Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5398_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 8
Biomaterials in Drug Deliver y: Design and Applications
Naveen Kumar
Abstract
Biomaterials have become integral to the fast-evolving fields of pharmaceuticals and medicine, playing a
vital role in diagnostics and therapeutics. Originally used in medical devices for tissue replacement or organ
support, their applications have expanded beyond mere implantation. Biomaterials, which can be natural or
synthetic, are designed to interact with biological systems, supporting or replacing damaged tissues while
being compatible with human biology. Over time, advancements in material science have led to significant
innovations in their use, par ticularly in drug delivery systems. Biomaterials now enhance the effectiveness of
therapeutic agents like antibodies, peptides, and vaccines, and are applied in tissue engineering, prostheses,
and dental implants. Recent research has focused on biomaterials as nanocarr iers for controlled drug
delivery, minimizing drug degradation and toxicity while optimizing therapeutic outcomes. As biocompatibility remains a crucial factor, new developments in biomaterials offer promising solutions for enhancing
drug delivery, wound healing, and overall patient care.
Key words Biomaterials, Drug delivery, Biocompatibility, Tissue engineering, Therapeutic agents
1 Introduction
From the last few decades, biomaterials have marked its presence in
the fast-advancing phar maceutical and medical fields. Biomaterials
are those materials which are intended to interact with biological
living tissue and used for therapeutic and diagnostic purpose. Earlier these materials were only used in medical devices to treat or to
replace any tissue or improve the functions of organ. But later it was
found that the term non-viable given to them is inappropriate as
biomaterials have its application more than just as implanted
devices. Biomaterials are a major part of our routine practice in
the diagnosis as well as for the treatment of several human diseases.
Biomaterials are basically, any materials (natural or synthetic) that
are biologically compatible with the human body and is used to
support, enhance, restore, or replace the biological function of
damaged tissues and is continuously in contact with the body fluids.
The use of the word “biomaterials” had been largely anticipated by
159
160 Naveen Kumar
the practical use of materials as biomaterials. Indeed, the presence
of exogenous materials in the human body can be dated back to
prehistory. In South Africa and India, the heads of large, biting ants
were exploited to clamp wound edges together [
centuries, other metals have been exploited: lead and silver among
others, with and without evidence of adverse reactions. Moreover,
4000 years ago, the Chinese carved bamboo sticks in the form of
natural teeth to be inserted into jaws just like current dental
implants. Egyptians used precious metals for dental implants [
Additionally, the purpose to replace diseased/damaged parts of
the human body has been pursued for centuries. During the sixteenth centur y, Gaspare Tagliacozzi and other pioneering plastic
surgeons successfully used autogenous skin flaps to replace missing
noses [
formed without any awareness of the problems and limitations
related to material science and biological phenomena; moreover,
no knowledge of sterilization, immunological reaction, inflammation, and biodegradation was available at those times [
their “unconscious” success clearly demonstrates that the human
body has an impressive ability to adapt itself and accommodate
foreign materials. This allowed for traveling on the road to biomaterials evolution before taking into account the fundamental interactions between the body and the implanted materials; the
systematic examination thereof only began about 150 years ago,
when scientists and physicians started to scientifically evaluate how
the body reacts to the presence of exogenous materials. The practical exploitation of materials as biomaterials then began to face the
issue of biocompatibility.
3]. All these original surgical procedures had been per-
1]. Over the
2].
1]. However,
2 Evolving Definitions of Biomaterials
As was described in the previous paragraph, biomaterials are characterized by a wide range of chemical compositions and properties,
and they can be exploited in very many applications. Therefore, it is
quite difficult to define them unambiguously. Marin et al. [
ascribed to Jonathan Cohen one of the earliest definitions of biomaterials, which dates back to 1967. Dr. Cohen was an orthopedic
surgeon and exogenous materials had been used in orthopedic
surgery for many years. He simply defined “biomaterials” as all
materials that are used as implants, with the exception of drugs
and soft biological tissues [
the practical use of biomaterials in surgery focusing on “hard”
materials that are typically applied in orthopedics.
