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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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96 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
5.3.1.3 Surface Properties
Surface of implantable DDSs is the first part interacting with the tissue. Topographic charac-
teristics regarding the texture, roughness, and stiffness of implants can define their abilities
of adhesion hydration, swellability, erosion, and drug release rate. Moreover, surface topol-
ogy is crucial for modulating cell–implant interactions, evaluating micro-environmental
biocompatibility and therapeutic outcome; thus, determining the pharmacodynamic and
pharmacokinetic potential of the system [35].
Interphase interactions between the surface of implants and the tissue environment
depend on physico-chemical properties of the surface. Hydrophilicity and hydrophobicity,
stiffness and roughness, charge of functional groups, and contact angle, are crucial param-
eters which characterise the interaction potential of implant with tissue. The hydrophilicity
of surfaces is estimated with the contact angle [32].
In a study by Shen et al., hydrophobic and cationic surfaces are efficient in preventing
microorganism development. Covalent bonding surface additions (e.g., hydroxylated titanium
alloy) contribute to surface stabilisation with specialised characteristics (e.g., antimicrobial
potential) that are efficient in providing long-lasting functionality and applicability. Moreover,
external triggers (e.g., hydrothermal process, augment hydrophilicity, roughness, and poros-
ity features) contribute to an increase in hydrophobicity achieved with silane addition [37].
5.3.2 Mechanical Properties
Polymeric properties related to mechanical features, such as type of polymer, MW, crosslink-
ing modifications, polymer density, iso-elasticity between materials, toughness, strut thick-
ness, and angle can affect cell adhesion and penetration to a certain degree. Mechanical
properties of scaffolds can determine interactions with cells. Cells can detect and distinguish
surface characteristics, which are related to mechanical properties of the scaffold; therefore,
adhesion, proliferation, and differentiation of cells are feasible when there is implant–cell
compatibility [38]. Consequently, the choice of materials is directly related to the man-
ufacturing method selected that reflects on the attributes of the final scaffold. Hence, it
is essential that material selection is examined under ranking procedures, which concern
process parameters (e.g., temperature, pressure, speed, etc.), shape of the scaffold (hollow,
circular, non-circular, etc.), physical attributes (e.g., thickness, surface roughness, etc.), and
economics and costs [39].
5.3.3 Biological and Physiological Parameters
A variety of physiological parameters play a significant role in implant tissue incorpora-
tion: cellular adhesion, degradation and absorption rates, and biocompatibility characteris-
tics regarding the potential of scaffold implantation.
5.3.3.1 Cellular Adhesion
Examining the micro-environmental conditions of the tissue after scaffold implantation,
a variety of cell and protein interactions is observed. Physico-chemical characteristics of
scaffolds, concerning surface and mechanical aspects, are the most crucial in determin-
ing scaffold incorporation potential, cell and immune system response, drug release rate,
and pharmacological and pharmacokinetic profiles. Integrins are proteins that are media-
tor factors in facilitating cell–implant interactions. Integrins, as signalling molecules, are
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3D Printed Implants for Long-Acting Drug Delivery 97
primarily attached in implants and activate cell clustering and adhesion. Henceforth, cells
transmit signals for cell proliferation and extracellular matrix (ECM) deposition and dif-
ferentiation. Therefore, by modifying scaffold structure and surface topography, different
mechanisms and processes of cell activation are created [40].
5.3.3.2 Absorption and Degradation Rates
The absorption profile of an active substance is a crucial parameter in formulating long-act-
ing implants. Solubility and permeability are criteria that characterise the Biopharmaceutics
Classification System (BCS) class of an active substance and determine its release rate and
physical interactions with the material used. Hence, release rate is required to be slower
than absorption rate, in order to achieve an extend drug release profile [41]. Long-acting
implantable scaffolds aim at drug bioavailability enhancement since they avoid the first-
pass metabolism, by releasing the drug directly in the systematic circulation. Therefore,
implantable scaffolds concern local drug delivery and targeted DDSs and are beneficial
candidates for increasing pharmacological potency of low-dose drugs [2].
