Principles of tissue engineering

PRINCIPLES OF
TISSUE ENGINEERING
 DR KYALO, RM
 PRAS PGY3
 UNIVERSITY OF NAIROBI
 DEPARTMENT OF PLASTIC SURGERY
 25TH MARCH 2021

OBJECTIVES
Definition
History
Goals of TE
Components of TE – Cells/Environment/Scaffolds
Application and use of TE
Strategies to engineer tissue
Tissues of significance in plastic surgery
Future of TE
Conclusion
References

Definition
The term “tissue engineering” as it is nowadays used was
introduced in1987.
“Tissue Engineering is the application of the principles and
methods of engineering and life sciences toward the fundamental
understanding of structure-function relationships in normal and
pathologic mammalian tissue and the development of biological
substitutes to restore, maintain, or improve function.”

Definition
Regenerative Medicine - "process of replacing, engineering or
regenerating human or animal cells, tissues or organs to restore or
establish normal function".
This field holds the promise of engineering damaged tissues and
organs by stimulating the body's own repair mechanisms to
functionally heal previously irreparable tissues or organs

History
Oldest written description - Genesis I:1:
“The Lord, breathed a deep sleep on the man and while he was asleep he
took out one of his ribs and closed up its place with flesh. The Lord God
then built up into a woman the rib that he had taken from the man.”
Tale of Eve created from Adam’s rib

History
Greek mythology
Prometheus
Doctor Faustus – Homunculus
“Healing of Justinian,” first historical
reference.

History – The Early Years
Early 1970s - Dr. W.T. Green, a surgeon at Children’s Hospital Boston.
 Experiments to generate new cartilage using chondrocytes seeded
onto spicules of bone and implanted in nude mice
Unsuccessful
Conclusion - possible to generate new tissue by seeding viable cells
onto scaffolds
1981 - Drs. John Burke and Iannas Yannos,
Tissue-engineered skin substitute using a collagen matrix to
support the growth of dermal fibroblasts.
Patents (U.S. Pat. 4,418,691 (December 6, 1983)) granted to MIT
IntegraTM by Integra LifeSciences Corp

Principles of tissue engineering

1983 - 1984 - Dr. Howard Green & Dr. Olaniyi Kehinde –Test tube skin;
Sheets of cultured keratinocytes transferred onto burn patients.
Formed a company - BioSurface Technology, later taken over by
the Genzyme Corporation – Epicel® (cultured epidermal autografts)
Dr. Eugene Bell seeded collagen gels with fibroblasts, referring to
them as contracted collagen gels.

Natural occurring scaffolds have physical and chemical properties that
cant be manipulated thus unpredictable outcomes.
Around 1985 - Dr. Joseph Vacanti, Dr. Robert Langer
Tasked to design appropriate scaffoldings for cell delivery
Extensive studies to generate functional tissue equivalents using a
branching network of synthetic biocompatible/biodegradable
polymers configured as scaffolds seeded with viable cells.

1991, a young patient with Poland’s syndrome
first human to receive a tissue-engineered implant
 composed of a synthetic polymer scaffold implant
 seeded with autologous chondrocytes,
Surgeons - Drs. J. Upton and J. and C. Vacanti.
 Interpore's Pro-Osteon coral-derived bone graft material was
introduced in 1993
 1996, Integra's Artificial Skin was approved for as an in vivo,
nonbiological tissue regeneration product

1998 - General and Plastic surgery approval of ‘Apligraf’, human skin
equivalent for the treatment of venous leg ulcers.

 Tissue engineering efforts had high degree of success especially in Boston
 Centers sprang up in various institutions in the United States and Europe.
 Outside of Boston;
>Pittsburgh Tissue Engineering Initiative (PTEI) (early 1990s) organized by Peter
Johnson,
>The cardiovascular tissue engineering effort under the direction of Dr. Robert
Nerem at Georgia Tec
>laboratories overseen by Drs. Antonios Mikos and Larry McIntire at Rice University
in Houston,
>and an effort established at UMass Medical School by Dr. Charles A. Vacanti

