[基础医学]第6章 组织工程人工器官与组织再生.doc

第6章 医用高分子材料的应用：-人工器官与组织再生Artificial Organ & Tissue Regeneration内容l 人工器官概述- 器官移植与人工器官，人工器官的分类l 范例：人工血管 & 人工心脏瓣膜- 心血管结构，人工血管及其应用、要求、材料，人工心脏瓣膜l 组织再生：组织工程- TE原理，TE三要素，支架，细胞/干细胞21Review: tissue & organl Tissue is a biological structure made up of cellsof the same type. Cells of the same phenotype ( i.e., same genesexpressed). An aggregation of morphologically similar cellsand associated extracellular matrix actingtogether to perform one or more specificfunctions in the body. There are four basic types of tissue: muscle,nerve, epithelia, and connective.l An organ is a structure made up of 2 or more tissuesthat can together perform a more complex functionthan a single tissue.3器官和组织的缺失或衰竭是人类保健中发生最频繁、最具危害性的问题之一pancreatic carcinoma42Solutions ?l Transplantation is the act of transferring anorgan, tissue, or cell from one place to another.l The field of organ transplantation has maderemarkable progress in the past many years.Transplantation has evolved to become thetreatment of choice for end-stage organ failureresulting from almost any of a wide variety ofcauses.l Transplantation of the kidney, liver, pancreas,intestine, heart, and lungs has now becomecommonplace in all parts of the world.5Transplantation Types· Broadly speaking, transplants are dividedinto three categories based on thesimilarity between the donor and therecipient: Autotransplants (自体移植) Allotransplants (同种移植) Xenotransplants (异种移植)63l Autotransplants involve the transfer of tissue ororgans from one part of an individual to another partof the same individual. They are the most commontype of transplants and include skin grafts and veingrafts for bypasses. NO immunosuppression isrequired.l Allotransplants involve transfer from one individualto a different individual of the same species themost common scenario for most solid organtransplants performed today. Immunosuppression isrequired for allograft recipients to prevent rejection.l Xenotransplants involve transfer across speciesbarriers. Currently, xenotransplants are largelyrelegated to the laboratory, given the complex,potent immunologic barriers to success.7供体缺乏是器官移植治疗面临的最主要问题据卫生部的统计数据，我国每年等待器官移植的患者超过150万人，但其中只有1万人能够幸运地得到供体，供需比1:150，超过99%的患者只能在等待中逐渐绝望和死去84Any other approaches ?人工器官。是医用高分子材料的主要发展方向9l Artificial Organs:用人工材料制成，能部份或全部代替人体自然器官功能的装置105Artificial Pancreas· For people with type 1 diabetes· Consists of: A continuous glucose monitor (CGM) Insulin Pump (programmed by acomputer algorithm)· Algorithm calculates the insulindosage required from the bloodglucose reading· Tells the pump to deliver the neededamount of insulin11Artificial Organsl An artificial organ is a man-made device that is implanted orintegrated into