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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5603_Библиотеки_им_академика_М_И_Перельмана.pdf
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
255
The components of drug delivery composites typically consist of biocompatible
matrix material and therapeutic agents [27]. The biocompatible matrix serves as the
structural framework of the composite, providing stability, support, and compatibility with biological systems. This matrix material can be selected based on mechanical strength, biodegradability, and compatibility with the targeted physiological
environment [28–30]. On the other hand, therapeutic agents encompass a broad
range of substances, including pharmaceutical drugs, growth factors, antibodies, or
genetic materials, depending on the intended application. Combining a matrix material with therapeutic agents introduces a dynamic interplay of properties within the
composite. The matrix not only serves as a carrier for therapeutic agents but also
inuences the release kinetics of these agents. This interdependence is crucial in
achieving controlled and targeted drug release, a key aspect of successful drug
delivery systems.
Integrating multiple components in drug delivery composites offers advantages
such as improved drug loading capacity, sustained release proles, and the potential
for site-specic targeting [31, 32]. This versatility makes composites an attractive
option for designing drug-delivery systems that address the diverse challenges
encountered in biomedical applications [33].
10.2.2 Role ofComposite Materials inDrug Delivery
The role of composite materials in drug delivery is pivotal, leveraging their unique
properties to address challenges associated with conventional drug administration
methods. Composites play a crucial role in drug delivery systems by providing a
versatile platform that combines structural integrity with controlled release properties [34]. This section delves into the key aspects of how composites are well-suited
for drug delivery, emphasizing their capacity to enhance both the physical integrity
of the delivery system and the controlled release of therapeutic agents.
10.2.2.1 Structural Integrity
Composites serve as the structural backbone of drug delivery systems, offering
mechanical strength and stability to the overall device. The choice of a biocompatible matrix material in the composite ensures compatibility with biological tissues
and organs, facilitating integration into the targeted physiological environment.
This structural integrity is particularly essential for implantable drug delivery
devices, such as stents or scaffolds, which need to withstand physiological forces
while maintaining their functional properties over time. The robust nature of composites contributes to the longevity and reliability of drug delivery systems, enhancing their efcacy in clinical applications.
In wound dressing materials, a limited number of natural substances have been
explored for their potential to inuence the wound environment beyond basic
256
A. K. Gupta et al.
moisture management, thereby eliciting a cellular response conducive to healing
[35]. Among these, collagen stands out as a signicant candidate due to its status as
the primary structural protein in the extracellular matrix (ECM) [36]. For over a
decade, collagen-based products have been widely utilized in various formats, ranging from gels and pastes to more complex sheets, sponges, and composite structures
[37]. However, collagen’s efcacy as a wound dressing ingredient is somewhat
compromised by its rapid biodegradation by collagenase and its susceptibility to
bacterial invasion. Nonetheless, collagen-based dressings loaded with drugs like
gentamicin have shown promise in promoting wound healing by accelerating granulation tissue formation, epithelialization and protecting the wound from potential
infections. For instance, gentamicin-collagen sponges have been demonstrated to
release high local concentrations of gentamicin at the wound site for extended periods while maintaining serum levels well below toxicity thresholds [38].
In recent studies, a novel approach to wound dressing materials has been proposed, focusing on the development of core/shell ber structures loaded with antibacterial drugs. These composite bers comprise a dense polyglyconate core ber
surrounded by a drug-loaded porous PDLGA (poly(D,L-lactide-co-glycolide)) shell
structure, allowing for localized delivery of bioactive agents to the wound site [39].
The porous shell structure prepared using freeze-drying of inverted emulsions facilitates controlled drug release and bacterial inhibition. The microstructure of the
shell, inuenced by emulsion parameters such as polymer content and
organic:aqueous phase ratio, plays a crucial role in determining drug release proles
and overall dressing efcacy [40]. The incorporation of substances like albumin
further modulates the release prole of the antibacterial drug, offering the potential
for tailored therapeutic interventions [39].
Figure 10.1 depicts scanning electron microscope (SEM) fractographs illustrating the core/shell ber structures of gentamicin-loaded composite bers [35].
