Fisher John P. e.a. (ed.) Tissue Engineering
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12-20 Tissue Engineering
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13
Drug Delivery
C. Becker
A. Göpferich
University of Regensburg
13.1 Introduction.............................................. 13-1
Significance • Goals of Drug Delivery
13.2 Mechanisms of Drug Delivery .......................... 13-2
Diffusion • Erosion • Swelling • Competing Mechanisms
and Overall Kinetics
13.3 Protein Drug Properties ................................. 13-5
13.4 Drug Delivery in Tissue Engineering ................... 13-8
The Use of Classical Drug-Delivery Systems • The Delivery
of Drugs via Cell Carriers
13.5 Outlook ................................................... 13-15
References ....................................................... 13-15
13.1 Introduction
13.1.1 Significance
The science of tissue engineering takes an integrated approach to replacing nonfunctional or missing tissue
by gathering input from many different scientific disciplines [1]. An integral part of the emergence of a
mature tissue from cells both in vitro and in vivo involves guiding cells through their development. Apart
from the choice of materials used for cell and tissue culture, the use of pharmacologically active substances
such as cytokines and growth factors has emerged as an important tool in tissue engineering research and
development in recent years [2–4]. By taking advantage of these substances at the right time and in the
right context, cells can be induced to proliferate, differentiate, or to migrate in a controlled way. The
positive impact of growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast
growth factor (bFGF), which both stimulate the vascularization of tissue in vivo, and members of the
bone morphogenic protein family, used to enhance bone formation, illustrate how useful drug-delivery
strategies have been for tissue engineering applications in recent years [5,6].
Although many drugs can simply be added to cell- and tissue culture media or administered in vivo
in the form of an injectable solution, we can take better advantage of many compounds, when they
are administered in a controlled way. Protein and peptide drugs, for example, have short half-lives [7]
and must, therefore, be administered continuously, which can be very cumbersome for large volumes of
solution. In addition, undesired side effects may arise when substances intended for local delivery to a
specific tissue are not spatially contained. It is obvious that for these and for many other reasons it has been
deemed necessary to administer drugs according to regimes that cannot solely be achieved through the
13-1
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13-2 Tissue Engineering
administration of solutions. The field of drug-delivery research has emerged over the last 30 years to
overcome such limitations. In recent years, tissue engineering has profited tremendously from integrating
drug-delivery technology into more traditional design schemes [8].
It is the goal of this chapter to elucidate the significance of drug delivery within the field of tissue
engineering. We first review a number of definitions and basic drug-delivery technologies with a special
focus on drug release mechanisms. We then briefly describe the fundamentals of tissue engineering within
the realm of drug delivery. We then have a look at the specifics of drugs that are attractive for tissue
engineering applications. Thereafter, we address classical drug-carrier systems that have already been used
to deliver drugs to cells and tissues and concomitantly give an outlook on systems that hold great promise
for similar applications in the future. We then give an overview over the area of using cell carriers for drug
delivery. Finally, we review the specifics of some growth factors that have special requirements with respect
to stability and pharmacokinetics. At the end, we provide a brief glance at the challenges that have still to
be addressed, in an attempt to give an outlook on the further developments that are currently under way.
More information can be found in a number of excellent reviews on related topics [9–12].
13.1.2 Goals of Drug Delivery
Defining the term “drug delivery” is not an easy task, because a plethora of definitions can be found in the
contemporary literature. They range from brief statements such as “method and route used to provide
medication” [13] to more detailed ones, such as “systems of administering drugs through controlled
delivery so that an optimum amount reaches the target site. Drug-delivery systems encompass the carrier,
route, and target.” [14]. Some of them already imply that there is a close relation to tissue engineering
research: “delivering agents to specific cells, tissues, or organs” [15].
