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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5446_Библиотеки_им_академика_М_И_Перельмана
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116 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
platelet
red blood cell
neutrophil
macrophage
broblast
Epithelial cell
brin
blood vessel
collagen ber
Figure 6.1 Differences in healing processes of normal and diabetic wounds. (Source: Adapted
from [6].) [Platelet derived growth factor (PDGF), transforming growth factor beta (TGF-β),
monocytes chemoattractant protein 1 (MCP-1), epidermal growth factor (EGF), vascular
endothelial growth factors (VEGF), and basic fibroblast growth factor (bFGF)].
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Wound Dressings by 3D Printing 117
6.1.1 Haemostasis/Coagulation
Immediately after injury, bleeding occurs to flush out bacteria and/or antigens from the
wound site and triggers haemostasis which is initiated by formation of a fibrin plug (coagu-
lation) consisting of platelets and provides an instant protection from the external environ-
ment and primary coverage of the wound [1]. Aggregated platelets secrete cytokines
(including leukotriene B4, platelet factor IV) and several growth factors (such as PDGF,
TGF-β, MCP-1, IGF-1, EGF) that recruit neutrophils and monocytes to the wound area,
which are extremely important for the first phase of new tissue formation process [7].
6.1.2 Inflammation
The inflammatory phase is initiated simultaneously with haemostasis, sometimes from a
few minutes after injury up to 24 hours and continues for about 3 days [3]. Once haemosta-
sis has been achieved, the blood vessels dilate (vasodilation) to allow pro-inflammatory
substances (growth factors) such as PDGF, TGF-β, MCP-1, IGF-1, and EGF, which attract
the migration of leukocytes, macrophages, and lymphocytes into the wound site [8].
6.1.3 Proliferation
The proliferative phase occurs just after 72 hours and lasts for 2–4 weeks after injury. The
phase is characterised by fibroblast migration, collagen synthesis, angiogenesis, and granu-
lation tissue formation [7]. The migration of fibroblasts activated by TGF-β and PDGF
produces the matrix proteins fibronectin, hyaluronan, and later collagen and proteoglycans;
subsequently rebuilding the extracellular matrix (ECM) to determine the synthesis and
remodelling of the tissue [9]. The synthesis of collagen plays a central role in wound repair
because of fibroblasts migration.
6.1.4 Re-epithelisation/Remodelling
The last phase of wound healing is re-epithelisation or remodelling, also known as matura-
tion. It occurs simultaneously with the development of granulation tissue and continues for
several months up to 2 years after wound closure [3]. Regeneration (remodelling) of the
tissue is characterised by continuous collagen synthesis and its breakdown as ECM.
6.1.5 Wound Classification
The Wound Healing Society defines a wound as the ‘breakdown or disruption of normal
anatomical structure of skin and a disturbance to its function to the immune system leading
to serious morbidity and mortality [3].’ Wounds can be broadly classified as acute and chronic.
Acute wounds are superficial wounds arising from mechanical injuries such as surgical
incisions, scratches, and tears and typically affecting the epidermis and superficial dermis.
These wounds heal within the expected timeframe of 8–12 weeks and progress through the
orderly sequential wound healing phases (i.e., haemostasis, inflammation, proliferation,
maturation, and remodelling [4]).
Chronic wounds, on the other hand, experience disruption in one of more of the above
wound healing phases [1] and result from tissue destruction of skin layers including epider-
mis, dermis, and subcutaneous fat tissue. This causes prolonged healing times beyond 12
weeks, which may remain for several months. Chronic wounds are usually associated with
underlying conditions such as diabetes, chronic renal failure, and hepatic failure which
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118 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
affects the balance between wound bioburden and the patient’s immune system [10, 11].
Furthermore, the occurrence of polymicrobial and mixed infections, coupled with poor
initial management and treatment of the wound could contribute to poor healing of chronic
wounds [12, 13]. Chronic wounds include diabetic foot ulcers, leg ulcers, pressure ulcers,
venous ulcers, arterial ulcers, and trauma, and their incidence has been exacerbated by
several factors such as obesity, ageing population, alcoholism, smoking, stress, poor nutri-
tion, or prolonged pressure [2].
6.1.6 Wound Dressings
Wound dressings play a key role in the management of both acute and chronic wounds.
Generally, dressings should possess certain ideal characteristics, as summarised in Figure 6.2
[3, 4, 10, 14–17]). The choice of wound dressings depends on several factors that affect wound
healing, such as heavy exudate, microbial load, biofilms, severity of pain, and infection.
However, no single dressing fulfils all the requirements of healing, due to complexities
of chronic wounds. Generally, dressings can be classified into three main categories [3, 4]
and these are summarised briefly in Table 6.1.