 London - Dr. Julia Polak, a pathologist and stem cell biologist in London
Spearheaded tissue engineering at the Imperial College
Organized a British-based society associated to TESI
 Germany
Dr. Una Chen ,Giessen Germany (1990s); Studies in tissue engineering and
stem cell research
Dr. R. Hetzer, a cardiovascular surgeon at the University of Berlin, , and Dr.
Christof Brelsch, a liver transplant surgeon in Hamburg, established
collaborations with the Children’s Hospital in Boston
 Japan
Collaboration - Boston-based labs and Kyoto University labs, headed by Dr.
Koichi Tanaka, resulting in the formation of tissue-engineering laboratories in
Kyoto

New Haven, Connecticut
Drs. Chris Brewer and Mark Saltzman established the Tissue
Engineering Institute at Yale University
In Asia
Dr. Minora Ueda, at the University of Nagoya, established a tissue-
engineering effort in Japan and organized the 1st meeting of the
Japanese Tissue Engineering Society (1997) in Nagoya.
China, Shanghai
The first Chinese tissue engineering effort sponsored by the
Chinese government was founded by Dr. Yi Lin Cao in Shanghai.

Mexico
 Dr. Clemente Ibarra - National Institute for Rehabilitative Medicine in Mexico City; founded the Mexican Tissue
Engineering Society.
Toronto, University of Washington
 Dr. Steven Kim/ Dr. Buddy Rattner in Seattle, at the University of Washington
 Michael Sefton in Toronto
Austria, Germany, Switzerland, France
 Dr. Wolfgang Pulacher opened a lab in Innsbruck.
 Organization of a tri-state effort in Germany, Switzerland, and Southern France, spearheaded by Drs. R.E. Horch and
G.B. Stark at the University at Freiburg.
By mid-1990s, efforts in almost every developed country in the world
and several privately funded ventures

History: Development of an organizational structure
1994, the Tissue Engineering Society (TES), founded by Drs. Charles A.
and Joseph P. Vacanti in Boston.
1997, the Japanese Tissue Engineering Society, established by Dr
Minoru Ueda
The Chinese Tissue Engineering Society and Shanghai-based Tissue
Engineering Center by Dr. Yi Lin Cao.
Aligned to form the Asian branch of the international Tissue
Engineering Society, now referred to as TESi.

History: Development of an organizational structure
Drs. Stark and Horch of Freiberg, Germany, encouraged the formation
of a European Tissue Engineering Society (ETES).
2004
merging of the former continental branches of the former TESi.
TESi renamed TERMIS, the Tissue Engineering Regenerative Medicine
International Society

The Journal
The journal Tissue Engineering
 Founded in 1994
By > Drs. Charles A. Vacanti, Massachusetts General Hospital and
Harvard Medical School
> Dr. Antonios Mikos of Rice University.

Tissue Engineering and the public arena
1997 - Vacanti Mouse/ Auriculosus - “mouse with the human
ear,”
Potential of tissue-engineered cartilage
COURTESY OF THE LABORATORY FOR TISSUE ENGINEERING AND ORGAN FABRICATION, MASSACHUSETTS
GENERAL HOSPITAL, BOSTON, MA, USA, DR. JOSEPH P. VACANTI, DIRECTOR.

Examples from nature
The liver has been known to self-regenerate
A salamander regrows its legs
The fetus repairs wounds with minimal scarring
Humans have the capacity to gain and lose adiposity rapidly
Ruptured tendons can regenerate across gaps when their ends are
retained within their synovial sheath where their matrix and cellular
environment are maintained and axial mechanical force signals are
transduced into biochemical stimulation.

The goal
 To assemble functional constructs that restore, maintain, or
improve damaged tissues or whole organs.
Growth of cell in three dimensional systems
Delivery systems for protein therapeutics
Cell cultivation methods for culturing recalcitrant cells
Transgenic protein expression in transplantable cells
Vehicles for delivering transplantable cells
Avoiding immunogenicity in transplantation systems
Development of markers for tracking transplanted cell
Developing in vivo and ex vivo biosensors for monitoring cell
behaviour during tissue production.

Tissue engineering
Tissues can be viewed as a composite of:
(1) cells (both parenchymal and stromal)
(2) matrix and
(3) blood vessels.
Cell maintenance and behavior including growth and regeneration are
influenced by biochemical and biomechanical interplay.
The development of a functional tissue must be vascularized to
ensure survival of the neotissue.
Each of these components is the purview of the tissue engineer.