Figure10.1a, b provide images demonstrating the concept of core/shell ber structures. These fractographs reveal the distinct morphology of the bers, showcasing
the dense core ber surrounded by a porous shell structure, which encapsulates the
gentamicin drug. The core/shell conguration allows for controlled drug release and
targeted delivery, enhancing the therapeutic efcacy of the bers for wound healing
applications. Furthermore, Fig.10.1 also presents SEM fractographs illustrating the
effect of the organic:aqueous (O:A) phase ratio on the shell microstructure of composite bers containing 20% w/v polymer and 20% w/w gentamicin. In Fig.10.1c,
d represent bers synthesized with a 6:1 O:A phase ratio, with Fig.10.1d addition-
ally incorporating 5% w/v albumin. Similarly, Fig.10.1e, f depict bers synthesized
with a 12:1 O:A phase ratio, with Fig.10.1f also containing 5% w/v albumin [35].
These images provide visual insights into how variations in the O:A phase ratio,
along with the addition of albumin, impact the microstructure of the shell surrounding the core ber [41]. The changes in shell morphology observed in these fractographs highlight the inuence of emulsion parameters on the structural properties of
the composite bers, which in turn affect drug release kinetics and overall dressing
performance in wound healing applications. These insights shed light on the structural characteristics of the composite bers and their potential implications for drug
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
257
Fig. 10.1 It presents scanning electron microscope (SEM) images illustrating two aspects: (a, b)
demonstrate the core/shell ber architecture in gentamicin-loaded composite bers, while (c)
through (f) exhibit how variations in the organic:aqueous (O:A) phase ratio affect the shell microstructure in composite bers containing 20% w/v polymer and 20% w/w gentamicin. Specically,
(c) and (d) depict bers synthesized with a 6:1 O: A phase ratio, with (d) additionally featuring 5%
w/v albumin. Similarly, (e) and (f) showcase bers produced with a 12:1 O:A phase ratio, with (f)
also containing 5% w/v albumin [35]
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A. K. Gupta et al.
release kinetics and therapeutic efcacy in wound healing applications [42]. These
images offer insights into the composite bers’ morphology and the interface quality between the core and shell components [43].
10.2.2.2 Controlled Release Properties
The controlled release of therapeutic agents is a critical aspect of drug delivery,
allowing for precise modulation of drug concentrations at the target site. Composites
offer a means to achieve controlled release by inuencing the kinetics of drug
release from the matrix material [44]. The interplay between the matrix and therapeutic agents within the composite allows for tailored release proles, including
sustained, pulsatile, or triggered release, depending on the specic requirements of
the therapeutic application. This controlled release capability is advantageous in
optimizing drug efcacy, minimizing side effects, and improving patient compliance [45–47].
10.2.2.3 Enhanced Drug Loading Capacity
Composites exhibit an enhanced drug-loading capacity compared to some singlecomponent materials. Combining a matrix material with therapeutic agents allows
for efcient encapsulation and delivery of a higher concentration of drugs [48]. This
increased drug-loading capacity is particularly benecial in cases where high doses
are required or when targeting specic tissues with limited drug diffusion [48–50].
10.2.2.4 Tailored Material Properties
The versatility of composites extends to their ability to be tailored to specic material properties. This customization allows researchers to select matrix materials with
properties such as biodegradability, porosity, or surface chemistry, depending on the
desired behavior of the drug delivery system. Tailored material properties contribute
to the adaptability of composites for diverse biomedical applications, accommodating the unique challenges presented by different therapeutic agents and physiological environments [51]. Therefore, the role of composite materials in drug delivery is
multifaceted, encompassing the provision of structural integrity, controlled release
properties, enhanced drug loading capacity, and the exibility to tailor material
properties. This versatile approach positions composites as promising candidates
for developing advanced drug delivery devices with improved performance and
functionality, addressing the evolving needs of biomedical applications [52, 53].
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
259
10.2.3 Importance ofSelecting Suitable Matrix Materials
The selection of suitable matrix materials is a critical aspect in the design of composite drug delivery systems, as it signicantly inuences the performance, efcacy,
and safety of the overall device. The choice of matrix material plays a pivotal role
in determining the biocompatibility, controlled release properties, and long-term
stability of the drug delivery system. In this section, we explore the importance of
selecting appropriate matrix materials by delving into the criteria and considerations, focusing on biocompatibility and other relevant factors [27, 53].
10.2.3.1 Biocompatibility
Biocompatibility is a paramount consideration when choosing matrix materials for
drug delivery composites. The selected matrix must be compatible with the biological environment to avoid adverse reactions, inammation, or immune responses.
