麻省理工大学：《生物材料——组织交互作用》教学讲义（英文版）TISSUE ENGINEERING

Massachusetts Institute of Technology yE图 Harvard medical school Brigham and women's hospital VA Boston Healthcare System 2.79J3.96JBE,441/HST522J TISSUE ENGINEERING OVERVIEW I.V. Yannas, Ph D and m. spector, ph. D

Massachusetts In Massachusetts Institute of Technology stitute of Technology Harvard Medical School Harvard Medical School Brigham and Wo Brigham and Women’s Hospital men’s Hospital VA Boston Healthcare System VA Boston Healthcare System 2.79J/3.96J/BE.441/HST522J 2.79J/3.96J/BE.441/HST522J TISSUE ENGINEERING: TISSUE ENGINEERING: OVERVIEW OVERVIEW I.V. Yannas, Ph.D. and M. Spector, Ph.D. I.V. Yannas, Ph.D. and M. Spector, Ph.D

TISSUE ENGINEERING What is tissue engineering? Production of tissue in vitro by growing cells in porous, absorbable scaffolds(matrices). Why is tissue engineering necessary Most tissues cannot regenerate when injured or diseased. Even tissues that can regenerate spontaneously may not completely do so in large defects(eg, bone). Replacement of tissue with permanent implants is greatly limited

TISSUE ENGINEERING TISSUE ENGINEERING What is tissue engineering? What is tissue engineering? • Production of tissue Production of tissue in vitro in vitro by growing cells by growing cells in porous, absorbable scaffolds (matrices). in porous, absorbable scaffolds (matrices). Why is tissue engineering necessary? Why is tissue engineering necessary? • Most tissues cannot regenerate when Most tissues cannot regenerate when injured or diseased. injured or diseased. • Even tissues that can regenerate Even tissues that can regenerate spontaneously may not completely do so in spontaneously may not completely do so in large defects ( large defects (e.g., bone). ., bone). • Replacement of tissue with permanent Replacement of tissue with permanent implants is greatly limited. implants is greatly limited

TISSUE ENGINEERING Problems with tissue engineering Most tissues cannot yet be produced by tissue engineering (ie, in vitro). Implantation of tissues produced in vitro may not remodel in vivo and may not become integrated with(bonded to) host tissue in the body. Solution Use of implants to facilitate formation regeneration) of tissue in vivo. Regenerative medicine Scaffold-based regenerative medicine

TISSUE ENGINEERING TISSUE ENGINEERING Problems with Tissue Engineering Problems with Tissue Engineering • Most tissues cannot yet be produced by Most tissues cannot yet be produced by tissue engineering ( tissue engineering (i.e., in vitro in vitro). • Implantation of tissues produced Implantation of tissues produced in vitro in vitro may not remodel may not remodel in vivo in vivo and may not and may not become integrated with (bonded to) host become integrated with (bonded to) host tissue in the body. tissue in the body. Solution Solution • Use of implants to facilitate formation Use of implants to facilitate formation (regeneration) of tissue (regeneration) of tissue in vivo. in vivo. – “Regenerative Medicine” “Regenerative Medicine” – Scaffold Scaffold -based regenerative medicine based regenerative medicine

TISSUE ENGINEERINGREGEN MED Historical Perspective, Selected milestones 1980 Yannas: Collagen-GAG matrix for dermal regeneration(“ artificial skin”); Integra 1984 Wolter/Meyer: lst use of the term, TE; endothel like layer on PMma in the eye 1991 Cima/Vacanti/Langer: Chondrocytes in a PGa scaffold: the ear on the nude mouse 1993 Langer/Vacanti: Science paper on TE; cells in matrices for tissue formation in vitro: PgA 1994 Brittberg/Peterson: NEJM paper on human autologous chondrocyte implantation; Carticel

TISSUE ENGINEERING/REGEN. MED. TISSUE ENGINEERING/REGEN. MED. Historical Perspective; Selected Milestones Historical Perspective; Selected Milestones 1980 Yannas: Collagen : Collagen -GAG matrix for dermal GAG matrix for dermal regeneration (“artificial skin”); Integra regeneration (“artificial skin”); Integra 1984 Wolter/Meyer: 1st use of the term, TE; : 1st use of the term, TE; endothel endothel . - like layer on PMMA in the eye like layer on PMMA in the eye 1991 Cima/Vacanti/Langer /Vacanti/Langer: Chondrocytes in a PGA : Chondrocytes in a PGA scaffold; the ear on the nude mouse scaffold; the ear on the nude mouse 1993 Langer/Vacanti Langer/Vacanti: Science paper on TE; cells in : Science paper on TE; cells in matrices for tissue formation matrices for tissue formation in vitro; in vitro; PGA 1994 Brittberg/Peterson Brittberg/Peterson: NEJM paper on human : NEJM paper on human autologous chondrocyte implantation; Carticel autologous chondrocyte implantation; Carticel

