Biomaterials for tissue

engineering of skin
Tissue-engineered skin has been in clinical use for 25 years and
has developed greatly during this time. This review looks at the role
biomaterials need to play in providing for epidermal cover, dermal
replacement, and epidermal/dermal replacement, and describes the
major problems that remain. The majority of biomaterials in clinical use
are based on natural or extracted collagen. The clinical challenges in
using these materials are highlighted throughout – specifically safety
issues, improving the take of cultured cells on wound beds, improving
the rate of neovascularization of tissue-engineered skin, and developing
scaffolds that resist contraction and fibrosis.
Sheila MacNeil
Department of Engineering Materials, Kroto Research Institute, University of Sheffield, Broad Lane, Sheffield S3 7HQ, UK
E-mail: s.macneil@sheffield.ac.uk

Tissue-engineered skin includes cells delivered on their own,
cells delivered within two- or three-dimensional biomaterials,
biomaterials for replacement of the skin’s dermal layer (both with
and without cells), and biomaterials to support the replacement
of both the epidermis and dermis. In discussing these scenarios,
it is useful to look first at the role of skin and determine what
functions biomaterials need to provide.
What does skin do and what do biomaterials
need to do?
Tissue-engineered skin needs to: (a) provide a barrier layer of
renewable keratinocytes (the cells that form the upper barrier layer
of our skin), which is (b) securely attached to the underlying dermis,
(c) well vascularized, and (d) provides an elastic structural support for
skin.
Skin physiology has been reviewed in depth in a series of articles
spanning skin development and stem cells1, skin pigmentation2, sensory
transduction3, and progress in tissue engineering of skin4.
This review gives a snapshot of the biomaterials currently in clinical
use in this field (summarized in Table 1), looking at how they are
used and in particular, flagging up where there are still major clinical,
practical, and safety challenges. Innovative materials could theoretically
help overcome many of these problems.
Skin barrier function
Fig. 1 illustrates the structure of normal skin, which provides an
essential water-, electrolyte-, and bacteria-proof barrier to the outside
world. When this function is lost through burns or chronic nonhealing
ulcers, then patients are susceptible to bacterial infection. In burns
patients with extensive skin loss, bacterial sepsis can be fatal.

26 MAY 2008 | VOLUME 11 | NUMBER 5 ISSN:1369 7021 © Elsevier Ltd 2008

Open access under CC BY-NC-ND license.
 Biomaterials for tissue engineering of skin REVIEW

Table 1 Biomaterials in use for tissue engineering of skin

Objective Approach Examples

Epidermal cover Delivers cultured keratinocytes so that they • Cultured epidermal sheets – Epicell5,6
‘take’ on the wound bed and form a new • Cultured epidermal sheets from plucked hair follicles – Epidex7
epidermal layer • Subconfluent cells on a synthetic carrier – Myskin8–11
• Cells delivered in a fibrin spray12
Dermal replacement Provides a dermal alternative to promote • Donor skin13
wound healing or is used in a two-stage • Permacol14
skin replacement protocol • Dermagraft15
• Transyte16
• Integra17,18
Epidermal/dermal replacement Acts as an alternative to a split-skin graft • Apligraf19,20
• Permaderm21
• Orcel22
• Tissue-engineered skin23
• Tissue-engineered oral mucosa24

