Biomaterials as Scaffolds for Tissue Engineering

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Biomaterials as Scaffolds for Tissue Engineering

• Anat Perets

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Goal of Tissue Engineering

• Tissue Engineering Goal regenerate tissue
• Tring to replicate the in vivo function of the
  tissue/organ being replaced

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Why Tissue Engineering?

• One person added to wait list every 14 min
• One patient dies every 85 min waiting for
  transplant

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Why Tissue Engineering?

• Millions suffer tissue or organ loss from
  diseases and accidents every year
• Yearly cost of treatment exceeds 400 billion
• Major medical treatment is transplantation
• Shortages of replacement tissue and organs
• Development of alternative sources for
  transplantations by engineering tissue
• In vitro tissue models may allow better
  understanding of disease pathology to avoid organ
  failure

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Why Scaffolding shape?

• Cell grown in flat dish behave as individuals
• Cell grown in 3D structure behave as they would
  in tissue organs.
• Cells need external cues to grow into functional
  3D tissues

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Biomedical Applications of Tissue Engineering

• In vitro Growth of Tissues for Implantation
• Replacement of Diseased or Damaged Tissues
• Skin replacement for treatment of serious burns
• Extracorporeal Support
• External Devices Containing Tissue that Replace
  the Function of Internal Organ
• Artificial liver
• Human Disease Models
• Differentiated Tissues for Pathogen Propagation
• Models for HIV, Cyclospora
• Three-Dimensional Cancer Models
• Prostate, Colon

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Advantages of Tissue Engineering

• Scaffolds provide biomechanical support for the
  cells until they produce their ECM
• Scaffolds can incorporate signals (GFs),
  important for maintenance of tissue viability and
  for inducing scaffolds vascularization
• Control on tissue formation (shape and size)
  prior to transplantation

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What is a biomaterial?

• What are the design constraints?

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Biomaterial A biomaterial is a nonviable
material used in a medical device intended to
interact with biological systems (Williams 1987)
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Some Commonly Used Biomaterials

• Material
  Applications
• Silicone rubber
  Catheters, tubing
• Dacron
  Vascular grafts
• Cellulose
  Dialysis membranes
• Poly(methyl methacrylate) Intraocular
  lenses, bone cement
• Polyurethanes
  Catheters, pacemaker leads
• Hydogels
  Opthalmological devices, Drug Delivery
• Stainless steel
  Orthopedic devices, stents
• Titanium
  Orthopedic and dental devices
• Alumina
  Orthopedic and dental devices
• Hydroxyapatite
  Orthopedic and dental devices
• Collagen (reprocessed) Opthalmologic
  applications, wound dressings

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Skin/cartilage
Drug Delivery Devices
Ocular implants
Bone replacements
Orthopaedics screws/fixation
Heart valves
Synthetic BIOMATERIALS
Dental Implants
Dental Implants
Biosensors
Implantable Microelectrodes
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A Little History on Biomaterials

• Romans, Chinese, and Aztecs used gold in
  dentistry over 2000 years ago
• Turn of the century, synthetic plastics came into
  use
• Parachute cloth used for vascular prosthesis
• 1960- Polyethylene and stainless steel being used
  for hip implants

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First Generation Implants

• specified by physicians using common and borrowed
  materials
• most successes were accidental rather than by
  design

Examples First Generation Implants

• gold fillings, wooden teeth, PMMA dental
  prosthesis
• steel, gold, ivory, etc., bone plates
• glass eyes and other body parts
• dacron and parachute cloth vascular implants

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Intraocular Lens glass eyes and other body parts
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Vascular Grafts dacron and parachute cloth
vascular implants
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Second generation implants

• engineered implants using common and borrowed
  materials
• developed through collaborations of physicians
  and engineers
• built on first generation experiences
• used advances in materials science (from other
  fields)

Examples Second generation implants

• titanium alloy dental and orthopaedic implants
• cobalt-chromium-molybdinum orthopaedic implants
• UHMW polyethylene bearing surfaces for total
  joint replacements
• heart valves and pacemakers

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Artificial Hip Joints titanium alloy dental and
orthopaedic implants
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Treatments in cardiovascular diseasePTCA heart
valves and pacemakers
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Treatments of cardiovascular disease STENTS
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LVAS Pump Drive Unit

