Expert Review of Medical Devices

ISSN: 1743-4440 (Print) 1745-2422 (Online) Journal homepage: www.tandfonline.com/journals/ierd20

Design and preparation of polymeric scaffolds for

tissue engineering

Thomas Weigel, Gregor Schinkel & Andreas Lendlein

To cite this article: Thomas Weigel, Gregor Schinkel & Andreas Lendlein (2006) Design and
preparation of polymeric scaffolds for tissue engineering, Expert Review of Medical Devices,
3:6, 835-851, DOI: 10.1586/17434440.3.6.835

To link to this article: https://doi.org/10.1586/17434440.3.6.835

Published online: 09 Jan 2014.

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CONTENTS
Scaffold preparation from
polymer solution by
nonsolvent-induced phase
separation or thermally
induced phase separation
Scaffold preparation from
the polymer melt by a
foaming process
Scaffolds by
microsphere sintering
Rapid prototyping/
solid free-form fabrication
Indirect methods using RP or
SFF fabrication methods
Self-assembly systems
Electrospinning
Scaffold fabrication
supporting processes
Method comparison
Summary
Expert commentary
Five-year view
Key issues
References
Affiliations
†
Author for correspondence
Institute of Polymer Research,
GKSS Research Center, Kantstr. 55,
D-14513 Teltow, Germany
Tel.: +49 332 835 2450
andreas.lendlein@gkss.de
KEYWORDS:
electrospinning, phase separation,
preparation methods, rapid
prototyping, scaffolds,
self-assembly systems,
tissue engineering
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Design and preparation of
polymeric scaffolds for
tissue engineering
Thomas Weigel, Gregor Schinkel and Andreas Lendlein†
Polymeric scaffolds for tissue engineering can be prepared with a multitude of different
techniques. Many diverse approaches have recently been under development. The
adaptation of conventional preparation methods, such as electrospinning, induced phase
separation of polymer solutions or porogen leaching, which were developed originally for
other research areas, are described. In addition, the utilization of novel fabrication
techniques, such as rapid prototyping or solid free-form procedures, with their many
different methods to generate or to embody scaffold structures or the usage of self-
assembly systems that mimic the properties of the extracellular matrix are also described.
These methods are reviewed and evaluated with specific regard to their utility in the area
of tissue engineering.
Expert Rev. Med. Devices 3(6), 835–851 (2006)
The technology of tissue engineering aims to formation in vitro and in vivo. Up to now
generate new or substitute damaged or malfunc- scaffolds made from biomaterials have temporar-
tioning tissue or organs and could well become ily substituted the extracellular matrix (ECM).
an alternative method to whole organ trans- Such biomaterials can be of natural origin, such
plantation [1–6]. In the last decade particularly, as organic collagen [74–76], fibrin glue [77–79],
enormous advances have been made in the area hyaluronic acid [80–82] or the inorganic-like cor-
of tissue regeneration for therapeutical purposes. alline [83,84]. Synthetic polymeric materials have
Tissue engineering is an interdisciplinary also been investigated, including, for example,
research area in which principles of material aliphatic, copolyesters [85–87], polyhydroxyal-
science/engineering and cell biology/life science kanoates [88–90] and polyethylene glycol [91,92], or
are combined. The methods of tissue engineer- inorganic materials, such as hydroxy-
ing have been applied to different types of tissue, apatite [48,93,94], tricalciumphosphate [95,96], glass
including skin [7–11], bone [12–16], liver [17–21], ceramics and glass [97–99].
intestine [22–27], esophagus [28–32], valve The intrinsic material properties, such as
leaflets [33–36], muscle [37–39] and tongue [40–42], the mechanical [100] or thermal [101,102] behav-
the vascular system [43–47], for craniofacial ior, of a polymer play a role in the utilization
defects [48–50], tendons and ligaments [51–55], of tissue engineering and also in the embodi-
cartilage [56–60] and nerve tissue [61–65]. Since the ment and the morphology of the shaped scaf-
early commercialization of tissue-engineered fold body. By ‘embodiment’, we mean the
applications, for example, the work of Bell and preparation with, for example, the use of
colleagues [66], research with stem cells [3,67–69] fibers [103], microspheres [104,105] or flat bod-
and the use of growth factors [70–73] that support ies, like particular structured films [106], to
cell differentiation and proliferation, have pro- become a scaffold body. The definition of
vided new opportunities in the field of tissue embodiment also includes the computer-
engineering. At present, tissue engineering aided construction of these bodies [107]. The
methods generally require the use of a porous morphology of a scaffold has to meet the
scaffold that serves as a matrix for initial cell demands of the targeted applications [108].
attachment and subsequently for tissue General requirements for the scaffold
10.1586/17434440.3.6.835 © 2006 Future Drugs Ltd ISSN 1743-4440 835
Weigel, Schinkel & Lendlein
morphology are interconnected pores in order to assure cell
growth and the transport flow of nutrients and metabolic
waste [109,110]. The scaffold surface should enable a suitable
cell attachment and promote the cell differentiation and pro-
liferation. Furthermore, the biocompatible degradation of the
scaffold material has to proceed appropriately and in sync
with the formation of the tissue [111]. The scaffold morphol-
ogy is determined by the fabrication method and/or the
embodiment. By varying the component dimensions
(e.g., reducing the diameter of filaments from the micrometer
to the nanometer scale), scaffolds can be formed with porosi-
ties and strengths that are significantly different to their origi-
nal morphology [112]. The mechanical properties of the scaf-
fold and the tissue, which need to be replaced, should
match [113] and, eventually, the material processing properties
need to be suitable for the scaffold formation.
In this review, different methods for scaffold design are
summarized with specific emphasis on fabrication methods.
The preparation of porous scaffold bodies can be realized by a
multitude of different techniques. Especially, new develop-
ments in the area of electronically controlled processes [114,115]
and the utilization of new research results, which mimic natu-
ral systems, such as the ECM [116], induce new progress in
scaffold formation. The spectrum of achievable scaffold types
with very different properties has been expanded by both the
process adaptation, which has been established initially in
other applications, such as membrane formation [117], and the
combination of different scaffold preparation methods [118].
Scaffold preparation from polymer solution by
nonsolvent-induced phase separation or thermally induced
phase separation
In order to fabricate scaffolds from polymer solution, poly-
mers are dissolved in a solvent and brought by casting onto a
solid surface to immerse this flat thin solution into a nonsol-
vent, to form a flat membrane-like structure for tissue engi-
neering applications [119]. By casting the solution through a
nozzle into the nonsolvent, a tubular structure can be
created [120,121]. A block structure is also possible by casting
the polymer solution into a mold and bringing the solution
surface into contact with the nonsolvent afterwards [122].