6.1.7 3D Printing
Various additive manufacturing (AM) techniques (3D printing) have recently been
employed for the production of different scaffolds, including films possessing controlled
micro-architecture and geometry [18]. These techniques present huge potential as an alter-
native for film dressing formation [19, 20]. The approach involves the printing of polymers
and bioactive substances to fabricate biocompatible film scaffolds that replace traditional
solvent cast approaches for producing films.
The controlled microstructures of these scaffolds can significantly enhance dressing per-
formance by aiding material exchange, adhesion, migration of cells, and ultimately tissue
regeneration in the wounds [20, 21]. In addition, the use of 3D printing and bioprinting
methods provides more flexibility and repeatability when compared with other scaffold prep-
aration methods [22]. This is because it is possible to design functional 3D structures
Debridement (cleansing)
Protect from infection and contaminants
Maintain moist environment
Absorb exudate
Gaseous exchange
Provide thermal insulation
Ideal Characteristics
Figure 6.2 Summary of the ideal characteristics of a wound dressing.
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Table 6.1 Summary of the classification of different dressings, showing evolution from traditional to advanced dressings.
Traditional dressings Modern moist dressings Advanced dressings
Key features
• Used as coverings and for absorbing
blood and exudate and for cleansing
• No active part in wound healing
• Maintain a moist environment to
facilitate proper cell migration and
proliferation.
• No active part in wound healing
• Generally made from biomaterials such
as collagen, hyaluronic acid, chitosan,
alginates, and elastin
• High biocompatibility and
biodegradability and ability to take active
part in the wound healing process
• Can be incorporated with biological
agents such as growth factors, nucleic
acids, and stem cells for delivery to the
wound site [4].
• Impregnation of naturally derived agents
such as aloe vera, honey, silver, iodine
that make them medicated drug delivery
dressings
• The polymer-based systems can maintain
moist environment
Advantages
• Good as secondary dressing covering
for moist or advanced dressings
• They are very readily available, cheap,
and easy to use. For example, gauze
dressings made of woven or nonwoven
fibres of cotton, rayon polyester, or a
combination of both, are used in the
packing of open surgical and cavity
wounds
• Sterile gauze pads are also used as
packing of open wounds to absorb
exudates and fluids
• Create a moist environment to facilitate
effective wound healing
• Provides adequate protection for the
wound and control of exudate levels
• Film dressings allow investigation of the
wound without removal
• Hydrogels are good for providing
autolytic debriding action (softening) of
necrotic tissue due to high moisture
content
• Generally cost-effective
• Biologically active; therefore, have
therapeutic/pharmacological effects
• Very effective in treating chronic wounds
(Continued)
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Traditional dressings Modern moist dressings Advanced dressings
Limitations
• Passive action with no active part in
wound healing process
• Can cause dryness and trauma upon
removal
• Poor moisture handling ability, therefore
leaks when saturated with moisture
• The use of these dressings is limited
when the outer surface becomes
moistened by heavy exudate and external
fluids thus resulting in maceration to the
wound sites.
• Removal of these dressings can promote
cross-contamination of the wounds by
dispersion of bacteria into the air
• Creams and gels have poor residence
time on the wound surface and cause
messiness
• Modern dressings are passive, target only
one phase of wound healing
• They depend on the body’s natural ability
to heal itself, which is compromised in
chronic wounds, therefore can be
ineffective
• Hydrogels and films have poor moisture
handling capacity and therefore not
suitable for highly exuding wounds
• Expensive, as experienced health
personnel are required for application
• In the case of skin grafts, another wound
has to be created in order to harvest fresh
skin to replace lost tissue. Such wounds
can be very painful and prone to also
becoming infected
Examples Cotton, gauze, creams, gels Hydrogels, hydrocolloids, alginates, films,
foams,
Tissue engineered substitutes, collagen, and
hyaluronic acid-based dressings and
scaffolds, drug loaded biological, and
modern moist dressings
Table 6.1 (Continued)
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Wound Dressings by 3D Printing 121
possessing pre-determined size and porosities with the help of computer-aided design (CAD)
software followed by printing with an automated 3D printer [23–25]. Furthermore, they
compare with other methods of fabricating scaffolds (films) employment of 3D bioprinting.
Rapid prototyping (RP), also sometimes referred to as AM or solid freeform techniques,
refers to a class of technologies that can automatically construct physical models from
CAD data. By using the RP system, almost any shape can be produced [18, 26]. The main
RP techniques that can produce scaffolds for biomedical applications, such as wound
dressings, have been summarised in Figure 6.3.
6.1.8 3D-Printed Dressings
3D-printed dressings are of increasing current interest in academic research and industry
R&D settings, especially due to the possibility of personalised production for specific
wounds and patients, depending on factors such as size, shape, and location of the wound.