• Stored energy propels pusher plates of blood sac
• When solenoid is de-energized, pump passively
  refills
• Balanced, symmetrical drive system eliminates
  torque

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New Medical Devices
AbioCor Artificial Heart www.heartpioneers.com
InDuo Glucose Monitor Insulin
Pump www.lifescan.com
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Third generation implants

• bioengineered implants using bioengineered
  materials
• few examples on the market
• some modified and new polymeric devices
• many under development

Example - Third generation implants

• tissue engineered implants designed to regrow
  rather than replace tissues
• Integra LifeSciences artificial skin
• Genzyme cartilage cell procedure
• some resorbable bone repair cements
• genetically engineered biological components
  (Genetics Institute and Creative Biomolecules
  BMPs)

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Biomaterials for Tissue Replacements

• Bioresorbable vascular graft
• Biodegradable nerve guidance channel
• Skin Grafts
• Bone Replacements

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Substitute Heart Valves
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SEM displaying the cross section of a composite
disk, which had been seeded with cultured bone
marrow stromal cells.
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Cartilage Repaircell seedingwith PLA scaffolds
5 mm
Wyre et al. (2000)
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Synthetic polymer scaffolds ... in
the shape of a nose (left) is "seeded" with cells
called chondrocytes that replace the polymer with
cartilage over time (right) to make a suitable
implant.
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• Biomaterials Companies
• BioForma Research Consulting, Inc.,
  fibrinolytic systems, protein-material
  interactions
• Baxter International develops technologies
  related to the blood and circulatory system.
• Biocompatibles Ltd. develops commercial
  applications for technology in the field of
  biocompatibility.
• Carmeda makes a biologically active surface
  that interacts with and supports the bodys own
  control mechanisms
• Collagen Aesthetics Inc. bovine and human
  placental sourced collagens, recombinant
  collagens, and PEG-polymers
• Endura-Tec Systems Corp. bio-mechanical
  endurance testing ofstents, grafts, and
  cardiovascular materials
• Howmedica develops and manufactures products
  in orthopaedics.
• MATECH Biomedical Technologies, development of
  biomaterials by chemical polymerization methods.
• Medtronic, Inc. is a medical technology company
  specializing in implantable and invasive
  therapies.

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Evolution of Biomaterials
Structural
Soft Tissue Replacements
Functional Tissue Engineering Constructs
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Tissue Engineering
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What are some of the Challenges?

• To develop novel materials and processing
  techniques that are compatible with biological
  interfaces
• To find better strategies for immune acceptance

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Material Selection Parameters (Requirements from
scaffold)

• Solid phase
• Mechanical properties match properties of
  component being replaced, such as elastic
  modulus. Stability and fixation.
• Chemical composition, structure, purity
• Surface properties smoothness, COF, geometry,
  hyrophilicity, surface charge
• Biostability
• Thermal/Electrical Conductivity

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Material Selection Parameters (Requirements from
scaffold)

• Cellular structure
• pore size 100-200mm
• interconnected porosity
• mechanical integrity
• high porosity gt90
• biodegradable and Bioerodible degrade into
  non-toxic components can be eliminated from the
  body over time
• Diffusion, Water Absorption (promote cell
  adhesion and growth)
• Biocompatibility

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Biocompatibility The ability of a material to
perform with an appropriate host response in a
specific application (Williams 1987) Host
Response The response of the host organism
(local and systemic) to the implanted material or
device.
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Biocompatibility

• Arises from differences between living and
  non-living materials
• Bio-implants trigger inflammation or foreign
  body response
• New biomaterials must be tested prior to
  implantation according to FDA regulation to
  validate biocompatibility

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Foreign Body Response

• Rapid dilation of capillaries, increased
  permeability of endothelial cell linings and cell
  reactions
• Macrophages release degradative enzymes
  (lysozymes) that attempt to digest the foreign
  material.
• Macrophages multiply (Mitosis) and serve as
  progenitor to the giant cell
• Undisgestable frustrated phagocytosis

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Response to the inflammatory challenge

• Decreased tissue mass and formation of new
  tissue through granulation
• Collagen and other molecules are
• synthesized
• Formation of scar tissue
• Remodeling process differs for various tissues

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Polymers for tissue engineering

• Synthetic polymers
• advantage
• fabrication of big repetitive amount of polymer
• Degradation, shape and mechanical properties can
  be modified for the purpose
• Disadvantage not mimics the ECM
• Natural polymers.