Attributes that determine and influence the degradation rate of biodegradable scaffolds
involve properties of utilised materials. Physical characteristics such as MW, chemical
structure and copolymer ratio, glass transition temperatures (T
g
), polymer structural mor-
phology (crystalline, amorphous), and chain orientation influence the potential of degrada-
tion process. Along with implant elimination, tissue regeneration occurs; thus, degradation
rate of implants should be followed by cell proliferation and differentiation [2].
5.3.3.3 Biocompatibility Aspects
Implantable devices that are designed for tissue regeneration should be defined by biocom-
patible features. Considering that the utilised materials can trigger immune system and
consequently inflammatory responses, it is essential that they possess biocompatible
characteristics. Hence, modification of materials (e.g., PEGylation, surface coatings,
micro-scale roughness) can circumvent immune system identification, enhancing tissue
growth and scaffold stability maintenance [42].
5.4 Critical Parameters in Selecting Materials for 3D-Printed Scaffolds
There is a range of materials used in the manufacturing of 3D-printed scaffolds as DDSs,
which vary according to their therapeutic functionality and the anatomical region where
they are designed to be inserted. Particularly, the examination of the materials’ physico-
chemical properties, addressed for long-acting scaffolds, is a crucial step, which has to be
initially performed. Characteristics of biomaterials are related to surface features such as
charge, stiffness, degradation, and wettability, with their efficiency in promoting functional
interactions between cells and DDSs, characterised by compatibility, adaptability, and deg-
radability properties [1]. Consistently, biomaterials have the potential to determine drug
release rate in tissues, in supporting cell proliferation and differentiation, and in progres-
sive physical elimination. Moreover, in order to ensure and ameliorate adhesive properties
of the system and release rate of the drug, biomaterials and accordingly scaffolds can be
modified [44]. Therefore, their surface can be amended either physically (e.g., particle size,
shape) [44], chemically (ligand addition) [45], or by applying coatings [7].
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98 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
The most common materials used concern the formulation of the polymer-, metal-, and
ceramic-based scaffolds. Metallic and ceramic materials are applied in bioprinting scaf-
folds for tissue restoration [46]. On the other hand, polymeric-based scaffolds are used
mainly in DDSs [47]. As far as polymeric materials are concerned, these are classified
according to their source into natural and synthetic and according to their physico-chemical
properties into biodegradable and non-biodegradable [1]. Natural polymers are sensible in
their modification, most of them possessing poor mechanical and stability properties when
used individually, and their physico-chemical properties are not easily defined due to their
complexity [48]. However, they are capable of chemical structural modifications, which
enhance their mechanical properties [49]. Contrarily, synthetic polymers are vastly applied
in 3DP due to their mechanical stiffness and their well-defined physical and chemical char-
acteristics. Synthetic polymers are broadly used due to their stability and predictable func-
tionality [47]. Moreover, with reference to biodegradability properties, these may concern
either natural or synthetic polymers. Non-biodegradable differ from biodegradable poly-
meric materials, as they present biodegradable and bioresorbable limitations, and surgical
invasion is required for their removal [50] (Table 5.1).
Table 5.1 Categories of biomaterials used in 3D-printed implantable scaffolds.
