Tissue Engineering: An Introduction

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Tissue Engineering An Introduction

• Robert M. Nerem

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Tissue Engineering

• Biological substitutes/therapies to repair,
  replace, or enhance tissue function
• An emerging biology-based industry that will
  produce the next generation of medical implants
• At the interface of the biological revolution and
  the traditional medical implant industry
• An industry where the engineering will be
  revolutionized by advances in biology

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Regenerative Medicine

• The replacement, repair, and/or regeneration of
  tissue/organs
• Tissue engineering term coined in 1987
• Regenerative medicine term began to be used in
  mid 1990s
• Many use these terms interchangeably

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Historical Perspective

• Prior to 1950 references to the concept of tissue
  engineering may be found in the literature
• In the 1970s and 1980s research on what we now
  call tissue engineering emerges
• In 1987 the term tissue engineering is coined
• In 1988 the first meeting called tissue
  engineering is held at Lake Tahoe
• In the 1990s research accelerates and an industry
  begins to emerge

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Ive thought a lot about this Charlie, and I
believe that when Historians look back at the
twentieth century the greatest scientific
achievement will not be space travel or
computers but will be in the fields of tissue
engineering and genetic medicine Dr Michael
Guillen, ABC Science Correspondent 29 September
1999
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Tissue Engineered Skin Substitutes

• Initial tissue engineering products have been for
  the most part skin substitutes
• Not just a covering, but a wound-healing agent
• Have not been as successful commercially as hoped
• Have provided insight, however, into what some of
  the critical issues are

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Tissue Engineered Products on the U.S. Market

• Carticel (Genzyme/1997)
• Transcyte (ATS/1997)
• Appligraf (Organogenesis/1997)
• Dermagraft (ATS/2001)
• Orcel (Ortec/2001)

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DERMAGRAFT on Traumatic Wounds
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Cartilage Repair

• Genzymes Carticel is on the market, works for
  focal defects
• Autologous cells are expanded and then implanted
• Next step is a chondrocyte-seeded scaffold
  substitute
• Everyone thought that after skin this would be a
  slamdunk it is not

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Issues for Cartilage Replacement

• Cell source and phenotype, scaffold
• Osteo-chondral integration
• Mechanical properties

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Critical Issues

• Addressing issues of cell sourcing
• Controlling cell function
• Developing interactive biomaterials
• Engineering 3D constructs/healing responses
• Scaling up manufacturing processes
• Preserving manufactured products
• Controlling in vivo biological responses
• Engineering immune acceptance
• Assessing post-implantation viability

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Georgia Tech / Emory Center for the Engineering
of Living Tissues (GTEC)

• NSF Engineering Research Center
• Established in 1998
• Built on the 1993 Whitaker Award
• 32 faculty principal investigators 16 from
  Georgia Tech, 12 from Emory, one from the
  University of Georgia, and three from Morehouse
  School of Medicine
• 19 industrial partners
• Focus on core, enabling technologies

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Industrial Educational Partners

• Aderans Research Institute, Inc.
• Allograft Solutions
• AtheroGenics
• Battelle Memorial Institute
• Boston Scientific Corporation
• BresaGen
• Cell Dynamics
• Cook Biotech
• Edwards Life Sciences
• EnduraTEC Systems

• Genzyme Corporation
• Guidant Corporation
• Johnson and Johnson
• Medtronic
• Organ Recovery Systems
• OrthoLogic Corporation
• Smith and Nephew
• St. Jude Medical
• Serologicals

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GTECs Matrix Strategy for the Enabling Core
Technologies
Integration into Living Systems
Clinical Application
Construct Technology
Cell Technology
Discovery
Blood Vessels Heart Valves Myocardial
Patches Diabetes Liver Failure Bone
and Cartilage Defects Neural Tissues Neural
Regeneration
Cardiovascular Substitutes
The tools made available by the
biological revolution
Metabolic, Secretory Organs
Orthopaedic Tissue Engineering
Neural Tissue Engineering
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Cell Technology

• Cell Source
• Autologous cells
• Allogeneic, xenogeneic cells
• Stem cells/progenitor cells
• Manipulation of cell function
• Extracellular environment
• Genetic engineering