The skin barrier function is achieved by layers of differentiated
keratinocytes fusing together in a tightly integrated epidermal sheet.
The lower, thicker dermal layer consists of collagen fibers that, at their
upper surface, form a specialized basement membrane (BM) zone
for secure attachment of keratinocytes to the dermis. The dermis is
vascularized and contains receptors for touch, temperature, and pain, as
well as hair follicles and sweat ducts, the latter lined with keratinocytes
that contribute to epidermal regeneration.
The epidermal layer is relatively thin, 0.1–0.2 mm in depth, and
consists of a self-renewing population of keratinocytes programmed to
be replaced continuously for a lifetime from basal cells located on the
BM zone1. The majority of keratinocytes move into the upper layers
of the epidermis, become progressively stratified, lose their nuclei, and
eventually fuse into the crucial barrier layers of keratin sheets that are
routinely shed from the skin surface.
Secure attachment to the dermis
The epidermis is securely attached to the collagen fibers of the
dermis by complex three-dimensional BM anchoring structures called
hemidesmosomes. (These are a collection of adhesion receptors that
extend through the cell membrane and act as anchoring filaments to
bind keratinocytes to the lower BM.) The proteins that form the BM,
collagen IV, collagen VII, and laminin, are vital for this attachment
and are synthesized by the dermal fibroblasts (the cells that form the

Fig. 1 Structure of human skin showing the upper epidermal barrier layer and the much thicker dermal layer with hair follicles and sweat glands lined with epithelial
cells. (Reprinted with permission from59. © 1999 McGraw-Hill.)

MAY 2008 | VOLUME 11 | NUMBER 5 27

REVIEW Biomaterials for tissue engineering of skin
lower spongy layer of skin) under instruction from the keratinocytes25.
Genetic problems with BM components result in a range of blistering
diseases (collectively known as Epidermylosis Bullosa26) that vary
in their severity, but some forms can be fatal. (If the epidermal
barrier layer cannot be maintained, then patients are wide open to
bacterial infection). The reconstitution of this BM zone on the patient
remains one of the major challenges for tissue engineering today (see
below).
Vasculature
Skin is well vascularized and this is essential for skin repair, which is
normally excellent for individuals in good health. However, if there is
extensive skin loss, such as occurs in burns injuries, then the patient
cannot repair skin rapidly enough27. Additionally, if the normal wound
healing mechanisms are compromised because of poor vasculature
(usually age or diabetes associated), then skin repair can be slow or
fail to occur. This is a major problem in the western world with aging
populations and increasing incidence of diabetes28. Achieving rapid
neovasularization in tissue-engineered materials is another major
challenge (see below).
Elasticity and support
The dermis also provides support and elasticity through a complex
architecture of enzymatically cross-linked collagen and elastin fibers29.
Failures of repair can result in skin contraction, fibrosis (where
fibroblasts produce scar-like material), and scarring. Contraction23
and fibrosis24 of tissue-engineered materials are emerging as other
problems (see below).
Why do we need tissue-engineered
materials?
In partial thickness burns, in which the upper epidermal layer is
completely lost but part of the dermis remains, the epidermal
(a)
(c)
Fig. 2 Reconstruction of full thickness burn injuries. In the majority of cases, (a) a full thickness skin defect is treated with (b) a split thickness skin graft taken from
elsewhere on the body. Where sufficient skin grafts are not available, then full thickness defects are repaired in two stages using (c) a dermal substitute, which is
then covered by (d) an epidermal material, usually a very thin split thickness skin graft. (Reprinted with permission from60. © 2008 Woodhead Publishing.)
28 MAY 2008 | VOLUME 11 | NUMBER 5
keratinocytes lining the dermal inclusions (the sweat glands and
hair follicles) will rapidly migrate out of the dermis and form a new
epithelium. However, if the epidermis and all of the dermis is lost,
then this represents a major problem. Any loss of full-thickness skin
of more than 4 cm in diameter will not heal well without surgical
intervention27,30. When this is the case, it is often necessary to
reconstitute the skin in two stages taking two separate operations31
(Fig. 2).
Ideally if a burn injury is not too extensive, then surgeons will take
a split-thickness skin graft (all of the upper epidermal layer of skin and
some of the underlying dermal layer) from elsewhere in the body and
use it to graft the damaged area (Figs. 2a and 2b). The site from which
the skin graft has been removed will then heal by keratinocytes within
the dermis migrating upwards and proliferating.
However, if the extent of burn injury is extensive, then it is often
necessary to ‘build up’ the skin in two stages. One material is used to
provide a dermal equivalent that must become vascularized before an
epidermal material (most often a very thin split-thickness graft, but
occasionally cultured cells or tissue-engineered skin) can be placed on
top (Figs. 2c and 2d)17,27,30.
In addition to burns injuries, tissue-engineered materials can benefit
patients with chronic ulcers and those requiring reconstructive surgery4.
The biomaterials in current use for tissue engineering are discussed in
the next three sections.
Epidermal cover
Culture of human adult skin cells from a small biopsy of the patient’s
skin was developed in the 1970s32,33 by expanding keratinocytes
on lethally irradiated mouse fibroblasts in the presence of mitogens
(small proteins that stimulate cells to divide) and bovine fetal calf
serum. This works well and gives reliable expansion of keratinocytes
even for the elderly. By the early 1980s, small sheets of keratinocytes
(referred to as cultured epithelial autografts, CEAs) were being used to
(b)
(d)
 Biomaterials for tissue engineering of skin REVIEW