Biomaterials Material-Based properties References
Natural
polymers
Cellulose (bacterial
and plant derived),
chitosan, silk fibroin,
collagen, hyaluronic
acid
• Bioadhesive
• Biocompatible
• Biodegradable
• Renewable
• Abundant availability
• Biomimetic
• Promote cell viability and tissue
ingrowth
• Non-toxic
• Low immunogenicity
• Pore formation
[5, 57–70]
Synthetic
polymers
Poly(lactic acid) (PLA),
poly(lactic-co-glycolic
acid) (PLGA),
poly(glycolic acid)
(PGA),
poly(caprolactone)
(PCL)
• Thermoplastic
• Biodegradable
• Biocompatible
• Bioresorbable
• High mechanical strength
• Controllable degradation
• Reproducible
• Lack of biological signals
[6, 7, 26,
52, 66,
70–73]
poly(siloxanes),
poly(ethylene-vinyl
acetate) (PEVA)
• Non-biodegradable
• Non-immunogenic
• Reproducible
• Tailored mechanical properties and
shapes
[71, 74–77]
poly(urethanes)
• Versatile (biodegradable or non-
biodegradable)
• Stimuli responsive
• Biostable
• Elastomeric
• Thermoplastic (TPU)
• Structure modifications
[72–75]
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3D Printed Implants for Long-Acting Drug Delivery 99
5.4.1 Materials Used in 3D-Printed Long-Acting Scaffolds
5.4.1.1 Natural Polymers
Natural-based biopolymers are widely used in implant fabrication technologies, due to
their biodegradability and tissue incorporation bio-suitability. Cellulose, chitosan, silk
fibroin, collagen, hyaluronic acid, and other natural co-polymers and proteins are claimed
as prospective materials for 3D-printed implants.
Bacterial and plant derived cellulose are vastly used in hydrogel-based 3DP scaffold formu-
lations, either in drug delivery or in tissue enhancement, as they possess considerable swelling
properties and significant mechanical integrity. They can be easily modified with crosslinking
adjustments, which contribute to mechanical advancement properties of scaffolds [5, 51–55].
Chitosan is characterised by high mechanical strength attributes; thus, it is used in tissue engi-
neering 3D-printed scaffolds. It is also ordinarily applied in modified release DDSs as a long-
term degradation polymer [56–58]. Silk fibroin is another natural polymer which possesses
high mechanical stability and is feasible in crosslinking modifications. Moreover, it is defined
by high elasticity and low viscosity properties that permit the fabrication of low-temperature
3D-printed systems. Therefore, silk fibroin is efficient in injectable DDSs, hydrogels, bioadhe-
sive systems, and tissue regeneration scaffolds [48 52, 56–60]. Collagen is mainly utilised in
tissue regeneration of 3D-printed scaffolds and in DDSs for the delivery of biological factors, as
it is characterised by low mechanical and fast degradation properties. However, collagen is
sensitive to manipulation and is potentially used in low-temperature 3D-printed systems [48,
58, 59, 61]. Hyaluronic acid can be applied in 3DP-implantable scaffolds for tissue engineering.
It is mostly used in combination with other materials, as it is characterised by low viscoelasticity
and hydrophilicity. Hence, it promotes cell proliferation, migration, differentiation, and inflam-
mation and wound healing processes [61–64].
5.4.1.2 Synthetic Polymers
Synthetic polymers that are used in implantable scaffold formulations are classified into
three categories: biodegradable, non-biodegradable, and versatile.
Thermoplastic and biodegradable poly(esters) (e.g., poly(lactic acid) (PLA), poly(glycolic
acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(caprolactone) (PCL)) are defined
by significant mechanical properties, such as high mechanical strength, thermoplasticity, and
Biomaterials Material-Based properties References
Ceramics Inorganic metal
compounds and/or
calcium salts,
phosphate salts
●
Bioresorbable
[16, 46,
76–78]
Metals Titanium, cobalt-
chromium, stainless
steel, tantalum, gold,
magnesium, gallium,
Iron alloys
●
High mechanical properties
[79, 80]
Table 5.1
(Continued)
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100 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
versatility in surface modifications. Moreover, they are characterised by low biological activ-
ity and biocompatibility, bioresorbability, and controllable degradation mechanisms; hence,
they are broadly applied in 3D-printed implantable DDSs or tissue engineering systems [6,
7, 15, 45, 62, 64–67].
Non-biodegradable polymers, such as poly(siloxanes) and poly(ethylene-vinyl acetate)
(PEVA), are synthetic polymers that differ from biodegradable in drug release mechanisms.
Biodegradable polymers permit drug release, both through diffusion of drug and/or degra-
dation of the matrix. Applications of non-biodegradable polymers are implemented mostly
in scaffolds concerning tissue regeneration, due to their adjustable mechanical properties
and shapes, chemical and thermal stability, non-immunogenic and antimicrobial proper-
ties, and compatibility with natural tissues [65, 68–71].