When adding the nonsolvent, the solvent diffuses out while
the nonsolvent diffuses into the polymer solution that will
form the scaffold structure. The nonsolvent concentration in
the polymer solution increases. After a short diffusion time,
which means a few fractions of a second, at the specific work-
ing temperature, the ternary system of solvent, nonsolvent
and polymer is no longer stable. The polymer begins to pre-
cipitate from the solution and it finally forms the
scaffold [119]. At the end of this exchanging process, the
porous morphology has been created and the shape is
solidified [122].
The average pore size that can be realized by this process can
be varied only from the nanometer [123] to the few micrometer
range [122]. However, applications in tissue engineering often
836
require pore sizes in the upper micrometer range, for example,
for skin (20–150 µm) or bone scaffolds (40–400 µm) [124],
which cannot be realized with this technique unless it is com-
bined with other processes, such as salt leaching [125]. Special
shaped bodies prepared by ‘pure’ nonsolvent-induced phase sep-
aration (NIPS) can also be used in biomedical applications [126],
for example, as a carrier for epidermal substitutes (FIGURE 1) [127].
As well as the initiation of phase separation by a nonsolvent,
it is also possible to initiate the phase separation thermally by a
thermally induced phase separation (TIPS). A homogeneous
solution of a polymer in a solvent is prepared at an elevated
temperature [128,129]. The solution is introduced into the
desired form and cooled afterwards by removal of heat energy
in a quenching process [130]. The solvent is typically removed by
sublimation [131,132] or extraction [133,134] to yield a micro-
porous scaffold. A liquid–liquid phase separation takes place, in
which the solution separates into a polymer-rich phase and a
polymer-poor phase (FIGURE 2) [135].
Depending on the nature and strength of the polymer sol-
vent interactions, further thermodynamic polymer solvent
systems are conceivable. Such a constellation is a solid–liquid
TIPS [136,137], in which the polymer crystallizes from the solu-
tion and, at least, in theory, a liquid–solid TIPS exists, in
which the solvent crystallizes first, before the polymer [138].
The microstructure of the resulting scaffold depends on
which of these three sequences is followed and on the kinetics
of structure development. Liquid–liquid TIPS seems to be the
preferred method because it has been proven to be a valuable
method of making scaffolds and it has been studied
extensively [130,139–141].
50 μm
Figure 1. Laser-scanning microscopic picture from poly(ether imide)
membranes prepared by nonsolvent-induced phase separation and
modified with poly(ethylene imine) (keratinocytes cultured for 4 days
stained for cell cytoskeleton). Reproduced with permission from [127].
Expert Rev. Med. Devices 3(6), (2006)
 Design and preparation of polymeric scaffolds for tissue engineering
200 μm
Figure 2. Scanning electron microscope micrograph of scaffold from a
multiblock copolymer prepared by thermally induced phase separation.
Reproduced with permission from [135].
Scaffold preparation from the polymer melt by a
foaming process
The foaming process of thermoplastics represents a fre-
quently used method for the fabrication of porous materials.
Methods differ mainly in the type of foaming agents, such as
water [142] or CO2 and nitrogen [143], as well as
fluoroform [144], and the processing procedure, for example,
by an injection molding with a foaming agent based on a
carboxylic acid to obtain porous cores [145] or by the use of a
high-pressure chamber in an autoclave [101]. Expanding sub-
stances are generated by chemical reaction, for example, dur-
ing polyurethane synthesis as well as ammonium bicarbonate
that spontaneously produces CO2 and ammonia gas
bubbles [146] or by a thermal decomposition of specially
added substances, such as azodicarbonamide [147,148]. The
foaming process can also be initiated by ‘physically’ acting
agents, which change their physical state via variation in tem-
perature and pressure during the process. Foaming processes
are realized as continuous [149] or discontinuous [150,151]
working processes. A common method of scaffold prepara-
tion is the exposure of polymers to high-pressure CO2 [152].
This method has the advantages that CO2 is cheap, simple to
access, gives, for example, a lower dense foam than
nitrogen [73,143] and it does not require removal before cell
seeding like other pore forming substances. The gas is dis-
solved in the solid polymer or polymer melt at high tempera-
ture and high pressure, for example, for poly(lactide-co-gly-
colide)acid (PLGA) 35–40°C, 10–20 MPa [153], for
poly(ε-caprolactone) (PCL) 70–90°C and 7–32 MPa [154] or
even cyclic olefin copolymer (COC) 100–180°C and
30 MPa [155].
The thermodynamic instability is then induced by reducing
the CO2 gas pressure to an ambient level [150]. During the
expansion process, the morphology of the scaffold may be gen-
erated by implementing a heterogeneous nucleation with, for
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example, closed cell foams and microsizes of approximately
10 µm [156] or a homogeneous nucleation with cell sizes in a
broad range of 30–700 µm [157]. It has been published regularly
that the foams possess closed cells [158–160], however, this means,
at the same time, that there is a low level of interconnectivity
and therefore their application in the area of tissue engineering
is limited. Thus, foaming processes are often coupled with
leaching methods in order to increase the porosity of the result-
ing scaffold [161–163]. Scaffold preparation by a foaming process
also allows the incorporation of bioactive [164] or
pharmaceutical [165] substances.
Scaffolds by microsphere sintering
Microspheres can be formed by different processes, such as
spraying a polymer solution followed by NIPS [166]. The use of
ultrasound [167] to emulsify water in a polymer solution is also
described. It aims to finally obtain a water-in-oil-in-water
emulsion. The water droplets may even be loaded with, for
example, DNA [164]. Then, the emulsion of water-in-polymer
solution is brought into an aqueous poly(vinyl alcohol) (PVA)
solution to complete the NIPS by stirring for 3 h. By the use of
a vortexer [168,169], a water-in-oil-in-water is achievable. Hot
stirring of a paraffin/gelatin–water emulsion at 80°C is also
reported. The stirring is followed by an ice water quenching to
obtain paraffin spheres for paraffin leaching [170]. The simplest
way is to pour the organic polymer solution into the aqueous
PVA solution and to stir for a few hours. It was chosen to iso-
late microspheres that could be brought into a 3D shape fol-
lowed by a sintering process to an in vivo characterized scaffold
body [171,172]. Microsphere sintering is, furthermore, a suitable
method of obtaining composite structures from polymeric and
inorganic substances for bone tissue engineering [173].
Rapid prototyping/solid free-form fabrication
Conventional fabrication techniques can not build up a complex
scaffold with an exactly predefined shape. Rapid prototyping
(RP) [174,175] or solid free-form (SFF) [115,176,177] fabrication, are
common terms for a group of techniques that model a scaffold
directly from a computer-aided design (CAD) data set. RP tech-
niques mostly build up a specific body shape by the selective
