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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5361_Библиотеки_им_академика_М_И_Перельмана.pdf
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
265
to initiate the release of therapeutic agents. This approach allows for precise control
over the release kinetics and, in some cases, enables on-demand or triggered release
based on external stimuli [83–85]. In contrast to controlled release, burst release
mechanisms involve the rapid and immediate release of a substantial number of
therapeutic agents from the composite. This mechanism is characterized by an initial peak in drug concentration, providing an immediate therapeutic effect. Burst
release is advantageous when a rapid onset of action is required, such as in acute
conditions or post-surgical interventions [86]. However, careful consideration is
essential to prevent potential adverse effects associated with high initial drug concentrations. In some instances, a combination of release mechanisms may be
employed to achieve a tailored release prole, allowing for both immediate therapeutic effects and sustained, controlled release phases. The choice of release mechanism in drug-eluting composites is a strategic decision that hinges on the specic
requirements of the therapeutic application. The ability to engineer composite materials with precise release kinetics enhances the therapeutic potential of drug delivery
systems, contributing to improved patient outcomes across various biomedical
applications [85]. Whether aiming for long-term sustained release or rapid onset of
action, understanding and strategically implementing these release mechanisms are
crucial for the success of drug-eluting composites in clinical and biomedical settings.
Emphasizing the importance of delivering medicine or nutrients at a controlled
rate and dosage, it is essential to ensure that factors like size, shape, surface morphology, bioavailability, and biodegradability are suitable and tailored to the
intended location. Biomimetic polymer nanoparticles, varying in sizes, have proven
effective in loading therapeutic ingredients and visualizing inammatory regions at
a molecular level, thereby resolving potential inammations and immune responses
[87]. The signicance of these concepts is illustrated in Fig.10.2, showcasing various types of carriers designed to control drug release mechanisms [88].
Polysaccharide-based composites like arabinoxylan, xanthan gum, and chitosan
have emerged as promising carriers for genes, biomolecules, and biological agents
in biomedical drug delivery applications [89]. These materials possess attributes
such as excellent bioactivity, low cytotoxicity, nonantigens, processability, reversible loading, and release mechanisms. They have been successfully applied in various medical contexts, including cartilage repairs, vascular grafts, and cancer
treatment [90]. Their advantageous features for medication delivery encompass
emulsication, gel formation, foaming, and moisture absorption [91]. The controlled drug delivery capabilities of these polysaccharide-based biomaterials are
attributed to unique mechanical and cross-link features, enabling suitable biodegradation in different environments and specic areas [92]. Whether directly synthesized or incorporated into engineered nano-carriers, they serve diverse functions as
hydrogels, lms, tubes, microspheres, and microneedles, all based on materials like
chitosan, guar gum, and arabinoxylan [93, 94].
The primary objective of controlled drug delivery is to administer treatments consistently at the intended location, typically in the blood, ensuring an effective therapeutic window [95–97]. This approach proves to be both cost-effective and desirable,
minimizing or eliminating unpleasant side effects and complications in dosing and
266
Fig. 10.2 Illustration of controlled drug release mechanism using diverse types of carriers [88]
A. K. Gupta et al.
enhancing patient recovery and comfort. The most sought-after pharmacological
properties of biomaterial systems involve regulated breakdown and sustainable
release upon accumulation at the target site [98]. Triggers such as temperature, pH,
and ion concentration play a crucial role in managing the controlled release of
implanted medicines or therapeutic substances. The targeted drug supply system
must activate cellular areas to optimize drug delivery systems, aligning with the
required release kinetics through tailored drug delivery approaches [99, 100].
10.3.3 Toxicity Evaluation ofComposite Materials
The toxicity evaluation of composite materials is a crucial step in the development
and application of drug-eluting devices, ensuring the safety and biocompatibility of
these materials in biomedical contexts. Biocompatibility is a fundamental consideration in the design of drug delivery systems, as the interaction between the composite material and the biological environment must not induce adverse effects on
living tissues [101]. Consequently, thorough toxicity assessments are imperative to
guarantee the safe use of drug-eluting composites and mitigate potential risks associated with their deployment in clinical settings. One primary concern in toxicity
evaluation is the potential for the composite materials to induce cytotoxicity, which
refers to their impact on cell viability and function [102]. Comprehensive invitro
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
267
studies assess the effects of composite extracts or direct contact on various cell
types, providing insights into the biocompatibility of the materials. These studies
aim to identify any adverse cellular responses, such as cell death or inammatory
reactions, and guide the renement of composite formulations to minimize cytotoxic effects [103]. Moreover, invivo, toxicity assessments are essential to bridge
the gap between in vitro ndings and the complex physiological environment.