While all of the definitions make it very clear that drug delivery is intended to control the kinetics of
drug release, it is not at all obvious, why one should do so. The reasons are manifold and some of them
date back more than 100 years to when Paul Ehrlich (
∗
1854–
†
1915) coined the term of the “magic bullet”
[16]. Since then it has been a well-accepted fact by the scientific community that hitting a biological target
with high precision has significant advantages. While Ehrlich intended to avoid side effects during an
antibacterial therapy by targeted drug delivery, we nowadays have more incentive than “only” avoiding
collateral damage to control the delivery of drug in a biological environment. Thus, the pharmacokinetics,
that is, the kinetics of drug resorption, distribution, and elimination processes, may force us to finely dose
a drug over a defined time interval to account for its rapid clearance from an application site. Another
motivation involves the short tissue half-lives of therapeutic agents, especially of protein and peptide
drugs, which are frequently inactivated by proteases and peptidases [17,18] and need, therefore, to be
substituted continuously by “fresh” compound from the drug-delivery device’s reservoir. These are just
a few of the many reasons that may illustrate the need for drug delivery. It is easy to imagine that in the
post genomic era, when the number of drug candidates dramatically increases with continuing progress
in proteomics [19], even more reasons may arise, leading us to use controlled drug-delivery devices for
tissue engineering applications.
Drug delivery is often linked to the concepts of “sustained release” or “controlled release,” meaning that
a pharmaceutical compound is released over a certain period of time or in a somehow predetermined way,
respectively. While “sustained” suggests only that the drug is released over an extended period of time,
“controlled” suggests that the kinetics are well defined, but does not necessarily imply that the release runs
over long time periods.
13.2 Mechanisms of Drug Delivery
The means that we can exploit to release a drug in a controlled way and which are an indispensable part of
a drug-delivery device are manifold and different in nature. We can roughly classify them into three major
mechanisms: diffusion, erosion, and swelling [20–23]. Besides these three major instruments that we have
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Drug Delivery 13-3
in our hands, a plethora of additional strategies have been used [24–27]. Among them are electric fields
[28–30] that allow for the transport of charged molecules, osmosis whereby molecules are “squeezed” out
of a reservoir due to a build up in osmotic pressure [31–33], convection by which the drug is moved along
some stream of gas or fluid [34,35], or even the mechanical stimulation of a drug carrier [36,37]. This
list of examples is not nearly complete, but it is beyond the scope of this chapter to describe all of them.
As excellent reviews on the topic can be found in the contemporary literature [38–42], we only further
describe the most important mechanisms with respect to applications in tissue engineering.
13.2.1 Diffusion
Diffusion is one of the most important transport mechanisms in drug-delivery applications. It is a ther-
modynamically driven process with well understood kinetics [43,44]. Diffusion is caused by Brownian
motion, which is a random walk of particles that are typically micrometer-sized or smaller. Macroscop-
ically, we observe that the particles appear to move along a concentration gradient. Fick’s second law of
diffusion describes the net transport of particles in time and space:
∂C(x, y, z, t)
∂t
=
∂
2
C
∂x
2
+
∂
2
C
∂y
2
+
∂
2
C
∂z
2
For this partial differential equation, numerous algebraic and numerical solutions have been derived,
two of which are depicted in Figure 13.1. The solutions depend strongly on the initial conditions (such
as the drug concentration inside a drug-delivery device) as well as the boundary conditions (such as
the geometry of a drug-delivery device) of the diffusion problem. An advantage of diffusion controlled
drug-delivery systems is certainly that we can usually predict the kinetics of drug release very well. One
of its major disadvantages is that the flux (the mass transport per unit area and time) out of a device is
usually, according to above outlined nature of the process, concentration dependent. Therefore, as the
release progresses, the process can lead to a break down of concentration gradients and, as a result, the
Release from a matrix
Release
Release
Release from a reservoir
through a membrane
(b)(a)
m
m
0
=1–Σ
∞
n =0
8
(2n +1)
2
·p
2
·e
–D·t·(2n +1)
2
·p
2
4·1
2
–D·t·2n
2
·p
2
1
2
Σ
∞
n =0
MD·t
1·c
don
1
2
=––
(–1)
n
n
2
2
p
2
1
6
·e
Time Time
FIGURE 13.1 Drug release profiles resulting from diffusion controlled release. Equations represent exemplery solu-
tions of Fick’s second law of diffusion in one dimension describing release profiles (a) from a matrix type device,
(b) via diffusion through a membrane.
