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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5919_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery to the Musculoskeletal System: Localized Therapies and Repair 359
9. Hybrid multi-mode microplate reader (Synergy™ H4,
Winooski, VT).
10. Dipping machine (Riegler and Kirstein GmbH, Berlin,
Germany).
2.2 Drugs
Therapeutic medications are without a doubt essential for treating
disorders and minimizing or eliminating injuries. The term “dr ug”
in musculoskeletal drug delivery has expanded significantly over the
last few decades to include growth factors, non-viral genes (DNAs,
RNAs), tissue engineering scaffolds, and regenerative tissues. It was
previously restricted to therapeutic agents like antibiotics, antiinflammatory drugs, and anti-cancer agents. The drugs listed
below are utilized in localized therapy and repair of the musculoskeletal system:
1. Non-steroidal anti-inflammatory drugs (NSAIDs).
2. Antibiotics (for musculoskeletal infection like superficial cellulitis, osteomyelitis).
3. Anticancer drugs (for cancer like osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, metastatic carcinoma).
(a) Tyrosine-kinase inhibitors.
(b) Drugs targeting epigenetic alterations.
(c) Monoclonal antibodies (immune-checkpoint inhibitors).
4. Growth factors (GF).
(a) TGF-βs
(b) BMPs
(transforming growth factor-βs).
(bone morphogenetic proteins).
(c) IGFs (insulin-like growth factors).
(d) PDGFs (platelet-derived growth factors).
(e) VEGFs (vascular endothelial growth factors).
5. Genes.
(a) SiRNA.
(b) TFEB (transcription factor EB) for Pompe disease.
6. Other regenerative dr
ugs- based
on cell therapies.
7. Ligand-gated drugs.
(a) Nerve growth factor (NGF) inhibitors (anti-NGF
antibodies).
3 Methods
Current development in the delivery of drugs to the musculoskeletal system have looked at new medications, creative ways to assemble delivery vehicles, and multipurpose delivery strategies.
360 Khumtya Debbarma et al.
3.1 ThreeDimensional (3D)
Bioprinting
3.1.1 Extrusion-Based 3D Bioprinting
Similar to conventional three-dimensional printing, the construct is
first created as a computer-designed file that is divided into discrete
strata. Though the initial procedures are similar, many methods
have been devised to deposit the components (Fig.
1a).
The three most prominent to these printing methods are
extrusion-based, inkjet, and light-based.
Extrusion-based bioprinting is the most commonly used threedimensional bioprinting.
(i) This method depends on forcing material out of a printhead—
typically a needle tip by applying either mechanical or pneumatic pressure, to a reservoir of bioink [26].
(ii) Introduction of microfluidic printhead as an alternative of
conventional reservoirs of printing has increased the accuracy
of extrusion bioprinting.
(iii) With microfluidic heads, printing with core-shell fluid flows
and crosslinking the material are made possible with greater
control over the composition of the material (Fig. 1b).
(iv) As a result, a material fiber is created that can be patterned by
dragging the machine’s printhead cross the print region.
(v) After the completion of print of each layer, the subsequent
layer starts printing when the distance between the print surface and the extrusion tip is raised.
3.1.2 Inkjet 3D Bioprinting
3.1.3 Light-Based Bioprinting
The first developed 3D bioprinting technique, which is based on
the similar idea as that of the conventional 2D Inkjet printing
[4, 36].
(i) The first step involves combining cells with a hydrogel pre-
polymer solution in an ink cartridge that is attached to a
printhead.
(ii) This printhead deposits the bioink material throughout the
printing process.
(iii) During the printing, a piezoelectric actuator or a thermal
process deforms the printerheads, which are then squeezed
to produced droplets of different sizes (Fig.
1c).
(iv) Finally, by sporadically applying pressure to the fluid reservoir,
pressure-driven can accomplish the same result.
Stereolithographic bioprinting: According to Wang et al. [42, 43],
(i) These devices form the desired construction by using laser light
to crosslink polymer solutions (Fig.