treat patients with extensive burns injuries5. These cells are grown on
a feeder layer of lethally irradiated mouse fibroblasts (used to provide
a good surface for the cells to attach to, and also to provide growth
factors to encourage proliferation of the keratinocytes) until they are
2–3 cell layers thick and the cells have joined to each other in a thin
sheet. To detach the cells, it is necessary to add an enzyme to loosen
the attachment of the cells to the underlying tissue culture plastic
and then gently scrape the sheet from the plastic using mechanical
force (a tricky job when one wants to avoid ripping these sheets
into pieces). Sheets of cells are then wrapped around a piece of inert
backing dressing for delivery to the patient.
There are practical problems in delivering keratinocytes as small
sheets. The sheets are fragile and many of the keratinocytes are already
differentiated beyond the point at which they can take any active part
in providing a new epithelium. Nevertheless, this was a breakthrough
methodology and is available commercially as Epicel6. The cells are
placed cell surface down onto the wound bed, and keratinocytes still
capable of leaving this integrated sheet of cells enter the wound bed
and form a new epithelium. The backing dressings with any residual
differentiated cells are removed some 7–10 days later31.
As handling cells in this way is quite difficult, alternative
approaches for detaching and delivering cells have since been
developed. For cell detachment, growing cells on temperature-sensitive
poly(N-isopropylacrylamide) (PNIPAM) has been advocated34. Cells
grow into sheets on PNIPAM-coated tissue culture dishes, then the
temperature is decreased to collapse the polymer chains and release
the cell sheet. Keratinocytes can also be expanded in culture, made
into suspensions, and sprayed onto wound beds in media35 or with
fibrin12. Alternatively, keratinocytes are expanded then seeded onto
various carrier/transfer dressings, ranging from bovine collagen
coated membranes36 to a chemically defined polymer carrier dressing
(Myskin37, Fig. 3).

(a) (b)

(c) (d)

Fig. 3 Plasma polymerization can be used to produce surfaces that are either nonadherent or keratinocyte adherent. (a) Plasma rig. The sample to be coated is
placed within the vacuum chamber and a high radiofrequency energy is used to break the material into fragments under vacuum. This introduces the material to be
coated as a gas, which becomes attached to the surface. (b) This technique is used to produce a background surface coated with octadiene, which is nonadhesive
for the majority of cells. Onto this is placed a template of the letters ‘TONY’ coated with acrylic acid. Skin cells from Tony Ryan of the University of Sheffield, UK,
were expanded in the laboratory and placed on this surface. They adhered to the acrylic acid-coated surface but failed to adhere to the octadiene-coated surface.
(c) The clean room conditions under which patients’ skin cells are expanded from a small skin biopsy. (d) An acrylic acid plasma polymerized silicone carrier
(Myskin™). Patients’ cells are placed on the acrylic acid-coated surface and kept in media for transport to the patient. The clinician or dressings nurse picks up the
Myskin carrier and places it with the cells facing downwards onto the wound bed.

