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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
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10.5.2 Evaluation ofDrug Release Kinetics
The zero-order, rst-order, and Higuchi models are commonly applied mathematical models for analyzing drug release kinetics [197]. These models help describe
the release mechanisms and predict the release behavior of therapeutic agents from
drug-eluting composites. The zero-order model assumes a constant release rate, the
rst-order model assumes a proportionate release rate, and the Higuchi model is
based on Fickian diffusion principles [198]. These models aid in understanding the
underlying mechanisms governing drug release and assist in designing and optimizing drug-eluting devices. Furthermore, researchers often consider the inuence of
various factors on drug release kinetics, including the properties of the composite
matrix, the type of therapeutic agent, and environmental conditions. The matrix
composition, porosity, and degradation characteristics signicantly impact the
release prole. Additionally, the solubility of the drug, its afnity to the matrix
material, and the presence of other excipients inuence the kinetics of drug
release [199].
The evaluation of drug release kinetics from drug-eluting composites involves a
combination of analytical techniques, mathematical modeling, and consideration of
various factors inuencing release behavior. This comprehensive approach allows
researchers to tailor drug release proles, ensuring precise therapeutic delivery
while minimizing the risk of adverse effects. By understanding and optimizing drug
release kinetics, drug-eluting composites can be designed to meet specic clinical
requirements, enhancing their effectiveness in diverse biomedical applications. In
the study conducted by [200], the investigation focused on the in-vitro release proles of sirolimus-in-poly (D, L-lactide) (PDLLA) coatings under various conditions. The research involved the preparation of single-layer, bilayer, and various
ratios of sirolimus/PDLLA coatings on biodegradable poly (L-lactide) (PLLA)
stents and tubes. Coatings with polyethylene glycol (PEG) additives were also prepared to assess their controlled release behaviors [59]. This research represents a
crucial step towards establishing an in-vitro release model, which will be further
validated through comparison with in-vivo release proles in future studies. In the
review article by Zhang etal. [201], various concepts for local intravascular drug
delivery with drug-eluting stents (DES) were discussed, emphasizing clinical evidence regarding desired release proles. Traditional methods to control drug
releases from DES, including diffusion through polymers, polymer degradation,
erosion, and dissolution of particulate drugs, were explored. The article underscored
the need for further experimental studies and clinical trials to investigate the duration of release favored for DES and the short release period sanctioned for drugeluting balloons. Evaluation of drug release kinetics in drug-eluting composites is
critical to ensuring controlled and targeted therapeutic delivery [59]. The assessment of drug release kinetics provides insights into how the composite materials
release therapeutic agents over time, inuencing the efcacy and safety of the biomedical device. Several methods and considerations are employed to measure and
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analyze drug release kinetics from drug-eluting composites. One commonly used
method for evaluating drug release kinetics is High-Performance Liquid
Chromatography (HPLC). This analytical technique allows for the quantication of
specic drugs or therapeutic agents released from the composite. By analyzing samples taken at different time points, researchers can construct a release prole that
illustrates the concentration of the drug over time. HPLC is particularly valuable for
assessing the drug release rate, identifying any burst release phenomenon, and
ensuring that the release prole aligns with the desired therapeutic goals.
Another study [202] delved into the mathematical modeling of the degradation
of a drug-loaded polymeric matrix and the subsequent release of the drug to adjacent biological tissues. The model considered mass-preservation equations for polymeric degradation and incorporated solubilization dynamics of drug particles,
diffusion of solubilized drugs through the polymeric matrix, and reversible dissociation/recrystallization processes. The tissue phase accounted for reversible dissociation/association and internalization processes of medicine. This two-phase
spatiotemporal model, represented by a system of partial differential equations, was
analytically solved with appropriate initial, interface, and boundary conditions.
Simulated results were compared with experimental data, demonstrating commendable agreement and validating the model’s applicability [59]. The model provides
insights into important drug kinetic parameters, offering a nuanced understanding
through local sensitivity analysis. The coatings exhibited no apparent delamination
or cracking on the stent-coating surface subjected to crimping and expansion.