Cell sources for tissue engineering
Cells used for TE,
Autologous - preferred due to the lack of immunogenicity
Heterologous,
Xenogeneic and each type may be
mature differentiated
precursor stem cell form.

Chondrocytes for cartilage
Osteocytes for bone
Schwann cells for nerves
Fibroblasts for ligament and tendon engineering
 All these have significant proliferative potential in vitro
Adult cardiomyocytes, hepatocytes, and adipocytes
Challenge - difficult to culture and expand in vitro

A second challenge
Collection of cells – biopsy; uncomfortable and impossible due to
diseased state of the tissue
Solution
Utilize stem cells; expanded and differentiated ex vivo.
Multiple types of stem cells exist
E.g. embryonic, adult, and induced pluripotent stem cells.
Discuss embryonic stem cells
Focus on stem cell types most relevant to the plastic surgeon; sources
of cells, advantages and disadvantages, use in TE

Embryonic stem (ES) cells
 Totipotent
 Infinitely proliferative
 Differentiate into all tissue types
 Are also unstable and form teratomas
 Ethical and legal concerns - sourcing and utilization
 Successful differentiation protocols have been found to induce ES cells along
specific lineage pathways from all germ layers towards many specific tissues and
organs.
 These cells are probably immunogenic and ethical issues will persist.
 Regulatory and organizational issues

Adult stem cells
Multipotent
Limited in their proliferation capacity and differentiation potential.
Collected and expanded from tissue biopsies through a process
referred to as the colony forming unit (CFU) assay
Adult stem cells in bone marrow:
Hematopoietic stem cells (HSCs), which differentiated into the white
blood cell population and
Mesenchymal stem cells (MSCs),
Progenitors of bone, cartilage, fat, and muscle.
Endothelial progenitor cells (EPCs) have been isolated and cultured from
adult peripheral blood.

Adult stem cells
MSCs and EPCs also present in fat tissue associated with the
microvasculature
Known as adipose-derived stem cells (ASCs).
Relevant stem cells in Plastics
Mesenchymal stem cell
 Adipose-derived stem cell
Endothelial progenitor cell.

Mesenchymal stem cells
Do not express MHC class II markers
Showed to be immune-privileged and may be used as allografts.

Mesenchymal stem cells
Paracrine-growth factor hormonal- cytokine immune-modulatory
effects probably account for the benefits seen with these stem cells.
 E.g., Ischemia increases homing of these cells to the injured site
MSCs release high levels of vascular endothelial growth factor (VEGF)
This modulates the repair of capillaries.
MSCs injected intravenously in cardiac infarct models do not implant in
the heart nor become heart tissue
Lodge in the lung
Activated to secrete the anti-inflammatory protein TSG-6
Probably the anti-inflammatory factor that induces the beneficial effects.

Adipose-derived stem cells
Abundant
Ease of harvest by liposuction
 Preferred autologous stem cell source
Similar properties to bone marrow-derived stem cells
More easily cultured
Grows more rapidly
Cultured for longer periods than bone marrow stem cells before
senescence
Richer source of stem cells
 One gram of adipose tissue can yield 5000 stem cells
ASC population may also have low immunogenicity

Endothelial progenitor cells
 Incorporation of a functional vasculature network in the neotissue is important
 Endothelial progenitor cell (EPC) most promising
 First identified in 1997 by Asahara et al.,
 Present in adult circulation
 Isolated and expanded from peripheral blood collected through simple
venipuncture.
 Two distinct EPC populations that participate in vascular repair and angiogenesis
via different mechanisms.
Circulating angiogenic cells (or colony forming unit–Hill cells) – support via paracrine
signalling
Endothelial colony forming cells (ECFCs) – regenerate an endothelial population

Challenges associated with adult stem cells
Advantages
An autologous and/or non-immunogenic source of cells.
Limitations
Patient-to-patient variations in their prevalence, proliferative
capacity, and differentiation potential
 Additionally, their utility is also a factor of age and disease
state of the donor
 Exit the cell proliferation cycle (prematurely senesce) or
prematurely lose differentiation potential during ex vivo
expansion
Schipper B, Marra K, Zhang W, et al. Regional anatomic and age effects on cell function of human adipose-derived stem cells. Ann Plast
Surg. 2008;60:538–544