(ii) The desired
pattern is crosslinked to each layer using light,
1d).
securing each layer to the previous one.
Drug Delivery to the Musculoskeletal System: Localized Therapies and Repair 361
Fig. 1 (a) Three-dimensional (3D) bioprinting. (b–e): Different methods of 3D bioprinting, (b) extrusion-based
bioprinting, (c) inkjet bioprinting, (d) stereolithographic bioprinting, (e) laser-assisted bioprinting
362 Khumtya Debbarma et al.
3.1.4 Laser-Assisted Printing
3.2 Multiple Drug Delivery
3.2.1 Multilayer Films with Capsule-Integrated Polypeptide/Polyelectrolyte
3.2.2 Multilayer Shells Using Polypeptides/ Polyelectrolytes (PL or PG) and LbL Assembly
(i) This technique eliminates direct contact between the dis-
penser and bioinks because it uses glass plate with bioinks on
one side and an energy-absorbing layer on the other [
35].
(ii) And when the laser strikes the energy-absorbing layer, the ink
is deposited from the substrate (Fig.
1e).
(iii) As a result, the resolution of this approach is restricted by the
homogeneity of the bioink on the glass surface, as aggregation
may lead to undesirable heterogeneities.
Multilayer films were constructed as per Zhang et al. [47].
(i) Microcapsules for drug administration were created by impreg-
nating polypeptides (PL or PG) into CaCo
particles by sub-
3
merging them in a solution containing 2 mg/mL of
polyelectrolytes for 30 min under 3 Torr Vacuum pressure.
(ii) The samples are then centrifuged to discard the supernatant
and further dried in a vacuum oven (310 Torr) overnight at
60 ° C.
The multilayer shells on these pre-impregnated particles were then
alternatively constructed using polypeptides and LbL self-assembly
to form shelled CaCO
particles.
3
(i) This process is similar to that of the procedure described for
coating on conventional substrates, but in this instance, a
centrifugation step of 3000 rpm for 1 min. Was added
between the two-coating process to make the coating processes on microparticles feasible.
(ii) In order to maintain the multilayer shell, the shelled CaCO
particles were next exposed to cross-linking by being incubated in a glutaraldehyde (25%) solution for 3 h.
(iii) These shelled particles were centrifuged, and the supernatants
were discarded to dissolve the CaCO
templates, further they
3
were incubated for 1 h in 0.1 M EDTA to form microcapsules.
(iv) Here, the CaCO
PG, as well as the ensuing capsules were referred to as
CaCO
PL
3
, CaCO
particles that were impregnated with PL and
3
PG
, Capsule
3
PL
, and Capsule
PG
, respectively.
3
3.2.3 Multilayer
Nanofilms and
Microcapsules
Utilizing the LbL self-assembly mechanisms of multilayer nanofilms and microcapsules, capsule-integrated polypeptide multilayer
films for multidrug delivery were constructed (Fig.
2a).
Drug Delivery to the Musculoskeletal System: Localized Therapies and Repair 363
Fig. 2 (a) Multilayer nanofilms using LbL assembly; (b) image showing use of iontophoresis of topical delivery
into the layers of the skin
Procedure
(i) Self-assembly of Polypeptide (PL/PG)
(ii) Deposition of PG-impregnated CaCO
(iii) Self-assembly of PG/ (PL/PG)
(iv) Deposition of
(v) Self-assembly of
PL-impregnated
PG(PL/PG)
multilayer nanofilms.
y
CaCO
multilayer nanofilms.
z
multilayer nanofilms.
X
particles (CaCO
3
particles (CaCO
3
PG
3
PL
).
3
).
364 Khumtya Debbarma et al.
(vi) Creation of multilayer films integrated into capsules through
the dissolution of CaCO
templates.
3
3.3 StimuliResponsive Drug
Delivery Systems
In this process, (PL/PG)
layer shells for CaCO
PL
3
films were optimized as the multi-
3.5
and CaCO
PG
particles. The nanofilms
3
were dipped into 2 mL suspensions of shelled particles (Density
6 × 10/mL) for a predetermined amount of time to deposit
CaCO
PL
or CaCO
3
PG
3
particles.
