saving材料导论材导module8-2015-201648h-bw-print

1、Zhao Jing, College of Materials Science and Technology, BUCTModule 8BiomaterialsTable of ContentsToday8.1 Introduction to Biomaterials8.1.1 Definitions8.1.2 Classification of Biomaterials8.1.3 Fundamental Requirements of Biomaterials8.4 Polymeric Biomaterials8.4.1 Naturally Occurring Polymers8.4.3 S

2、ynthetic Biodegradable PolymersJing Zhao8.1.1 Definition of Biomaterialsn Any substance (other than a drug) or combination of substances synthetic or natural origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, o

3、r function of the body.n 除药物以外，用于治疗和置换人体的组织、器官或增进其功能的任何合成、天然或两者结合的物质。 Treats治疗Augments增强Tissue组织Organ器官 Replace置换 Function功能 Medical and pharmaceutical applications of biomaterials Implants (植入剂) and supporting materials bone plates骨板 joint replacements关节置换 ligaments韧带 vascular grafts人造血管 heart valv

4、es心脏瓣膜 intraocular lenses眼内透镜（人工晶状体 ） dental implants牙科植入物 Medical and pharmaceutical applications of biomaterials (continued)n Medical devices医疗装置 n Pacemaker起搏器 n Biosensors生物传感器 n Artificial hearts人工心脏 n Blood tubes血管 n Components of diagnostic assays诊断设备 Biomaterials for drug delivery and gene d

5、eliveryControlled drug delivery systems 药物控制释放体系 Rate control定速控释 Temporal control定时控释 Distribution control定位控释 9Controlled drug delivery systems 药物控制释放体系 Rate control定速控释Intravenous administration of drug loaded dendrimer Active targeting Nucleus Receptor internalization of conjugates Endosomal upt

6、ake Acidified endosomal drug release Tumor tissue Endosome recycling Distribution control 定位控释Temporal control定时控释Biomaterials for drug delivery and gene deliveryMedical and pharmaceutical applications of biomaterials (continued)n Tissue engineering scaffolds组织工程支架 组织工程(tissue engineering)n 上世纪80年代，

7、Langer和Vacanti提出再生医学新概念 n 背景：组织和器官的衰竭、损伤，最主要的临床医学问题；现有的治疗方法，如器官移植、外科修复、人 工取代物、医疗器械均存在问题。 n 定义：利用生命科学与工程学的原理和方法，研究和开发具有修复或改善人体组织或器官功能的新一代临床应用的取代物，用于替代组织或器官的一部分或全部分 功能。 n 将体外培养的组织细胞吸附扩增于一种生物相容性良好并可被人体逐步降解吸收的生物材料上，形成细胞- 生物材料复合物。该生物材料为细胞提供一个生存的三维空间被称为生物支架。 Robert S. LangerJoseph P. VacantiTissue enginee

8、ring组织工程scaffold支架Biomaterials Industry 生物材料工业 n The biomaterials industry is currently worth ca. $28 billion with an annual growth rate of 15% expected for the next few years and the market is expected to be worth $58.1 billion() by 2014.n As a population ages, there is a g

9、rowing need to replace and repair soft and hard tissues such as bones, cartilage, blood vessels or even entire organs.n Orthopedic implants make up the bulk of all devices implanted (approximately 1.5 million per annum worldwide) at a cost of around $10 billionn The expenditure on biomaterials and d

10、evices for the treatment of cardiac disease will double this amount.8.1.2 Classification of Biomaterials1.Based on the common characteristics of materialsn Metallic biomaterials金属类生物材料 n Ceramic biomaterials陶瓷类生物材料 n Polymeric biomaterials聚合物类生物材料 n Composite biomaterials复合材料类生物材料 8.1.2 Classificati

11、on of Biomaterials2.Based on the biological properties of materialsn Inert biomaterials 惰性生物材料 n Resorbable or bioactive biomaterials可吸收或生物活性生物材料 n Biomaterials with resorbable and bioactive properties in combination可吸收和生物活性生物材料 n Smart or biomimeticbiomaterialsinert惰性的 resorbable可吸收 bioactive生物活性 E

12、volution of biomaterialsB.M. Holzapfel et al. / Advanced Drug Delivery Reviews 65 (2013) 581603Four generations of biomaterials1. Off-the-shelf materials with a common feature of biological “inertness”.2. Exhibit clinically relevant controlled chemical breakdown and resorption in the physiological e

13、nvironment.3. Be designed to simulate specific cellular responses at molecular level.n Bioactive materials are being made resorbable, whereas resorbable polymers are being made bioactive.4. To capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue.8.1.3 Fun

14、damental Requirements of Biomaterialsn Be highly dependent on a particular applicationn Example 1: Poly (-hydroxy acids) used as carriers in controlled drug deliveryn sufficient amount of drug incorporated into the matrixn homogeneous distribution of drug throughout the matrixn sufficient binding af