Induced pluripotent stem cells (iPS)
Unlimited proliferation capacity
Ability to differentiate into cells from all germ layers both in vitro/vivo
Major problem - Requires genetic manipulation of the cells
 Two of the genes used in this process (c-Myc and KLF4) are oncogenes
Zhou et al. (2009) delivered the 4 proteins that the above-mentioned
genes code for directly into the cell
Protein-induced pluripotent stem cells (piPSCs)
Bypasses the need for viral or plasmid transfection and reduces the risks of
cancer formation.
Drawback - efficiency of the protein induction is very low
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell (2006) 126(4):663–76.
doi:10.1016/j.cell.2006.07.024

Induced pluripotent stem cells (iPS)
Challenge
Not immune privileged requiring collection, induction, expansion, and
differentiation of autologous cells.
Costly and time-consuming
Solution
Create a bank of iPS cells that can be HLA matched to the patient

Cellular interactions with their environment
Many cell types are exquisitely sensitive to stimuli present in the
environment.
Stimuli include;
Soluble molecules
Molecular recognition sites present in the solid phase (ECM or
biomaterial)
Interactions with other cells
Substrate stiffness and the micro/nanostructure of the
surroundings

Soluble signals
Soluble biomolecules eg Metalloproteins
Growth factors
Chemokines
Play vital roles locally and systemically in repair and tissue
development.
Understand the appropriate soluble signaling molecules
to maintain cell viability both during culture and in vivo,
 to maintain cellular phenotype,
to drive lineage specific differentiation of stem cells

Matrix signals
Cells also possess receptors such as integrins and syndecans that bind
to a variety of ligands present in the extracellular matrix (ECM)
Many cell types are adhesion dependent
Also the number and strength of bonds with the external matrix
affects a wide variety of cellular behaviors ranging from adhesion,
focal adhesion formation and migration to morphology.
Additionally, the ECM binds and sequesters growth factors that also
drive cellular function.

Intercellular signals
 Cells also interact with neighboring cells in both native tissue and in ex vivo culture
 Two main methods: >Direct contact via receptors such as cadherins
>Soluble signaling through paracrine factors
 In traditional cell culture, single populations of cells are grown in isolation,
implanted and rely on recruitment of supporting cellular structures and matrix to
evolve into a stable, functional tissue
 However, co-culturing cells with other types prior to implantation can facilitate
their survival and function. E.g.
Endothelial cells for vasculature
MSCs for paracrine effects or for their ability to incorporate into developing
tissues in vivo like blood vessels
Beating cardiomyocytes with ASCs in vitro to differentiate into cardiac lineage

Mechanics and structure of the environment
Cells respond to the mechanical properties and dimensionality of
their environment.
Response of cells to environmental stiffness and dimensionality is a
tool that can be used to direct cell function.
E.g. chondrocytes change morphology and lose their chondrogenic capacity in
2D monolayer culture but can maintain these features in 3D culture
Uses;
Distraction osteogenesis
Periods of stretch promote proliferation and migration
Relaxation incites cells to cluster together and terminally differentiate
into bone

Mechanics and structure of the environment
3D cultures on biomaterial supports such as
Porous scaffolds
Hydrogels
Microspheres
Under conditions designed for the desired cell attachment, migration,
proliferation, and differentiation
Development of new biomaterials with tailored properties
Direct the fabrication of these materials into three-dimensional
scaffolds to maximize the healing process

Biomaterials used in tissue engineering
Components of solid tissues
Cells
Extracellular matrix - structure and biochemical signals to the cells
When cells are expanded outside the body, they grow in monolayers,
not the intricate patterns of a fully realized 3D tissue
Thus, cells are seeded onto a 3D scaffold
Biomaterial scaffolds can be thought of as artificial ECMs

Early tissue engineering used known materials.
Polymers used in degradable sutures
Natural materials such as coral, alginate and collagen.
Recently, numerous alternatives have been formulated
Biomaterials for TE
Naturally occurring in the body
From other natural or synthetic sources
Ceramics
Polymers
Hydrogels
Composites of these
Decellularized tissues

The physical form of biomaterials can also vary to suit the application
Solid materials
Porous scaffolds
Microspheres
Hydrogels
Injectable materials that may cross-link in situ etc.
Simplicity - facilitate regulatory approval and translation into clinical
application
Selection depends on the specific requirements of the tissue being
targeted

Biodegradable materials
Most are biodegradable, to be replaced by neotissue
Rate of degradation and loss of integrity will depend on;
Type of biomaterial
Site of implantation
Properties of the biomaterial construct such as surface area to
volume ratio, size, and surface chemistry
Challenges - Prevention of sudden loss of physical integrity
- Rapid degradation - excessive concentrations of the
degradation products and can cause adverse tissue
reactions.