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13-4 Tissue Engineering
release rates may decline. This is usually the case whenever we release a substance from a monolithic
system (Figure 13.1a).
A method that allows the system to maintain a fairly constant flux over an extended period of time
utilizes release through a membrane. In that case, an almost constant release overtime is possible, especially
when the drug reservoir contains large amounts of substance (Figure 13.1b). This is the more the case
when the drug reservoir hosting the substance is oversaturated, so that a constant drug concentration can
be maintained over an extended period of time.
13.2.2 Erosion
The materials and design of a drug carrier may be chosen to either encourage or hinder release via erosion.
A carrier that erodes over time either precludes the necessity of postapplication removal or does not persist
at the application site, which is an additional advantage for applications in tissue engineering.
Erosion is usually defined as the sum of all processes leading to a mass loss from a drug-delivery device
[45]. In some cases, the material can simply dissolve in an aqueous environment, while in other cases,
like with lipophilic degradable polymers, the material degrades into water soluble oligomers that allow
for the initiation of matrix erosion. Polymers that are insoluble in water have been classified according to
their erosion mechanism into surface-eroding and bulk-eroding materials [46,47]. While in the case of
the first class, erosion phenomena are confined to the material surface [48], bulk-eroding materials tend
to degrade over extended periods of time until a critical degree of degradation is reached, after which the
whole material bulk is undergoing erosion (Figure 13.2) [49].
It is obvious that surface-eroding polymers allow for the control of drug release via the erosion process,
which usually proceeds at constant velocity. A classification of polymers as surface and bulk eroding can be
made based mainly on the nature of the bond between the monomers. As a rule of thumb, one can assume
that the faster a bond is cleaved (usually by hydrolysis) the more the material is likely to undergo surface
erosion. In recent years, models have been developed that allow for the calculation of a dimensionless
“erosion number” that predicts the erosion mechanism of a polymer device [50].
13.2.3 Swelling
The swelling phenomena of polymers has widely been used to control the release of drugs from a device
[46,51]. The major mechanism thereby is an increase of polymer chain mobility due to the uptake of
water, which lowers the glass transition temperature of the polymer [52,53]. Drugs that are trapped
inside a polymer matrix profit from the resulting increase in flexibility by an enhanced diffusivity and
consequently an enhanced release rate [54]. In many cases, one can observe the formation of swelling
fronts that separate a glassy polymer matrix core from the swollen polymer surface. It is obvious that
diffusion plays a major overall role, as both the process of water uptake and drug release are diffusion
controlled. Excellent reviews are available that provide more detail [55–57].
Surface erosion Bulk erosion
Time
FIGURE 13.2 Schematic illustration of surface erosion and bulk erosion. (Reprinted from Gopferich, A. and
Tessmar, J., Adv. Drug Deliv. Rev., 54, 911, 2002.)
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Drug Delivery 13-5
Linear
Concave
Repetitive
Burst/bolus
(a) (b)
(c) (d)
FIGURE 13.3 Schematic illustration of release profiles (closed lines) and resulting tissue concentrations (broken
line). (a) Pulsatile release, (b) constant (zero order) release, (c) concave release kinetics, (d) repeated pulsatile release
kinetics.
13.2.4 Competing Mechanisms and Overall Kinetics
In many drug-delivery systems, the mechanisms outlined above compete with one another. Release from
a degradable polymer, for example, is usually a complex mixture of all three pathways of drug-release
control. However, from a design point of view, it is highly desirable that one of the mechanisms dominates
the overall release kinetics, as otherwise unfavorable release profiles may result.
A plethora of release profiles are available to choose from, ranging from the continuous delivery of a
drug over an extended period of time to pulsatile release kinetics, by which an incorporated compound
is set free according to a preprogrammed pattern [58]. Excellent overviews on the multitude of release
kinetics can be found in the literature [59]. Figure 13.3 illustrates schematically typical drug-release profiles
and the resulting tissue concentrations that one may expect, assuming that the substance is cleared from
the application site according to first order kinetics, that is, in a concentration dependent way.