Versatile synthetic polymers (e.g., poly(urethanes)) are assessed as either biodegradable
or non-biodegradable, according to their synthetic process, thus can appear in a rubber- or
polyol-based structure. They are considered biostable with notable thermoplastic and elas-
tomeric properties. Regarding their diverse functionality, such as their facility in structure
modifications and their stimuli responsiveness, they are effectively incorporated into DDSs
and tissue engineering 3D-printed scaffolds [72–75].
5.4.1.3 Ceramics and Metals
Ceramic 3D-printed implantable systems mainly consist of inorganic metal compounds and/
or calcium salts and phosphate salts (e.g., silicon dioxide (SiO
2
), calcium sulfate (CS), α- and
β-tricalium phosphate (β-TCP, α-TCP), hydroxyapatite (HA)). Pursuant to their bioresorba-
ble, osteoinductive and brittle properties are vastly proposed and applied in 3D-printed bone
implants [16, 46, 76–78]. As far as metallic-based 3D-printed scaffolds are concerned, a
variety of metals and metal alloys are used (e.g., titanium, cobalt-chromium, stainless steel,
tantalum, gold, magnesium, gallium, iron alloys). High corrosion resistance and high
mechanical strength properties, surface roughness, and tissue-implant interlock potential are
significant parameters in designing implantable scaffolds. Metallic biomaterials are mostly
applied in 3D-printed implants for tissue engineering and regeneration [80, 81].
5.4.1.4 Composites
Composite material combinations describe multiparametric systems characterised by varia-
bility. The functionality of each material affects the properties (physico-chemical, biological,
mechanical) of the system and define the quality of the final product. Along with material
combination properties, the formulation process parameters are considered as crucial and
properly defined by screening processes, comparative analyses, and evaluations, in order to
specify different formulation performances and incompatibilities. Parameters regarding the
function, cost, and environmental characteristics of the materials and machines used are part
of a sequential algorithm concerning decision-making for the design criteria [39].
5.5 Manufacturing Techniques for Implantable Scaffolds
Critical material attributes (CMA) and critical process parameters (CPP) are considered
crucial factors in designing and developing novel pharmaceutical implantable scaffolds [1].
Polymers that are used in long-acting scaffold formulations are considered to be suitable
with the applied method and show biocompatible properties [81]. Various techniques have
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3D Printed Implants for Long-Acting Drug Delivery 101
been developed for the manufacturing of polymer-based implantable DDSs, with the most
common techniques being hot-melt extrusion (HME), compression, injection moulding,
solvent casting, and 3DP [1]. An overview of the advantages and disadvantages of the tech-
niques is given in Table 5.2.
Table 5.2 Advantages and disadvantages of 3DP-coupled manufacturing methods for
3D-printed implantable scaffolds.
Manufacturing
method Advantages Disadvantages References
Hot-melt
extrusion
• Variety of thermoplastic
materials/polymers available
• Continuous manufacturing
process
• Scalable
• Solvent free method
• Suitable for lipophilic drugs
• Unsuitable for
thermosensitive
materials
• High-temperature
application
[84–89]
Compression
• Suitable for thermosensitive or
solvent sensitive materials
• Limited
application for
hydrophilic
materials
• Unpredictable
surface
characteristics:
unsuitable for
controlled drug
release rate
profiles
[44, 47]
Injection
moulding
• Variety in use of thermoplastic
materials
• Suitable for incorporating low
soluble drugs into solid disperse
systems
• Ease in creating multi-shaped
solid formulations
• Modifying DDSs
• High-cost
equipment
• Slow formulation
procedure for
tailor-made
implants, due to
mould
modification
requirements
[95]
Solvent-casting
• Cost-effective
• Coating of implants: long-acting
drug release profile.
• Relatively lower temperatures for
solvent removal compared to
HME.
• Not scalable
• Need of a volatile
solvent (stability
issues)
[2, 7, 8, 87]
3D printing
• Personalised implantable
scaffolds
• Variety of material combinations
• Variety in types of 3DP
technique (e.g., FDM, SLA, SLS,
etc.)