addition of material, layer-by-layer, guided by a computer
program [178]. RP systems were not developed for biomaterials
originally; for example, the 3D-Printing system Model
Maker II™ [179] but the manifold of RP designs also enables
their biomedical application. The step-by-step construction of
scaffolds facilitates improved reproducibility. In contrast to con-
ventional fabrication methods, parameters, such as porosity,
interconnectivity, pore size and geometric stability, can be con-
trolled more precisely [180]. Furthermore, cells can be printed on
surfaces [181] and so it seems to be possible that living biological
substances could be incorporated into the prefabricated layer
before the final assembly [114,182]. However, the method is
restricted in the choice of materials and limited by its resolution
determined by the use of engineered precision machine tools and
tools like nozzles and the frequent small final size of the scaffold
837
Weigel, Schinkel & Lendlein
(e.g., 0.4–3.5 cm3) [183–185], depending on the fabrication. In
most cases, scaffolds with resolutions in a range of 200–500 µm
are described [107] – depending on the RP technology used. The
usage of a special RP fabrication technique demands specific
material properties. Although many different applications to
embody scaffolds under RP processing conditions are described,
the special requisitions of the polymer material limit the
utilization of RP fabrication techniques.
Shape deposition manufacturing
Shape deposition manufacturing involves the fabrication of a lay-
ered scaffold in a tailor-made geometry by a computer-controlled
cutting machine [114]. The scaffolds are built up incrementally
from prefabricated cross-sectional layers of formed materials.
Layers are assembled manually and joined to form 3D bodies
using biodegradable or biostable fasteners. The concept of
robotic microassembly follows the same principle [114,182]. Differ-
ently designed block units are first prepared [186], for example, by
lithographic methods or other previously mentioned techniques.
The blocks are assembled with a precision robot with microgrip-
ping capabilities. However, this interesting and innovative
method is still awaiting broad application in tissue engineering.
Fused deposition modeling
Compressed polymer melts are starting points for the prepara-
tion of porous scaffolds using a 3D-fiber deposition
technique [187–190]. In this procedure, a polymer melt is formed
into a fiber with a temperature–controlled extruder. Its nozzle
deposits the fiber or the filaments on a motor–driven x-y-z table.
The machine first builds a layer of fibers with a well defined dis-
tance. On the top, fiber layers are deposited, which form a 3D
scaffold with an exact porous morphology and 100% intercon-
nectivity. The positional control of the table is often computer
aided and allows for the construction of 3D structures (FIGURE 3).
Models could also use data from computer tomography,
magnetic resonance imaging scans or data created from 3D
object digitizing systems [191]. In a modification of the fused
deposition modeling (FDM) process, the filament preparation
to feed the extrusion head as described, for example, with a
diameter of 1.78 mm [57], is no longer necessary. Instead, the
polymer material can be used in its commercial form as pellets
and granules by precision extruding deposition (PED), which
forms, for example, PCL scaffolds with a pore size of
250 µm [192] or even 200 µm 193].
A specific demand on the material is that it demonstrates a suit-
able thermoplastic behavior. Therefore, meltable polymers are
used frequently, such as the slow biodegrading PCL [110,191,194,195]
or the nonbiodegradable acrylonitrile butadiene styrene
(ABS) [188,196] or polypropylene (PP) [197]. The use of the good
biodegradable PLGA or poly(lactic acid) (PLA) in FDM is rarely
reported. A disadvantage of the biodegradability may also be the
thickness of the pore walls stemming from the fiber diameters, for
example, approximately 200–300 µm [110,191,198] and the dimen-
sions of the scaffold bodies are often rectangular and with a size of
a few hundred mm3 to several cm3 [110,183,199].
838
Nonfused liquid deposition modeling
The deposition of extruded strands, filaments or the plotting of
dots in 3D is not necessarily connected with high temperatures
and polymer melts. A further possibility is the usage of pastes or
slurries, solutions and dispersions of polymers or reactive
oligomers [200]. Special experimental equipment, with adapted
processing options, is required for processing of these materials
into 3D scaffolds. The described multiphase jet solidification
(MJS) process for biomaterials [201] generally means the use of a
dispersion of different phases, for example, solid ceramic particles
and a binder solution [202] in RP. The bioplotter™ [203,204] or
reactive plotter [205] dispenses pastes or dispersions into a match-
ing plotting liquid with the right density. After leaving the nozzle
and contacting the previous layer of the body that is being fabri-
cated, the plotting medium is becoming solid. No supports are
needed owing to the fact that the plotting liquid medium
compensates the gravity [107].
3D printing
In 3D printing technology (3D-P), the shaped bodies are cre-
ated by a layering printing process with adhesive bonding,
using powder as a base material [301]. In the beginning, a layer
of powder is spread over a building platform. Then a binder
solution is deposited precisely by an ink-jet print head on the
powder layer to join single powder particles, resulting in a 2D
layer profile [206]. A fresh layer of powder is laid down and the
process is repeated. After drying of the binder, the nonjoined
powder is removed by an air jet flow [184] and the finished scaf-
fold retrieved. The resolution of 3D-P is influenced by the par-
ticle size of the powder, the nozzle size and degree of control
over the position controller that defines print-head movement.
An achievable channel diameter of 500 µm has been
reported [206]. The powder of materials that can be used for bio-
medical applications is not always available in the appropriate
particle size (usually 80–250 µm) and often requires certain
pretreatments [207]. Powder particles have to flow well with a
defined size range and have to demonstrate good interaction
with the liquid binder in an amount of at least 500 ml granu-
late [208]. The successful realization of the 3D-P process also
depends on the adaptation of an appropriate binder for differ-
ent base materials. A preferred solvent with regard to biocom-
patibility is water, suitable for natural biopolymers, such as
starch-based [209], gelatin or collagen. Organic solvent as bind-
ers (e.g., chloroform or methylene chloride) might be harmful
to the human body and difficult to remove completely [210].
Selective laser sintering
This technique uses deflected laser beams (infrared laser, CO2
laser) to sinter thin layers [211] of powdered materials, such as
wax, synthetic polymers (polycarbonate [207], polyamides [210],
PCL [212]) or mixtures/coatings with polymers, such as ultra
high molecular weight polyethylene [213], poly(etherether-
ketone)/hydroxyapatite [214] or polyvinyl alcohol/hydroxy-
apatite [213], to prepare solid 3D scaffolds. The laser beam selec-
tively scans over the powder surface [210]. The interaction of the
Expert Rev. Med. Devices 3(6), (2006)
 Design and preparation of polymeric scaffolds for tissue engineering