The kinetics that one should choose depends on the biological needs of the specific application. In tissue
engineering, this may for example be defined by a desired cell phenotype or by the pharmacokinetics of the
drug when applied to a tissue or administered in vivo. Typically, more continuous release profiles will lead
to more constant tissue levels in vivo, while the pulsatile application of a drug will result in concentration
peaks that rapidly fall.
13.3 Protein Drug Properties
Prior to a detailed look at the various drug-delivery strategies, it seems necessary to have a glance at
the properties of active compounds that are currently in use for tissue engineering applications. Most
of these drugs are growth factors and, therefore, peptides or proteins. A brief list of compounds that
have been formulated to drug-delivery systems for the use in tissue engineering applications is given in
Table 13.1.
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13-6 Tissue Engineering
TABLE 13.1 Growth Factor and Delivery Systems That Have Been
Developed
Growth factor Carrier/delivery system Regenerated tissue Ref.
BMP PLA Long bone [60]
Porous HA Skull bone [61]
rhBMP-2 Porous PLA Spinal bone [62]
Skull bone [63]
Collagen sponge Skull bone [64]
Gelatin Skull bone [65]
PLA-coating Long bone [66]
Porous HA Skull bone [67,68]
PLA–PEG copolymer Long bone [69]
Si–Ca–P xerogels [70]
rhBMP-7/ OP-1 Collagen Spinal bone [71,72]
Long bone [73]
HA Spinal bone [74]
aFGF PVA Angiogenesis [75]
Alginate Angiogenesis [76]
bFGF Alginate/heparin Angiogenesis [77]
Agarose/heparin Angiogenesis [78]
Gelatin Skull bone [79]
Fibrin gel Long bone [80]
Chitosan Dermis [81]
Collagen Cartilage [82]
EGF Gelatin Dermis [83]
TGF-β1 Alginate Cartilage [84]
Poloxamer; PEO gel Dermis [85]
PLGA Skull bone [86]
Collagen Dermis [87]
PDGF Fibrin Ligament [88]
CMC gel Dermis [89]
VEGF Alginate Angiogenesis [90]
Collagen Angiogenesis [91]
PLGA scaffold Angiogenesis [92]
Fibrin mesh Angiogenesis [93]
VEGF/PDGF PLGA scaffold Angiogenesis [94]
NGF PLGA Nerve [95]
Collagen minipellet Nerve [96]
BMP, bone morphogenic protein; rhBMP; recombinant human bone morpho-
genic protein; OP-1, osteogenic protein 1; aFGF, acidic fibroblast growth factor;
bFGF, basic fibroblast growth factor; EGF, endothelial growth factor; TGF-β1,
transforming growth factor beta 1; PDGF, platelet derived growth factor; VEGF,
vascular endothelial growth factor; NGF, nerve growth factor; PLA, poly lactic
acid; PLGA, poly(lactic-co-glycolic) acid copolymer; PEG, poly(ethylene glycol);
HA, hydroxyapatite; PVA, poly(vinyl alcohol).
In the case of these proteins we have to deal with highly efficient substances with often substantially
limited stability, such as in physiological fluids, due to proteolytic enzyme activity [97]. The choice of an
appropriate delivery system for these substances is, therefore, not only a matter of the intended therapeutic
use or the pharmacokinetics but also of the physicochemical properties of the drug. Special attention
must be paid to the chemical stability and physical integrity of a protein drug even during the formulation
process. Examples for chemical and physical instabilities are deamidation, redox reactions, hydrolysis,
and aggregation. These and other instability mechanisms have been extensively reviewed by numerous
authors [98–100]. In addition environmental effects like pH, organic acids, metal ions, detergents, and
temperature can induce a denaturation of proteins [101].
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Drug Delivery 13-7
Another source of inactivation is the biological environment that we expose a protein to. Even if a
growth factor of choice can be stabilized during formulation and inside a delivery system the biological
environment can pose another severe threat. Half-lives of growth factors are typically in the range of
minutes due to degradation by peptidases. Intravenous injections are indicative of this problem [102].