• Ease in combination with
different manufacturing
techniques (e.g., HME, injection
moulding, solvent-casting, etc.)
• Challenging in
scale-up process.
• Capacity
• Cost
[3, 6, 44,
81]
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102 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
5.5.1 Hot-Melt Extrusion
Hot-melt extrusion (HME) is well-known as a pharmaceutical manufacturing technology,
especially for amorphous solid dispersion [82]. The principle of the method is based on
melting and mixing a variety of thermoplastic excipients, such as aliphatic polyesters and
active substances [82, 83]. This manufacturing technique involves simultaneous melting
and continuous mixing of the formulation materials. The mixing process is controlled
through the designs of the screw and combinations of various screw elements and tempera-
ture zones, i.e., the process includes zones with various mixing elements and temperatures.
Finally, the melt is extruded through an orifice as a filament, which for tableting is milled
to obtain granules, but for 3DP is deposited to form the desired geometry (Figure 5.4).
HME is capable of continuous manufacturing and a fully scalable process that combines a
broad variety of dosage forms produced by less unit operations. Moreover, it is a solvent
free method and has, for example, been described as suitable in enhancing the solubility of
lipophilic drugs [84, 85]. However, there are some limitations in its use, as it is considered
an unsuitable technique for thermosensitive drugs, where there is a limited number of ther-
mal stable polymers and a great energy density needs to be applied during high process
temperature thermal manufacturing [86, 87].
A combined technological method of HME-3DP can be applied in modifying release system
implants [88, 89]. An HME-FDM combination has shown that HME defines the crystallisation
of polymers, which affects the mass and content uniformity of filament (e.g., thermal stability,
melt viscosity, etc.), consequently the rigidity of filament, which determines the product’s
mechanical properties (e.g., tensile strength, yield stress, etc.). On the other hand, extruded fila-
ment can be printed in different shapes and geometries with FDM; thus, creating customised
products. HME-FDM coupling can be used in a single-step manufacturing procedure, aiming at
a more cost-effective and efficient process for printing tailor-made implants [91, 92].
5.5.2 Compression
The compression manufacturing technique is considered an appropriate method in formu-
lating solid implantable scaffolds which consist of materials that are thermosensitive or
solvent sensitive. It is a three-step, simple procedure, which includes the API, excipients,
and lubricant grinding, blending, and compression. Initially, API and excipients are ground,
and then subsequently mixed along with the added lubricant, and finally compressed
Figure 5.4 Illustration of a typical hot-melt extruder.
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3D Printed Implants for Long-Acting Drug Delivery 103
directly into a dimension-defined matrix (Figure 5.5). Materials have to be selected by
good flowability and compressibility properties [93].
However, there is a limitation in using hydrophilic materials for prolonged release
implant formulations, as an initial burst effect can accelerate the release rate of the drug.
The compression method does not provide a predictable release profile due to the diversity
of surface features and topology of the implant, thus it is not used extensively as a manu-
facturing method for implantable scaffolds [44, 47].
5.5.3 Injection Moulding
Injection moulding technology can be applied in formulating implants that consist of ther-
moplastic polymers [1]. This technique includes heat, injection moulding, and solidify of
the polymers. In more detail, the injection moulding machine consists of two parts, the
injection unit and the moulding unit. Materials are inserted into the injection unit, where
they undergo melting and subsequently injection procedure (Figure 5.6). During the manu-
facturing process, temperature, pressure, and speed affect the quality of the final product.
Moreover, it is mainly combined with a twin-screw HME, as a first-step manufacturing
procedure, in order to improve the dispersion of materials [93, 94].
Injection moulding permits the formulation of low soluble drugs into solid dispersal
systems, thus enhancing their solubility properties. This method can be used for modifying
drug release systems, as it enables creating multi-shaped solid formulations. However,
Figure 5.5 Illustration of a typical compression machine.
Figure 5.6 Illustration of a typical injection moulding machine.
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104 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
injection moulding requires high-cost equipment, and is a slow formulation procedure for
personal-based implants, compared to the fused filament fabrication (FFF) technique, due
to mould-modification requirements [95].
