의료용 고분자

Professor, Ph.D. Kim, Hong Sung Biomaterials, Applied Life Science, Pusan National University

http:// 203.232.243.139/bm/, Polymeric Biomaterials Lab., Medical Polymers & Functional Scaffolds, khs@pnu.kr

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CTS hydrogel by crosslinking • glutaraldehyde, glyoxal, diethyl squarate, etc • CTS-PEO diacrylate by UV • CTS-PEO by glyoxal • CTS-fibroin by glutaraldehyde • CTS-PAA

CTS based gel by acetylation • attach C10-alkyl glycosides • hydrophobic palmitoyl • produce water-soluble chitosan derivatives

Medical Polymers, Functional Polymers, and Biomaterials

Thin CTS film for electrode of sensors • casting carbon electrode • grafting Lucifer Yellow VS dye • crosslinking with glutaldehyde • fast ion transport (aquous-like diffusion coefficient) of

Ru(NH3)6+ and dopamine

• for selective and reversible sensors gel as sustained release vehicles

• for pooly soluble drugs • degree of deacetylation, important for release

Medical Polymers, Functional Polymers, and Biomaterials

• indomethacin: non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling • papaverine: to treat spasms of the gastointestinal tract, use as a cerebral and coronary vasodilator • lidocaine: common local anesthetic and antiarrhythmic drug

CTS-gelatin sponge • dissolve in acid solu., frothing up solu., freeze-

drying • with prednisolone use as immunosuppressant in in autoimmune diseases

and inflammatory diseases

• Mechanical and drug release properties manipulate by acidic solvent type tartaric or citric acid: unstable, soft, elastic sponge with

fast drug release hydrochloric or lactic acid: elastic, harder acetic or formic acid: stable, soft, elastic sponge with

low drug release

Medical Polymers, Functional Polymers, and Biomaterials

Gentamicin-loaded CTS bar • Implant in proximal bone for osteomyelitis • Low blood conc., • higher conc. in local bone and hematoma

CTS-ethylene diamine tetraacetic acid(EDTA) gel • Link carboxyl of EDTA to amino of CTS • Neutralize with sodium hydroxide • Binding bivalent cations Cofactor for intestinal proteolytic enzyme

• inhibit zinc protease, carboxypeptidase A, aminopeptidase N

• Not inhibit serine protease trypsin, α-chymotrypsin, elastase

Medical Polymers, Functional Polymers, and Biomaterials

Berberine-CTS hydrogel ointments • Viscosity of CTS increase on increasing lactic acid or EDTA • Viscosity, inversely proportional to release rate

Heparin-CTS gel • Ionically linked complex • Stimulation of re-epithelialization of full thickness

wound in human skin • After 7 days, 9/10 re-epithelialization of wound

Pluronic-grafted CTS hybrids • Temp. responsive copolymer, Gellation at 4-37°C • Extension of drug release

Medical Polymers, Functional Polymers, and Biomaterials

Berberine: water-soluble alkaloid in subterranean stem of medicinal plant Coptis japonica, use as antipyrotic, antimicrobial, stomachic, etc

Interaction forces • Electrostatic, hydrophobic, hydrogen bonding,

van der waals, their combinations • Affect solubility, rheology, conductivity, turbidity

interpolymer complex: • polymeric acid form complex by proton transfer

to polymeric base Intrapolymer complex: polyampholytes Gel formation: polyelectrolytes with

multivalent ions

Medical Polymers, Functional Polymers, and Biomaterials

Complex stability by • Charge density, solvent, ionic strength, pH, temp. • High charge density form insoluble complex

Characteristics of polymer complex are based on higher Mw: ‘Polymer effect’

Gel technology, ionic linked PS, in use • As DDS and mechanochemical device • Several biomedical applications

Medical Polymers, Functional Polymers, and Biomaterials

CTS binding was increased on • Reducing Mn <20,000 Da • Increasing porosity of alginate gel • Decreasing acetylation 0.3~0 • Increasing pH 4~6 • Reducing capsule diameter 1500~500 um

Porosity was increased by • Producing homogeneous gel • Adding calcium chloride

Medical Polymers, Functional Polymers, and Biomaterials

Spray-dried composite particles • Aqueous solu. of lactose and sodium alginate • Acetic acid solu. of CTS • Concomitantly feed in rotary atomizer • Long induction period, rapid release in intestinal

fluid • Induction period was increased with Increase of deacetylation and of amounts of CTS

• Strong capsule: react calcium alginate beads in CTS and calcium chloride solu.

