., Volume XV,

4 M. Kucharska, D. Ciechańska, A. Niekraszewicz, M. Wiśniewska Wrona, I. Kardas Figure 2. Action schematic of dressing TROMOGUARD+. Studies in vitro and in vivo on animals in the Department of Experimental Surgery and Biomaterials Research, Medical University Wroclaw showed that dressing TROMBO- GUARD + is characterized by bleeding the braking ability (haemostatic effect). Confirmed the antimicrobial activity against Escherichia coli and Staphylococcus aureus, which allows for protection against infection and secondary infection without the use or the limited participation of antibiotics. Usefulness dressing for specific tasks and is evaluated in clinical conditions. These tests are conducted at two clinical centers: Central Clinical Hospital Ministry of Interior in Warsaw and Military Institute of Medicine in Warsaw. Currently, in cooperation with the Department of Applied Pharmacy, Medical University is developing a functional composite dressing material produced on the basis of polysaccharides: chitosan and sodium alginate, with the participation of anti-inflammatory agent. Such obtained materials, characterized by suitable physic-mechanical and biological properties should be useful for treatment of bedsores in the first phase of healing. Developed dressing material in form of film will be prone to biodegradability and resorption within the wound. 3. Implants 3.1. Modified chitosan hernia meshes In IBWCh developed a method of manufacturing composite, surgical meshes for tension-free hernia treatment. Modified meshes characterized by partially resorbable allow for faster treatment and reduce rigidity of the implant to overwhelm the tissue, thus improving blood supply of organs located in the vicinity of the implant. Implants manufactured by a combined method [16], by plotting on the semi-finished product surface as non-resorable surgical mesh OPTOMESH TM Macropore (TRI- COMED S.A.) microporous resorbable chitosan layer (Figure 3). Functional chitosan forms developed in the Institute of Biopolymers and Chemical Fibres (IBWCh) were used to modify [17]. 172 Progress on Chemistry and Application of Chitin and Its..., Volume XV, 2010

5 Potential Use of Chitosan Based Materiale in Medicine Figure 3. Polypropylene surgical mesh modified by microcrystalline chitosan. The susceptibility to enzymatic degradation in the presence of lysozyme (180 days), and biocompatibility testing produced implants were evaluated. Susceptibility testing to hernia mesh degradation was performed in the Institute of Technical Biochemistry, Technical University of Lodz. Evaluation of cytotoxicity against on murine fibroblasts in accordance with BS EN was performed at the Department of Experimental Surgery and Biomaterials Research, of the Wrocław Medical Academy, studies of intracutaneous irritating action in rabbits and studies of the guinea pigs skin sensitization was performed using the Buehler method PN-EN the National Institute of Health in Warsaw. The study showed that chitosan coating plotted on a meshes from a polypropylene fibres biodegradable under the influence of lysozyme, while already at the lowest applied concentration of the enzyme (10μg/cm 3 ) after 180 day weight loss amounted to more than 50%. Studies using experimental animals showed a weak cytotoxic effect of not limiting the possibility of the use of modified meshes in surgical procedures, as well as the lack of irritation and sensitization Bone glue In cooperation with the Academy of Mining and Metallurgy, Krakow developed composite chitosan-hydroxyapatite in the form of glue. Used modified chitosan lactate to produce a preparation. Conducted specialized tests have shown the usefulness of this preparation in the surgical joining of bones endeavors. Developed glue may be used in surgery as a preparation to assist the process of uniting broken bones and to speed up their fuses (Figure 4). Progress on Chemistry and Application of Chitin and Its..., Volume XV,

M. Kucharska, D. Ciechańska, A. Niekraszewicz, M. Wiśniewska Wrona, I. Kardas Figure 4. Bone joining by chitosan-hydroxyapatite glue. 3.

prosthesis. Prosthesis is made from various forms of utility polysaccharides (Figure 5).

6 M. Kucharska, D. Ciechańska, A. Niekraszewicz, M. Wiśniewska Wrona, I. Kardas Figure 4. Bone joining by chitosan-hydroxyapatite glue Peripheral nerve prostheses In cooperation with Department of Physiology, Medical University of Silesia in Katowice, research is elaboration of peripheral nerve prosthesis. Prosthesis is made from various forms of utility polysaccharides (Figure 5). The main objective of research is to develop a replacement implants are not rejected by the body of the recipient and offering the ability to regenerate damaged nerve. Figure 5. Peripheral nerve protheses from chitosan. 174 Progress on Chemistry and Application of Chitin and Its..., Volume XV, 2010

Potential Use of Chitosan Based Materiale in Medicine Figure 6. Prosthesis Dacron modified by chitosan. 3.4.