a human to replace a natural organ, for thepurpose of restoring a specific function or a group of relatedfunctions so the patient may return to as normal a life aspossible . The replaced function doesn't necessarily have tobe related to life support, but often is.l Reasons to construct and install an artificial organ mightinclude: Life support to prevent imminent death while awaiting atransplant (e.g. artificial heart) Dramatic improvement of the patient's ability for self care(e.g. artificial limb) Improvement of the patient's ability to interact socially (e.g.cochlear implant) Cosmetic restoration after cancer surgery or accident12http:/en.wikipedia.org/wiki/Artificial_organ6l 当人体器官病损而用常规方法不能医治时，有可能给病人使用一个人工制造的器官来取代或部分取代病损的自然器官，补偿或修复或辅助其功能。人工器官是暂时或永久性地代替身体某些器官主要功能的人工装置。l 人工器官是生物医学工程专业中一门新的学科。它主要研究模拟人体器官的结构和功能，用人工材料和电子技术制成部分或全部替代人体自然器官功能的机械装置和电子装置。1320世纪80年代以来，人工器官的研究和应用迅速发展，可以说，人体除大脑尚无人工大脑替代外，几乎人体各个器官都在进行人工模拟研制中，其中有不少人工器官已成功地用于临床。人工器官的进步有赖于材料尤其是高分子材料的进展。在人工器官制造中，有机高分子材料占据了相当大的比例。据统计，世界上应用医用高分子有近百个品种，近两千种制品，大约消耗高分子材料的1015，并且每年以812的速度在增长。147加拿大科学家制成迄今为止最复杂人造大脑这种“大脑”能够处理视觉线索，并在纸上复制它们简图展示Spaun的处理信息的过程1530 Nov 2012, Vol. 338 no. 6111 pp. 1202-1205· 目前医用高分子材料制成的人工器官中，比较成功的有人工血管、人工食道、人工尿道、人工心脏瓣膜、人工关节、人工骨、整形材料等。· 巳取得重大研究成果，但还需不断完善的有人工肾、人工心脏、人工肺、人工胰脏、人工眼球、人造血液等。· 另有一些功能较为复杂的器官，如人工肝脏、人工胃、人工子宫等，则正处于大力研究开发之中。168人工器官按功能分为11类I.支持运动功能的人工器官，如人工关节、人工脊椎、人工骨、人工肌腱、人工假肢等。II. 血液循环功能的人工器官，如人工心脏及其辅助循环装置、人工心脏瓣膜、人工血管、人工血液等。III. 呼吸功能的人工器官，如人工肺（人工心肺机）、人工气管、人工喉等。IV. 血液净化功能的人工器官，如人工肾（血液透析机）、人工肺等。V. 消化功能的人工器官，如人工食管、人工胆管、人工肠等。VI. 排尿功能的人工器官，如人工膀胱、人工输尿管、人工尿道等。VII. 内分泌功能的人工器官，如人工胰。VIII. 生殖功能的人工器官，如人工子宫、人工输卵管、人工睾丸等。IX. 神经传导功能的人工器官，如心脏起搏器、膈起搏器等。X.感觉功能的人工器官，如人工视觉、人工听觉（人工耳蜗）、人工晶体、人工角膜、人工听骨、人工鼻等。XI. 其他类，人工硬脊膜、人工皮肤等。17l一些用于人工器官的重要医用高分子材料polysiloxane (PDMS)polyethylene (PE)polypropylene (PP)polyurethane (PU)polytetrafluoroethylene (PTFE)poly(vinyl chloride) (PVC)polyamide (PA)poly(methyl methacrylate) (PMMA)polyacetal (POM)polycarbonate (PC)poly(ethylene terephthalate) (PET)polyetheretherketone (PEEK)polysulfone (PSU)189The top 10 causes of death worldwideplaque formation in thecoronary arteryblood vessel blockagewithin the brain冠心病脑血管疾病Vascular diseases, both at the heart and in the arterial tree (periphery),are very common among most of the people, as they grow older.192010Myocardial InfarctionPlaque formation inside the blood vessel to disrupt the blood supply to LVto induce MIMyocardial infarction means that part of the heart muscle suddenly loses its blood supply.Without prompt treatment, this can lead to damage to the affected part of the heart 21心血管系统血液流动方向为：上下腔静脉右心房右心室肺动脉肺循环肺静脉左心房左心室主动脉体循环上下腔静脉2211l Blood vascularsystem Distributesnutritivematerials,oxygen, andhormones Removescellular