The final capsule-integrated polypeptide multilayer films were
named: (PL/PG)
(PL/PG)
(Fig.
and are topically delivered into the layers of the skin
Z
2c).
/capsule PL/PG(PL/PG)y/capsule PL/PG
x
Further simplification:
L
=CG =Ly=CL =L
x
z
where
L = PL/PG layers.
CG & CL = PG and PL-impregnated capsules.
x, y, and z = numbers of PL/PG bilayers.
SEM (scanning electron microscopy) images of LbL-assembled
microchambers constructed from a pure polyelectrolyte film functionalized by graphene oxide (Fig.
2b).
A new frontier in the molecular knowledge of disease has been
made possible by stimulus-based medication delivery devices. “Stimuli-responsive materials,” often referred to as “environmentallyresponsive materials,” are components of the stimuli-based drug
delivery system that affect an activity at a specific site or target tissue
to bring about beneficial activities for the drug release via a variety
of processes [
19]. The controlled and focused release of the drug at
the site of action makes the stimulus-based drug delivery system
extremely valuable in the fields of nanomedicines and
nanotechnology [
6].
The stimuli-responsive drug delivery systems can be categor-
ized into two types: physical and chemical.
3.3.1 Physical Stimulation-Responsive Drug Delivery Systems
Thermoresponsive
Temperature-responsive
systems are the most researched among
various stimuli-responsive systems, particularly in the field of cancer
27]. In such a system, changes in the tumor environment’s tem-
[
perature control the release of drugs. The drug load is retained by
the thermoresponsive carriers at body temperature, which is around
37 °C. Nevertheless, the drug is delivered at the approximate
40–42 °C local temperature of the tumor area [
37].
Drug Delivery to the Musculoskeletal System: Localized Therapies and Repair 365
A thermoresponsive drug delivery system is considered as one
possible addition to hyperthermia therapy. When treating hyperthermia, the body tissue is subjected to high temperatures through
microwave, ultrasonic, or radiofrequency; cancer cells may be killed
or rendered more vulnerable to the targeted effects of radiation
therapy or chemotherapy.
The hyperthermia treatments are harmful not only to cancer
cells but also to healthy cells. Parallel to this, both cancer cells and
healthy cells are toxically affected by chemotherapy.
Therefore, as a combinatorial approach, the combined effects
of
chemotherapy and
and cancerous cells [
hyperthermia are hazardous to both normal
16].
Thus, it is suggested to develop thermoresponsive drug delivery systems that make use of the temperature of the tumor microenvironment, i.e., mild hyperthermia (~40 °C), which releases
drugs specifically for the tumor while being non-toxic to healthy
cells (Fig.
3a). Typically, thermoresponsive systems consist of poly-
meric micelles, liposomes, or nanoparticles that release drugs at
significant rates only when they are exposed to temperatures higher
than that of normal body cells, such as cancerous tissue [
27].
Thermoresponsive Liposomes
3.3.2 Magnetic FieldResponsive Drug Delivery
Systems (MRDD)
• Thermoresponsive liposomes work by concentrating drug
within the heated tumor’s vasculature while reducing drug
metabolism, absorption, and clearance. Enhancing the drug’s
penetration and concentration at the tumor site, the released
drug diffuses into the tumor (Fig.
3b). This method does not
rely on the tumor’s passive targeting. The thermoresponsive
liposomes are given during the mild hyperthermia treatment to
allow for the sudden release of the medicine that has been
contained inside the tumor [
37].
• Liposomes that possess appropriate gel to liquid phase transition
temperatures, like lysolipids or dipalmitoyl phosphatidylcholine,
are typically employed in thermoresponsive liposome
development [
Examples Doxor
liposomes (ThermoDox
38].
ubicin-loaded ther
®
, Doxil® , Myocet® ).
moresponsive lysolipid-based
A magnetic-responsive system typically comprises of a core-shell
structure with polymer, lipids, mesoporous silica, or squalonylgemicitabine in the shell and magnetite (Fe3O4) or maghemite
(Fe2O3) in the core.