Platelet-derived growth factor (PDGF), bFGF, and VEGF, for example, have plasma half-lives of 2 [103],
3 [104], and 50 [105] minutes respectively. Besides rapid degradation, unfavorable distribution [104]
or elimination by glomerular filtration [97] are problematic after intravenous administration. Direct
systemic administration of growth factors, therefore, requires substantial drug doses that may lead to
side effects [2,106], or if direct injection into the target site is possible, repeated administration to achieve
biological efficacy is required. Prolonging the half-life of growth factors is, therefore, an important research
goal. A promising approach to increase half-life is to conjugate proteins with poly(ethyleneglycol) (PEG)
chains. Pegylation seems to cause a significant reduction of protein clearance from plasma [107–109].
The pegylation of growth hormone-releasing hormone (GRF) analogues, for example, led to an enhanced
in vivo stability with acceptable biological activity [110]. In addition pegylation seems to reduce the
velocity of enzymatic degradation [111]. Detailed reviews on protein and peptide pegylation can be found
in the literature [112–115].
The incorporation of proteins into a controlled release drug-delivery device can protect it from inac-
tivation, but the formulation process is sometimes another source of protein inactivation. One class of
problem that occurs frequently is related to the interaction of proteins with interfaces. Considering the
small quantities that have to be handled when growth factors are formulated to applicable systems, physical
phenomena like protein adsorption to solid–liquid or liquid–liquid interfaces and subsequent denatur-
ation can lead to massive protein loss in some instances [116–118]. Approaches to minimize protein
adsorption to glass or plastic include competitive “coating” with bovine serum albumin [119,120], the
use of PEG and glycerol solutions or the application of surfactants [121,122]. Enhanced denaturation and
aggregation of proteins at interfaces have been observed under certain conditions like the application of
mechanical forces [123]. It has, for example, been shown that simple vortex mixing of a 0.5 mg/ml porcine
growth hormone solution for 1 min can lead to a loss of 70% of the protein due to aggregation [124,125].
Unfortunately the problem of adsorption on solid surfaces is not the only one that can occur during
formulation. When microparticles are prepared by using emulsion techniques [126], for example, there is
frequently the need for the use of organic solvent and vigorous mixing. The liquid–liquid interfaces and
the high shear forces are two factors that may lead to denaturation and hence activity loss [125,127,128].
Moreover during the degradation of polymers a very harsh microclimate can be created [129] in which
even chemical reactions such as an acylation of proteins and peptides can occur [130,131]. To stabilize
proteins in polymers numerous approaches have been tried [132–135], many of them being very specific
for an individual drug-delivery system.
The unfavorable interactions of growth factors with synthetic materials made many groups have a
closer look at how they are created and stored in their natural biological environment. Transcription of
genes encoding for growth factors create unstable mRNA [136–138], which leads to short half-life and only
limited growth factor synthesis. Growth factors are released by cells either for instant signalling or arestored
in the extracellular matrix (ECM). Some growth factors such as transforming growth factor beta (TGF-β)
are secreted as biologically inactive latent precursors [139]. The release of growth factors from the ECM is
controlled by matrix degradation. This natural environment provides a dynamic and responsive growth
factor delivery system which can react according to specific cellular requirements and can, therefore, also
serve as a cell guidance system [2,139,140]. This led various research groups to the development and use
of ECM [141] derived materials for the design of controlled delivery systems for growth factors. Especially
gel like systems can simulate the interaction of growth factors and the extracellular matrix [142,143] and
can, therefore, provide similar stabilizing effects like the natural ECM. Interestingly, it was found that
the bioactivity of vascular endothelial growth factor (VEGF) delivered from alginate microspheres was
higher than VEGF alone [144]. It was speculated that that effect was due to stabilization of the factor in
the system over alginate interaction. A detailed review about on the interactions between growth factors
and the ECM can be found in the literature [145].
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13-8 Tissue Engineering
Isolated cells
Matrix
material
Suitable
culture conditions
Growth factors/
tissue inducers
Engineered tissue
FIGURE 13.4 Schematic illustration of components of tissue engineering.
13.4 Drug Delivery in Tissue Engineering
It is certainly beyond the scope of this chapter to provide the reader with a complete overview of tissue
engineering; however, it is necessary that we review several aspects that may be crucial (or beneficial) for
a better understanding of drug-delivery applications in this field.