Natural biomaterials
Chemically similar or identical to molecules in the body
Readily degraded in vivo
Interact with cells on a molecular level
Difficult to obtain and purify
Vary in properties between batches
Difficult to sterilize
Alter their properties during storage,
Elicit significant immunogenic responses.

Natural biomaterials
Examples;
Proteins (e.g., collagen, gelatin, silk)
Polysaccharides (e.g., chitosan, hyaluronic acid)
Polynucleotides
Extracts of ECM components
Increased interest - Decellularized extracellular matrix (dECM)
In decellularization, cells are removed from allografts or xenografts to
reduce immunogenicity but much of the complex composition and
architecture of the ECM may be retained

Decellularization is the process used in biomedical engineering to isolate the extracellular
matrix (ECM) of a tissue from its inhabiting cells, leaving an ECM scaffold of the original tissue.

Polymeric biomaterials
1. Hydrophobic polymers
Biodegradable polymers that could be used in TE
The polyesters
poly(glycolic acid) (PGA)
poly(lactic acid) (PLA)
poly(ε-caprolactone) (PCL)
and their copolymers such as poly(lactide-co-glycolide) (PLGA)
 Mechanical strength & degradation rate – altered by changing the
polymer properties (molecular weight, composition, molecular
architecture, crystallinity, hydrophobicity)

Polymeric biomaterials
2. Hydrogels
Water-swollen cross-linked polymer networks which can absorb up to
thousands of times their dry weight of water.
Advantage of being more like most natural tissues and allowing mass
transport to and from cells.
Naturally derived
Collagen
Gelatin
Hyaluronic acid
Alginate
Synthetic
Poly(ethylene glycol) (PEG)-based polymers

Ceramic biomaterials
Ceramic biomaterials are primarily utilized in tissue engineering of
hard tissues.
Calcium phosphates, such as hydroxyapatite, and bioactive glasses
have been developed as bioceramics for bone tissue engineering.
Characteristics
Bioceramics are brittle but have high compressive strength, can bond
strongly to bone, and can be osteoinductive.

Advanced biomaterials for tissue engineering
1. Tailored delivery systems
Growth factors, anti-inflammatory peptides, and drugs may be
incorporated into biomaterial delivery vehicles for release at the
desired time during tissue development.
Release systems are designed to deliver multiple molecules over
different timescales via continuous or pulsatile delivery, which may
be programmed or triggered by some change in the local
environment.
Fabricated from biodegradable polymers in the form of
micro or nanoparticles
capsules,
within walls/surfaces of scaffolds or hydrogels

2. Smart Polymers
Changes in environmental conditions - changes to the molecular
conformation of many materials.
Environmentally-induced changes may be harnessed, thus smart
polymers.
 Used to >encapsulate and release payloads of cells or drugs,
>form gels upon injection in vivo
>for cell sheet engineering.
Example - Thermo-responsive polymer N-isopropylacrylamide
(NIPAM)
Used to grow confluent cell sheets and then to detach the intact
sheet along with the ECM that the cells have deposited.

3. Non Fouling Materials
Successful strategies - use of chemical surface modifications
Initial stage of FBR is the adsorption of a complex layer of
biomolecules from body fluids that can be denatured and lead to an
immune reaction.
Non-fouling materials (or stealth materials) resist the adsorption of
these proteins.
New generations of non-fouling materials - active area of research
Zwitterionic polymers
Mixed charged polymers
Polyoxazolines

4. Biofunctionalized materials
Is based on a “blank slate” from the non fouling materials/surfaces.
Decorated with bioactive molecules, through covalent
immobilization.
These biofunctionalized materials interact with receptors on the cell
surface and drive cellular behavior with biological specificity.
Most common strategy - materials with ligands that engage specific
integrin receptors.
Thus, only cells that express the appropriate integrin are able to
adhere to the material.