The possibility of scanning the contours of a specific wound to produce scaffolds or dress-
ings, having the exact same dimensions as that of the target wound, is an interesting prospect,
which will most likely influence the future of wound management and tissue regeneration.
Furthermore, advancements in biomaterial polymer science, bioengineering, and tissue cul-
ture technologies have opened a new field of 3D bioprinting, where 3D scaffolds mimicking
the natural dermis and epidermis can be laden with relevant skin cells to produce ‘artificial skin’
that significantly helps to trigger better skin regeneration in hard-to-heal chronic wounds [28].
Though most of the polymers used in modern and advanced biomaterial-based dressings
are effective, their use in 3D printing of dressings is challenging, as most are not printable
in their native form. Therefore, they require some form of modification to improve their
gel viscosities to enable them to be printed without losing their structure and collapse and
represents one of the current knowledge gaps exercising various researchers and practi-
tioners. In addition, several researchers have investigated the use of new inks/bioinks from
both natural and synthetic sources [29]. The rest of this chapter will critically review and
evaluate the published literature around 3D-printed and 3D-bioprinted dressings and/or
scaffolds in the form of case studies, as outlined below.
Rapid prototyping techniques
with biomedical applications
Laser-based systems
Nozzle-based systems
Printer-based systems
* Laser selectivity
sintering
* Stereolithography
* µ-Stereolithography
* Solid ground curing
* 2 photon-
polymerization
* Fused deposition modelling
* Precision extruding deposition
* Paste extrusion modelling
* Material jet systems
* 3D bre deposition
* Pellet additive manufacturing
* 3D- bioplotter™
* 3DP™
* TheriForm™
* Inkjet printing
Figure 6.3 Classification of RP techniques with biomedical applications. (Source: Adapted
from [27] with permission.)
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122 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
6.2 Case Studies
Yang et al. [30] reported on 3D-printed antibacterial dressing comprising N-halamine/TiO
2
bound to gelatin methacrylate combined with xanthan gum in a composite system, as illus-
trated in Figure 6.4. The 3D-printed dressings exhibited excellent swelling and moisture
handling properties as well as good antibacterial activity, with 100% elimination of
Escherichia coli and Staphylococcus aureus within 60 minutes and prevented bacterial
biofilm formation. The 3D-printed dressings were biocompatible and demonstrated accel-
erated wound healing effect in mice and showed good potential for use in wound healing.
Shafiee et al. [31], designed biomimetic dressing comprising medical grade polycaprol-
actone via 3D printing and demonstrated microporous architecture and mechanical proper-
ties that helped to reduce skin scarring during wound healing. The 3D-printed scaffolds
were further seeded with human gingival tissue multipotent mesenchymal stem/stromal
cells and compared with full thickness excisional wound in rats over a six-week period.
The former showed a decrease in wound contracture followed by significant improvements
in skin regeneration (including decreased scarring) through increased granulation and re-
epithelialisation when compared with the control groups.
Altan et al. [32] proposed a composite chitosan-xanthan gum patch via a 3D-printing
approach, with the aim to achieve cell-mimicking, adhesion, proliferation, and differential
characteristics for wound healing applications. The study involved preliminary investiga-
tions of viscosity of xanthan gels at different concentrations to determine ease of printing,
which was achieved at higher xanthan concentrations. Furthermore, higher xanthan content
resulted in better mechanical, hydrophilic, and slow degradation characteristics. The opti-
mised patches showed improvement in cell proliferation rate, adhesion and viability, with
potential for use as dressing for wound healing.
Hafezi et al. [33] reported on a 3D-printed chitosan dressing crosslinked with genipin to be
applied to chronic wounds. The gels required plasticisation with polyethylene glycol prior to
printing to achieve flexible and mechanically stable film dressing matrices. The 3D-printed
Pressurized air
365 nm UV light
(iii) Photo-crosslinking
(iv) Freeze
drying
(v) Antibacterial dressing
(ii) 3D printing
(i) Bio-ink preparation
N-halamine (PSPH-Cl)
GelMA
Titanium
source
Xanthan gum
Inactivate bacteria
Figure 6.4 Schematic illustration of the fabrication of antibacterial 3D-printed dressings.
(Source: tarasov_vl/Adobe Stock Photos.)
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Wound Dressings by 3D Printing 123
films were characterised for their functional physico-chemical properties, including tensile,
fluid handling, mucoadhesion, drug dissolution, morphology, and cell viability. Films compris-
ing equal proportions of chitosan and plasticiser were deemed optimum, demonstrating amor-
phous nature, molecular interactions between the three main components, and appropriate
adhesion and moisture handling ability. Finally, the 3D-printed scaffolds demonstrated high
biocompatibility with human skin fibroblast cell lines, showing greater than 90% of cell viabil-
ity after 48 hours, which suggests their non-toxic nature and ability to sustain cell proliferation,
which is essential for effective wound healing. In a follow-up study [34], the same group
employed extrusion-based 3D bioprinting to print cell-laden chitosan-genipin bioinks to obtain
composite scaffolds containing skin cells (keratinocytes and fibroblasts). A summary of their
bioprinting setup is provided in the schematic shown in Figure 6.5, with crosslinked alginate
used as the base layer before bioprinting of the cell laden chitosan–genipin constructs. Nuclear
magnetic resonance spectroscopy was used to confirm the chitosan–genipin crosslinking.