7 Potential Use of Chitosan Based Materiale in Medicine Figure 6. Prosthesis Dacron modified by chitosan Modified vascular prosthesis Technology of sealing dakron outlet prosthesis and cannulas ventricular heart support of natural polymer with a group polysaccharidesis being developed in IBWCh (Figure 6). These research are conducted within a strategic research project consistent with the multi-annual program for , Polish Artificial Heart. Sealing effectiveness is assessed based on the water permeability test (according to PN-79/P Test methods for textile products. Knitted medical-vascular prostheses. Determination of the permeability of water ) and an assessment of the structure of modified vascular prostheses using scanning electron microscope SEM Quanta 200 FEI Co. USA. 4. Acknowledgment His work was partially supported by the Polish Ministry of Science and Higher Education, research project No: 3 T08E , 236/BO/C, N N , N N , 6/02/ WK/P01/ References 1. Muzzarelli R. A. A.: Carbofydrate Polym, 1993, 20, pp Muzzarelli R. A. A.: Formulary of wound management products, Euromed Communications, Hemorrhage Control in the Battlefield: Role of New Hemostatic Agents, MILITARY MEDICINE, 170, 2005, pp Kucharska M., Niekraszewicz A., Wiśniewska-Wrona M., Struszczyk H.: Manufacture and assessment of medical dressing from Various forms chitosan, monograph Vol. VIII edited by Progress on Chemistry and Application of Chitin and Its..., Volume XV,

8 M. Kucharska, D. Ciechańska, A. Niekraszewicz, M. Wiśniewska Wrona, I. Kardas H. Struszczyk,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2002 pp Niekraszewicz A., Struszczyk H., Kucharska M., Gonera H., Paluch D., Pielka S., Staniszewska-Kuś J., Solski L.: Wound dressing non woven containing chitosan fibres monograph Vol. VIII edited by H. Struszczyk,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2002 pp Wiśniewska-Wrona M., Niekraszewicz A., Struszczyk H., Guzińska G.; Estimation of Polymer Compositions Containing Chitosan for Veterinary Applications Fibres & Textiles in Eastern Europe, Vol. 10, 2002 No 3(38), pp Kucharska M., Niekraszewicz A., Wiśniewska-Wrona M., Wesołowska E., Struszczyk H.; Preparation and estimation of chitosan usable dressing forms monograph vol. IX ed. by H. Struszczyk,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2003 pp Niekraszewicz A., Kucharska M., Wiśniewska-Wrona M., Wesołowska E., Struszczyk H.; Chitosan in medical application monograph, vol. X ed. by H. Struszczyk,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2004 pp Strobin G., Kucharska M., Ciechańska D., Wawro D., Stęplewski W., Jóźwicka J., Sobczak S., Haga A.; Biomaterials containing chitosan and fibroin monograph, vol. XI ed. by M. Jaworska,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2006 pp Niekraszewicz A., Lebioda J., Kucharska M., Wesołowska E.; Research into Developing Antibacterial Dressing Materials, Fibres & Textiles in Eastern Europe, vol.15, No 1(60), 2007, pp Kucharska M., Niekraszewicz A., Lebioda J., Brzoza-Malczewska K., Wesołowska E.; Bioactive composite materials monograph, vol. XII edited by M. Jaworska,,Progress on Chemistry and Application of Chitin and Its Derivatives, Polish Chitin Society, 2007 pp Patent Application P (2008). 14. Patent Application P (2008). 15. Patent Application P (2010). 16. Patent Application P (2006). 17. Polish Patent (1989). 176 Progress on Chemistry and Application of Chitin and Its..., Volume XV, 2010

HAEMOSTATIC, RESORBABLE DRESSING OF NATURAL POLYMERS - HEMOGUARD

HAEMOSTATIC, RESORBABLE DRESSING OF NATURAL POLYMERS - HEMOGUARD Magdalena Kucharska 1*, Maria Wiśniewska-Wrona 1, Kinga Brzoza-Malczewska 1, Marcin H. Struszczyk 2, Magdalena Cichecka 2, Bożena Wilbik-Hałgas