wasteproducts ofmetabolism andcarbon dioxide 60,000 miles(http:/www.cardio.bvascular/vascular/)23图动脉内皮弹性组织平滑肌纤维组织小动脉毛细血管小静脉平滑肌含量：主动脉<大动脉<分置动脉静脉2412Arteries, Capillaries, and Veinsl Arteries Carry blood from the heartto the extremities Pulsating pressurel Capillaries Major location of biologicalinterchange Meshwork of fine tubulesl Veins Return blood fromextremities to heart Constant pressure25Pressure/Area Profile2613人工血管l 人工血管是以尼龙(Nylon)、涤纶（Dacron）、聚四氟乙稀（PTFE）等合成材料人工制造的血管代用品，适用于全身各处的血管转流术。当人体某部位的血管由于老化、动脉硬化、栓塞或破损等原因不能保证人体正常供血时, 需采用人工血管进行置换、搭桥或介入等外科手术进行治疗。l 目前大口径的人工血管已经广泛的被应用在临床上，但是小口径(<6mm)的人工血管因为畅通率不佳，在临床的应用上明显受到限制，因此许多研究着眼于改良人工血管的特性，包括人工血管的顺应性、材料与表面的改质等。l 世界范围内的市场达$200M27人工血管的应用l 动脉疾病：用替代或者架桥（血管旁路手术）的方式来恢复血液的通路从而来治疗胸主动脉、腹主动脉、骼动脉等血管段。动脉疾病，如动脉栓塞或者动脉瘤。l 静脉疾病：可以替代或者架桥（血管旁路手术）的方式治疗静脉疾病，如布加氏综合症(下腔静脉血液回流因之障碍)。l 动-静脉瘘：可以运用在慢性肾病的血液透析过程中，在四肢部分连接自身动脉和静脉，形成一条可反复穿刺的血液透析通路。架桥用人工血管血液透析2814传统的腹主动脉瘤手术示意图腹主动脉瘤是腹主动脉在病理因素作用下局部薄弱后发生扩张而向外膨出（不是“瘤”）。腹主动脉瘤的直径越大其瘤壁受到的压力也越大，一般上，直径大于5cm 的动脉瘤破裂的机率将大大增加，动脉瘤的破裂将导致患者因大量失血而死亡，因此主动脉瘤被称为是“患者体内的定时炸弹”。Endovascular Exclusion of Abdominal Aortic Aneurysm 腹主动脉瘤腔内隔绝术29覆膜支架The EndurantTM Abdominal Stent Graft is designed to treat abdominalaortic aneurysms using a minimally invasive procedure calledendovascular stent grafting. It is used to reinforce the weakened wall ofthe vessel to prevent the aneurysm from rupturing.3015冠状动脉支架l 动脉粥样硬化是动脉硬化的一种，大、中动脉内膜出现含胆固醇、类脂肪等的黄色物质，多由脂肪代谢紊乱、神经血管功能失调引起。常导致血栓形成、供血障碍等。l 心脏支架最早出现在20世纪80年代，经历了金属支架、镀膜支架、可溶性支架的研制历程，主要材料为不锈钢、镍钛合金或钴铬合金。31可降解血管支架l The worlds first drug-elutingbioabsorbable vascular scaffold hasbeen launched and will revolutionize thestent industry.l On Sept. 25, 2012, Abbottannounced the launch of its drug-elutingbioabsorbable stent, Absorb, in Europe,the Middle East and parts of AsiaPacific and Latin America. Absorb,which received CE mark certification in2011, is used to treat coronary arterydisease.l Bioabsorbable stents, such asAbsorb, will broaden treatment anddiagnostic options, reduce the need forlong-term anti-platelet therapy andreduce the risk of in-stent restenosisand thrombosis.Abbotts BVS can be completely metabolized and resorbed by the body3216心脏支架：高利润、高需求l 一个国产的心脏支架，出厂价不过3000元，到了医院便成了2.7万元；一个进口的心脏支架，到岸价不过6000元，到了医院便成了3.8万元。9倍的心脏支架暴利已经超过了贩毒。 在用于临床的进口的支架中，最便宜的要3万元左右，国产支架在1.5万元至1.8万元之间。l 中国是心脏介入手术的大市场，且增速惊人。2000年中国心脏介入手术的数量是两万例，到了2011年，这个数据激增至40.8万例，增长了20倍！有业内人士称，目前中国每台心脏介入手术平均使用约1.6个支架，依此推算，2011年中国介入支架使用量超过65万个l 支架的疯狂首先跟心血管病的爆发有关。截止2009年，中国心血管病人至少有2.3亿，高血压患者两亿，脑卒中患者700万，心肌梗死患者200万，心力衰竭患者420万，先心病患者200万，平均每10个成年人中就有两个人患心血管病。同时，该报告还预估中国每年心血管病死亡人数大约在300万人，平均每10秒就有1人死于心血管病。另一个原因是暴利。l 支架泛滥是中国医学界非常可悲的现象。2012年10月14日，心血管专家胡大一在第23届长城国际心脏病学会议上称心脏支架一半不靠谱，暴利达9倍。