In April
established and organized its inaugural annual symposium at Clemson University (SC, USA) [
of biomaterial was coined: “A biomaterial is a systematically,
1974, the Society for Biomaterials (SFB) was formally
4]
5]. Indeed, this definition comes from
6]. In this symposium, a new definition
Biomaterials in Drug Delivery: Design and Applications 161
pharmacologically inert substance designed for implantation within
or incorporation with a living system” [
formulated in 1982 during the “National Institutes of Health
Consensus Development Conference Statement on the Clinical
Applications of Biomaterials” (Bethesda, MD, USA): biomaterial
is “A substance (other than a drug) or combination of substances,
synthetic or natural in origin, which can be used for any period of
time, as a whole or as a part of a system which treats, augments, or
replaces any tissue, organ, or function of the body” [
ence from a drug
materials of “natural” origin and specifies what biomaterials are
intended for: they are part of a system that is conceived not only
to replace but also to potentially treat and augment each tissue,
each organ, and each function of the body.
As an immediate consequence, possible applications increase as
much as the availability of biomaterials increases. In this aspect, the
definition given by Prof. D. F. Williams “A biomaterial is a
non-viable material used in a medical device, intended to interact
with biological systems” seems to be more appropriate [
the current use of biological tissues from human cadavers (tissue
banks) and from animals (after chemical treatments), tissue engineering techniques appear as extremely promising approaches to
create viable tissues (and organs) by combining cells, scaffolds
(biomaterials!), and biochemical signals. During the European
Society for Biomaterials 9th European Conference (Chester, UK)
in 1991, the definition, approved in 1982, was improved including
“in order to maintain or improve the quality of life of the individual” [
10]. It clearly affirms that the aim of any biomaterial is not
only the “survival” of the patient but also the maintenance/
improvement of their quality of life.
is maintained, but now the definition includes
7]. A broader definition was
8]. The differ-
9]. Besides
3 Basic Features Required for the Biomaterial
Since the biomaterials are in direct contact with the body tissues
and body fluid, there are some basic features required for the
biomaterial such as biocompatibility, inertness, safety, stability,
cost effectiveness, and ease of fabrication as shown in Fig.
4 Characteristics of Biomaterials
The requirement of designing and selection criteria of biomaterial
depends upon the type of medical application. The biomaterial
must have some unique characteristics that can have potent application in biomedical field for longer duration without immune
rejection (Fig.
[
11, 12].
1). Some of these characteristics are described here
1.
162 Naveen Kumar
Fig. 1 Diagrammatic demonstration of substance design requirements of
biomaterials
1. Outstanding biocompatibility
2. Sufficient mechanical properties
3. High-quality physical and chemical properties
4. Enough resistance to wear
5. Enough resistance to rust
6. Osseo-integration (For
5 Classification of Biomaterials
Biomaterials can be broadly classified on the basis of its source, such
as natural and synthetic biomaterial which can also be further
sub-classified as shown in Table 1.