• more strength: reduce Mn (15,000Da), more homogeneous, reduce diameter (300um)

Medical Polymers, Functional Polymers, and Biomaterials

CMC and xanthan – CTS complex • Water-insoluble hydrogel: blocking hydrophilic

groups(R-COOH, R-NH2) • Ionic reticular network • Stable hydrogel Lower deacetylation Higher xanthan ratio

• poor complex at low pH Ion impede carboxyl in xanthan

• Decomposition depends on pH Stable pH 1.2~9.2

Medical Polymers, Functional Polymers, and Biomaterials

COO- +H3N

COO- +H3N

Figure 1.1

Porous and fibrilar structure (Fig. 1.3)

• Pore size 0.1-1 um • Fibril diameter 100nm • Immobilize and release enzyme through gel

Evaluation of biocompatibility • L929 fibroblast for cytotoxicity • J774 macrophage for inflammatory response Secrete cytokines and nitric oxide as indicator TNF-α, IL-β, NO as markers for macrophage activation Induce T lymphocyte and activation factors

Medical Polymers, Functional Polymers, and Biomaterials

Effect of CTS-X complex in vivo • No cytotoxic effect • Conc. of 1mg/ml, stimulate TNF-α production • No effect IL-1β secretion by conc. • Bring nitric oxide with TNF-α secretion

wound healing mechanism • Inflammatory reaction, essential for new ECM in

wound • Inflammatory cell releases cytokines and growth

factors • The factors attract fibroblasts into wound (Fig. 1.8)

Degradation of matrix (Fig. 1.9)

• Macrophages, phagocytosis of materials, degradation in vivo, lead to entire resorption Medical Polymers, Functional Polymers, and Biomaterials

Encapsulation of chitosan with sodium carboxymethyl cellulose • Lower Mw of CTS More compact structure, Lower permeability

• With increase in salt conc. Reduction in effective charge by shielding effect

(prevent CTS from reacting with CMC) Increase permeability, decrease equilibrium adsorption Lower mechanical strength Because of lower density of interpolymer bridge

• Adsorption rate of CTS in CMC substrates Electrostatic interaction of carboxylic acid content Surface area due to swelling by hydrophilic groups

Medical Polymers, Functional Polymers, and Biomaterials

Complex at suitable pH Slower rate of dissolution Absorption of wound fluid Slowly release wound-treating drug Release profile and biodegradability,

controlled by glutaraldehyde crosslinking Optimal conditions were coincident with

CTS-polysaccharides complex

Medical Polymers, Functional Polymers, and Biomaterials

CTS-potassium metaphosphate complex • Glycol and methyl glycol chitosan • Water-insoluble complex

CTS-tripolyphosphate complex • Enzymatic hydrolyzed chitosan • CTS-polyphosphoric acid gel beads • Release of anticancer agents, 6-mercaptopurine • CTS beads gel in potassium triphosphate or

polyphosphoric acid solu. • Insulin-loaded nanoparticles nasal absorption Mw, not effect on insulin response

Medical Polymers, Functional Polymers, and Biomaterials

Glycosaminoglycan (GAG) • In cell-cell, in cell-matrix interaction • Modulator of cell morphology, differentiation,

movement, synthesis, function CTS, structural similarity to GAG

• Modify using proteins (collagen, albumin, gelatin, etc) to increase surface area and biocompatibility

CTS-collagen matrix • More readily attachment to chromaffin cell • Survive for at least 2 weeks in vivo • Improve bovine adrenal medullary chromaffin cell

attachment

Medical Polymers, Functional Polymers, and Biomaterials

For cell culture, too fragile • Crosslinking by glutaraldehyde (GA)

GA-CTS gel, seeded rat heptocyte • Attach with stability • Retaining spherical form • Release very small amount of lactate dehydrogenase(LDH) • By contrast, on collagen-coated surface Spread flat shape of heptocyte Much more release lactate dehydrogenase

• Retain higher urea synthesis activity and liver-specific function

CTS scaffold, promising of hepatocyte attachment • effective bioartificial liver support system

Medical Polymers, Functional Polymers, and Biomaterials

Engineered cartilage depends • on chemical composition • able to support chondrocytic phenotype

Chondroitin sulphate-A(CSA)-CTS hydrogel • Ionic crosslinking results in hydrogel • Form discrete, focal adhesion • Maintain characteristics of differentiated phenotype Round morphology, limited mitosis, collagen II and

proteoglycan production

Medical Polymers, Functional Polymers, and Biomaterials

CTS sponge containing PDGF-BB for bone • platelet-derived growth factor-BB (PDGF-BB) • Fabrication Freeze-dried CTS solu., crosslinked, refreeze-dried Soaking sponge into PDGF-BB solu.

• Release rate, controlled by initial loading content to optimal therapeutic efficacy

• High cell attachment and proliferation • Good cellular adaptability • Increase in new bone formation and rapid

calcification • Enhance periodontal bone regeneration • Degradation of scaffold replaces with new bone

Medical Polymers, Functional Polymers, and Biomaterials