15、finity between drug and matrixn provide a predetermined release kineticsn keep the structure and activity of drug intact at physical temperatures over a prolonged period of timePoly (-hydroxy Acids) 聚羟基酸酯Release Kinetics释放动力学Controlled drug delivery药物输送系统 Carrier载体材料 Matrix基体 8.1.3 Fundamental Requi

16、rements of Biomaterials (continued)n Be highly dependent on a particular applicationn Example 2: Poly (-hydroxy acids) used as tissue engineering scaffoldsn acceptable mechanical properties and biocompatibilityn good interface adhesion and biological responsen appropriate degradability atpredetermin

17、ed period of timebiocompatibility 生物相容性 degradability 降解性能 Biocompatibility生物相容性 n Williams definition of Biocompatibilityn the ability of a material to perform with an appropriate host response in a specific applicationn “appropriate host response” implies that the biomaterial displays good or harm

18、onious behavior in contact with tissue and body fluid.n Depending on whether a medical device is usedin contact with blood or tissue，biocompatibility is divided inton hemocompatibility ( 血液相容性)n tissue compatibility (组织相容性)General requirements of biomaterials for devices design and manufacturen Func

19、tional performance (or biofunctionality), biostability, biocompatibility, andsterilizability.n To accomplish the desired functional performance of biomaterials, a varietyof properties are consideredn chemical, physical and mechanical properties, degradability, stability, and processibilityn Manufact

20、urability, long-term storage,and appropriate engineering designbiofunctionality 生物功能性 sterilizability可灭菌性 Toxicological testing of biomaterials for eventual regulatory approvaln In Vitro testing of biomaterials体外试验 n In vitro: a Latin-based word means “(with) in the glass”n biomaterials are evaluate

21、d for biofunctionality and biocompatibility in a test tube or in a controlled artificial environment, i.e.: a controlled environment outside a living organism.n In Vivo testing of biomaterials体内试验 n In Vivo: a Latin word means “in life” or “(with) in the living”n the biofunctional and biocompatible

22、experimentation of biomaterials is done in or on the living tissue of a whole living organism.In Vitro 体 外 In Vivo 体 内 living organism 生 命 体 8.4 Polymeric biomaterialsPolymeric biomaterialsBiodegradable polymersNonbiodegradable polymerspossess labile functional groups accessible to biological or non

23、biological mechanisms of degradationNatural polymersBiopolymers or biological polymers 生物聚合物 Synthetic polymersNatural Polymers天然高分子材料n Biopolymers, biological polymers, naturallyoccurring polymersn The most commonly used biopolymersn Polysaccharides聚多糖 n Cellulose纤维素 n Starch淀粉 n Chitin & chitosan甲

24、壳素和壳聚糖 n Alginates海藻酸盐 n Hyaluronic acids透明质酸 n Pectin果胶 n Protein蛋白质 n Collagen胶原 Cellulose纤维素 1. The primary structure component of plant cell walls, accounts for over one-half of carbon in the biosphere.2. Cellulose is by far the most abundant organic substance in nature.b (1-4) glycoside bondsLi

25、near homopolysacchrideb-1,4-糖苷键联结线性均多糖 D-glucose residuesb-D-葡萄糖残基 Cellulose is unexpected water insoluble, modified to form cellulose derivativesImportant cellulose derivatives as biomaterialsn Hydroxypropyl cellulose (HPC): gel-forming drug carriern microcrystalline cellulose (MCC)n Methylcellulos

26、e, tear substitute for dry eyesn Sodium carboxymethylcellulose (NaCMC) in conjunction withn Gelatin，(IPN) microspheresn hydroxypropylmethylcellulose (HPMC)，polymeric carriers to improve controlled release performances of matrix tabletsn anionic polymers (NaCMC, PAA, sodium hyaluronate)， sustained de

27、livery systems of cationic therapeuticagentsHPC羟丙基纤维素 MCC微晶纤维素 NaCMC羧甲基纤维素 HPMC 羟丙甲纤维素 microspheres 微球 sustained delivery systems 缓释系统 Starch淀粉a (1-4) glucosidic linkagesa-1,4-糖苷键联结 直链淀粉 amylosea (1-6)glucosidic linkagesa -1,6-糖苷键联结 支链淀粉 amylopectinb-1,4- glucosidic linChitin & Chitosan甲壳素 & 壳聚糖 kag

28、es2-amino-2-deoxy-D-glucopyranose 2-氨基-2-脱氧-D吡喃葡萄糖单元 2-acetamido-2-deoxy-D-glucopyranose2-乙酰氨基-2-脱氧-D吡喃葡萄糖单元 They are found naturally in the shell of crustaceans krQs5teiFjEn 甲壳 动 物 such as crabs and shrimps, insect exoskeletons 7eksEu5skelitEn 外骨骼, fungal cell walls, micro fauna动物区系 and plankton浮游生