Tissue engineering constructs
These biomaterials are fabricated into a tissue scaffold to support
regeneration.
Structures
Porous scaffolds and hydrogels
Meshes or microspheres
Techniques
Polymer phase separation
Particle or foam templating
Cryogelation,
Electrospinning
Rapid prototyping methods like 3D-printing.

Scaffold morphologies produced by thermally induced phase separation

Scaffold morphologies produced by Particulate leaching

Scaffold morphologies produced by Electrospinning

Scaffold morphologies produced by Rapid prototyping

Vascularization in tissue engineering
Cells and tissues vary in their oxygen needs
But generally, cells do not survive beyond 150 μm from a capillary
Survival, growth and function of an engineered construct are
highly dependent on an adequate and timely blood supply
Initial TE efforts - tissues of low oxygen requirements( cartilage,
tendon), very small thickness(skin) able to survive by diffusion
Currently, fabrication of thicker and more “oxygen-demanding”
surrogates - address the issue of vascularization

Vasculogenesis, Angiogenesis and Inosculation
Vasculogenesis refers to the development of new blood vessels from
progenitor stem cells.
In the embryo, mesoderm cells are stimulated by FGF-2 to form
hemangioblasts. Pool into blood islands. Peripheral hemangioblasts
differentiate first into angioblasts and then into endothelial cells.
Endothelial cells coalesce to a primary vascular plexus.
Vasculogenesis is not exclusive to the embryological period, it also takes
place in adult life driven by bone marrow-derived endothelial progenitor
cells.

Angiogenesis - sprouting of blood vessels from preexisting ones.
Endothelial cells respond to an angiogenic signal
Increase vascular permeability - extravasation of plasma proteins that
form a transient matrix
A tip cell then migrates out of the vessel into the matrix
Leads the sprouting followed by stalk cells, which form a lumen.
Neighboring sprouts fuse
Neovessel becomes perfused
Stabilized by recruitment of pericytes and basement membrane
restitution

Inosculation describes the process by which capillaries from a grafted
tissue connect to those of the wound bed where it is applied.
Exact mechanism - not clear.
Because it takes several days, is a limiting factor affecting prompt
perfusion of a tissue-engineered construct
Period of time is too long to survive the transplantation anoxia.
Faster inosculation - Fibroblasts or FGF-2

Elements and strategies of vascularization in TE
Extrinsic or Intrinsic approach.
Extrinsic approach
Direct implantation of a seeded scaffold that is gradually invaded by the
host’s vasculature, meanwhile relying solely on diffusion for survival.
Pre-vascularization -A capillary bed fabricated in vitro and then
implanted in vivo where it will become perfused by inosculation rather
than by capillary invasion
Intrinsic approach
Organism is used as a bioreactor so that capillary sprouting occurs either
before or concomitantly with cell differentiation and tissue growth

Elements and strategies of vascularization in TE
Elements - similar to tissue engineering itself - Cells, Scaffolds and
Growth factors
CELLS
2 cell lines,
Endothelial cells
Supportive cells.

Scaffolds
Natural scaffolds
Collagen, Fibrin, Starch, Matrigel ®,Decellularized matrix & Silk fibrion
Synthetic materials
Polyethylene glycol, Poly (lactic glycolic) acid and Polyurethane
Clinically approved dermal substitutes such as Integra® and
Matriderm ® have also been used for prevascularization purposes by
seeding them with endothelial colony forming cells (ECFCs) in
association with either human dermal fibroblasts (hDFs) or bone
marrow-derived mesenchymal stem cells (BMSCs).

Growth factors
VEGF-A - most important in angiogenesis.
Acts mainly by binding to
VEGF receptor 1 (VEGFR1) expressed in endothelial cells, hematopoietic
stem cells and inflammatory cells,
VEGF receptor 2,(VEGFR2) expressed mainly in endothelial cells.
FGF-2 (aka basic fibroblast growth factor, bFGF)
Mostly involved in angiogenesis
Produced by a number of differentiated cells e.g. keratinocytes, mast
cells, fibroblasts, endothelial cells and smooth muscle cells, as well as
by adult mesenchymal stem cells derived from bone marrow, adipose,
and dermal tissue.