bone
implants
Biomaterials in Drug Delivery: Design and Applications 163
Table 1
Classification based on occurrence of biomaterials
Biomaterials Example
Naturally extracted biomaterials
Protein-based biomaterials Collagen, fibrin, and silk
Polysaccharide-based
biomaterials
Gum-based biomaterials Pectin, xanthum gum, dextran
Biologically derived materials Porcine/bovine pericardium
Synthetically derived biomaterials
Polymer-based biomaterials Polymethylmethacrilate (PMMA), ultra-high molecular weight
Peptide-based biomaterials Short amino acids and self-assembling peptides
Ceramic-based biomaterials Bioactive glass, alumina, zirconia, hydroxyapatite, beta tricalcium
Metal-based biomaterials Stainless steel, CoCrMo, titanium, Ti6Al4V, nitinol, nickel, platinum,
Biocomposites or composites
biomaterials
Chitosan (CS), alginate, and hyaluronan
polyethylene (UHMWPE), polylactic acid (PLA),
polytetrafluoroethylene (PTFE), nylon, polyethylene, polyurethane,
celluloid, cellophane, polycaprolactone (PCL), polyglycolic acid
(PGA), polylactic acid (PLA), poly-lactic-co-glycolic acid (PLGA), poly
(ethers) including polyethylene glycol (PEG), polyvinyl alcohol (PVA),
and polyurethanes (PUs)
phosphate, pyrolytic carbon
tantalum
Polysaccharides,
proteins, sugars,
lignins, synthetic polymers
6 Biocompatibility as the Crucial Item
Biocompatibility assessment is a complex procedure aimed at verifying the capacity of a given material to avoid adverse reactions and
also to correctly perform the intended function when in contact
with (or inserted into) the biological environment. The ISO
10993-1 establishes criteria for the biological evaluation of medical
devices, again confirming that biological tests have to be “performed on the final medical device, or representative samples
from the final device or materials processed in the same manner as
the final medical device (including sterilization, if needed)”
Thus, the term “biocompatibility” has to include not only
13].
[
what is commonly meant as “biological compatibility” but also a
functional evaluation of the entire implantable system. For sure,
several aspects determine the biocompatibility of a given material
also considering the duration of the contact with the biological
164 Naveen Kumar
counterparts: chemical composition, mechanical behavior, and also
physical shape.
7 Biomaterials in Drug Delivery
The expeditious development of science and technology has led the
application of biomaterials in different fields of biology, physics,
chemistry, tissue engineering, as well as medicine [
last 50 years, biomaterials have been researched and used in pharmaceutical drug delivery and found to enhance the delivery and
effectiveness of many therapeutic agents along with antibodies,
peptides, vaccines, and enzymes [
tant role in diverse fields like medicines, food manufacturing units,
pharmaceutical companies, fashion designing, and other household
appliances. In the area of medical sciences, biomaterials are significantly applied in dental fixture fabrication, implants, prosthesis, and
tissue scaffolds. In pharmaceutical sector, in addition to the production of tablets and capsules, these biomaterials are employed in
the designing of customized implants for drug delivery [
Biomaterials have
for nanocarriers which have good biocompatibility, good biodegradability, high drug-loading capacity, and pH-responsive drug
release ability, and, therefore, are used for the drug delivery
18]. The well-designed drug delivery systems by synthetic biomin-
[
eral nanocarriers can help prevent the prior leakage of drug and
protect the drug from inactivation during the circulation.
Biomineral-based nanocarriers are used for the delivery of chemotherapeutic drugs, genes, and proteins [
terials are used for drug delivery because of their great potential and
structural features that are same to extracellular matrix. Different
natural as well as polymeric materials can be used to make nanofibrous biomaterials [
depends on the state of neural cells and also on various extracellular
components which arranges the cellular behavior into proper tissue
functions. Biomaterials have a crucial role in regaining or increasing
the role of extracellular components in CNS for the event of injury
and disease. Biomaterials are also used for cell transplantation as
well as for the delivery of proteins or drug [
derived from extracellular matrix are emerging as origin of biomaterials for engineering, which are able to induce desired cell-specific
response. Use of various biomaterials that are derived from naturally available extracellular matrix proteins for regulating the cell
function has been reported [
patches from polyacrylate as a biomaterial for the transdermal drug
delivery through the high internal phase emulsion technique for
the wound healing. Kim et al. [
14, 15]. From
16]. Biomaterials play an impor-
17].
a huge number of advantages and are used
Nanofibrous bioma-
18].
19]. The central nervous system (CNS)
20]. The components
21]. Corti et al. [22] have developed
23]
have developed atenolol
Biomaterials in Drug Delivery: Design and Applications 165
imprinted polysaccharide biomaterial by using mungbean starch
and polyvinyl alcohol and evaluated them for drug release behavior.