2 mm 1 mm 1 mm

A B C

2 mm D 2 mm E 1 mm F

Figure 3. Scanning electron microscope photos of scaffolds from fibers with different deposition geometries. (A) Homogeneous fiber spacing of 1 mm
showing typical fiber diameters and pore geometries; (B) top view; (C) staggered fiber spacing of 1 mm; (D) inhomogeneous pore-size gradient;
(E) inhomogeneous pore-size gradient deposited on a dense basal layer of fibers; (F) superficial layer of gradient scaffold. Reproduced with permission from [190].

laser beam with the powder elevates the powder temperature Furthermore, different adaptations and variations concern-
just beyond the glass transition temperature but below the ing the improvement of the hydrogel stability (usage of
melting temperature of the used material. The powder particles polymer mixtures) [216] were developed to incorporate living
that are in contact are deformed and fused together. New layers cells during the formation process (adaptation of processing
of powder are deposited by a roller, building a new sintered conditions to prevent toxic free radicals) [218,219] or to
layer on top of the previous one (FIGURE 4). improve the acuteness of prepared structures – more precise
The laser-beam diameter (∼400 µm) or powder–particle laser beam moves connected with the expansion of the
size limits the dimension of generated scaffold structures. material base [114] or using photolithographic techniques
Owing to Gaussian distribution of the laser energy and the with x-rays, electron or ion beams [220]. The specific property
principle of powder bonding (different powder-particle
forms), it is usually difficult to build up special shaped bodies
with sharp corners or clear boundaries. Improvements in
selective laser sintering are expected, especially concerning
laser spot size, powder size and new ways to remove trapped
loose powder from scaffolds [215]. The restrictions to the mate-
rial properties are given by the demand for it to be available as
a powder and that the powder must demonstrate a suitable
melting and welding behavior.

Stereolithographic working principles

The principle of this technique is based on the initiation of a
chemical reaction (photopolymerization [216] or cross-
linking [217]) in special polymer liquids by electromagnetic radi-
ation. Light from a laser beam is directed onto selected regions
of a layer of liquid polymer causing solidification in the
exposed areas. By lowering of the nascent-shaped body, which
is arranged in a polymer liquid bath, a new layer of polymer Figure 4. Scanning electron microscope micrographs of a 3D structure
solution can be exposed to the laser beam for the initiation of obtained by selective laser sintering from a composite containing
the chain reaction. The stereolithographic working principle is 90 wt% polyetheretherketone and 10 wt% hydroxyapatite. Reproduced
repeated, generating 3D scaffolds (FIGURE 5). with permission from [107].