Arthroscopic Microfracture” Debridement Image removed due considerations Image removed due to copyright considerations Osteochondral Autograft Current clinical Practice Image removed due Image removed due to copyright considerations considerations Total Knee Replacement Autologous chondrocytes injected under a periosteal flap (act)

Arthroscopic Debridement “Microfracture” Osteochondral Autograft Autologous chondrocytes injected under a periosteal flap (ACT) Total Knee Replacement Current Clinical Practice Image removed due Image removed due to copyright to copyright considerations considerations Image removed due Image removed due to copyright to copyright considerations considerations Image removed due Image removed due to copyright to copyright considerations considerations Image removed due Image removed due to copyright to copyright considerations considerations

Future Clinical Practice Implementing Tissue Engineering Implantation of a cell-seeded matrix Image removed due copyrig considerations “ Tissue engineered” cartilage implanted in a rabbit model did not remodel(Advanced Tissue Sciences, Inc )

Future Clinical Practice Implementing Tissue Engineering Implantation of a cell-seeded matrix Image removed due Image removed due to copyright to copyright considerations considerations “Tissue engineered” cartilage implanted in a rabbit model did not remodel (Advanced Tissue Sciences, Inc.)

Future Clinical Practice Implementing Tissue Engineering Implantation of the matrix alone Image removed due to Image removed due copyright considerations to copyright considerations “ Microfracture” Stem cells from bone marrow 500um infiltrate the defect

Future Clinical Practice Implementing Tissue Engineering Implantation of the matrix alone “Microfracture”: Stem cells from bone marrow infiltrate the defect 500 µ m Image removed due to copyright considerations. Image removed due Image removed due to copyright to copyright considerations considerations

TISSUE ENGINEERING ENDPOINTS Morphological/ Histological/Biochemical Match the composition and architecture of the tissue. Problem: A complete analysis is difficult and no clear relationships yet with functional and clinical endpoint Functional Achieve certain functions; display certain properties (e.g, mechanical properties). Problem: Difficult to measure all properties; Which properties are the most important? Clinical Pain relief Problems: Can only be evaluated in human subjects and he mechanisms (including the placebo effect) and kinetics of pain relief(e.g, how long it will last) are unknown

TISSUE ENGINEERING ENDPOINTS TISSUE ENGINEERING ENDPOINTS • Morphological/Histological/Biochemical Morphological/Histological/Biochemical – Match the composition and architecture of the tissue. Match the composition and architecture of the tissue. – Problem: A complete analysis is difficult and no clear Problem: A complete analysis is difficult and no clear relationships yet with funct relationships yet with functional and clinical endpoints. ional and clinical endpoints. • Functional Functional – Achieve certain functions; display certain properties Achieve certain functions; display certain properties (e.g., mechanical properties). ., mechanical properties). – Problem: Difficult to measure all properties; Which Problem: Difficult to measure all properties; Which properties are the most important? properties are the most important? • Clinical Clinical – Pain relief. Pain relief. – Problems: Can only be evaluated in human subjects and Problems: Can only be evaluated in human subjects and the mechanisms (including the placebo effect) and kinetics the mechanisms (including the placebo effect) and kinetics of pain relief ( of pain relief (e.g., how long it will last) are unknown. ., how long it will last) are unknown

Which Tissues Can Regenerate? Yes No Connective Tissues Bone 旬 ° Articular Cartilage., Ligament Intervertebral Disc. others Epithelia(e.g, epidermis) Muscle Cardiac Skeletal Smooth Nerve 旬

Which Tissues Can Regenerate? Which Tissues Can Regenerate? Y e s N o C o n n e c t i v e T i s s u e s • B o n e  • A r t i c u l a r C a r t i l a g e, L i g a m e n t, I n t e r v e r t e b r a l D i s c, O t h e r s  E p i t h e l i a ( e.g., e p i d e r m i s )  M u s c l e • C a r d i a c, S k e l e t a l  • S m o o t h  N e r v e 

FACTORS THAT CAN PREVENT REGENERATION Size of defect e, g bone does not regenerate in large defects Collapse of surrounding tissue into the defect e g, periodontal defects Excessive strains in the reparative tissue e.g unstable le fractures

FACTORS THAT CAN PREVENT FACTORS THAT CAN PREVENT REGENERATION REGENERATION • Size of defect Size of defect – e.g., bone does not regenerate in large defects ., bone does not regenerate in large defects • Collapse of surrounding tissue into the Collapse of surrounding tissue into the defect – e.g., periodontal defects ., periodontal defects • Excessive strains in the reparative tissue Excessive strains in the reparative tissue – e.g., unstable fractures ., unstable fractures