For making effective formulation of a drug, it should be kept in
mind that the active constituent is present at the target site in
maximum amount inside the human body. It has been observed
that in the pharma sector the drug delivery system depends on
several factors like the delivery device or dosage form, and the active
component at the requisite site of action. The consumption of
tablets and capsules as conventional dosage is restricted by the
requirement of elevated doses that coupled with higher toxicity
profiles. To remove this obstacle, a novel drug therapy has been
developed. In novel drug therapy, the active ingredient is modulated in such a way that it confers maximum advantage to the target
site and side effects get minimized. Some examples based on this
therapy comprises of nano-formulations, liposomes, microspheres,
and osmotic drug delivery systems. These can be applied as oral
administration or parenteral use. Mucoadhesive drug delivery system is another example that is based on transdermal
.
applications [
24]
The quest for controlled drug release emanating from side
effects associated with the application and delivery of conventional
drugs has necessitated the need for materials that can transport
drugs to target site without difficulty or problem during and after
delivery. Normally, drugs are delivered repeatedly on prescription
to the body in measures that will bring about remediation and
quick recovery to the patient during the treatment period. In this
way, drug concentration levels will increase and when above the
body’s tolerance level, the problems associated with over therapeutic concentrations could occur that could result into toxic side
[
25].
It is also possible that the drug release rate is so fast that
therapeutic actions are no longer effective owing to low drug
concentrations at the delivery site, which may occur through drug
metabolism, degradation, and transport out of the target
25]. Consequently, this phenomenon would result in drug wast-
[
age and transport medium loss with high-risk offside effects on
surrounding body cells, tissues, and organs. The solution to these
problems is to have drug carriers that can provide controlled release
rate to the target and would allow for complete therapeutic rehabilitation before degradation and transport of excess concentration
The drug and its carrier in form
of drug and carrier medium [
26].
of capsules are orally administered and may be formulated for
parenteral administration [
16]. The drug release rate of the capsule
can be controlled via the use of cellulose coatings exhibiting slow
dissolution, incorporation of drug-complexing elements or compounds which hinder fast dissolution of drug, use of compressed
tablets, and the inclusion of emulsion and suspensions. Materials
that can permit drug release without changing or decaying over
time with longer therapeutic windows (days to years) are required.
166 Naveen Kumar
These carries are such that they can be injected and/or implanted
directly to target diseased tissues/cells for enhancing delivery efficiency [
ligands deposited on biomaterial surfaces to allow for a set retention and usage by infirm tissues and cells have been employed
28]. The design of biomaterials for drug carriers aside permitting
[
surface modification using ligands should also shield drugs from
speedy break down and/or degeneracy within the target site.
8 Controlled Drug Delivery
With the emergence of genetic engineering in the 1970s, largescale production of proteins and other complex macromolecules
became a reality. Similar to small-molecule delivery, controlled
release of proteins and other macromolecules (i.e., insulin, heparin,
enzymes) required the development of new biomaterials or new
biomaterial designs. Synthetic materials were required that could
ensure the delivery of proteins and macromolecules in unaltered
forms to preserve their biological function, while simultaneously
providing protection from degradation in vivo. Furthermore, it was
largely thought within the controlled release community that proteins and other macromolecules could not be encapsulated and
released at controlled rates from polymers. Polymers are large
molecules formed from simple monomers and may be synthetic
or biopolymers that are the constituents of living organisms like
proteins, nucleic acids, and sugars.
Biopolymers are
biochemical and biophysical functions of living cells, and thus can
participate in cooperative interactions, resulting in nonlinear
response to external stimuli. The cooperative interaction mechanism of biopolymers is utilized in producing synthetic polymers
that are similar in behavior to biopolymers, which are used as
biomaterials with ability to interface with biological systems for a
variety of living cells functions. Polymeric, biodegradable materials
are often useful in biomedical applications, as the polymers degrade
into normal metabolites of the body or eliminated from the body
with or without further metabolic transformation [
oped polymeric biomaterials have physical and chemical properties
that are maintained and are not tampered with during synthesis.