MAY 2008 | VOLUME 11 | NUMBER 5 29

REVIEW Biomaterials for tissue engineering of skin
(a)
Fig. 4 (a) A neuropathic diabetic ulcer that has failed to heal for 3 years, and (b) after eight applications of the patient’s own cells delivered on the Myskin carrier9.
Myskin is a synthetic polymer of acrylic acid coated onto medical
grade silicone by plasma polymerization37,38. This avoids the use of
bovine collagen. Cells attach readily to this surface (after conventional
expansion in the laboratory), but when cells on the transfer dressing
are placed on the wound bed, the surface has been designed so that
cells can leave it without the need for trypsinization (using an enzyme
to detach the cells from the substrate), change in temperature, or any
outside intervention. Fig. 4 shows an example of a diabetic ulcer that
resisted healing for three years but did heal after eight applications of
the patient’s own cells delivered on the Myskin carrier in an outpatient
clinic9.
Thus biomaterials can assist in the transport and delivery of
keratinocytes to a wound bed. Depending on the design of the
material, cells will leave the carrier dressing in a passive36,37 or active34
manner. However, a major issue that none of these materials directly
addresses is how to improve the attachment of the keratinocytes to
the underlying wound bed, given that clinical wound beds that require
the use of cultured cells are often less than ideal.
Dermal replacement
Currently, three types of biomaterials are in use for dermal
replacement: natural dermal collagen obtained from human allodermis
(dermis derived from skin donated to skin banks) or porcine dermis
(Permacol14), extracted bovine collagen, and nonwoven polygalactic
acid scaffolds (Dermagraft15 and Transcyte16).
Donor skin obtained from accredited skin banks can be used as a
temporary wound dressing or to provide a permanent allodermis4.
Permacol is cross-linked porcine collagen that is sometimes used as a
temporary skin dressing14.
30 MAY 2008 | VOLUME 11 | NUMBER 5
(b)
Integra17,18 was developed for the treatment of full-thickness
burns injuries. It consists of a dermal replacement material, composed
of bovine tendon collagen with a glycosaminoglycan (chondroitin-6-
sulphate) added to it, onto which a silicone membrane is sealed to
the upper surface to act as a temporary epidermal substitute layer.
This artificial membrane is designed for temporary use only. (In the
absence of living cells, it is very difficult to see how one could create
a permanent artificial dermal barrier.) It controls moisture loss from
the wound and bacterial entry into the wound. The most important
function of Integra is that it serves as a template to generate a
neodermis. Following vascularization of the material from the patient’s
wound bed, which normally takes about three weeks, the silicone layer
is peeled off and an epidermal layer is provided, usually using a very
thin skin graft.
The neodermis that forms under either Integra or donor skin gives a
better wound bed for take of future skin grafts than if the wounds were
allowed to heal through the formation of disordered granulation tissue.
Integra has been evaluated in an economic study for its use in chronic
wounds compared with using split-thickness skin39. Donor skin has now
been used for more than 20 years with good results40. The advantages
of both donor skin and Integra are that they can give immediate barrier
protection.
Dermagraft is a cryopreserved human fibroblast dermal substitute
for chronic wounds that has been shown to increase the rate of
healing15. In this product, donor fibroblasts are seeded onto a
bioabsorbable polyglactin mesh scaffold. Transcyte16 is similar to
Dermagraft15 in design, in that it contains human donor fibroblasts
that have been grown on a porcine collagen coated bioabsorbable
polyglactin scaffold. But this product also has a silicone membrane
 Biomaterials for tissue engineering of skin
(a)
(c)
Fig. 5 (a) Split thickness skin is (b) sectioned and stained with haematoxylin. (c) Once denuded of all cells, the remaining de-epidermized acellular dermis is pliable
and (d) can be reconstituted with laboratory-expanded keratinocytes and fibroblasts for experimental or clinical use41.
attached to it to act as a temporary barrier (as in Integra17). Transcyte
is recommended for use in major burns to provide a dermal alternative
and a temporary epidermal barrier.
Epidermal/dermal replacement
As is evident from the previous section, collagen is the favorite
biomaterial for tissue engineering, whether in the form of mature
human cross-linked collagen (donor skin obtained from skin banks) or
collagen extracted from bovine or porcine skin or tendon. However,
there are three issues to be tackled: safety, neovascularization, and
contraction.
With respect to safety, currently bovine collagen is approved by the
US Food and Drug Administration (FDA) for clinical use as the risks are
viewed as low, if the collagen is sourced from herds known to be free
of bovine spongiform encephalitis (BSE). The other major source of
collagen dermal substitute is natural dermis from cadaveric skin. Here
screened donors from accredited tissue banks must be used to reduce
the risk of transmission of viral diseases.
Fig. 5 illustrates tissue-engineered skin based on natural dermis.
Fig. 5a shows the appearance of normal skin before processing
and Fig. 5b is a haematoxylin and eosin (H&E) stained section
through the skin visualized using light microscopy. Fig. 5c shows
the gross appearance of the dermis that remains after epidermal
and dermal cells have been removed by a mixture of NaCl and
phosphate-buffered saline washing41. Fig. 5d shows the appearance
REVIEW
(b)
(d)
of reconstructed skin in which the de-epidermized acellular
dermis is reconstituted with keratinocytes and fibroblasts isolated
from a patient’s skin biopsy. These cells are expanded up in the
laboratory and then added back to the acellular dermis. However,
when this reconstructed skin is taken to the clinic (as shown in
Fig. 6), then problems with delayed vascularization23 can lead to
loss of relatively thick reconstituted tissue-engineered skin grafts
and for those grafts that survive, some may undergo significant
contraction23,42,43.
Neovascularization has been identified as a problem for tissue-
engineered constructs (not just skin). Constructs lacking any intrinsic
vasculature can be slow to vascularize and fail to integrate. This is one
of the major problems in the field at present. Novel approaches to
improve the rate of neovascularization of tissue-engineered skin are
badly needed.
The problem of contraction is also a challenge. It is possible to
alter the cross-linked structure of the dermal scaffold so that it resists
contraction (as is seen in the case of Permacol14) but this leads
to another interesting and important problem. Scaffold materials
that are extensively cross-linked can initiate fibrosis, encapsulation
(formation of a thick layer of connective tissue around an implant),
and a relatively extreme immune response44. A recent theory on
this proposed by Badylak44 and others45 is that unless neutrophils
and macrophages can degrade implanted collagenous structures,
they will activate lymphocyte TH2 cells, which provoke an extreme
MAY 2008 | VOLUME 11 | NUMBER 5 31
REVIEW Biomaterials for tissue engineering of skin