Animal studies help elucidate the systemic effects and overall biocompatibility of
drug-eluting composites. These evaluations consider factors such as tissue responses,
inammation, and potential systemic toxicity arising from releasing therapeutic
agents [104]. Understanding how composite materials interact with living organisms provides critical information for predicting their behavior in humans and
informs the development of safe and effective drug delivery systems [105].
The importance of toxicity evaluation extends beyond immediate cytotoxic
effects, encompassing considerations of long-term biocompatibility and potential
immunological responses. Chronic exposure to composite materials may elicit
immune reactions, necessitating comprehensive assessments of inammatory markers, immune cell responses, and overall tissue compatibility [106]. Rigorous toxicity evaluations contribute to establishing a comprehensive safety prole, ensuring
that drug-eluting composites do not compromise the host immune system or trigger
chronic inammatory responses that could undermine the intended therapeutic outcomes [107]. Furthermore, the biodegradability of composite materials is a signicant aspect of toxicity evaluation. For biodegradable matrices, assessing the
byproducts of degradation and their impact on the surrounding tissues is crucial
[108]. The degradation process should be controlled to avoid the accumulation of
potentially toxic substances and ensure that the composite remnants are metabolized or eliminated without adverse effects [109].
10.3.4 Biocompatibility Assessment
Assessing the biocompatibility of composite materials in drug delivery is a critical
aspect of ensuring the safety and efcacy of these systems in biomedical applications. Biocompatibility assessments involve evaluating the interaction between the
composite materials and living tissues, aiming to determine the degree to which the
materials elicit a favorable response without causing adverse effects. Various methods and considerations are employed to comprehensively assess biocompatibility in
the context of drug-eluting composites [110, 111].
10.3.4.1 In Vitro Cell Culture Studies
In vitro cell culture studies serve as an initial step in biocompatibility assessment,
involving exposing relevant cell lines to composite materials or extracts. Cell viability, proliferation, and morphology are evaluated to understand how the materials
268
A. K. Gupta et al.
interact with cells [112]. Additionally, assessing inammatory responses, apoptosis,
and other cellular behaviors provides insights into the biocompatibility of the composite. Cell culture studies are valuable for screening potential cytotoxic effects and
guiding the optimization of composite formulations [112, 113].
10.3.4.2 Hemocompatibility Studies
Hemocompatibility studies are particularly relevant for drug-eluting composites
intended for use in contact with blood or vascular tissues. These studies assess the
interactions between composite materials and blood components, focusing on factors such as hemolysis, coagulation, and platelet activation. Evaluating hemocompatibility ensures that the materials do not induce adverse effects on blood
components, preventing issues such as thrombosis or hemolysis [59, 114].
10.3.4.3 In Vivo Animal Studies
In vivo, studies involving animal models are crucial for assessing the biocompatibility of composite materials in a complex physiological environment. These studies
allow for a more comprehensive evaluation of tissue responses, inammation, and
overall systemic effects. Animal models provide insights into the long-term effects
of the composite, including tissue integration, immunological responses, and potential systemic toxicity. Biocompatibility assessments in vivo help bridge the gap
between invitro ndings and the complex invivo context, providing a more holistic
understanding of the materials’ interaction with living organisms [115].
10.3.4.4 Histological Analysis
Histological analysis involves examining tissue samples from in vivo studies to
assess the histopathological changes induced by the composite materials [116]. This
analysis provides information about tissue compatibility, the extent of inammation, and any potential tissue reactions. Histological examination is essential for
understanding the local effects of the composite within the implantation site and its
impact on surrounding tissues [117, 118].
10.3.4.5 Immune Response Evaluation
Biocompatibility assessments should include an evaluation of the immune response
elicited by composite materials. This involves studying inammatory markers,
immune cell inltration, and the overall immune reaction within the implantation
site. Understanding the immune response is critical for predicting the host’s reaction to the composite and ensuring that the material does not induce chronic inammation or adverse immune reactions [119].
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
10.3.4.6 Biodegradation Assessment
Assessing the degradation process is integral to biocompatibility evaluation for biodegradable composite materials. This involves monitoring the breakdown of the
composite over time, studying the byproducts of degradation, and determining their
impact on surrounding tissues. Evaluating the biodegradation characteristics ensures
that the composite remnants are metabolized or eliminated without causing undue
harm [120]. Considering these methods collectively contributes to a comprehensive
assessment of the biocompatibility of composite materials in drug delivery. The
information obtained from these assessments guides the renement of composite
formulations, ensuring that the materials are safe, well-tolerated by living tissues,
and suitable for their intended biomedical applications [121, 122].
