组织工程第3章医用高分子天然材料第2节.docx

第3章3.2 医用天然高分子材料Natural polymeric biomaterials Polypeptides (Proteins)- a chain of amino acids attached by the peptide bond Polysaccharides (Carbohydrates)- a chain of sugar/monosaccharide units attached by theglycosidic bond Application examplesRatner BD, et al., Biomaterials Science, 2nd edition, 2004. pp128.1General Functions of Biological Polymers Proteins Structural (fibrous proteins) Biological catalysts (enzymes) Recognition (immunoglobulins) Carbohydrates Energy storage (starch, glycogen) Structural (cellulose cell walls or chitin exoskeletons) Recognition (carbohydrates of glycoproteins and glycolipids) Nucleic Acids Information storage (genome) Translational molecules (mRNA & tRNA) Biological catalysts (RNA ribozymes)Proteins Made from monomers called amino acids Very different structures, very different functionsHOAminogroupH2NCRCOHCarboxylgroupSide chainAmino acids are made of the five elements C H O N S2The R groups of anamino acid may behydrophobic orhydrophilicAmino acids are joined together by adehydration reactionH2NHCHCarboxylgroupOCOH+AminogroupHNHHCCH3COOHH O H HH2N C C N C CH CH3PeptidebondOOHH2O3Many amino acids joined together = Polypeptide chainN-terminusC-terminusH HO H HO HHO H HO HHO H HO H HOH HOHNCC NCCNCCN CCN CC N CC NCC N CCOHHCH3CH2CH2CH2CHCH2CH2OHC OHH3CCH3SHOOHAlanineAspartic acidValineCysteineGlycineSerinePhenylalanineTyrosineProteins have multi-level structures Primary structure (1)- The sequence of amino acidsfrom N- to C-terminus in apolypeptide chain- Ultimately determines all higherorder structure and function- Driven and stabilized by covalentbonds4Secondary structure (2)- Local, spatial interactions in terms of forming hydrogenbonds between the C=O groups and the N-H groups inthe polypeptide backbone.- Not usually a determinant of function- The two secondary structures (regular sub-structures):a-helix and b-sheetBoth the alpha-helixand the beta-sheetrepresent a way ofsaturating all thehydrogen bond donorsand acceptors in thepeptide backbone./chem/V.27/page_id_27148.html5Tertiary structure (3)-Three-dimensional folding of a polypeptide-Driven and stabilized largely by hydrogen bonds ,ionic bonds , disulfide linkages , and dispersion forcesbetween side chains-Often dictates biological activity6Quaternary Structure (4)- Specific interactions between two or more proteins- Can be driven and stabilized by any combination ofbond typesHaemoglobin (血红蛋白),the oxygen-carrying proteinin red blood cells, consistsof four globular subunitsarranged in a tetrahedral(pyramid) structure. Eachsubunit contains one ironatom and can bind onemolecule of oxygen.CollagenCollagen is a group of naturally occurring proteins.In nature, it is found exclusively in animals, especially in theflesh and connective tissues of mammals, making up about25% to 35% of the whole body protein content .Collagen, in the form of elongated fibrils, is mostly found infibrous tissues such as tendon (90%), ligament and skin(50%), and is also abundant in cornea, cartilage, bone, bloodvessels, the gut, and intervertebral disc.In animals, these collagen proteins play critical roles in tissuearchitecture, tissue strength, and cell to cell relationships.7l Primary structure the complete sequence of amino acids along eachpolypeptide chain.l An example is the triple chain sequence of type I calf skin collagen atthe N-end of the molecule. Roughly 5% of a complete molecule is shownabove.l Amino acid residues participating in the triple helix are numbered, andthe residue-to-residue spacing (0.286 nm) is shown as a constant withinthe triple helical domain, but not outside it.l Bold capitals indicate charged residues which occur in groups(underlined)Ratner BD, et al., Biomaterials Science, 2nd edition, 2004. pp129.l Secondary structure the local configuration of a polypeptide chain.l The triplet sequence Gly-Pro-Hyp illustrates elements of collagentriple-helix stabilization. The numbers identify peptide backbone atoms.l The conformation is determined by trans peptide bonds (3-4, 6-7, and9-1); fixed rotation angle of bond in proline ring (4-5); limited rotation ofproline past the C=O group (bond 5-6); interchain hydrogen bonds (dots)involving the N-H hydrogen at position 1 and the C=O at position 6 inadjacent chains; and the hydroxy group of hydroxyproline, possiblythrough water-bridged hydrogen bonds.8l Tertiary structure the global