5.5.4 Solvent Casting
The principal of the solvent casting technique concerns the initial dissolution of polymers
and active substances in the presence of a volatile solvent. After the stage of material dis-
solution, the solution is casted into an implant scaffold followed by solvent evaporation
(Figure 5.7) [8]. Solvent casting is also used in coating long-acting implantable DDSs.
Coated implants are considered more efficient as they are defined by fine-tuning properties,
providing a more controlled and precise drug release profile [7].
Solvent casting is a simple and cost-effective technique, in which lower HME evaporat-
ing temperatures can be applied. Nevertheless, constraints in production scale-up are com-
mon, due to mixing speed, heating, drying, and parameters that affect implant quality
attributes, such as the uniformity of content, thickness, and surface, etc. [87]. Moreover, the
significant use of volatile solvents, especially the use of organic solvents, can provoke sta-
bility issues in the final product, as their removal may be difficult and infeasible [96].
5.5.5 3D Printing
Additive manufacturing (AM), or 3DP, is considered as an innovative technology in developing
personalised implantable DDSs. 3DP enables the combination of biomaterials with different
physico-chemical properties in designing and formulating simple or diverse structures that are
characterised by their variable pharmacological and pharmacokinetic potential [6, 81].
Furthermore, 3DP can be combined with different techniques, such as HME, injection mould-
ing, and solvent casting with the prospect of developing implantable systems with long-acting
drug release profiles [44]. 3D-printed implants are gaining ground in medicinal field and treat-
ments, for example in the areas of contraception, bone healing, cancer, and chronic diseases [3].
5.5.6 Scale-Up in 3D-Printing Process for the Manufacturing of Scaffolds
The need of scaling up in AM is essential, due to the increasing demand for tailor-made
drug delivery devices; however, there are many considerations that set limitations in sev-
eral stages concerning their production development process and market disposition.
Figure 5.7 Illustration of a typical solvent casting machine.
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3D Printed Implants for Long-Acting Drug Delivery 105
Engineering equipment and applied technology that reflect in product quality should be
developed and assured by precise standards and criteria. Moreover, guidelines that refer
to regulatory policy should be established in accordance with scale-up steps, in order to
ensure a quality assurance framework. Therefore, quality and material attributes, continu-
ous manufacturing process, and ongoing regulatory oversights concerning industrial pro-
duction scale, are essential to be examined in real time [79, 81].
5.6 Drug Release Mechanism of Long-Acting 3D-Printing Polymeric
Implantable Systems
Mechanisms which determine the release kinetic profile of drugs from long-acting implant-
able systems are based on a variety of parameters and variables that concern properties of
utilised materials and their combinations used, drug incorporation protocols, manufactur-
ing methods of scaffolds, geometry, surface chemistry, and topology of scaffolds (Table5.3).
Hence, degradation, erosion, or swelling effects of polymeric scaffolds define the dissolu-
tion, desorption, or diffusion mechanisms of drug release [99, 100]. Considering the
Table 5.3 Advantages and disadvantages of drug release mechanisms of long-acting
implantable DDSs.
Type of
long-acting
implant
Drug
release
mechanism Advantages Disadvantages References
Monolithic
type
• Passive
diffusion
• Erosion
• Hydrophilic or
hydrophobic systems
• Ease in manufacturing
process
• Burst effect issues [102]
Reservoir
type
• Passive
diffusion
• Polymer properties
define the release rate of
the drug
• API form (crystalline vs.
amorphous)
• Controlled delivery
systems
• Target-specific therapies
• High-cost
manufacturing
process
[103]
Swelling-
controlled
• Swelling • Polymeric hydrogel-
based systems with a
high-MW drug load
capacity
• High absorption of water
• Degradable-based
systems
• Stimuli responsive
systems
• Variability in polymers
used
• Stability issues
(need for
lyophilisation)
[5, 47]
Drug-
eluting
coated
• Passive
diffusion
• Enzymatic or chemical
degradation protection
• Non-biodegradable
systems
[7]
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