www.future-drugs.com 839
Weigel, Schinkel & Lendlein
A
Z axis movement
X–Y movable Elevator
UV laser
Resin surface
Vat
SL pattern
B
Figure 5. Stereolithography. (A) UV light is used to crosslink the material in
specific regions of a layer. The elevator is then lowered to reveal a new layer of
polymer and the process is repeated to create the desired shape. (B) A
prototype scaffold designed using stereolithographic technique.
Reproduced with permission from [217].
that a material requires in order to be employed in
stereolithographic techniques is the ability to react to light,
activating a chemical reaction.
Indirect methods using RP or SFF methods
The manufacturing methods for scaffold preparation
resuming under the terms RP or SFF fabrication allow
manifold usage of different materials. Nevertheless, every
technique requires certain material properties as prerequisites.
The indirect SFF fabrication technique [221] is an emerging
method designed to partly overcome these limitations
regarding biomaterials. In this procedure, a negative mold is
generated by one of the SFF fabrication techniques
(e.g., stereolithographic working principles [220], the 3D
printing system Model Maker II [222,223]) as a first step. In the
second step, the scaffold is formed by adding the casting
solution [224] to the negative mold using the desired polymeric
and/or ceramic biomaterials. After solidification, the negative
mold is removed by dissolution, melting or other procedures
(FIGURE 6) [225].
840
Furthermore, the porosity of the scaffold can be increased by
combining the solidification process, which is caused either by
conventional phase separation or by the TIPS technology, with a
porogen leaching process in order to form sponge-like
morphologies [223,225]. Scaffolds prepared by indirect RP or SFF
fabrication methods sometimes inherit errors and defects caused
by additional processing steps of mold manufacturing and elimi-
nation. Whenever RP techniques for biomaterials require, for the
respective application, specific materials with additional and often
specific properties – this method allows the use of a wider range of
biomaterials and combination of materials. For the mold building
step, it is remitted to select the best material for a precise RP proc-
ess that hardly directly depends on the biological behavior of the
scaffold. The scaffold is made with this mold from a biomaterial,
for example, by a molding or casting process.
Self-assembly systems
Molecular self-assembly is also an approach for fabrication of scaf-
folds for tissue engineering [226,227] and scaffolds from self-assem-
bling peptide scaffolds may be used, for example, in nerve tissue
engineering [228] or cartilage repair [229]. Molecular self-assembly
requires the molecules to undergo self-association and thus form
hierarchical structures from the bottom-up, molecule by molecule
without any external manipulations. Self-assembly systems are
omnipresent in nature. There are endeavors to mimic such natural
systems, such as the ECM, for scaffold formation [230]. Materials
used for these systems range from bi- or tri-block copolymers [231],
complex DNA structures [232] and lipids to simple or complex
peptides and proteins. Important principles of self-assembly are
chemical complementarity and structural compatibility through
weak and noncovalent interactions. Different construction units,
such as well ordered nanofiber scaffolds [233,234], peptide
nanotubes [235–237], segmented surface assembling peptides as a
‘molecular carpet’ [238–240] and dipolar molecules with changeable
conformation as a ‘molecular switch’ [241–243], can be realized by
specially designed peptide units and sequences. However, the real-
ization of peptide scaffolds by molecular self-assembly is extremely
extensive and it depends on elaborate techniques.
Electrospinning
Corresponding to the ambition to mimic the supramolecular
structure and biological functions of the ECM, the 3D-fiber
network of collagen composed of nanoscale multifibrils is often
the focus of consideration.
Electrospinning (ELSP) is an established process capable of
fabricating ultrafine fibers, in the micrometer [244] or nanometer
scale [245,246], by electrically charging a suspended droplet of pol-
ymer melt [244,247] or solution [248,249]. A high-voltage electro-
static field (10–20 kV) operated between a metallic nozzle of a
syringe and a metallic collector is used to generate a sufficient
surface charge to overcome the surface tension in a pendent
drop of the polymer fluid. Nanofibers are formed by the nar-
rowing of the ejected jet stream as it undergoes increasing sur-
face charge density due to the evaporation of the solvent [250,251].
Different processing parameters (e.g., kind of polymer/solution,
Expert Rev. Med. Devices 3(6), (2006)
 Design and preparation of polymeric scaffolds for tissue engineering
A B
Figure 6. Scaffold fabrication using rapid prototyped negative replica. (A) A computer-generated, 3D negative replica of a scaffold with a cubical pore shape.
(B) The negative replica of the scaffold fabricated using a rapid prototyping machine. (C) A photograph of the polymer scaffold fabricated using the negative
replica. (D) A scanning electron micrograph of the internal pore structure of the scaffold. Reproduced with permission from [225].
viscosity, surface tension, net charge density, polymer mass flux
in the syringe or ambient parameters, such as temperature,
humidity and air velocity) control the ELSP process, especially
the diameter and morphology of the resulting fibers [252]. The
fibers with diameters ranging from several µm down to 100 nm
and less are deposited in the form of a nonwoven fabric on a
collector through a random deposition process (FIGURE 7) [253].
Nonwoven sheets with 2D profiles are usually obtained by
ELSP and can be extended to nonwoven 3D fibrous meshes by
the prolongation of processing time [252].
Various polymer nanofibers can be deposited together into one
multilayered structure by ELSP of different polymer solutions
layer-by-layer. If different polymer solutions are ejected by several
orifices simultaneously, a mat consisting of a composition of dif-
ferent nanofibers is realizable [254]. The nanofiber-based scaffolds
possess a wide range of pore size distribution, high porosity and a
high surface area:volume ratio, which are favorable parameters
for cell attachment, growth and proliferation [255].
Scaffold fabrication supporting processes
Besides the methods for scaffold preparation discussed above,
the following two techniques are presented. They have a com-
prehensive character and often act as a supporting method to
realize the targeted parameters in the fabrication process.
Leaching technique
The leaching technique is described mostly in connection
with the solvent casting/particulate leaching [12,256,257] to
form tissue engineering materials but it has also been applied
as a supporting process in combination with many other dif-
ferent scaffold fabrication methods. Different porogens are
used frequently for the leaching techniques. These are, for
example, NaCl [258], as perhaps the most common leaching
substance, as well as paraffin spheres [170,259,260], sugar
crystals [261–263] or gelatin [264], which serve as place holders
for pores and their interconnections in the actual scaffold for-
mation process. These spacers are removed by leaching fol-
lowing the main processing step. Thus, the objective of the
leaching procedure is usually the realization of bigger pore
sizes and increased interconnectivity. The use of the leaching
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C D
1 mm