Subsequently, the degradation performances of drug-free PDLLA lms were studied to analyze the effects of changes in molecular weight and mass loss. The in-vitro
sirolimus release proles of different coating formulas in phosphate-buffered saline
(PBS) were then investigated using high-performance liquid chromatography
(HPLC). The results revealed similar two-phase release kinetics, although the initial
release rates varied [59].
In the research conducted by Zhang etal. [201], the investigation aimed to understand the drug-release proles of biodegradable polymer sirolimus- or paclitaxeleluting stents with an asymmetrical coating (BPSES-A or BPPES-A). Both invitro
and invivo assessments were conducted, with the drug-release prole characterized
by measuring drug concentration using HPLC over time. The results demonstrated
that the drug release rates of BPSES-A and BPPES-A were slower, more stable, and
less burst-releasing compared to conventionally coated stents (BPSES-C and
BPPES-C). In addition to HPLC, other spectroscopic techniques, such as UV-Vis
spectroscopy, may be employed. UV-Vis spectroscopy is useful for characterizing
compounds that absorb light in the ultraviolet and visible regions, making it applicable for analyzing specic drugs with distinct absorbance properties. This method
aids in monitoring drug release by measuring changes in absorbance as the therapeutic agents are released from the composite. Moreover, the dialysis method is
often utilized to study drug release kinetics. In this method, the drug-eluting
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
composite is placed in a dialysis bag, allowing for the separation of released drugs
from the composite while preventing the loss of larger particles. The dialysis bag is
immersed in a release medium, and samples are collected at different time points to
determine the concentration of the released drug. This approach is advantageous for
mimicking physiological conditions and providing a controlled environment for
studying drug release [203].
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10.5.3 Analysis ofStructural Integrity andControlled
Release Properties
Analyzing the structural integrity and controlled release properties of drug-eluting
composites is a fundamental aspect of developing drug delivery systems with optimal performance and therapeutic efcacy. The structural integrity of these composites is directly correlated with the overall reliability of the drug-delivery device.
Rigorous evaluation of mechanical strength, durability, and resistance to deformation is essential to ensure that the composite material can withstand the physiological conditions within the body, mechanical stresses during implantation, and
potential degradation over time. A device with robust structural integrity not only
enhances its longevity but also mitigates the risk of failure, which could lead to
unintended consequences such as premature release of therapeutic agents or device
fragmentation [174].
Understanding structural integrity is crucial for promoting tissue compatibility.
A mechanically stable drug-eluting composite minimizes the risk of fragmentation
or abrasion, which could induce adverse tissue reactions or inammation. This
aspect is particularly signicant for ensuring the long-term success of drug delivery
devices within the complex biological environment. Tissue compatibility is essential for preventing adverse reactions and promoting a harmonious interaction
between the composite and the surrounding tissues. Controlled release properties
play a pivotal role in determining the precision of therapeutic delivery from drugeluting composites. These properties dictate the rate and way therapeutic agents are
released, directly impacting the therapeutic outcomes. Controlled release analyses
are essential for tailoring drug release kinetics to meet specic medical requirements. This involves adjusting factors such as matrix composition, porosity, and
degradation characteristics to achieve a desired release prole. Tailoring drug
release kinetics is crucial for addressing diverse clinical scenarios, ranging from
chronic conditions requiring long-term therapy to acute interventions necessitating
rapid and targeted drug delivery [174, 204].
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10.6 Advanced Fabrication Techniques
10.6.1 Overview ofAdditive Manufacturing inDrug Delivery
Additive manufacturing, commonly known as 3D printing, has emerged as a transformative technology in various industries, including the biomedical eld, where it
plays a pivotal role in the fabrication of drug delivery devices. This advanced manufacturing technique enables the layer-by-layer construction of complex structures
based on digital models, offering unprecedented exibility and precision in designing intricate geometries. In the context of drug delivery, additive manufacturing has
revolutionized the traditional methods of device fabrication, allowing for the production of customized and patient-specic drug delivery systems [205].