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Synthetic polymers

• Polyesters polylactic acid (PLA),
  polyglycolic acid (PGA) , poly(lactic-co-glycolic 
  acid) (PLGA)
• Polyurethane
• poly(2-hydroxyethylmethacrylate) (pHEMA) ,
  poly-(N-(2-hydroxypropyl)methacrylamide (pHPMA).
• Linar Polyether poly(ethylene oxide) (PEO).

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Neutral Polymers

• Polymers that are part of our ECM body Collagen
  type II, IV
• Not ECM Polymers Alginate, Chitosan

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Biological materials

• Structural biological materials
• Bone, Cartilage, Collagen, Elastin
• muscle fiber,lipids,vitreous humor, etc
• Problems as restorative biological materials
  infection, resorption, inflammation, donor site
  morbidity

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Synthetic Biomaterial Classes

• POLYMERS Polyglycolic Acid, Polylactic acid,
  polyesters Uses sutures,drug delivery, in-growth
• HYDROGELS Alginate, Cellulose, Acrylic
  co-polymers Usesdrug delivery, vitreous
  implants,wound healing

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Examples of bioerodible polymers
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PLGA, PLA, PGA
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Polyglycolic acid (PGA)

• Highly crystalline -
• High melting point and low solubility in organic
  solvents
• Degradation to non-toxic monomers upon exposure
  to water
• Tendency to lose mechanical strength rapidly
  (2-4 weeks after implantation)
• Limits use for sutures and pins

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Polylactic acid (PLA)

• Hydrophobic polymer
• Undergoes less hydrolysis than PGA
• Greater stability than PGA
• Led to the development of PGA/PLA copolymers
• Choice of application based on crystallinity

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Physical mechanisms of bioerosion

• Two distinct modes of bioerosion
• Bulk erosion
• Rate of water penetration into solid exceeds rate
  at which polymer is transformed into water
  soluble material
• Uptake of water followed by an erosion process
  throughout the bulk of the material

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Physical mechanisms of bioerosion

• Surface erosion
• Rate at which water penetrates into polymer is
  slower than rate of water-solubility
• Transformation of polymer into a water- soluble
  material is limited to surface

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Mechanisms of chemical degradation
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Hydrolytic backbone cleavage affects bioerosion...

• Chemical stability of polymer backbone
• Hydrophobicity of monomer
• Morphology of polymer
• Initial molecular weight of polymer
• Presence of catalysts, additives, and
  plasticizers
• Geometry of implanted device

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The Problems With the Current Scaffolding
Techniques

• Cell seeding is limited to scaffold periphery
• Scaffold vascularization is inefficient
• Scaffold fabrication involves toxic reagents
• Control over scaffold degradation is poor

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• Thick Tissue-Engineered Construct

mass transport limitation
Oxygen is the major limitation factor for the
survival of transplanted cells. Oxygen
diffusion factor in a tissues indicates that
cells cannot be more than 200mm from a capillary,
if they are to survive.
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The Challenge

• Enhancing matrix vascularization by incorporating
  growth factors

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Alginate
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Advantages of Alginate Sponges

• Highly interconnecting porous structure (gt90
  porosity)
• Large pores 100?m-200?m
• Biocompatible bioerodible
• Simple preparation method (The gelation-freeze
  dry method)
• Good mechanical properties

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Microspheres Loaded onto Preformed Matrix

• Some microspheres penetrate into the matrix but
  most of them accumulate on the surface in an
  aggregated form.

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Microspheres Incorporated During Matrix
Preparation

• Microspheres average diameter d3.27µm

• Microspheres do not affect porous morphology.

• Microspheres are distributed homogenously
  throughout the matrix.

• Microspheres are an integral part of the alginate
  matrix.

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VEGF Composite 21 Days Post Implantation
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Primary Cells vs. Cell Lines
Primary cells are used for most tissue
engineering applications.
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Further Classification of Cell Types