Growth factors
FGF-2 - Stimulating migration and proliferation of endothelial cells in
vivo,
Mitogenesis of smooth muscle cells and fibroblasts, which induces
the development of large collateral vessels with adventitia.
FGF-2 - In the prevascularization of scaffolds - Faster inosculation of
the scaffold in vivo
PDGF-B released by endothelial cells - Angiogenesis process mainly by
attracting pericytes that will subsequently provide stability and
structural support to the newly formed vessel.

REPRESENTATIVE EXAMPLES OF ENGINEERED TISSUES
1. SKIN

1. SKIN
Functions of TE Skin products
Protection—establishing a mechanical barrier to microorganisms and
vapor loss;
Procrastination—providing wound cover after early wound
debridement until permanent wound closure
Promotion—delivering to the wound bed dermal matrix components,
cytokines, and growth factors, which can promote and enhance
natural host wound healing responses
Provision—new structures, such as dermal collagen or cultured cells,
that are incorporated into the wound and persist during wound
healing and/or thereafter

1. SKIN
Scaffold
Collagen and fibrin most common
Cells
Keratinocytes, Fibroblasts, Human Embryonic Stem cells ,Human Adult
Stem Cells and Preadipocytes
Growth Factors
Transforming growth factor- b (TGF- b), Platelet-derived growth factor
(PDGF), Fibroblast growth factors (FGFs)

Approaches to Skin TE
Placing a
biodegradable
matrix in the
wound to
promote the
regeneration of
the skin dermis
through a process
of host cell
migration and
proliferation

Emerging technologies
3D printing
Termed bioprinting or bioplotting when biological components are
included.
A wide variety of materials can be processed using different kinds of 3D
printers,
Polymers, Hydrogels, Metals, Ceramics and even Living cells.
Methods via solid freeform fabrication
Stereolithography
Selective laser sintering
3D printing
Wax printing
Fused deposition modeling

Emerging technologies
Others
In vitro bioreactors
Control the microenvironment of cells in vitro
To encourage the desired cellular processes and tissue development
whilst also optimizing the mass transport of oxygen, nutrients and
waste products to allow 3D tissue constructs to be developed
Computational modeling
Mathematical modeling in design of TE constructs and processes
Insights into factors governing tissue growth e.g. different cell seeding
patterns and timing can be investigated using a mathematical model

References
1. TISSUE ENGINEERING Volume 12, Number 5, 2006 © Mary Ann Liebert, Inc.
History of Tissue Engineering and A Glimpse Into Its Future CHARLES A.
VACANTI, M.D.
2. The History of Tissue Engineering and Regenerative Medicine in Perspective.
U. Meyer
3. Harvard Medical School YouTube Channel Interviews
https://www.youtube.com/watch?v=Eo7vSI4LiIs&ab_channel=HarvardMedica
lSchool
4. Tissue engineering Andrea J. O’Connor, Diego Marre, Kiryu K. Yap, Daniel E.
Heath, and Wayne A. Morrison; Peter C. Neligan 4th Edition Plastic Surgery,
Volume 1
5. Regen Med . 2008 Jan;3(1):1-5. doi: 10.2217/17460751.3.1.1. A brief
definition of regenerative medicine Chris Mason, Peter Dunni

References
6. Bell, E. (1991). Tissue engineering: a perspective. Journal of Cellular
Biochemistry, 45(3), 239–241. doi:10.1002/jcb.240450302
7. Tissue-engineered Solutions in Plastic and Reconstructive Surgery: Principles
and Practice Sarah Al-Himdani
8. Tissue Engineering in Plastic Surgery: A Review Victor W. Wong, M.D. Kristine
C. Rustad, B.S. Michael T. Longaker, M.D., M.B.A. Geoffrey C. Gurtner, M.D.
Stanford, Calif
9. Locke M, Windsor J, Dunbar P. Human adipose-derived stem cells: isolation,
characterization and applications in surgery. ANZ J Surg. 2009;79:235–244.
10. Cui L, Yin S, Liu W, et al. Expanded adipose-derived stem cells suppress mixed
lymphocyte reaction by secretion of prostaglandin E2. Tissue Eng.
2007;13:1185–1195.

References
11. Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human
adipose tissue-derived adult stem cells: comparison with bone marrow
mesenchymal stem cells. Br J Haematol. 2005;129: 118–129.

Principles of tissue engineering

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