(a) (b)

Fig. 6 (a) The use of tissue-engineered skin to treat extensive contraction following burns injury. (Reprinted with permission from23. © 2003 Blackwell Publishing.)
(b) Keratinocytes contract human allodermis in the laboratory.

inflammatory reaction, rather than the induction of TH1 helper
immune cells, which lead to constructive remodeling of natural
scaffolds45.
Fig. 6b illustrates the ability of skin cells to contract natural dermis,
the subject of some investigation in our laboratory43,46,47. This suggests
that skin cells, particularly keratinocytes, use a collagen cross-linking
enzyme, lysyl oxidase, to cross link the gathered-in collagen fibers. An
inhibitor of lysyl oxidase found in sweet peas, beta-aminoproprionitrile
(β-APN), can reduce this42.
Fig. 7 illustrates natural human dermis used to make tissue-
engineered oral mucosa. Fig 7a shows the morphology of normal
buccal mucosa (the lining of the mouth), and Fig. 7b is tissue-

(a) (b)

(c) (d)

Fig. 7 (a) Normal buccal mucosa stained with haematoxylin and eosin. (b) Tissue-engineered buccal mucosa. (c) A 10 cm x 2 cm piece of tissue-engineered buccal
mucosa used to treat scarring of the urethra. (d) Some 18 months post treatment with tissue-engineered buccal mucosa to replace scarred tissue, the patient’s
urethra remains open and unscarred. (Reprinted with permission from24. © 2008 Elsevier.)

