Tissue Engineering

Hottest job for 21st Century

Five hottest jobs for the next millennium will bebioengineering/biomedicalrelated.

Bones that lose minerals after age 30

Fallible spinal disks

Muscles that losemass and tone

Leg veins prone to varicosity

Joints that wear

Shorter limbsand stature

Forward-tilting upper torso

Curved neck with enlarged vertebrae

Thicker disks

Extra muscles and fat

Leg veins with more check valves

Larger hamstringsand tendons

Knee able to bendbackward

Thicker bones

Larger ears

If Humans Were Built to Last

Adapted from Olshansky, Carnes, Butler, Sci Am 2001 Mar

Current Design Alternative Design

Phil Campbell, Carnegie Mellon

Replacing diseased or injured tissues with tissue constructs designed and fabricated for the specific needs of each individual patient.

What are Biomaterials?A material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function in the body.

What is Tissue Engineering/Regenerative Medicine?

Forecasts of the American Population Aged 85 Years and Over

Oxford Textbook of Geriatric Medicine 2000

Hea

lth E

xpen

ditu

res

% o

f gr

oss

dom

estic

pro

duct

in19

96

0

2

4

6

8

10

12

14

16

GermanySwitzerland

Canada

USA TurkeyMexico

South KoreaPoland

USA $3898United Kingdom $1317Turkey $232

(1996 US dollars per capita)

1987-1995 Hip replacements among women rose from 143/100,000 to 1444/100,000

US Medicare expenditures for last year of life is double for aged 65 to 69 years compared to 90+ years. (excluding nursing home costs)

Medical costs

Oxford Textbook of Geriatric Medicine 2000

FDA approved products

Infuse Bone GraftBone morphogenetic protein-7,

Osteogenic peptide-1RegranexCarticelTranscyteIntergra Dermal Regeneration TemplateDermagraftApligraftOrtec

Apligraft

Adult Stem Cells

Example

Bone marrow-derived mesenchymal stem cells

Adult Stem Cells

Example

Bone marrow-derived mesenchymal stem cells

Inadequate understanding of the basic biology of regenerative processes

Lack of adequate biomimetic materials to act as scaffolds for either induction of regeneration in vivo, or to build bioartificial tissues in vitro

Inadequate cell sources for transplantation or building bioartificial tissues

Problem of immunosuppressive regimens introduced by allogeneic and xenogeneic cells.

Bioethical issues associated with the use of fetal and embryonic stem cells as sources

Tissue Engineering Roadblocks

Cells

Principles of Tissue Engineering

ECM

Hormones BloodSupply

Defect Regeneration

Phil Campbell, Carnegie Mellon

-Hormonal-based tissue engineering has been around for thousands of years

Castration as a means to control behavior and tissue quality in domesticated animals

 -Systemically targeted (purified) protein hormone therapies –

mid 1900s.

-Systemically targeted (recombinant) protein hormone therapies (insulin) – 1980s

 -Locally targeted (recombinant) protein hormone therapies

(PDGF-BB, BMP-2, BMP-7) – late 1990s to present

Endocrinology Applied to Tissue Engineering: A Quick History

Phil Campbell, Carnegie Mellon

Spinal CordSpinal Cord

Upper and Lower JawUpper and Lower Jaw

LimbLimb

Retina and LensRetina and Lens

An Ultimate Vision for Regenerative Medicine: Complete Tissue Regeneration

An Ultimate Vision for Regenerative Medicine: Complete Tissue Regeneration

Adapted from BrockesAdapted from Brockes

TailTailHeartHeart

The NewtThe NewtFrom Dr. Susan Bryant, Univ. of Calif., Irvine

Phil Campbell, Carnegie MellonPhil Campbell, Carnegie Mellon

What controls biological pattern formation associated with morphogenesis-

Cells to Tissues to Organism?• How can patterns emerge from an initial structureless system?

• How do developing parts of an organism become different?

• How can different genetic information be activated at different spatial positions?

This requires cell-to-cell communication and feedback.

• Cell-cell communication via secreted molecules: hormones

• “Morphogen” gradients provide directional cues for cell recruitment and the interaction of those gradients provide the cues for organization.

Phil Campbell, Carnegie Mellon

3D Inkjet Printing

Tr: ThrombinFg: FibrinogenGF: Growth factor

Co-jetting and local mixing of bio-inksLee Weiss, Carnegie Mellon

Fibrin/Growth Factor Printer

Lee Weiss, Carnegie Mellon

Example of a Biologically-Inspired, Engineered Design With Solid-Phase Spatial Patterning

Why fibrin:• Provisional extracellular matrix in wound healing• Binds numerous growth factors of interest, i.e., the-solid-phase• Supports cell attachment and migration• Degrades in register with new tissue formation• FDA approved

(Coronal view)

Fibrin scaffold

Critical size defectGradient of VEGF or FGF-2

bone bonebraindura

Direction of cell migration(up from the dura)

Calvarium

Lee Weiss, Carnegie Mellon

In Situ Printing

Lee Weiss, Carnegie Mellon

Conclusions

• Our approach is to develop toolsets to understand the biology…. control the biology…. translate that control into cost effective, clinically relevant therapies.

• As important as developing the bioprinter is developing the bioimaging and biological response toolsets.

• The most critical roadblock to overcome remains our inadequate understanding of the basic biology…what do we print?

Phil Campbell, Carnegie Mellon

No One Discipline Can Tackle the Problem Alone

Lee Weiss, Carnegie Mellon

• Harvested tissues from

cloned transgenic animals

• Human cloning

• Gene therapy

• Fetal stem cells

• Our approach is to understand how the body naturally heals itself and then provide the minimal set of cues needed to restore the body’s healing capacity.

…… but all have significant technical, ethical, political, and religious issues

Alternatives to Traditional Grafts/Implants

Lee Weiss, Carnegie Mellon

CellsGrowth factors

Biomimeticextracellular

matrix

Culture Implant

If needed, harvest cells from patient.

Guided Tissue Repair

Lee Weiss, Carnegie Mellon

CellsGrowth factors

Biomimeticextracellular

matrix

Culture Implant

If needed, harvest cells from patient.

Guided Tissue Repair

Lee Weiss, Carnegie Mellon

CellsGrowth factors

Biomimeticextracellular

matrix

Culture Implant

If needed, harvest cells from patient.

Guided Tissue Repair

Lee Weiss, Carnegie Mellon

In addition to custom geometry, key factors are:• Development (adolescent, adult, geriatric)• Wound site• Alcohol• Smoker• Diabetic

Libraries of surrogate models.

There are no ‘one-design fits all’ silver bullets…

Bon

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gene

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Design Paramete

r1 2

Lee Weiss, Carnegie Mellon