configuration of polypeptide chains,representing the pattern according to which the secondarystructures are packed together within the unit substructure.l A schematic view of the type I collagen molecule, a triple helix 300nm long.l Quaternary structure the unit supermolecular structure.l The most widely accepted unit is one involving five collagenmolecules (microfibril).l Several microfibrils aggregate end to end and also laterally toform a collagen fiber that exhibits a regular banding pattern in theelectron microscope with a period of about 65 nm.9The hierarchical structure of collagenCollagenNanofibersAFMImagesColoured transmission electron micrograph(TEM). A tendon is made up of parallelbundles of collagen fibres. Tendons areinelastic, though with a degree of flexibility,and attach a muscle to a bone.10From “Biological Interactions with Surface Charge in Biomaterials”Banding pattern with the so-called D-periodicity between 6467 nm based onthe staggered arrangement of the collagen monomersAll collagens contain a unique triple helix. However,the length of the helix and the nature and size of non-helical portions (major source of antigenecity) of the moleculevary from type to type.Collagen occurs in many places throughout the body. Sofar, there are 29 types of collagen identified. Over 90%of the collagen in the body, however, is of type I. Collagen I: skin, tendon, vascular, ligature, organs,bone (main component of bone) Collagen II: cartilage (main component of cartilage) Collagen III: reticulate (main component of reticularfibers), commonly found alongside type I. Collagen IV: forms bases of cell basement membrane Collagen V: cells surfaces, hair and placenta11Hypermobile fingersDiseases associated with collagenEhlersDanlos syndromeA group of inherited connective tissuedisorders, caused by a defect in thesynthesis of collagen (usually Type I and III) leading to significant deterioration in themechanical integrity of tissues.Named after two doctors, Edvard EhlersHyperelasticityof Denmark, and Henri-AlexandreDanlos of France, who identified it at theturn of the 20th centuryCollagen as a biomaterial *Advantages:uAvailable in abundance and easilypurified from living organisms (constitutesmore than 30% of vertebrate tissues);uNon-antigenic;uBiodegradable and bioreabsorbable ;uNon-toxic and biocompatible ;uSynergic with bioactive components;uBiological plastic due to high tensilestrength and minimal expressibility;uHemostatic promotes bloodcoagulation;uFormulated in a number of differentforms;uBiodegradability can be regulated bycross-linking;uEasily modifiable to produce materials asDisadvantages:u High cost of pure type Icollagen;u Variability of isolated collagen(e.g. crosslink density, fiber size,trace impurities, etc.);u Hydrophilicity which leads toswelling and more rapid release;u Variability in enzymaticdegradation rate as compared withhydrolytic degradation;u Complex handling properties;u Side effects , such as bovinespongeform encephalopathy(BSE mad cow disease) andmineralizationdesired by utilizing its functional groups;uCompatible with synthetic polymers;12Denaturation1. Heats2. Acids or bases3. Organic compounds4. Heavy metal ionsOccurs when there is a disruption of the bondsthat stabilize the 2, 3, 4 structures of proteins no longer biologically active5. Agitation13GelatinA collagen-derived translucent brittle solid substance, it is colorless orslightly yellow, nearly tasteless and odorless.Produced by partial hydrolysis of those collagen-rich tissues , e.g., bone,skin, tendon from the animals such as domesticated cattle, pigs, andhorses.The gelatin obtained from acid treated raw material has been called type-Agelatin, and the gelatin obtained from alkali treated raw material is referredto as type-B gelatin.The natural molecular bonds between individual collagen strands arebroken down into a form that rearranges more easily, but its chemicalcomposition is, in many respects, closely similar to that of its parentcollagen.Gelatin forms a solution of high viscosity in water, which sets to a gel oncooling, and melts to a liquid when heated.Applications of Gelatin Pharmaceuticals Capsules as drug delivery systems Gelatin patch for wound dressings Blood plasma expander: a life saving drug to compensateexcess blood loss Food Jelly mix Yoghurt and ice-cream Confectionaries Photographic In silver halide emulsions Coating for