269
10.4 Surface Engineering Considerations
10.4.1 Impact ofSurface Engineering onWear andFriction
Surface engineering plays a pivotal role in inuencing the wear and friction properties of drug-eluting composites, impacting the performance and longevity of these
biomedical devices. The surface characteristics of drug-eluting composites are critical not only for their mechanical integrity but also for their interaction with biological tissues and uids. In this context, we delve into how surface engineering
considerations can signicantly affect wear and friction properties in drug-eluting
composites [123, 124]. The wear prole of the surface produced by CNC machine
and additive manufacturing varies signicantly [119].
One key aspect of surface engineering is the modication of surface topography
and roughness. The topographical features of a material’s surface can inuence its
interaction with surrounding tissues and the surrounding physiological environment. By engineering the surface topography, researchers can tailor the contact
mechanics and reduce friction-related wear [125]. Smoother surfaces with optimized roughness can minimize abrasive wear and enhance the overall biocompatibility of the composite. This is particularly important for implants or devices that
come into direct contact with tissues, as reduced wear can mitigate the risk of tissue
damage or adverse reactions. Surface modications can also involve the application
of coatings or lms to alter the material’s surface properties. For drug-eluting composites, coating technologies can serve multiple purposes, including improving
lubrication, reducing friction, and enhancing the controlled release of therapeutic
agents. Lubricious coatings can minimize friction between the composite and surrounding tissues or other medical devices, contributing to the device’s overall performance and reducing the likelihood of mechanical failure or wear-induced
complications [126].
270
Additionally, surface modications may include incorporating biocompatible
polymers or hydrogels that exhibit low friction characteristics. These materials can
act as protective layers, reducing the direct contact between the composite and biological tissues. Furthermore, lubricious coatings can enhance the ease of insertion or
implantation of drug-eluting devices, particularly in minimally invasive procedures,
by reducing the resistance encountered during placement. Surface engineering also
plays a crucial role in controlling the release kinetics of therapeutic agents from the
composite. By modifying the surface properties, such as porosity or coating thickness, researchers can inuence the diffusion rates of drugs through the matrix. This
tailored control over drug release not only ensures precise therapeutic concentrations
at the target site but also minimizes premature release, contributing to the overall
efcacy and safety of the drug-eluting composite [127]. Moreover, advances in nanotechnology allow for the incorporation of nanoparticles or nanocoating’s with specic surface properties. These nanostructures can provide unique surface
functionalities, such as enhanced lubrication, reduced friction, or targeted drug
delivery. Nanoscale surface modications improve tribological properties and controlled drug release, addressing both mechanical and therapeutic aspects of drugeluting composites [128].
A. K. Gupta et al.
10.4.2 Techniques forEnhancing Surface Properties
ofDrug-Eluting Composites
Enhancing the surface properties of drug-eluting composites is a critical aspect of
surface engineering, aiming to improve their performance in biomedical applications. Various techniques are employed to modify the surface characteristics of
these composites, inuencing factors such as wear, friction, and drug release kinetics. Below are several techniques used to enhance the surface properties of drugeluting composites.