32 MAY 2008 | VOLUME 11 | NUMBER 5

 Biomaterials for tissue engineering of skin REVIEW

engineered buccal mucosa in which de-epidermized acellular dermis is
reconstituted with epithelial cells and fibroblasts from a small biopsy
taken from the patient’s mouth. Fig 7c illustrates the gross morphology
of a tissue-engineered oral mucosa produced in this way. Fig 7d is
taken 18 months after this tissue-engineered construct has been used
to replace scar tissue in the urethra. The urethra is free of scarring. We
have recently reported a pilot study getting tissue-engineered buccal
mucosa into clinical use24. The initial vascularization was excellent
because this is a very well vascularized wound bed, but we did find
fibrosis occurred in two out of the five patients studied, suggesting that
further work needs to be undertaken to produce scaffolds that resist
fibrosis.
Biomaterials challenges in tissue engineering
skin
The problems of existing materials have been flagged up throughout
this review and can be summarized as follows:
• Safety issues – avoiding animal-derived materials;
• Improving the ‘take’ of cultured keratinocytes on wound beds – can
we make a synthetic BM glue?
• Improving the rate of neovascularization of tissue-engineered skin;
and
• Developing scaffold materials that resist contraction and fibrosis.
How can the safety of biomaterials be ensured?
While natural collagen scaffolds can work well, the devil is in the
detail of how they are extracted, processed, and sterilized to be fit for
purpose with low risk for the patient. The risk of disease transmission
from human skin can be reduced with good skin banking practices,
especially if combined with skin sterilization41,48,49, but cannot be
completely eliminated. Bovine-derived collagen approved by the FDA
is currently perceived as low risk, but this depends on herds not being
previously exposed to BSE. Accordingly, the development of alternative
synthetic scaffolds is to be welcomed. Frontrunner materials are poly-L-
lactide (PLLA), polycaprolactone (PCL), and polyglycolic acid (PGA)50,51.
These have been approved by the FDA and used clinically for a number
of years in a range of applications, such as resorbable sutures, fracture
plates, and stents52. (Dermagraft15 and Transcyte16 are both based on
synthetic scaffolds and have been in clinical use for several years.)
There is much interest in producing scaffolds by electrospinning
(Fig. 8a). This versatile method can produce three-dimensional open
porous structures that approximate the structure of collagenous dermis.
Natural materials, such as collagen and chitosan, can be spun on their
own or together with synthetic polymers. One can spin parallel
(Fig. 8b), or random (Fig. 8c) fibers, depending on the speed of
spinning. These fibers can be used in vitro to determine optimal fiber
diameter and the spaces between fibers that cells can bridge.

(a) (b)

(c) (d)

Fig. 8 (a) Electrospinning of fibers. Production of (b) parallel and (c) random fibers. (c),(d) Polylactic fibers have had rhodamine added to help in visualization, and
cell nuclei have been stained blue with DAPI. (c) Fibroblasts are seen throughout the random scaffold. (d) Fibroblasts are able to bridge gaps between fibers61.