Biocompatible matrix materials promote the integration of the drug delivery system
with surrounding tissues, reducing the risk of rejection and enhancing the overall
safety prole. Commonly used biocompatible materials include polymers, hydrogels, and certain metals, each with specic advantages depending on the intended
application [54].
10.2.3.2 Degradability andBiodegradability
The degradability or biodegradability of the matrix material is crucial, especially for
implantable drug delivery systems. Degradable matrices allow for the controlled
release of therapeutic agents over time, eventually breaking down into biocompatible byproducts that can be safely metabolized or excreted by the body. This feature
is particularly relevant for applications where the presence of a permanent implant
is undesirable or when extended drug release is needed [27, 55].
10.2.3.3 Mechanical Properties
The mechanical properties of the matrix material are essential for maintaining the
structural integrity and functionality of the drug delivery system. Depending on the
application, the matrix should possess adequate strength, exibility, or rigidity to
withstand physiological forces without compromising its performance. For example, in the case of orthopedic implants or cardiovascular stents, materials with
appropriate mechanical properties are crucial to ensure longevity and stability [30,
56, 57].
260
10.2.3.4 Drug Compatibility
The matrix material must be compatible with the therapeutic agents encapsulated
within the composite. It should not interact with or degrade the drugs, ensuring the
stability and efcacy of the pharmaceutical payload. Compatibility considerations
include the drugs’ solubility, diffusion, and chemical stability within the chosen
matrix, ensuring that the desired drug release kinetics are achieved without compromising the therapeutic activity [46].
10.2.3.5 Fabrication Compatibility
The ease of fabrication and processing of the matrix material is another signicant
factor. The chosen material should be amenable to the selected manufacturing techniques, such as additive manufacturing or traditional molding processes, to ensure
efcient and reproducible production of drug delivery devices. Compatibility with
fabrication methods contributes to the scalability and practical implementation of
composite-based drug delivery systems [58].
10.2.3.6 Cost andAccessibility
A. K. Gupta et al.
Practical considerations, such as the cost and accessibility of the matrix material,
are also important. Cost-effective materials readily available in sufcient quantities
contribute to the feasibility and scalability of producing composite drug delivery
devices for widespread clinical use. Hence, the importance of selecting suitable
matrix materials for composite drug delivery systems lies in their inuence on biocompatibility, degradation characteristics, mechanical properties, drug compatibility, fabrication feasibility, and practical considerations such as cost. A thoughtful
and informed selection of matrix materials is crucial for the success of drug delivery
systems, ensuring optimal performance and safety in diverse biomedical applications [58].
10.3 Factors Inuencing Composite Selection
10.3.1 Matrix Material Properties
The properties of matrix materials in drug-eluting composites are central to the
overall performance and functionality of these biomedical devices. Matrix materials
are the structural framework that encapsulates therapeutic agents, providing support, controlled release properties, and compatibility with biological tissues. The
selection of appropriate matrix material properties is a critical consideration in
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
261
designing drug-eluting composites, and these properties signicantly inuence the
device’s efcacy and safety [59, 60].
Firstly, the mechanical properties of the matrix material play a crucial role in
determining the overall structural integrity of the drug-eluting composite. The
mechanical strength and exibility of the matrix are essential, especially for devices
that may experience physiological forces or mechanical stresses invivo [61, 62].
For instance, cardiovascular stents or orthopedic implants require materials with
sufcient strength to withstand dynamic forces while maintaining their integrity
over time. Choosing a matrix with the appropriate mechanical properties ensures
the longevity and reliability of the drug-eluting device during its intended application. Secondly, the biocompatibility of the matrix material is of utmost importance.
Biocompatibility ensures that the matrix does not induce adverse reactions, inammation, or immune responses when in contact with biological tissues [63]. The
matrix should be well-tolerated by the host organism to minimize the risk of rejection or complications. Biocompatible matrix materials promote the integration of
the drug-eluting composite with surrounding tissues, facilitating its successful
incorporation into the physiological environment. The degradation characteristics
of the matrix material represent another crucial property [64]. Depending on the
application, matrices may need to be either non-degradable, slowly degradable, or
fully biodegradable. Non-degradable matrices are suitable for long-term applications, providing sustained structural support. Slowly degradable or biodegradable
matrices, on the other hand, are advantageous for devices that require controlled
release of therapeutic agents over a specied duration. The matrix’s degradation can
inuence drug release’s kinetics, aligning with the desired treatment strategy [65].