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Stem Cell Technology Beyond the Science

• Cell expansion/bioreactor technology
• Process quality control
• Delivery systems/incorporation into constructs

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Construct Technology

• Construct engineering
• 3D architecture
• Functionality
• Manufacturing technology
• Process scaleup
• Product preservation

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Integrating Cells into Scaffolds

• A multi-cellular system is needed to mimic native
  tissue
• A three-dimensional architecture can be provided
  by a scaffold into/onto which cells are seeded
• The scaffold could be biological, made of a
  synthetic material, e.g. a polymer, or be a
  hybrid
• Cells in three dimensions are very different from
  cells in monolayer culture

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Biological Responses and Their Control

• Immune acceptance/rejection
• Remodeling
• Thrombotic responses

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The Transplantation Crisis

• A record 75,131 Americans await single- and
  multiple-organ transplants
• Of those on the waiting list, 15 die each day
• There is an ever increasing patient need, but not
  much of an increase in donor organs
• Tissue engineering has the potential to confront
  this crisis

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Transplantation Crisis
People on List Days to Wait

• Heart
• Liver
• Kidney
• Pancreas

4,121 12,070 38,270 725
206 517 1,099 179
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Transplantation Crisis Liver
1990 1,237 43
1998 12,070 512

• People on Waiting List
• Days to Wait

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Some Tissue Engineering Applications

• Blood Vessels
• Heart Valves
• Myocardial Patches
• Heart
• Bioartificial Pancreas
• Kidney
• Liver

• Severe Burns
• Skin ulcers
• Facial reconstruction
• Cartilage
• Tendons
• Ligaments
• Bone

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Cardiovascular Tissue Engineering

• Small Diameter Blood Vessels
• Heart Valves
• Myocardial Patches
• Basic Components of the Heart

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Cardiovascular Tissue Engineering

• Myocardial repair cell implantation in clinical
  trials
• Myocardial patches technology under development,
  at least five years away
• Small diameter blood vessel substitutes a number
  of different concepts being pursued, but clinical
  trials at least five years away and FDA approval
  10 years
• Heart valves may be the biggest challenge, more
  than a decade away

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Bioartificial Pancreas

• Sourcing of functional cells
• Materials
• Architecture for construct function and
  preservation
• Immune acceptance
• Monitoring for in vivo function

Cell technology
Construct technology
Technologies for integration into living systems
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Liver Tissue Engineering

• Liver is a very complex organ, has the ability to
  regenerate
• Extracorporeal systems under development
• An implantable bioartificial liver is decades away

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Functional Tissue Engineering

• What functional characteristics are essential?
• How do we engineer in functionality?
• How do we assess functional properties?
• What are the standards used to measure success?

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Tissue Engineering Industry 2001

• 66 Companies
• 3100 employees
• 580 million annual investment
• 16 annual growth rate

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Tissue Engineering Industry 2003

• 99 companies
• 3400 employees
• 675 million annual investment
• 14 annual growth rate

Source M.J. Lysaght (2002)
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Key Trends Since 2001

• 26 firms increased in size
• 21 firms decreased in size
• 4 have gone out of business
• 3 no longer have tissue engineered products
• 70 of new firms are in stem cells
• 40 of new firms located outside of the U.S.

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2003 Product Scorecard
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Tissue Engineering 2003

• Lack luster sales of approved products
• A high failure rate of mandated clinical trials
• A threadbare pipeline of products in clinical
  trials

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Bringing a Product to Market

• Even for a simple product a 150-250 million
  investment
• Compared to early expectations, it has been more
  complicated, more costly, and more time consuming
• This is a pharmaceutical size investment, with
  the return on investment of a device size

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A Challenge for Tissue Engineering
The introduction of a tissue-engineered product
into the clinical arena requires major changes in
treatment, in the financial management of the
treatment, and in the reimbursement process.
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Tissue Engineering Industry 2003

• A fledgling industry, combined sales in 2001 less
  than 50 million
• None of the current clinical trials suggest
  products that will be blockbusters
• Over 200 million has been invested in the
  bioartificial pancreas to date without a real
  product on the horizon
• Even so, tissue engineering has tremendous long
  term potential