数据来源：互动百科Requirements for Vascular Grafts33·········Good structure retention (kink resistant).Appropriate compliance.Adequate burst strength.High fatigue resistance.Porous / Permeable.Biostable.Nonimmunogenic, noncarcinogenic.Low thrombogenecity.Good handling properties.3417人工血管的制造，国外的研究，近年来绝大多数是采取医用高分子材料进行编织。目前用机器编织的人工血管有两种：一种是平织(weaving)又称机织，另一种是针织（Knitting）又称线圈编织。平织是用经线和纬线进行编织,经线的纤维上下交互活动，而纬线纤维左右横行穿梭编织。针织通常使用纬编横机进行纬编编织也可用圆机编织(图二)，以细丝作线圈或连琐编织，前者称为纬编，后者称为经编。平织是因纤维上下交左右穿梭编织即经纬线编织，织物纤维紧密，具有丰富的伸展性，多孔性细致而小，但其断端容易松散，呈毛刷状，质地坚硬、缝合困难。针织是用纤维作线圈式编织，伸展性较差，多孔性大，质地柔软，其断端不易松散、缝合容易。此外，经编比纬编多一层（图三、图四），故纤维致密更不易松散。35Polymers for Vascular GraftsllllllVinyon è Polyvinyl chloride (PVC)Orlon è Polyacrylonitrile (PAN)Nylon è Polyamides (PA 6, PA 66)Dacron è Polyethylene terephthalate (PET)Teflon è Polytetrafluoroethylene (PTFE) è ePTFEPolyurethanes (PU)3618PTFE & ePTFE from the ordinary to the extraordinaryDiscovered by Dr. Roy Plunkett in 1938 while working at DuPont, polytetrafluoroethylene (PTFE) is anamazing polymeric material. Due to the molecular bonding within the polymer chains, PTFE withstands attackfrom the harshest chemicals concentrated acids and bases alike. It has a very wide temperature range andcan be used at temperatures constantly in excess of 250°C. It has a very low coefficient of friction, is notaffected by UV radiation, and is totally biocompatible.In 1969, Bill Gore discovered expanded polytetrafluoroethylene (ePTFE) which he introduced to the worldas GORE-TEX®.The microstructure of ePTFE is characterized by nodes that are interconnected byfibrils . There are no loose ends or particles to be shed or to contaminate a fluidstream. Because ePTFE membranes are extremely microporous and hydrophobic,37The predominant success of ePTFE as abiomaterial is owed to its microporous structureePTFE process flow(Fine powder)+Lubricating agentTheresultingthat allows bio-integration for fixation and long-term stability in vivoPhysical properties of ePTFE(Microporous PTFE)product is100% PTFE38From “Filtration and Purification in the Biopharmaceutical Industry”19they retain water droplets, while allowing water vapor to readily pass through.Sterilization issue39Poly(ethylene terephthalate)(PET, Dacron)· Two ester linkages on either side of an aromatic ring inthe backbone· The ester groups are susceptible to hydrolysis. However,local hydrophobic moieties and high crystallinity slow thisreaction considerably.· Strong dipole-dipole-type van der Waals-London forcesbetween adjacent carbonyl groups contribute to its high-strength characteristics· PET grafts (since 1970s) are produced frommultifilament yarn, which is woven or knitted into a fabrictube for medium and large arterial replacements4020From Mechanics of Biomaterials4142