The porosity and surface characteristics of the matrix material also impact the
drug release kinetics and overall performance of drug-eluting composites. Porous
matrices can enhance drug loading capacity and provide additional surface area for
controlled drug release. Surface properties inuence the interaction between the
matrix and therapeutic agents, affecting the release prole and bioavailability of the
drugs. Tailoring the surface characteristics allows for ne-tuning the drug release
behavior and optimizing therapeutic outcomes [66]. Moreover, the choice of matrix
material can inuence the compatibility with various fabrication techniques, including additive manufacturing or traditional molding processes. The ease of fabrication
is crucial for ensuring reproducibility and scalability in producing drug-eluting
devices. Compatibility with fabrication methods facilitates the practical implementation of composite-based drug delivery systems. Hence, the properties of matrix
materials in drug-eluting composites are multifaceted, encompassing mechanical
strength, biocompatibility, degradation characteristics, porosity, and surface properties [67]. The careful consideration of these properties ensures the successful integration of therapeutic agents, controlled release, and overall efcacy of the
drug-eluting composite in diverse biomedical applications. The subsequent sections
of this review will explore additional factors inuencing composite selection,
including release mechanisms, toxicity evaluation, biocompatibility assessment,
surface engineering, and advanced fabrication techniques.
262
A. K. Gupta et al.
In the eld of drug-eluting devices, the utilization of various biodegradable polymers, both natural and synthetic, has witnessed signicant advancements in recent
years. These polymers serve as carriers for antibiotics and are designed to release
controlled quantities of these therapeutic agents, providing tailored degradation
properties for specic biomedical applications [68, 69]. Notably, the choice of biodegradable polymers plays a pivotal role in inuencing critical processes such as
cell growth, tissue regeneration, drug release, and host response. Among the synthetic biodegradable polymers employed in antibiotic-eluting devices, poly-(lactideco-glycolide) copolymers [68, 70, 71], polycaprolactone [72, 73], polyanhydrides,
and polyhydroxybutyrate-co-hydroxyvalerate (PHBV) [74] have been extensively
reported. Additionally, natural polymers like collagen and chitosan, prized for their
superior biocompatibility and facilitation of cell growth, offer attractive alternatives
due to their cost-effectiveness and ready availability [74, 75]. Table10.1 provides a
comprehensive overview of antibacterial drugs utilized in controlled-release systems, presenting the essential properties of each drug [76, 77]. These properties
include molecular weight, water solubility, pH-induced effects, solubility in organic
solvents, melting temperature, and antibacterial spectrum. For instance, aminoglycosides like Amikacin, Gentamicin, and Tobramycin exhibit high water solubility
and broad-spectrum activity against both Gram-positive and Gram-negative bacteria [78]. Cefalosporins, such as Cefazolin and Cefoperazone, and glycopeptides,
like Vancomycin, demonstrate specic antibacterial properties against Grampositive bacteria. The table offers a valuable resource for researchers and practitioners in the design and development of antibiotic-eluting systems, requiring a
nuanced understanding of drug properties for effective biomedical applications.
10.3.2 Release Mechanisms (Controlled andBurst Release)
The controlled release mechanism is a fundamental strategy in drug delivery systems, particularly in drug-eluting composites [79]. This mechanism ensures a gradual and sustained release of therapeutic agents over an extended period, contributing
to optimized therapeutic efcacy and patient outcomes. Controlled release mechanisms are achieved through various approaches, such as diffusion-controlled release,
matrix degradation, and chemical reaction-controlled release. In a diffusioncontrolled release, the passive diffusion of therapeutic agents through the matrix
material governs the release kinetics [80]. This method is advantageous for achieving a consistent therapeutic concentration at the target site, making it particularly
suitable for chronic conditions or long-term drug delivery applications [81].
Matrix degradation represents another controlled release mechanism, especially
in biodegradable or biocompatible matrix materials. As the matrix undergoes controlled degradation, additional surface area for drug release becomes available [82].