29、物.Degree of Deacetylation (DD)脱乙酰度 n Representing the proportion of deacetylated unitsn Be used to differentiate between chitin and chitosann Chitin: DD 55%, dissolves readily in dilute organic acids solutions and inorganic acids except phosphoric and sulfuric acids, metabolised by certain human enz

30、ymes, especially lysozymen Converting chitin into chitosan causes a reduction in the molecular weight and a considerable increase in the degree of deacetylation diE7siti5leiFEn脱乙酰作用.Chitinase甲壳素酶enzymes酶lysozyme 溶菌酶 phosphoric acids磷酸 sulfuric acids硫酸 Properties of chitin, chitosan & derivativesn Fi

31、lm- or gel-forming ability成膜性 n Biocompatibility生物相容性 n Biodegradability生物可降解性 n Non-toxicity无毒性 n Adsorption properties吸附性能 n Antimicrobial and antifungical activities抗微生物性、抗真菌性 n Mucoadhesive properties粘膜粘附性 n Transdermal absorption promoting characteristics透皮吸收促进性 Medical and pharmaceutical appli

32、cations of chitin, chitosan & derivativesPeppas, 1986 & Rinaudo, 2006n Hydrogels水凝胶: which is defined as macromolecular networks swollen in water or biological fluidsn topical ocular application, contact lensesn Implantation植入 n controlled drug delivery, nano- and microparticlesn wound-dressing创伤辅料

33、n self-hardening injectable composite for bone repair or filling用于骨修复或填充的自固化型可注射复合材料 n tissue engineeringn penetration enhancers渗透促进剂 n mucosal drug delivery粘膜药物释放 n especially for nasal and oral delivery of hydrophilic macromolecules亲水性大分子药物的经鼻和口服给药 Alginate 海藻酸盐 Alginate exists in brown algae (sea

34、weed海藻 and kelp巨藻) Linear heteropolysaccharide线性杂多糖 1, 4-glycosidic linkageb-D-mannuronic acid (M)bD甘露糖醛酸残基 a-L-guluronic acid (G)aL古罗糖醛酸残基 Structure of alginate and alginic acidM-blockG-blockthe block of alternating M and G unitsStructure of calcium alginate gel“egg-box model”calcium ionStrength of

35、 a high-G and high-M alginate gels prepared at constant calcium concentration versus the alginate amount in a gelling formulationguluronic acid unitn polyguluronic blocks is mostsuitable for complexation络合with calcium ionsBiomedical & pharmaceutical applicationsn Alginate gel can be prepared by the

36、simple andlow- cost encapsulation processes under mild conditionsn Encapsulation of proteins, enzymes, living cells, growth factors, and other active ingredients suchas drugs and pesticides.n Controlled-release drug carriers药物控释载体材料 n Tissue engineering scaffolds组织工程支架 n Wound dressings创伤辅料 Encapsul

37、ation囊化pesticides农药 Hyaluronic 7haiElju5rCnik acid (HA)透明质酸 A glycosaminoglycan laIkEJsEmi:nEJlaIkAn 粘多糖 component of synovial sInEJvIEl, saI- fluid 滑 液 and the extracellular matrix (ECM), and is present in large amounts in the vitreous humor (眼睛的)玻璃状液 of the eye, the synovial fluid of the joints, a

38、nd in soft tissues such as umbilical cord mblkl k:d脐带 and rooster comb鸡冠.Hyaluronic acid (HA)透明质酸 Linear heteropolysaccharide线性杂多糖(b-1,3)-N-acetyl- D-glucosamineb1,3 N-乙酰基-D葡萄糖胺 b-1,4-linked D-glucuronic acid 1,4D葡萄糖醛酸 Properties and applications of HAn extraordinary water-retaining capability 保 水 性

39、 , viscoelasticity, biodegradability, biocompatibility, and lack of immunogenicity无免疫性，biological functionsn Applicationsn Crosslinked HA hydrogelsn drug deliveryn tissue engineeringn viscosupplementation粘液补充 n viscosurgery粘弹手术 n wound healing伤口愈合 n arthritis treatment关节炎治疗 n ophthalmic surgery眼科手术

40、Collagen 胶原 A major protein of connective tissues in animals, which accounts for approx. 1/3 of the total protein in mammals螺旋上升一圈有 3个氨基酸残基 aamino acida氨基酸 Gly, Glycine甘氨酸 Gly-X-Yn the smallest amino acidX，proline 脯氨酸 peptide linkage 肽键 Applications of collagenn tissue engineeringn skin replacement,

