cardiovascular tissue engineering devin nelson july 2010 department of bioengineering, university of...
TRANSCRIPT
![Page 1: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/1.jpg)
Cardiovascular Tissue Cardiovascular Tissue EngineeringEngineering
Devin NelsonDevin NelsonJuly 2010July 2010
Department of Bioengineering, University of PittsburghDepartment of Bioengineering, University of PittsburghMcGowan Institute for Regenerative MedicineMcGowan Institute for Regenerative Medicine
![Page 2: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/2.jpg)
OverviewOverview
Tissue EngineeringBiomaterialsCellsTissue Engineered Heart ValvesTissue Engineered Blood VesselsTissue Engineered MyocardiumDiscussion
![Page 3: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/3.jpg)
Tissue EngineeringTissue Engineering In recent years, the field of tissue engineering (TE) has
emerged as an alternative to conventional methods for tissue repair and regeneration
Health care costs in the U.S. for patients suffering from tissue loss and/or subsequent organ failure are $100,000,000,000’s of dollars a year
TE has grown to encompass many scientific disciplines Bioengineers Clinicians Pathologists Material Scientists Molecular Biologists Mechanical Engineers etc
![Page 4: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/4.jpg)
SignalsScaffolds
Tissue Engineered Construct
CellsAutogeneicAllogeneic
XenogeneicPrimary
Stem
NaturalSynthetic
Growth FactorsCytokines
Mechanical StimulationDifferentiation Factors
From An Introduction to Biomaterials. Ch 24. Fig. 1. Ramaswami, P and Wagner, WR. 2005.
![Page 5: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/5.jpg)
What do these have in common?What do these have in common?All BiomaterialsAll Biomaterials
![Page 6: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/6.jpg)
BiomaterialsBiomaterials Synthetic biomaterials
Engineer can control the properties such as mechanical strength, biological activity, degradation rates etc
Natural biomaterials Built-in structure, environment and cues similar to native
body (extracellular matrix ECM, collagen, etc) Deliver drugs, cytokines, growth factors, and other
signals for cell differentiation, growth, and organization
Design criteria: proper mechanical and physical properties adequate degradation rate without the production of toxic
degradation products suitable cell adhesion integration into surrounding tissue without extensive
inflammatory response or support of infection proper mass transfer
![Page 7: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/7.jpg)
CellsCells There has recently been much excitement
surrounding the use of stem cells for tissue repair and regeneration
In vitro differentiation of stem cells via humoral factors and direct in vivo utilization of these cells have been proposed as a method for tissue regeneration
The use of a biomaterial to guide stem cell commitment provides cells a scaffold on which to grow and permits cell differentiation in vivo while minimizing in vitro manipulation
The ideal cell source for various TE applications is still elusive
![Page 8: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/8.jpg)
3-Dimensional Environment3-Dimensional Environment The context in which a cell is grown is critical to its The context in which a cell is grown is critical to its
development and subsequent functiondevelopment and subsequent function
Cells cultured Cells cultured ex vivoex vivo on TCPS are in a 2-D on TCPS are in a 2-D environment which is far-removed from the 3-D environment which is far-removed from the 3-D tissue from which the cells originated as well as the tissue from which the cells originated as well as the 3-D tissue into which the cells will be implanted 3-D tissue into which the cells will be implanted
Culture of cells in a 3-D vs. 2-D environment AND Culture of cells in a 3-D vs. 2-D environment AND WITH APPROPRIATE MECHANICAL STIMULATION WITH APPROPRIATE MECHANICAL STIMULATION has been shown to alter cell behavior, gene has been shown to alter cell behavior, gene expression, proliferation, and differentiationexpression, proliferation, and differentiation Especially for cardiovascular applicationsEspecially for cardiovascular applications
![Page 9: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/9.jpg)
Tissue Engineered Heart Valves Tissue Engineered Heart Valves (TEHV)(TEHV)
An estimated 87,000 heart valve replacements were performed in 2000 in the United States alone
Approximately 275,000 procedures are performed worldwide each year
Heart valve disease occurs when one or more of the four heart valves cease to adequately perform their function, thereby failing to maintain unidirectional blood flow through the heart
Surgical procedures or total valve replacement are necessary
Adapted from http://z.about.com/d/p/440/e/f/19011.jpg
![Page 10: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/10.jpg)
TEHV ReplacementsTEHV ReplacementsMechanical prostheses
Bioprostheses
Homografts
Each of these valve replacements has limitations for clinical use
Can you think of any limitations?
InfectionThromboembolismTissue deteriorationCannot remodel, repair, or grow
From http://www.rjmatthewsmd.com/Definitions/img/107figure.jpg
![Page 11: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/11.jpg)
Requirements for a TEHVRequirements for a TEHV
BiocompatibleShould not elicit immune or inflammatory response
FunctionalAdequate mechanical and hemodynamic function,
mature ECM, durability to open and close > 31 million times a year
LivingGrowth and remodeling capabilities of the construct should mimic the native heart valve structure
![Page 12: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/12.jpg)
What’s being done?What’s being done?
Cells Vascular cells Valvular cells Stem cells (MSCs)
Scaffolds• Synthetic (PLA, PGA)• Natural (collagen, HA, fibrin)• Decellularized biological matrices
Mechanical Stimulation• Pulsatile Flow Systems• Cyclic flexure bioreactors
From An Introduction to Biomaterials. Ch 24. Fig.3 Ramaswami, P and Wagner, WR. 2005.
![Page 13: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/13.jpg)
R.T. Tranquillo Biomaterials 30 (2009) 4078–4084.