This process can be precisely engineered to align with desired release kinetics,
ensuring a controlled and gradual release of therapeutic agents. Chemical reactioncontrolled release involves leveraging specic chemical reactions within the matrix
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
Predominantly active against Gram-
Broad spectrum, many Gram-positive
and Gram-negative bacteria
positive bacteria
against Gram-negative bacteria
Mycobacteria
Gram-positive and fastidious Gram-
negative bacteria
263
(continued)
Melting
temperature (°C) Antibacterial spectrum
(decomposes)
Solubility in organic
solvents
pH induced in
the surrounding
Base Insoluble 220–230
Water
solubility (mg/
ml)
(185mg/ml)
Molecular
weight (g/
mol)
585.6 Highly soluble
102–108
(Hydrochloride
194–209)
DMF, MeOH, EtOH,
ether, CHCI, acetone.
Low solubility: DMSO
Low: EtOH 168
(100mg/ml)
(538mg/ml)
198–200
(decomposes)
MeOH 169–171 Gram-positive, with increased activity
acetone.
Low: EtOH, methanol
Weak acid DMF, pyridine,
soluble
(0.487mg/ml)
454.5 Slightly
Amphoteric DMSO 185–188 Mainly Gram-positive bacteria.
soluble
(0.286mg/ml)
1449.3 Highly soluble
191
acetone, ACN, CHCI,
EtOAC, ether, DMF,
DMSO.
Low: hexane, toluene
Weak base High: MeOH, EtOH,
(>100mg/ml)
soluble
(1.44mg/ml)
733.9 Slightly
158–160 Most anaerobes
High: EtOH.
Low: ether, CHCI
Lipophilic, low
ionization
(10mg/ml)
171.2 Soluble
Class/drug
Aminoglycosides
Amikacin
Table 10.1 The properties of various kinds of antibacterial drugs [35]
Gentamicin 477.6 Highly soluble
Tobramycin 467.5 Highly soluble
Cefalosporins
Cefazolin
Cefoperazone 645.7 Slightly
Glycopeptides
Vancomycin
Macrolides
Erythromycin
Nitromidazoles
Metronidazole
264
Gram-positive and some Gram-negative
bacteria.
A. K. Gupta et al.
Gram-positive and fastidious Gram-
More effective against Gram-negative
than Gram-positive bacteria, but active
Broader spectrum than most penicillin’s.
Broad spectrum.
Active against both Gram-positive and
Gram-negative bacteria
against several important pathogens in
negative bacteria. Mycobacteria
both groups
and Gram-negative bacteria
Negative bacteria, mycoplasma,
doxycycline and minocycline are more
active against S. aureus and various
streptococci than tetracycline
199–202
Melting
Solubility in organic
pH induced in
Water
solubility (mg/
Molecular
weight (g/
(decomposes)
temperature (°C) Antibacterial spectrum
solvents
EtOH, acetone, DMF,
the surrounding
Acid High: MeOH, DMF,
ml)
(10.1mg/ml)
mol)
349.4 Soluble
200–220 Mainly Gram-negative bacteria
3
DMSO.
Low: CHCl
Base MeOH, DMF, DMSO.
1155.4 Highly soluble
255–257
(decomposes)
Low: Dioxane
DMSO.
Amphoteric High: MeOH, DMF,
(564mg/ml)
(0.001mg/ml)
331.4 Insoluble
250–257
(decomposes)
.
3
Low: EtOH, MeOH
Low: Dioxane
CHCl
(28.3mg/ml)
183–188
, ethyl
3
DMSO, CHCl
Lipophilic, low
823.0 Slightly
201 Broad spectrum, many Gram-positive
acetate methanol, THF.
Low: acetone
Amphoteric High: MeOH, Dioxane,
ionization
soluble
(1.4mg/ml)
444.5 Slightly
N.A.
165
DMF
Low: EtOH
High: Toluene, ether,
soluble
(0.63mg/ml)
Soluble (52mg/ml)
Slightly soluble (0.23mg/ml)
457.5
444.5
, DMF, Dioxane
3
EtOAc, acetone.
Low: MeOH, EtOH,
CHCl
Table 10.1 (continued)
Class/drug
Penicillins
Ampicillin
Polypeptides
Colistin
(polymyxin E)
Quinolones
Ciprooxacin
Ooxacin 361.4 Soluble
Rifamycins
Rifampin/
Tetracyclines
rifampicin
Doxycycline
Minocycline
Tetracycline