An MTT assay showed high cell viability values above 85% for keratinocytes and fibro-
blast cells within the bioinks, both before and after bioprinting, showing the gentle process-
ing conditions which maintained the cell viability as well as confirming the biocompatibility
of the scaffold matrices containing the cells. In addition, cell viability was further con-
firmed using live–dead assay to differentiate the living cells from non-viable ones using
confocal microscopy. The confocal microscopy imaging showed a high cell viability for
the bioprinted constructs at each time point, as shown in Figure 6.6, and confirmed that the
number of cells increased during the testing period from day 0 to day 7. Finally, scanning
electron microscopy showed a microporous structure that is expected to support cell growth
and allow supply of nutrients to the cells, while the keratinocytes and fibroblasts showed a
polygonal and spindle shape, respectively.
Figure 6.5 (a) Schematic illustration of the design of each layer of skin 3D-printed constructs.
(b) 3D bioprinting of alginate layer and KCs and HDFs encapsulated with CH-GE-PEG layers.
(Source: [34]/MDPI/CC BY 4.0.)
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124 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
Long et al. [35] developed polysaccharide-based biodegradable 3D-printed composite
hydrogel dressing scaffolds (Figure 6.7) comprising pectin and chitosan encapsulating
lidocaine as a model drug with immediate release characteristics. The scaffolds were
designed in cubic mesh format using Solid works with grid size of 2.50mm
–2
and line
width of 0.50 mm and printed using an extrusion-based printer. The resulting scaffolds
were characterised for fluid handling (swelling and water absorption), morphology, poros-
ity, bioadhesion, chemical interactions, and in vitro drug release characteristics. The
3D-printed scaffolds exhibited dimensional integrity and ability to self-adhere to the skin
with high swelling ratio and water absorption for maintaining a moist wound healing envi-
ronment. Furthermore, loading of lidocaine did not affect functional performance of the
scaffolds and were able to release the drug over six hours, which was explained by the
Korsmeyer–Peppas model.
Muwaffak et al. [36] reported on the development and characterisation of patient-specific
3D-scanned and 3D-printed polycaprolactone-based wound dressings (Figure 6.8) with
antimicrobial properties. The authors followed various formulation approaches to finally
obtain the 3D-printed dressings. First, filaments containing different antimicrobial metals
Figure 6.6 Confocal images of bioprinted CH-GE-PEG cell-laden constructs throughout 7
days showing live (light spots) and total number of the cells (dark spots). All images shown in
this graph are representative of three independent experiments with similar results. (Source:
Reproduced from [34] under the Creative Commons Attribution (CC BY) licence.)
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Wound Dressings by 3D Printing 125
including silver, zinc, and copper were prepared using hot-melt extrusion. Subsequently,
they used 3D scanning to generate 3D models of nose and ears as a means of producing
dressings with customised shapes for specific patients. The extruded filaments containing
different amounts of the metals were used to produce 3D-printed dressings and the metal
release tested by means of inductivelycoupledplasma atomic emission spectroscopy and
demonstrated fast initial release in the first 24 hours followed by a more sustained release
up to 72 hours. Further in vitro antibacterial activity showed that the 3D-printed dressings
loaded with silver and copper exhibited more potent bactericidal activity against selected
bacteria than zinc loaded equivalent.
In a recent study, Teoh et al. [37] reported on the development of personalised 3D-printed
hydrogel-based dressings (Figure 6.9) that could be loaded with multiple drugs with tune-
able dosages based on varied architectures. The hydrogel dressings were based on chitosan
methacrylate, using lidocaine and levofloxacin as model analgesic (pain) and antibiotic
(infection) to achieve medicated scaffolds able to take an active part in the wound healing
process. The researchers were able to customise the drug loading amounts and with varied
release rates by loading them at different locations within the dressings and also changing
the thickness of blank (drug-free) layers surrounding the drug-loaded layers. The study
Figure 6.7 3D-printed chitosan-pectin (CS-PEC) hydrogel scaffold: a) freshly printed; b) lyophilised;
and c) flexibility of a lyophilised scaffold. (Source: Reproduced from [35] with permission from
Elsevier.)
Figure 6.8 3D scan model of a nose (left) and the printed wound dressing of this model with
Cu-PCL (right). (Source: Reproduced from [36] with permission from Elsevier.)
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