![Page 14: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/14.jpg)
Tissue Engineered Blood Tissue Engineered Blood Vessels (TEBV)Vessels (TEBV)
From An Introduction to Biomaterials. Ch 24. Fig.4 Ramaswami, P and Wagner, WR. 2005.
Atherosclerosis, in the form of coronary artery disease results in over 515,000 coronary artery bypass graft procedures a year in the United States alone
Many patients do not have suitable vessels due to age, disease, or previous use
Synthetic coronary bypass vessels have not performed adequately to be employed to any significant degree
![Page 15: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/15.jpg)
TEBV ReplacementsTEBV Replacements
Synthetic GraftsSynthetic GraftsWork well in large-Work well in large-
diameter replacements (6-diameter replacements (6-10 mm)10 mm)
Fail in small-diameter Fail in small-diameter replacements (3-5 mm)replacements (3-5 mm)
WHY???WHY???Intimal hyperplasiaIntimal hyperplasiaThrombosisThrombosis
![Page 16: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/16.jpg)
Requirements for a TEBVRequirements for a TEBV
BiocompatibleBiocompatibleShould not elicit immune/inflammatory responseShould not elicit immune/inflammatory response
FunctionalFunctionalAdequate mechanical (burst pressure) and hemodynamic function, mature ECM, durability, nervous system response
LivingLivingGrowth and remodeling capabilities of the construct should
mimic the native blood vessel structure
LOOK FAMILIAR???LOOK FAMILIAR???
![Page 17: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/17.jpg)
What’s being done?What’s being done?Cells Endothelial cells Smooth muscle cells Fibroblasts &
myofibroblasts Genetically modified cells Stem cells (MSCs & ESCs)
Scaffolds• Synthetic (PET, ePTFE, PGA, PLA, PU)
• Natural (collagen)
• Decellularized biological matrices
Mechanical Stimulation• Pulsatile Flow Systems
• Cyclic & longitudinal strain
Signalling Factors• Growth Factors (bFGF, PDGF, VEGF)
•Cytokines
![Page 18: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/18.jpg)
Cell-Seeded CollagenCell-Seeded Collagen
Cells can remodel and reorganize in collagenCells can remodel and reorganize in collagen Collagen may be weak but is strengthened through Collagen may be weak but is strengthened through
various techniques (magnetic pre-alignment, glycation, various techniques (magnetic pre-alignment, glycation, mechanical training)mechanical training)
![Page 19: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/19.jpg)
Mechanical TrainingMechanical Training
Seliktar et al. Ann Biomed Eng 2000
![Page 20: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/20.jpg)
Self-Assembled SheetsSelf-Assembled Sheets
Good 3D architectureGood 3D architecture Good mechanical strengthGood mechanical strength Disadvantages: need cell Disadvantages: need cell
source, requires > 2 months in source, requires > 2 months in vitro to makevitro to make
![Page 21: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/21.jpg)
Seeding and CultureSeeding and Culture
![Page 22: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/22.jpg)
ElectrospinningElectrospinning
Stankus et al. Biomaterials 2007
![Page 23: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/23.jpg)
Tissue Engineered MyocardiumTissue Engineered Myocardium
From www.aic.cuhk.edu.hk/web8/Hi%20res/Heart.jpg
Ischemic heart disease is one of the leading causes of morbidity and mortality in Western societies with 7,100,000 cases of myocardial infarction (MI) reported in 2002 in the United States alone
Within 6 years of MI, 22% of men and 46% of women develop CHF
MI and CHF will account for $29 billion of medical care costs this year in the US alone
Cardiac transplantation remains the best solution, but there is an inadequate supply of donor organs coupled with the need for life-long immunosuppression following transplantation
![Page 24: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/24.jpg)
Requirements for a Myocardial PatchRequirements for a Myocardial Patch
Biological, Functional, and Living (same as TEHV and TEBV)
High metabolic demands High cell density Complex cell architecture High vascularity Mechanical and Electrical
anisotropy
VERY DIFFICULT!!!VERY DIFFICULT!!!
![Page 25: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/25.jpg)
What’s being done?What’s being done?
Cells Cardiocytes Cardiac progenitor cells Skeletal muscle cells Smooth muscle cells Stem cells (MSCs &
ESCs)
Scaffolds• Synthetic (PET, ePTFE, PEUU)
• Natural (collagen, ECM proteins, alginate)
• Cell sheets
• Injectables
Mechanical Stimulation• Pulsatile Flow Systems• Rotational seeding• Cyclic mechanical strain
Signalling Factors• Growth Factors
•(Insulin-like, bFGF, PDGF, hGH)
• Cytokines
• Conditioned media
• Co-culture
![Page 26: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/26.jpg)
Cardiac PatchCardiac Patch
![Page 27: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/27.jpg)
Cell Sheet EngineeringCell Sheet Engineering
![Page 28: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/28.jpg)
Artificial Muscle – Be CreativeArtificial Muscle – Be Creative
NATIVE
TISSUE ENGINEERED
![Page 29: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/29.jpg)
Extracellular MatrixExtracellular Matrix
![Page 30: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/30.jpg)
Injectable MaterialInjectable Material
![Page 31: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/31.jpg)
![Page 32: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/32.jpg)
In Conclusion…In Conclusion…
We have a lot of work to doWe have a lot of work to do
Taking these tissue engineered Taking these tissue engineered constructs from benchtop to bedsideconstructs from benchtop to bedside
Better understanding the human body Better understanding the human body and how to manipulate cellsand how to manipulate cells
![Page 33: Cardiovascular Tissue Engineering Devin Nelson July 2010 Department of Bioengineering, University of Pittsburgh McGowan Institute for Regenerative Medicine](https://reader031.vdocuments.mx/reader031/viewer/2022032723/56649cf95503460f949cb397/html5/thumbnails/33.jpg)