technique in combination with injection [265] or compression
molding [210,266], in combination with a NIPS [125], in gas
foaming processes [150], as addendum of indirect SFF fabrica-
tion techniques [267], in combination with soft lithographic
methods [268], photopolymerization [269] or in combination of
coagulation with thermal processing [176], documents the
comprehensive character of this technique.
Computer-aided tissue engineering technique
Another supporting utility is computer-aided tissue engineering
(CATE) [270,271]. Sun and colleagues see, in this concept, the
combination of three major categories [272–274]. These are:
• Computer-aided tissue modeling, including 3D anatomical
visualization with imaging-data acquisition, 3D
reconstruction and CAD-based tissue modeling [185];
• Computer-aided tissue informatics [275], including computer-
aided tissue classification and the application for tissue
identification and characterization at different tissue
hierarchical levels;
• Computer-aided tissue scaffold design and manufacturing
[113,276], including SFF of tissue scaffolds and bioblueprint
modeling [275], for 3D cell and organ printing [181,277].
Under the term CATE, summarized methods are not
restricted to the control and the design [180] of the internal
architecture [185,278] of scaffolds of the RP technologies by CAD
methods. They have opened up new possibilities to match the
different mechanical and geometrical requirements of the origi-
nal patient computed tomography data to create, for example,
exact bone scaffolds [275,279,280].
Method comparison
Different authors have given short [204,281,282] or more
detailed [57,124,180] tables showing the advantages and dis-
advantages of different fabrication methods. However, such
tables can only partially provide what the reader requires, such
as: a plan to avoid the loss of time and money in attempting to
create a suitable scaffold for its own application. So it is often
reported in overviews in diverse articles [57,180,204] that the
heating to a molten state, for example, in a molding or a FDM
841
Weigel, Schinkel & Lendlein
10 μm
Figure 7. Scanning electron microscope micrograph of electrospun
poly[(dl-lactide)-co-glycolide] nanofibrous nonwoven composed of
randomly oriented ultrafine fibers. Reproduced with permission from [253].
process may badly affect the polymer. But it may also
accelerate the designated and demanded degradation of the
biomaterial in a special application. Or the use of organic sol-
vents during the prepration seems to be harmful [124,282] but if
they can be removed completely, for example, by an annealing
step after the scaffold fabrication, so the former employment
of organic solvents is no longer an issue for cell culturing. The
utilization of CO2 foaming can show a higher amount of
closed cells [124]. Then the interconnectivity may be increased
frequently by combining with salt leaching. But the leached
NaCl crystals leave a partly cubic porous morphology [283]
with a difficult interconnectivity control in comparison to
other leaching processes [170,259]. The TIPS is described in
overviews as a long-time method [282] but the use of extrac-
tion methods [133,134] instead of freeze drying for many
days [86,130] lowers the fabrication time, increases the produc-
tion scale and does not require the expensive equipment
either [281]. RP techniques demand specific material proper-
ties and still show a low resolution in many cases. But the
exact building of 100% interconnected porous scaffolds
from, for example, CT data is impressive. In the end, the suc-
cessful application of a scaffold in medicine or biology will
only decide that a preparation method is able to fabricate
good materials in tissue engineering.
Summary
The field of scaffold-based tissue engineering is still in an early
state of development but has been growing rapidly over the last
few years. Many different approaches of scaffold fabrication are
under investigation currently. One strategy is the advancement
and adaptation of conventional fabrication technologies, such
as ELSP, methods of coagulation agent induced-phase separa-
tion or leaching methods developed originally for other
research areas. But novel fabrication techniques, like RP or SFF
procedures with their many different embodiments or usage of
self-assembly systems mimicking properties of the ECM, also
have potential for future developments.
842
The requirements of scaffolds for tissue engineering are com-
plex and tissue specific, regarding structure and function. Even
for a specific tissue, it is not quite clear what defines an ideal scaf-
fold/cell or scaffold/neotissue construct. Thus, only the inclusion
of several different scientific disciplines with a high level of multi-
disciplinarity will enable further successful development of scaf-
fold-based tissue engineering. Manifold different techniques of
scaffold fabrication have been introduced. These methods and
the deduced possible combinations describe a pool of procedures
allowing preparation of scaffolds with defined morphologies and
suitable properties regarding application in tissue engineering.
Expert commentary
In recent decades, success in modern medicine has mainly influ-
enced the therapy of infectious and cardiovascular diseases. A
constant increase of life expectancy and a relevant increase of life
quality is connected with this development, including the
understandable demand of the population to accept no loss in
advanced age during the whole life. Because of the shifting mor-
bidity spectrum from now on, the clinic medicine deals with
diseases referring to creeping loss of cell or organ functions.
Mechanical overstressing, chronic inflammations cellular
degeneration, defects in immunological system or organ damage
by injuries and by exogenic-toxic influences can be consequences.
In most cases, these diseases cannot be healed by classical
therapies. They have to be under permanent treatment causing
considerable efforts. Sometimes organ transplantation might be
helpful but limited availability of organs and immunological
incompatibility narrows this option. An increasing need for
suitable organs and a nearly equal number of transplantations
in the last 10 years is also evidence of the recent situation.
Thus, the desire for more transplantable cells, tissues and
organs with good tissue compatibility by reduced rejection or
aggression reaction are an integral part of clinical strategy in the
future. Nonbiological organ replacement through hybridized
systems will bridge the development to fully biological systems
and finally to human regenerative systems in vivo. The forma-
tion and design of scaffolds are an essential part of this
progression of tissue engineering.
Five-year view
In the future, solutions to problems in the fileds of tissue engi-
neering and regenerative medicine will probably be determined
by a causal treatment mode that expects the complete func-
tional replacement of damaged or destroyed tissue. New thera-
pies with this background should be superior to conventional
approaches owing to the duration and extent of recovery or by
the reduction of potential side effects. Thus, the mechanism of
regeneration will be a standard therapy approach. Tissue engi-
neering also provides great promise for posed tasks but there is
also a considerable responsibility to quickly identify the best
treatements with the greatest potential.
For the preparation of scaffolds, the advancement and
adaptation of conventional fabrication technologies
(e.g., electrospinning, methods of coagulation agent-induced
Expert Rev. Med. Devices 3(6), (2006)
 Design and preparation of polymeric scaffolds for tissue engineering