10.4.2.1 Surface Coatings
Applying coatings to the surface of drug-eluting composites is a common technique to modify their properties. Coatings can comprise polymers, hydrogels, or
biocompatible materials that improve lubrication, reduce friction, and control drug
release [129, 130]. Lubricious coatings, for example, can minimize friction
between the composite and surrounding tissues, reducing wear and improving
overall biocompatibility [131]. The evolution from rst- and second-generation
stents to the latest fourth-generation reects a continuous effort to surmount limitations and enhance the efcacy of coronary artery disease treatments. Integrating
biodegradable polymers in stent design tackles issues related to non-biodegradable
polymers, offering a potential solution to complications associated with metal
scaffold retention and polymer accumulation [132]. The in-depth overview
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
Table 10.2 Biodegradable polymer-coated drug-releasing stents (DES) for advanced vascular
interventions [59, 133]
Drug
Stent
Trade name
Synergy™ Pt-Cr PLGA Everolimus (60) 50%
Axxess™ Nitinol PLA Biolimus A9(30) 45% Biosensors
BioMatrix
Flex™
Nobori SS PLA Biolimus A9(30) 45% Terumo
Supralimus SS PLLA–
Orsiro Co-Cr PLLA +
BioMime™ Co-Cr PLLA +
Inspiron Co-Cr PLLA,
Firehawk®Co-Cr POLLA Sirolimus (90) 90% Micro Port
DESyne BDCo-Cr PLA Novolimus M(90) 90% Elixir (Milpitas,
MiStent
SES
Tivoli Co-Cr PLGA Sirolimus (7) 50%
platform
SS PLA Biolimus A9(30) 45% Biosensors
Co-Cr PLGA Sirolimus (270) 100% Micelle
Polymer
system Drug
Sirolimus (48) 100% SMT (Mumbai,
PLGA–
PCL− PVP
Sirolimus (30) 50%
silicon
carbide
Sirolimus (30) 100% Meril (Gujarat,
PLGA
PLLA +
PLGA
Sirolimus (10) 60%
PDLLGA
PLLA
PDLLGA
release
(days) Manufacturer Approval
(90) 100%
(90) 80%
(45) 100%
(28) 80%
Boston Scientic
(Marlborough,
MA)
(Irvine, CA)
(Irvine, CA)
(Somerset, NJ)
India)
Bortnick (Poznan,
Poland)
India)
SciTech Medical
(Aparecida de
Goiania, Brazil)
Medica
(Shanghai, China)
CA)
Technologies
(Durham, SC)
Essen Technology
(Beijing, China)
FDA, CE
CE
CE
CE
CE
CE
CE
Phase IV
NCT01856088
CE
CE
CE
Phase III
NCT02448524
271
presented in Tables 10.2, 10.3, and 10.4 is a valuable reference for researchers and
clinicians engaged in cardiovascular interventions and stent development [59, 133].
The drawback associated with rst- and second-generation stents lies in the presence of nonbiodegradable polymers on the stent post-complete drug release. This
issue can lead to local hypersensitivity, tissue inammation, and delayed vessel
healing, potentially causing late-stage thrombosis in drug-eluting stents (DES).
Third-generation stents have been introduced in response to this limitation, featuring fully biodegradable polymers like PLGA and PLA.An illustrative example is
the everolimus-eluting stent, composed of a platinum-chromium platform coated
272
Table 10.3 The composition and outcome of the degradation process in biodegradable polymers
[59, 133]
A. K. Gupta et al.
Table 10.4 Mechanical and thermal characteristics of frequently employed biodegradable
polymers in medical applications [59]
Total
Tg
T
Material E (GPa)σ (MPa) ε (%)
PLLA 3.4–4.8 10–100 2–6 60–65 170–180 6 24–67
PGA
PLGA
(D/L/PLG)
85/15–50/50
PCL 0.3–0.4 16–23 300–700 −60 59–64 0.8 >34
Note: Tg refers as glass transition temperature and T
6.8–12.5 70–647 Min 35–40 180–230 1–2 6–12
2 20–50 3–10 45–55 – 1–4 2–6
(°C)
melt
(°C)
as melting point
melt
Loss of mech.
prop. (months)
degradation
(months)
with a biodegradable PLGA copolymer [134–136]. Table10.2 provides a detailed
list of FDA and Conformity Europeanness (CE)-approved DES based on biodegradable polymers, offering valuable insights into the current landscape of these
advanced stents [59, 133, 137].
Despite advancements with third-generation stents, the challenge of metal scaffold (BRS) retention in the artery after biopolymer degradation persists.
Nonbiodegradable implants pose a risk of polymer accumulation in the body,
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
273
necessitating surgical removal. Hence, the quest for fully biodegradable stents that
the body can efciently excrete post-degradation remains an ongoing pursuit [133].
The latest breakthrough in coronary artery disease (CAD) treatment comes from the
fourth generation of DES, incorporating a biodegradable polymer core modied with
an active substance. This innovative approach aims to enhance the effectiveness and
viability of stents by combining the benets of drug-eluting capabilities with complete biodegradability. These advancements signify a signicant step towards overcoming the limitations of earlier generations of stents [138]. Shifting the focus to
biodegradable polymers, thermoplastic aliphatic poly(esters) like poly (lactic acid)
(PLA), poly (glycolic acid) (PGA), and poly(lactic-co-glycolic acid) (PLGA) have
undergone extensive study due to their favorable characteristics, including biodegradability, biocompatibility, and mechanical strength [139–141]. Commonly employed
as construction materials for stent scaffolds and surface coatings, these polymers
have proven successful in nanoparticle-based drug delivery systems and parenteral
implants. PLA, especially notable for its FDA approval and popularity in medical
applications owing to its biodegradability and bio- restorability, is extensively discussed. Table10.3 outlines the chemical structures and degradation mechanisms of
PLA, PGA, PLGA, and PCL.In contrast, Table10.4 provides a comprehensive overview of the mechanical and thermal properties of these medical biodegradable polymers, serving as valuable information for researchers in the eld [142–145].