One of the key advantages of additive manufacturing in drug delivery lies in its
ability to create highly complex and personalized structures that were previously
challenging or impossible to achieve with traditional manufacturing methods. The
layering process allows for precise control over the internal architecture of drug
delivery devices, facilitating the incorporation of intricate features such as controlled release compartments, microuidic channels, or patient-specic geometries
tailored to the anatomical requirements [206]. The storage of microuidic devices
should be in a controlled temperature and efcient laboratory using an efcient
HVAC system [207, 208]. Additive manufacturing also enables the seamless integration of multiple materials within a single drug delivery device, allowing for the
incorporation of both matrix materials and therapeutic agents in a precisely controlled manner. This capability is particularly advantageous in developing composite drug-eluting devices, where combining a biocompatible matrix with therapeutic
agents requires meticulous engineering for optimal performance [209]. Additive
manufacturing allows for strategically placing drug-loaded regions within the
device, facilitating controlled release and targeted delivery to specic anatomical
sites. The versatility of additive manufacturing extends to the fabrication of complex drug delivery systems, such as multi-drug release platforms or devices with
gradient drug concentrations. This level of sophistication in device design is crucial
for addressing diverse therapeutic needs, providing tailored solutions for conditions
that may require multiple drugs or specic dosing proles. Moreover, additive manufacturing in drug delivery aligns with the principles of precision medicine, offering
the potential for patient-specic customization. Patient-specic drug delivery
devices can be tailored based on individual anatomical variations, ensuring optimized therapeutic outcomes while minimizing the risk of adverse effects. This level
of personalization is particularly relevant in elds like oncology, where targeted and
localized drug delivery can enhance treatment efcacy while minimizing systemic
side effects.
Figure 10.6 illustrates the paradigm of tailored dosing criteria, exemplifying the
potential of additive manufacturing in the creation of individualized drug delivery
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
Fig. 10.6 Concept of personalized dosing criteria [210]
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systems. The visual depiction delineates the sequential stages integral to the fabrication of drug delivery devices, accentuating the incorporation of additive manufacturing within pharmaceutical production workows. The schematic provides a
comprehensive overview of the process, spanning from initial design to the ultimate
production of the pharmaceutical product. It specically underscores the pivotal
role of additive manufacturing in the progression of personalized medicine and the
real-time manufacturing of pharmaceutical entities. This graphical representation
underscores the critical importance of additive manufacturing in advancing the
frontier of patient-specic drug delivery systems characterized by nely tuned
release proles, thereby presenting a promising trajectory for personalized medicine [210].
Hence, additive manufacturing has revolutionized the fabrication of drugdelivery devices by offering unparalleled design exibility, precision, and customization. The layer-by-layer construction process enables the creation of intricate
structures, facilitating the integration of complex drug release mechanisms. This
technology opens new avenues for developing advanced drug delivery systems with
enhanced therapeutic precision, paving the way for innovative and personalized
solutions in the biomedical eld. As additive manufacturing continues to evolve, its
impact on drug delivery device fabrication is poised to grow, offering transformative
possibilities for tailored and patient-specic healthcare interventions [210].
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Fig. 10.7 Schematic illustration of the combination of HME and 3D process for printing tablets [211]
A. K. Gupta et al.
Figure 10.7 delineates the Hot-Melt Extrusion (HME) process, a predominant
method for producing laments utilized in Fused Deposition Modeling (FDM) techniques for additive manufacturing of pharmaceuticals [211]. The HME apparatus
comprises an extruder with a motor, an extrusion barrel, and an orice. Within the
extruder, either a rotating screw or pair of screws, driven by the motor, facilitates the
mixing of ingredients fed into the barrel, typically in pellet form via a feeder [212].
The heating unit melts the ingredients, ensuring homogeneous mixing, and produces laments with uniform shape and density due to push force and thermal input.
The entire HME process, integrated with FDM, is visually represented in Fig.10.7.
The extruded lament from the HME nozzle serves as the feedstock for the Fused
Deposition technique [211].
Two types of extruder setups are available: Single-Screw Extruder and TwinScrew Extruder. While the single-screw extruder is cost-efcient, compact, and easy
to maintain, the twin-screw extruder offers superior mixing and output capabilities.
Numerous efforts have been made to employ this technique for printing drug delivery forms using FDM.Solid drug APIs, in pellet or powder form, can be introduced
into the screw alongside polymers serving as drug carriers after the fabrication of
the drug form. This method provides exibility in adjusting the drug loading percentage, albeit with consideration for potential impacts on lament quality. However,
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
Fig. 10.8 Two strategies to load drugs onto scaffolds and their release proles [215]
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it is crucial to note that this technique is limited to drugs unaffected by thermal
degradation at elevated temperatures [213, 214].