phase separation or leaching methods developed originally for
other research areas) will be pursued. But novel fabrication tech-
niques (e.g., rapid prototyping or solid free form procedures with
their many different embodiments or the usage of self-assembly
systems) will also have the potential for future developments.
Progress in tissue engineering can be only achieved by inter-
actions among natural scientists, engineers and physicians. A
high level of multidisciplinarity is prerequisite of successful
work for the development of scaffold design and functional-
ity. Future scaffold constructs will only be successful if an
improved compatibility regarding the ECM is realized. The
variation or selective modification of prestructured scaffolds,
as well as the reproduction of natural systems, could be pass-
able procedures that account for both the variation of physical
and chemical properties and the special morphological
aspects, such as usage of materials with self-assembly proper-
ties. The utilization of external stimuli (biological acting by
growth factors, chemical acting by adsorption processes or
mechanical acting by alternating material stress) with scaf-
folds as alloplastic guide track will enable or improve cell
settlement behavior.
It will expect that progress in stem cell investigation will gener-
ate essential impulses for in vitro breeding of cells and tissue in
the next years. Intermediate goals on the way to fully biological
implants and finally the human regenerative system in vivo
could be biodegradable tissue support systems and smart mate-
rial implants within 5 years and organ-assist systems based on
human cell-lines within 10 years. Functional autologous tissue
systems, such as implantable autologous heart valves, will need
at least another 15–20 years.