The use of synthetic polymeric biomaterials includes artificial corneal substitute, blood contacting devices, hip joint replacements,
and formation of intraocular lenses [
mers are either natural or synthetic. Natural polymers are derived
from natural resources and have potential to be considered for
biomedical and pharmaceutical applications owing to biocompatibility, biomimicking environments, unique mechanical properties,
and biodegradability. Natural polymers are prone to viral infection,
27]. To achieve target drug delivery, the use of affinity
active in controlling and regulating many
29, 30].
31, 32]. Biodegradable poly-
Devel-
Biomaterials in Drug Delivery: Design and Applications 167
antigenicity, and unstable material supply, which limit biomedical
application. On the other hand, synthetic polymers are flexible in
synthesis procedure technique with excellent reproducibility which
made them useful for surgical and short-term medical application,
orthopedic applications that may slowly transfer the load as it
degrades [
an oral or
increase concentration and performance. But this may reach an
extreme level before it declines rapidly, especially when the elimination rate from the body is high. A too low or too high drug
concentration in the body will not benefit the patient because of
the side effects. This phenomenon then becomes a concern requiring the use of controlled drug relea
offered by
apeutic and bioactive
insoluble biodegradable subnano, nano, micropolymer matrix cavity where the therapeutic agents are released in a controlled fashion.
These pioneering technologies led to rapid progress in the fields of
biomaterials and drug delivery, with the development of a new
generation of polymers which release macromolecules in a controlled manner.
33
]. The drug administration into the body is either via
intravenous route with repeated administration done to
se mechanism which can only be
biomaterials [
34]. For controlled drug release, the ther-
agents are enveloped or encapsulated in an
9 Clinical Need for Controlled Drug Delivery
The need for materials for controlled drug release arose from the
general problems associated with conventional dose delivery methods. Generally, drug administration required frequent, repeated
doses that result in high variability of circulating drug concentrations throughout the treatment period (Fig.
Upon administration,
centrations, but in some cases, toxic side effects arise when the
concentration rises above the maximum safe levels [
methods also result in rapid drug level decreases to concentrations
that are no longer therapeutic, which can be a result of metabolism,
degradation, and transport away from the therapeutic target
25]. Collectively, this results in both wasted drug and material,
[
and increased risk to patients due to reduced therapeutic efficacy as
well as potential toxic side effects [
approaches for slowing the rate of release were developed
[26]. These “sustained release” technologies contained the desired
therapeutic in the form of capsules which were generally administered orally, and in some cases formulated for parenteral administration [
slowly dissolving cellulose coatings, the addition of
drug-complexing substances to decrease drug solubility, the use
of compressed tablets, as well as the employment of emulsion and
suspensions, all housed within capsules. Sustained release
16, 35]. Drug release was dampened through the use of
2).
drug levels increase to therapeutic con-
25]. These
35]. To address these issues,
168 Naveen Kumar
Fig. 2 Schematic representation of drug plasma levels after various dosing
regimens
formulations, however, still were influenced strongly by patient-topatient variability, environmental effects, and required repeated
dosages [35].
As an alternative to sustained release, the ideal controlled drug
release system offers several advantages. Such delivery materials
release drugs at rates that do not change with time (i.e., zeroorder release), maintaining release within the therapeutic window
and avoiding the inefficiencies of the drug concentration peaks and
valleys of conventional formulations (Fig.
2). By avoiding “peaks
and valleys” and remaining within the therapeutic window, controlled release materials provide the benefit of reducing the total
amount of dr ug required to achieve therapeutic efficacy. By decreasing the number of required doses, these materials would also
improve patient adherence, which is only 50% in developed nations
[
By controlling drug release over longer therapeutic windows
36].
(i.e., days to years), such materials can also be injected and/or
implanted directly within a specific diseased tissue, thereby limiting
off-target side effects and increasing potency. In addition to avoiding “peaks and valleys,” controlled release systems must enhance
the targeting of drugs to specific tissues and cells within the body to
avoid off target effects [
27, 37]. To enhance tissue specificity, active
targeting strategies utilizing affinity ligands on the surface of biomaterials have been employed for specific retention and uptake by