366 Khumtya Debbarma et al.
Fig. 3 (a) Schematic of thermoresponsive drug delivery system (polymeric micelle-drug carrier system,
ABMES), (b) liposome-based drug delivery
Protocol
• A drug is entrapped in magnetic nanoparticles (MNPs) in magnetically responsive drug delivery (MRDD).
• Next, an exter
nally applied high magnitude magnetic field is
used to direct and concentrate the drug/carrier complex to the
Drug Delivery to the Musculoskeletal System: Localized Therapies and Repair 367
Fig. 4 (a) Magnetic field-responsive drug delivery (from Ref. [2]), (b) ultrasound-responsive drug delivery (from
32]), (c) schematic showing light-responsive drug delivery
Ref. [
desired places after it has been delivered into the subject either
intravenously or intra-arterially.
• Upon reaching the intended location in vivo, the drug is
liberated from the magnetic carrier through either enzymatic
activity or modifications in physiological parameters including
pH, osmolality, and temperature (Fig.
4a).
• This leads to a reduced medication concentration throughout
the body and a greater localization at the site of the tumor [
11].
Superparamagnetic iron oxide nanoparticles, or SPIONs, are
among the magnetic-responsive nanomaterials under investigation
because of their ease of guidance to the target site and lack of
residual magnetism, which is attributable to quantum phenomena
at the nanoscale [
33].
The following characteristics are appropriate for magnetically
responsive drug delivery systems:
1. Nanosized constituent particles to facilitate capillary perfusion.
2. They ought to be sufficiently magnetically sensitive.
3. They ought to be able to transport a broad range of potent
medicinal substances.
4. They may be designed to serve as targeted or controlled drug
delivery systems.
5. They are
minimally toxic and antigenic, and they have great
biocompatibility and biodegradability.
368 Khumtya Debbarma et al.
3.3.3 UltrasoundResponsive Drug Delivery
Systems (URDDS)
The primary application of low frequency ultrasound (LFUS) was
to reduce the size of micro to nanoscale vesicles. These days,
targeted and controlled drug release is induced by ultrasound.
Protocol
• An ultrasonic wave can be used to stimulate the release of drugs
that are responsive to ultrasound waves by producing a variety of
physical ef fects in the body’s tissue. Localized heat, cavitation,
simple pressure change, and acoustic fluid streaming are some of
these physical effects (Fig.
4b) [9].
• The significant effects of ultrasonography are cavitation.
• This effect occurs when an ultrasonic wave passes through a
liquid medium and creates a large number of microbubbles
that expand and contract in extremely brief amounts of time.
Through a technique called sonoporation, the permeability of a
cell membrane can be momentarily altered in sonic cavitation to
improve medication uptake [
45].
• In cancer therapy, the easy application of ultrasonic to a thermoresponsive system makes it a crucial component. Acoustic cavitation, a method of energy vibration, causes hyperthermia when
exposed to ultrasound waves. Anticancer medication buildup at
the tumor site is facilitated by the application of these sonic
waves as a release mechanism through cavitation [
46].
3.3.4 Light-Responsive Drug Delivery Systems (LRDDS)
Light is regarded as one of the most interesting external stimuli for
controlled drug release because it has an on/off switching pulsatile
nature that allows for remote drug release with extreme temporal
and spatial precision [
23].
LRDDS are mostly used in photodynamic therapy (PDT), a
combination therapy that uses light and photoactivatable photosensitizer in the presence of tissue oxygen.
In photodynamic therapy
•
After injecting the photosensitizer intravenously, tissue oxygen
is transformed into radical oxygen species (ROS) via lightmediated activation.
• PDT is a prime candidate for cancer treatment since these ROS
result in cellular necrosis.
• In PDT, UV or visible light can cause photoreactions. Only
topical treatments applied to the skin or mucosa contain UV or
visible light (Fig. 4c).
– Only topical treatments
applied to the skin or mucosa contain
UV or visible light.