Key issues

• In recent decades successes in modern medicine have contributed to increased life expectancy connecting with the understandable
demand of the population to accept no loss of life quality in advanced age.
• Recently employed tissue engineering will bridge the development to fully biological systems and finally to human regenerative
systems in vivo by nonbiological organ replacement through hybridized systems.
• At present, tissue engineering methods generally require the use of porous scaffolds that serve as a matrix for initial cell attachment
and subsequently for tissue formation in vitro and in vivo and in so far temporarily substitutes the extracellular matrix.
• The advancement and adaptation of conventional fabrication technologies (e.g., electrospinning, methods of coagulation agent
induced phase separation or leaching methods) as well as novel fabrication techniques (e.g. rapid prototyping or solid free-form
procedures or the usage of self-assembly systems) have a potential for future scaffold developments.
• Successful development of scaffold-based tissue engineering demands a high level of multidisciplinarity between natural scientists,
engineers and physicians to answer questions regarding efforts to develop scaffolds for specific tissue function and structures and
the ‘ideal’ scaffold/cell or scaffold/neotissue construct.

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Affiliations
• Thomas Weigel
Head of Department of Polymer Technology,
Institute of Polymer Research, GKSS Research
Center Geesthacht, Kantstr. 55,
D-14513 Teltow, Germany
Tel.: +49 332 835 2492
thomas.weigel@gkss.de
• Gregor Schinkel
Research Associate, Institute of Polymer Research,
GKSS Research Center Geesthacht,
Department of Polymer Technology, Kantstr. 55,
D-14513 Teltow, Germany
Tel.: +49 332 835 2321
gregor.schinkel@gkss.de
• Andreas Lendlein
Director of Institute, Institute of Polymer
Research, GKSS Research Center Geesthacht,
Kantstr. 55, D-14513 Teltow, Germany
Tel.: +49 332 835 2450
andreas.lendlein@gkss.de
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