41、 bone substitutes, and artificial blood vessels and valvesn carriers in drug delivery systemsn mini-pellets and tablets for protein delivery, gel formulation in combination with liposomes 脂 for sustained drug delivery, controlled-release carriers for transdermal delivery透皮给药, and nanoparticles for g

42、ene delivery基因释放 and basic matrices for cell culture systems.n bioresorbable materials in medicinen resorbable surgical sutures 5sju:tFE可吸收手术缝线 n resorbable hemostatic agents可吸收止血剂 n wound-dressing agents 创伤辅料 Advantages of Biopolymers Excellent properties Biodegradability Biocompatibility with tiss

43、ue and blood Non-toxicity Biological activity Availability Low costDisadvantages of Biopolymers Structural complexity Significant batch-to-batch variations of the polymersWhich cause difficulties in purification and modification of biopolymersBiodegradable Polymers Biodegradable polymers normally po

44、ssess labile functional groups accessible to biological (i.e. living microorganisms and their enzymes) or non-biological mechanisms of degradation (i.e. hydrolysis, oxidation, reduction, and photodegradation).Why Synthetic Biodegradable Polymers? Biodegradable polymeric biomaterials will gradually d

45、egrade into water soluble oligomers and monomers that eliminate from a human body after fulfilling their intended use. Their mechanical and physical properties can readily be adjusted by varying the preparation techniques and molecular structure.Oligomers: A polymer that consists of two, three, or f

46、our monomers.A polymer has relatively low molecular weight8.4.3 Synthetic Biodegradable Polymers “Degradation” specifically refers to bond cleavagen a chemical processn Biodegradation is the destruction and assimilation消化of organic polymers by living organisms and their enzymes, particularly fungi a

47、nd bacteria. “Erosion” refers to depletion of material.n a physical phenomenon depending on dissolution and diffusion processes.n Surface eroding polymers undergo erosion at constant velocity at any time during erosion.n Bulk eroding polymers have no constant erosion velocity.srsSA, sebacic acid 癸二

48、酸 degrade within days frPoly(fatty acid dimer-sebacic acids) synthesized om hydrophobic dimers of erucic acid芥(子)酸and sebacic acid癸二酸 Schematic illustration of the changes a polymermatrix undergoes during surface erosion and bulk erosion表面溶蚀本体溶蚀 the rate of bond cleavage the rate of water penetratio

49、nthe rate of bond cleavage the rate of water penetrationBurkersroda, et al., 2002Widely used synthetic biodegradable polymern aliphatic/aromatic polyesters脂肪族/芳香族聚酯 n poly(ortho esters)聚原酸酯 n poly(anhydrides)聚酸酐 n poly(amides)聚氨基酸 n phosphorus-containing polyme含磷聚合物 n Polyphosphazene聚磷腈 n poly(phosp

50、hoester)聚磷酯 聚赖氨酸PLAL聚乳酸-赖氨酸聚磷腈聚磷酯Surface eroding polymers Poly(anhydrides)聚酸酐 Poly(anhydride-imides) poly(anhydride-esters) Poly(ortho esters)聚原酸酯 Constant erosion ratesSurface eroding polymers-Poly(anhydrides)Robert Langer， professor of chemical and biomedical engineering at MIT, discovered polyanh

51、ydrides as a new family of polymershundreds of polyanhydrides structures developedTypes of polyanhydridesSurface eroding polymers-Poly(anhydrides) highly labile groups that ensure rapid hydrolysis of polymer chains encountering water molecules Water permeation is retarded by hydrophobic monomer unit

52、s hydrophobic excipients excellent in vivo biocompatibilityX= 3(propane) (CPP, p-(carboxyphenoxy) propane) 6(hexane) (CPH, p-(carboxyphenoxy) hexane)degrade over several yearsPoly(anhydrides)-continuedModification of Poly(anhydrides)1. Poly(anhydride-imides) To increase the mechanical properties (e.

53、g., Youngs modulus and compressive strength) of the poly(anhydrides). Amino acid-containing units can then be copolymerized with activated monomers such as SA and/or CPH Undergo predominantly surface erosion similar to the poly(anhydrides)2eq.H2N-R-COOHR=CH2(glycine甘氨酸), CH(CH3)(alanine丙胺酸)supplemen

54、taryPoly(anhydrides)-continuedModification of Poly(anhydrides)2. poly(anhydride-esters) Two different types of hydrolytically cleavable bonds in the polymer backbone. low molecular weight carboxylic acid-terminated prepolymers of poly(e-caprolactone) were coupled via anhydride linkages. carboxylic a

55、cid-terminated monomers that contain ester bonds are activated and then polymerized using the same chemistry described for the poly(anhydrides)H2OPoly(anhydride-esters) that degrade into salicylic acid, an antiinflammatory agentSurface eroding polymers-Poly(ortho esters) inhibited drug release by diffusion mechanisms and allowed drug release only after the hydrolysis of polymer chains at the s