Figure 10.8 illustrates the Soaking/Absorption method commonly employed for
drugs and polymers soluble in water or ethanol. In this approach, the base polymer,
often in pellet or lament form, is immersed in a solution containing the drug for a
specic duration. The polymer absorbs the drug-containing solution, which is subsequently utilized for 3D printing. Drying may be necessary before printing to
eliminate any residual solution adhered to the surface. The loading percentage of
the drug is calculated as the ratio of the weight gain after loading (wf− wi) to the
initial weight of the base polymer (wi). However, the loading percentage tends to be
lower compared to other techniques, and not all polymers can be easily loaded
using this method [215]. Figure10.8 presents two strategies for loading drugs into
scaffolds made of PLA material. In one process, an unloaded scaffold is initially
printed, followed by loading the drug through soaking it in the desired solution. In
the other approach, one drug is loaded into the lament before printing, and another
drug is loaded after printing using the soaking technique. Additionally, the Coating
method is discussed in the context of oral tablets, where enteric coating has been
incorporated to release the drug at intestinal locations. This technique is extended
to drug- eluting transdermal patches, scaffolds, and implants. Successful inkjet coating on microneedle patches has been demonstrated using inkjet deposition of
drugs [215].
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10.6.2 Application ofAdditive Manufacturing
inTissue Engineering
Additive manufacturing has signicantly advanced the eld of tissue engineering by
offering innovative solutions for the fabrication of complex and functional biomedical devices. This technology has revolutionized traditional tissue engineering
approaches by providing precise control over the spatial arrangement of biomaterials, cells, and growth factors. The application of additive manufacturing in tissue
engineering encompasses many areas, contributing to developing advanced and customized biomedical devices [216–221].
One primary application of additive manufacturing in tissue engineering is the
fabrication of biomimetic scaffolds. Scaffolds play a crucial role in tissue regeneration by providing a three-dimensional framework that supports cell attachment, proliferation, and differentiation [222]. Additive manufacturing allows for the creation
of scaffolds with intricate architectures that mimic the natural extracellular matrix
(ECM). This biomimicry is essential for promoting cell adhesion, guiding tissue
formation, and facilitating the integration of engineered tissues with the host environment [223]. AM techniques enable the incorporation of multiple materials within
a single scaffold, allowing for the creation of composite structures. These composites may consist of a combination of biodegradable polymers, ceramics, and even
bioactive molecules. The ability to precisely control the distribution of these materials within the scaffold is advantageous for tailoring mechanical properties, degradation rates, and bioactivity to match the requirements of specic tissues. In tissue
engineering, cell viability and spatial organization are critical factors for successful
tissue regeneration. Additive manufacturing facilitates directly incorporating living
cells into the fabrication process. Integrating cells into the scaffold during printing
makes it possible to create complex tissue-like structures with dened cell distributions. This approach is particularly relevant for developing organs or tissues with
intricate architectures, such as blood vessels, skin, or cartilage [224–228].
Furthermore, additive manufacturing enables the creation of patient-specic
implants and prosthetics. By utilizing medical imaging data, such as CT or MRI
scans, it is possible to generate personalized 3D models of anatomical structures.
Additive manufacturing allows for the fabrication of implants that precisely match
the patient’s anatomy, reducing the risk of rejection and improving overall compatibility. This is especially signicant in areas like craniofacial reconstruction or joint
replacement surgeries. The versatility of additive manufacturing extends to the fabrication of drug delivery systems within tissue-engineered constructs. By incorporating microchannels or reservoirs directly into the scaffolds, therapeutic agent
release can be controlled. This integration benets localized drug delivery to
enhance tissue regeneration, modulate the immune response, or provide antiinammatory support during the healing process [229–231].
10 Composites forDrug-Eluting Devices: Emerging Biomedical Applications
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10.6.3 Role ofAdditive Manufacturing inRegenerative
Medicine Applications
Additive manufacturing has emerged as a transformative technology in regenerative
medicine, offering innovative solutions for developing advanced biomedical
devices. In regenerative medicine, additive manufacturing plays a pivotal role in
fabricating personalized and complex structures that facilitate tissue regeneration.