In the early days of tissue engineering, pioneers like Langer and Vacanti stressed its interdisciplinary
character in their definitions [1]. At that time four fundamental components of tissue engineering were
identified (Figure 13.4):
1. Cells that will form the desired type of tissue
2. A matrix that allows for cell proliferation and differentiation
3. Suitable cell culture conditions
4. Finally the use of cytokines and other drugs
While each of these components alone may be sufficient for an application, it is obvious that for
in vivo as well as in vitro approaches it is important to guide cell- and tissue development into the right
direction. Cytokines and growth factors have therefore emerged in recent years as precious substances for
tissue engineering applications. That a controlled delivery of these and other pharmacologically active
substances is very beneficial for tissue engineering applications is well accepted in the field.
The strategies to deliver a drug to cells or tissues are diverse. However, we can classify them into
four major categories, which follow immediately from the blue print of tissue engineering as depicted in
Figure 13.4.
A first strategy, which is all too obvious, is to use classical established technology for the delivery of
substances either in cell culture media or near a tissue site in vivo (Figure 13.5a).
Doing so has the advantage that we can use systems that have been developed and described thoroughly
in the contemporary literature [38,146–148]. Among these systems, we find essentially everything that
has been developed for the parenteral application of drugs, such as implants, microspheres, and injectable
gels, just to name a few. Despite their advantages, they may also cause some problems. They must always
be administered in addition to tissue engineering specific components, such as cells and cell carriers.
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Drug Delivery 13-9
Cells as drug
delivery systems
Controlled release
devices
(a) (b)
(c) (d)
Biomimetic
systems
Scaffold as
delivery system
FIGURE 13.5 Drug-delivery strategies for tissue engineering applications: (a) Use of “classical” controlled delivery
devices such as microspheres or monolithic systems incorporated into a cell carrier, (b) genetically altered cells serving
for protein and peptide drug expression, (c) the cell carrier itself serving as a drug-delivery system, (d) covalent
attachment of drugs to the polymer surface.
Moreover, they may not unequivocally allow for a homogeneous distribution in the tissue and may
thereby cause undesirable drug concentration gradients.
A second approach is to deliver drugs via cells (Figure 13.5b) [149]. It is possible to genetically alter
a portion of the cells or all of them to produce a certain protein or peptide drug. For this approach,
numerous viral and nonviral gene delivery approaches are available [150–154].
A third approach is to use the scaffolds intended for cell attachment and proliferation as a drug-delivery
system (Figure 13.5c). Many of these materials provide tremendous opportunities to control the release
of drugs. Especially biodegradable polymers and hydrogel materials have been used extensively as porous
scaffolds to allow for erosion controlled drug or DNA release.
Finally, we can implement the pharmacologically active substances that we want to use for signaling to
cells into the design of materials that are used for cell proliferation and differentiation. In this scheme,
drugs and cytokines are tethered to the surface of a material [155] (Figure 13.5d). The term “biomimetic”
has been coined in recent years to describe materials that have been modified in this way [156,157]. There
are numerous publications that illustrate the principle behind and advantages of this strategy [158–162].
In the following pages, we focus on aspects of classical drug-delivery systems and on the use of scaffolds
as release systems, as the other two delivery strategies are covered in the sections on gene delivery and
biomimetic materials of the handbook. We try to give a brief overview of the vast number of devices that
have already been used for the delivery of drugs in tissue engineering applications and some of the more
recent trends, such as the use of scaffolds concomitantly as a cell carrier and for the delivery of a drug.
13.4.1 The Use of Classical Drug-Delivery Systems
When designing a drug-delivery device for an application in tissue engineering, there are numerous
aspects to be considered beyond the pharmacological aspects that are usually linked to the nature of the
drug to be administered. Of utmost significance is the pharmacokinetics of the drug. The clearance rate
from the site of application, in particular, should be determined as this, together with the drug efficacy
and the intended time of application, dictates the dosing regimen. Once the required dosage is known, the
corresponding release kinetics may be determined. The type of drug-delivery system to be used may then
be chosen, taking the drug loading and release into account. Thereafter, further fundamental questions,