photographic film and printing paper Cosmetic A component of shampoos, lotions, and ointments14药用胶囊厂用皮革废料所生产明胶作原料(组图) 2012年04月15日13:53 央视每周质量报告江西公布人造猪耳检测结果 成分为明胶和油酸钠 2012年05月15日10:42 央视网Polysaccharides Also known as glycans consist of simple sugars(monosaccharides, e.g. glucose) linked togetherby glycosidic bonds Can be homo-polysaccharides (one type ofmonomer) or hetero-polysaccharides (more thanone type of monomer Functions Structure (cellulose, chitin) Storage (starch, glycogen) Extracellular space (glycoaminoglycans)15Disaccharides: formed when two monosaccharides are joinedtogether by a glycosidic bond . The reaction involves the formation ofa molecule of water (H2O) .Oligosaccharides: a few monosaccharides covalently linked.Polysaccharides: long chains of many monosaccharides joinedtogether by glycosidic bonds.Chitinl A polysaccharide found in the outer skeleton of insects, crabs,shrimps, and lobsters and in the internal structures of otherinvertebrates.l The second most abundant natural polysaccharide on theearth next to cellulose.l Chitin serves as a fibrous element in biological compositematerials. Thus, except in some Diatomea(硅藻类), it isalways associated with proteins which function as the matrix polyphenols (M.G. Peter, Chem. uns. Zeit, 27, 189 (1993) minerals: predominantly calcium carbonate (calcite) incrustacea.l A highly insoluble material and possesses a low chemicalreactivity.l Composed of (1-4) linked units of the amino sugar N-acetyl-glucosamine.16Chitin SourcesCrawfish/CrabsShrimpFungiComposition (Based upon Dry Weight)ChitinProteinCaCO3Lipids25-30%15%55%2-5%30-40%35%30%5-10%15-40%5-10%Glycans5-10%Chitosanl Chitosan, composed of -(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit), is usuallyobtained by a partial deacetylation of chitin .l The amino group in chitosan can be protonatedin acidic to neutral solution which makeschitosan soluble in weak acids (acetic acid).l Chitosan and its derivatives can be easilyfabricated into fibers, films, porous scaffolds,hydrogels, and micro- and nanospheres, whichare highly interesting for manufacturing manydifferent medical devices.17Chitincrustacean (e.g.,shrimp, crabs)Chitosan甲壳素、壳聚糖的提取和制备方法18(14) linked D-glucose units(14) linked N-acetylglucosamine units-(14)-linked D-glucosamine(deacetylated unit) andN-acetyl-D-glucosamine (acetylated unit)mDegree of acetylation (DA)l The molar fraction of N-acetylated units, astructural parameter influencing charge density,crystallinity and solubility, including thepropensity to enzymatic degradation, with higherDAs leading to faster biodegradation rates .l Degree of deacetylation (DD)l The DA of chitosan is usually 40%19Key properties of chitosan Biocompatibility Nonantigenicity Nontoxicity (its degradation products are knownnatural metabolites) The ability to improve wound healing or clot blood The ability to absorb liquids and to form protectivefilms and coatings, and Selective binding of acidic liquids, therebylowering serum cholesterol levels.Chemical Properties of ChitosanHOCH 2OHOONH-C-CH 3ONH 2OCH 2OHOHOCH 2OHONH 2Ox Cationic polyamine with low pKaHigh charge density at pHs below 6.5 Adheres to negatively charged surfaces Forms gels with polyanions Chelates transition metals Amenable to chemical modification, bothamino and hydroxyl groups can beselectively modified20HOApplications of Chitosan21Applications of ChitosanApplications of Chitosan22Glycosaminoglycans (GAG)- Structure of GAGs: linear copolymers; the repeat unit consisting ofdisaccharide: a hexosamine (glucosamine or galactosamine) and ofanother sugar (galactose, glucuronic acid, or iduronic acid)- In their native form, several GAG chains are covalently linked to acentral protein core and the protein-polysaccharide conjugates aretermed proteoglycans （蛋白多糖） .- a bottle brush configuration, typical MW 1000Daiduronic acidglucosaminegalactosaminegalactoseglucuronic acidProteoglycans:proteins with covalently attached GAGCallistemon23Hyaluronic acidChondroitin-4-sulfate:R1 = H; R2 = SO3H; R3 = H.HeparinChondroitin-6-sulfate:R1 = SO3H; R2, R3 = H.Dermatan sulfateKeratan sulfateHeparan sulfate24GAGLocalizationHyaluronatesynovial fluid, vitreous humor, ECMof loose connective tissueChondroitinsulfatecartilage, bone, heart valvesHeparinmast cells lining the arteries of thelungs, liver and skinHeparan sulfatebasement membranes,components of cell surfacesDermatansulfateskin, blood ve