Its contributions extend beyond traditional tissue engineering to encompass drug
delivery systems, where it provides unique advantages for controlled and targeted
therapeutic delivery [232–235].
One of the signicant contributions of additive manufacturing in regenerative
medicine is its role in creating patient-specic scaffolds. These scaffolds serve as
the foundation for tissue regeneration by providing a supportive environment for
cell attachment, proliferation, and differentiation. Additive manufacturing allows
for the precise customization of scaffolds based on patient-specic anatomical data
obtained from medical imaging [236]. This patient-specic approach enhances the
compatibility of the scaffold with the host tissue and contributes to improved regenerative outcomes. In drug delivery applications within regenerative medicine, additive manufacturing facilitates the creation of smart and responsive drug delivery
systems. The controlled release of therapeutic agents can be achieved through the
integration of microscale features, such as channels, reservoirs, or porous structures, within the fabricated scaffolds. This is particularly advantageous for delivering growth factors, cytokines, or other bioactive molecules that guide tissue
regeneration. The ability to tailor the drug release kinetics to match the dynamic
needs of tissue regeneration processes enhances the effectiveness of regenerative
interventions. Moreover, additive manufacturing enables the incorporation of biologically relevant materials into drug delivery systems. By using biomimetic materials, such as bioactive ceramics or tissue-derived extracellular matrix components,
additive manufacturing allows for developing drug delivery devices that closely
mimic the natural microenvironment of tissues. This biomimicry contributes to
improved cellular interactions, enhances tissue integration, and supports the overall
regenerative process [237].
The precision and versatility of additive manufacturing also facilitate the creation of multi-material constructs for regenerative medicine applications. These
constructs may include both synthetic and natural materials, offering a combination
of mechanical strength, bioactivity, and controlled drug release [238]. This multilateral approach is valuable for creating complex structures that closely resemble the
heterogeneity of native tissues, fostering a more biomimetic environment for regeneration. Additive manufacturing is crucial in developing implantable devices for
regenerative medicine. Whether it’s the fabrication of customized implants for bone
regeneration or creating scaffolds for organ transplantation, additive manufacturing
allows for the production of devices with intricate geometries and tailored functionalities. This contributes to advancing regenerative interventions, enabling the repair
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or replacement of damaged tissues with engineered constructs that closely match
the physiological requirements [236].
A. K. Gupta et al.
10.7 Challenges andFuture Directions
In drug-eluting devices, the application of composites presents both challenges and
promising future directions for emerging biomedical applications. One notable
challenge lies in achieving optimal biocompatibility and long-term safety of these
composite materials. The intricate interplay between the composite components and
the biological milieu can lead to varied responses, necessitating a comprehensive
understanding of the host-material interaction. Furthermore, issues related to the
controlled release of therapeutic agents from these composites, such as achieving
precise kinetics and sustained efcacy, pose signicant challenges. The intricate
balance between achieving the desired drug release prole and maintaining the
structural integrity of the composite material requires careful consideration and
optimization [239–244].
Looking toward the future, advancements in nanotechnology offer exciting prospects for enhancing the capabilities of drug-eluting composites. Tailoring composite structures at the nanoscale allows for precise control over drug release kinetics,
enabling the development of personalized and patient-specic therapeutic interventions. Additionally, integrating smart and responsive features into these composites,
such as stimuli-responsive drug release triggered by environmental factors like pH,
temperature, or specic biomarkers, holds immense potential. The evolution of
additive manufacturing techniques provides avenues for the fabrication of intricate
and customized drug-eluting devices with improved structural integrity and drug
delivery precision. Harnessing these innovative approaches will contribute to overcoming current challenges and propel the eld toward the development of highly
efcient and patient-tailored drug-eluting composites for diverse biomedical
applications.
10.7.1 Current Challenges inComposite-Based Drug
Delivery Devices
While promising, the development and utilization of composite-based drug delivery
devices are not without challenges. Several current issues and obstacles need to be
addressed to optimize the performance and applicability of these devices in biomedical applications. Understanding and navigating these challenges is crucial for