In the domain of medical materials technology, several less commonly utilized
biodegradable polymers are employed for drug delivery. This includes poly(amides),
poly(anhydrides), poly (phosphazines), and poly(dioxanone) [146, 147].
Poly(anhydrides), characterized by low hydrolytic stability, exhibit rapid degradation rates, rendering them suitable for short-term controlled delivery systems
[148–150]. The controlled degradation of poly (phosphazenes) can be nely tuned
by appropriate substitution with specic chemical groups. These polymers have
been investigated for applications in skeletal tissue regeneration and drug delivery,
showcasing their versatility [148]. Another noteworthy polymer is poly(dioxanone),
akin to PCL, functioning as a polylactin utilized in drug delivery and tissue engineering applications [150]. In addition to the polymers mentioned above, there are
several other biodegradable polymers with distinct properties and applications.
Poly(caprolactone) (PCL) is another aliphatic polyester commonly used for drug
delivery due to its biocompatibility and slow degradation rate. Moreover, poly (glycolic acid) (PGA) is widely employed in developing biodegradable sutures and drug
delivery systems, characterized by its fast degradation rate. Polylactic acid (PLA),
derived from renewable resources, nds applications in drug delivery and tissue
engineering due to its biocompatibility and controllable degradation rate [151].
Poly (ester urethane) represents another class of biodegradable polymers with
tunable mechanical properties, making them suitable for various biomedical applications. Poly (propylene fumarate) (PPF), a thermosetting polyester, is investigated
for use in bone tissue engineering due to its biocompatibility and injectability.
Poly (ortho esters) (POEs) are notable for their pH-sensitive degradation, offering
potential applications in controlled drug release systems. Additionally, poly
274
A. K. Gupta et al.
(ε-caprolactone-co-ethyl ethylene phosphate) (PCLEEP) is a biodegradable copolymer investigated for its potential in drug delivery and tissue engineering. These
diverse biodegradable polymers cater to various requirements in the biomedical
eld, emphasizing the importance of selecting the appropriate polymer based on the
intended application and desired properties. Their versatility and tunable characteristics contribute to their widespread exploration in developing advanced drug delivery systems and biomedical devices [152].
10.4.2.2 Plasma Treatment
Plasma treatment involves exposing the surface of drug-eluting composites to a
plasma discharge. This process can modify the surface chemistry, introducing functional groups or enhancing surface wettability. Plasma treatment is effective in
improving the adhesion of coatings, promoting better drug release control, and
inuencing the tribological properties of the composite surface.
In recent developments in coating designs for drug-eluting stents (DES),
researchers have introduced plasma treatments as a novel approach to enhance the
chemical bonds in the drug-release layer through polymer cross-linking. This innovative technique involves subjecting the base metal or polymer-coated stent surface
to a gaseous plasma beam for varying durations. Specically, a study led by
Hagiwara investigated the potential of plasma-treated coatings for DES by applying
this technique to silicon wafers coated with curcumin-loaded polyethylene vinyl
acetate (PEVA). The research focused on assessing the effects of exposure to argon,
oxygen, and nitrogen plasma over time. The study’s ndings demonstrated the efcacy of plasma treatment in modulating drug release from the coated surfaces. In
comparison to untreated stents, which released up to 120 μg of the drug within
14days, the highly treated samples exhibited a signicantly reduced release, ranging between 5 and 50μg, depending on the type of gas used in the same timeframe
[153]. This highlights the potential of plasma treatment as a means to control and
optimize drug release kinetics from DES coatings. The technique offers a relatively
straightforward approach to enhance the intermolecular strength of the stent coating, showing promise for improved precision in drug delivery [59].
It is important to note that, despite the promising results, the application of
plasma-treated coatings for DES is still in its early stages of development. Further
research and exploration are needed to rene and validate the effectiveness of this
technique. As researchers delve deeper into the intricacies of plasma treatments, it
is anticipated that this method may emerge as a valuable tool in tailoring the drugrelease characteristics of DES, contributing to advancements in cardiovascular
interventions.