MAY 2008 | VOLUME 11 | NUMBER 5 33

REVIEW Biomaterials for tissue engineering of skin
(a)
(c)
Fig. 9 A random biodegradable 75% PLA, 25% PGA electrospun scaffold (a) before and (b) after culture with small vessel endothelial cells, here stained with Toto
red. (c),(d) Three months after implantation of cell-free scaffold fibers into the flank of rats. Scaffold fibers seen at (c) low and (d) high magnification show good
vascularization and penetration of granulation tissue.
It is possible to vary the ratio of PLA to PGA to produce scaffolds
with different rates of degradation in vivo. Fig. 9 shows the appearance
of a random spun scaffold of 75% PLA and 25% PGA. Fig. 9b shows
a culture of small vessel endothelial cells on this scaffold in vitro, and
Figs. 9c and 9d show the appearance of the scaffold implanted into
the flank of rats at three months. In Fig. 9c, taken at deliberately
low power, one can see that there is good tissue penetration and
vascularization of the scaffold (introduced cell-free into these rats).
Fig. 9d shows a higher power to illustrate the appearance of these
fibers, which break down over a period of several months.
Alternative approaches are to get skin cells to generate their
own scaffold in vitro. This can be achieved either with some existing
scaffold support (as in Dermagraft15 and Transcyte16) or as recently
demonstrated53, seeding fibroblasts into human fibrin and encouraging
the cells over seven weeks to produce their own matrix, which is then
subsequently freeze dried and sterilized to be used as a scaffold for
repopulation with living cells for future clinical use.
How can attachment of cultured skin cells to wound
beds be promoted?
Keratinocytes delivered on their own as sheets, as a spray, or from
carrier dressings lack components of the BM, and have an uphill
struggle in attaching well to challenging wound beds. Laboratory-based
34 MAY 2008 | VOLUME 11 | NUMBER 5
(b)
(d)
research to improve take of cells by attaching avidin (a naturally
occurring protein with an extremely high affinity for binding to
the natural vitamin biotin) to the cells and biotin to a collagen
substrate shows that this approach can improve attachment54.
But a major challenge is that whatever is to be used on the wound
bed must be something that’s clinically acceptable. In recent years
there has been considerable research into developing synthetic,
often self-assembling, biomimetic matrices incorporating natural
cell adhesion sequences as microenvironments for directing tissue
morphogenesis55. The task of making a synthetic BM-equivalent
glue that one could ideally spray on the wound bed before delivering
cultured cells (on their own or in scaffolds) is a major challenge, but
one which these new generations of three-dimensional synthetic
scaffolds may achieve.
How can materials improve neovascularization of
tissue-engineered skin?
The biomaterials commonly in use, such as donor skin or Integra
often take two–three weeks to become well vascularized. A number
of biomaterials are being developed to enhance angiogenesis, ranging
from the introduction of large pore sizes into scaffolds to promote
faster vascularization56, to the release of potent angiogenic factors
such as basic fibroblast growth factor (bFGF) from a three-dimensional
 Biomaterials for tissue engineering of skin
peptide-amphiphile injectable scaffold57, and synthetic biomaterials
representing simplified components of the extracellular matrix
(ECM)55. However, none of these are yet in clinical use to the best of
my knowledge and there is a real clinical need to improve the rate of
vascularization for tissue-engineered skin products to prevent loss of
grafts.
How can scaffolds resist contraction and fibrosis?
Finally, if even standard skin grafts can contract when moved from
one position on the body to another43, what chance do we have of
producing natural or synthetic scaffolds that resist contraction and
fibrosis? How skin cells affect the biophysical properties of the dermis
is poorly understood but the natural elasticity of skin is based on its
elastin content. There is a growing body of research investigating
elastin as a biomaterial for tissue engineering that should offer new
insights and approaches for producing scaffolds better able to resist
contraction58.
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REVIEW
Summary and future outlook
Tissue engineering of skin is a maturing field and the biomaterials
(mostly collagen) used in tissue-engineered products have benefited
patients since the 1990s. However, it would be wrong to conclude
that there is no room for improvement. In the future, it is hoped that
new biomaterials will be produced to overcome at least some of the
problems identified in this review.
Eliminating or reducing the risk of disease transmission could be
achieved either by using synthetic collagen-mimetic materials or
recombinant-produced collagen. Next, can biomaterials be designed to
improve the attachment of cultured cells to the underlying wound bed?
Hopefully, our knowledge of angiogenesis and biomaterials design will
lead to materials that become vascularized more rapidly than current
ones. Finally, we need to combine our understanding of wound healing
and immune responses with biomaterials to produce biodegradable
scaffolds that lead to rapid healing without suffering significant
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