9 / 13 의료용고분자. Professor, Ph.D. Kim, Hong Sung Biomaterials, Applied Life Science, Pusan National University

Transcription

1 9 / 13 의료용고분자 Professor, Ph.D. Kim, Hong Sung Biomaterials, Applied Life Science, Pusan National University /bm/, Polymeric Biomaterials Lab., Medical Polymers & Functional Scaffolds, khs@pnu.kr

2 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

3 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(NH 3 ) 6 + and dopamine for selective and reversible sensors gel as sustained release vehicles for pooly soluble drugs degree of deacetylation, important for release indomethacin: non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and s welling papaverine: to treat spasms of the gastointestinal tr act, use as a cerebral and coronary vasodilator lidocaine: common local anesthetic and antiarrhyth mic drug

4 CTS-gelatin sponge dissolve in acid solu., frothing up solu., freezedrying with prednisolone use as immunosuppressant in in autoimmune diseases and inflammatory diseases Mechanical and drug release properties manipul ate 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

5 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

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

7 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

8 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

9 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

10 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)

11 CMC and xanthan CTS complex Water-insoluble hydrogel: blocking hydrophilic groups(r-cooh, R-NH 2 ) 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 COO - + H 3 N COO - + H 3 N Figure 1.1

12 Porous and fibrilar structure (Fig. 1.3) Pore size 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

13 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

14 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

15 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

16 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

17 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

18 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

19 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

20 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