Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 539 - файл
.pdf
23 Translational Challenges inSoft Tissue Regeneration
https://t.me/medicina_free
251
Fat defect
Fat tissue aspiration and
reimplantation by injection
Nerve transfer
Autologous conduits (veins, arteries, soft
tissues, muscle- vein- combined conduits)
Autologous muscle/tendon
transplantation
tendons
Natural polymers (collagen,
silk, brin, gelatin,
hyaluronan, adipose-derived
ECM, decellularized human
placenta, and matrigel)
Synthetic polymers (PLA,
PGA, PEG, PLGA)
decellularized allogenic/xenogenic neural/
nonneural tissues
Muscle-derived matrix Decellularized nonneural tissues,
Biodegradable synthetic polymers
(aliphatic polyesters, polyurethanes,
piezoelectric polymers and some
electrically conducting polymers, PGA,
PLC, etc.)
Small intestine submucosa, porcine
bladder acellular matrix
Growth factors (VEGF,bFGF)
Naturally derived polymers (collagen,
laminin, brin, chitosan, polysaccharides,
based
Biomaterials (polyurethane-
porous scaffold, binogen/
Growth factors
silk broin, keratin, biodegradable
synthetic polymers)
Growth factors (BMP, myostatin,
Laminin-
111,PLLA,PCL,PLGA,CEB)
ADMSCs, adipose-derived
stromal cells
3,GDNF,CNTF,FGFs,VEGF)
(NGF,BDNF,NT-
Neural stem cells, embryonic stem cells,
Schwann cells, bone marrow stromal cells,
MSCs
Gliogenic secondary neurospheres derived
from iPSc
TGF-b, HIF-PHDs, PDGF-BB)
Fibrin microthreads with adult
human stem cells (MSCs)
Autologous multipotent stromal
cells in a vicryl mesh tube
of autologous cells
Platelet-rich plasma Electrical stimulation, genetic engineering
Description of each soft tissue
Skin and subcutaneous tissue defect Muscle, tendon, and ligament defect Nerve defect
Tissue transfer (FTSGs, STSGs, aps) Autologous muscle/tendon transfer Autologous nerve graft transplantation Fat tissue transplantation
Tissue expansion (skin expansion,
DermaClose RC)
Vacuum assisted closure system Reconstruction of ligaments with
Strategies
Surgical
Table 23.1 Current methods of advancing skin tissue regeneration
technique
Transverse tibial bone transport Tendon or tissue allograft
Acellular dermal matrix (AlloDerm
Regenerative Tissue Matrix)
Cellular dermal matrix (Apligraf,
Dermagraft)
Other tissue derived matrix (DHACM,
PSIS)
Scaffold-
based
therapy
Biomaterials (Collagen-GAG sponge,
Integra Dermal Regeneration Template,
Growth factors (PDGF, EGF, IGF,
gelatin, PEG, brin)
Drug-
VEGF, FGF, TGF), Deferoxamine
Cultured cell therapy (broblasts,
keratinocytes, bone marrow- derived
MSCs, ADMSCs, cultured epidermal
cell sheet)
No cultured cell therapy (ReCell
based
based
therapy
Cell-
therapy
system)
cold atmospheric plasma
Others Platelet-rich plasma, Emacure system,
252
https://t.me/medicina_free
J. Liu et al.
23.4.2.3 Nerve Defects
Nerve defects are typically classied based on
the classication by Seddon (1943) [99] and
Sunderland (1951) [100]. This allows selection
of the required treatment (Fig.23.3) and allows
an estimated prognosis for recovery [101].
Current strategies for nerve defects are mainly
based on microsurgical connection of the two
sides by autologous nerve graft or approaches
of tubulization [102, 103]. Despite the advantages of existing approaches, complete recovery is inauspiciously infrequent, misdirection
and development of debilitating neuropathic
pain unfortunately common [101].
Currently, autologous nerve grafts or nerve
allografts have been widely used for replacing
the defects [104]. Nerve transfer is another way
of replacing the proximal part of the involved
nerve.
23.4.2.4 Fat Tissue Defects
Historically, the primary method was to cover
subcutaneous defects of fat tissue according to
the philosophy “replace like with like” via fat
transfer. The rst surgeons who used fat grafts
were Neuber in 1893 [105] for unilateral facial
atrophy, followed by Czerny [106], who performed one of the rst breast enlargements with
autologous fat, which he had isolated from a
lipoma, and Lexer [107] for soft tissue lling
after zygomatic bone fractures. In the following
years, autologous fat grafts were used in several
other elds [108].
The liposuction technique, introduced by
Fisher in 1974 [109], accelerated the development of the lipolling technique, which started in
1986 when Illouz and Pug [110] and Chajchir
and Benzaquen [111] published their works
about reinjection of liposuctional fat tissue; however, in the following years the use of fat as an
implant material was not favored, because the
method of harvesting was standard liposuction
[112–115]. Standard liposuction caused signicant damage to the fat cells by rupturing cell
membranes and subsequently causing cell death.
Since then, autologous fat transfer has been
improved. Coleman [116] described a new way
to harvest fat with atraumatic low-vacuum technique to increase intact and viable lipocytes in
transplanted fat for transfer. His technique
remains the gold standard for liposuction and
lipolling, but it has undergone some technical
modications [
transplantation is one of the most popular procedures performed by plastic surgeons.
Despite fat grafting being a well-established
method, the long-term survival rate of autologous fat grafting remains unpredictable. Peer
[118, 119] studied the long-term survival of
autologous fat grafts and showed in 1950 that,
of the autologous transplanted fat grafts, more
than 50% of their weight and volume was
reduced after 1 year; several other studies in the
following years conrmed this [
authors described 30–70% reduction in graft
volume within a year [120]. Additional, although
rare, severe complications could be seen in the
literature related to autologous fat grafting
including vision loss, stroke, and even death
[121]. That is why recent research up to this
point has included attempts to further improve
autologous fat transfer and numerous natural,
synthetic, and hybrid materials have been used
to act as adipose surrogates.
Every step in fat transplantation—harvesting,
processing, and transplantation—is important,
but the viability of the harvested fat cells is crucial [122]. The chances of survival are higher if
the fat graft is manipulated less and reinjected
quickly [123].
Typical donor site complications include
swelling, hematoma formation, paresthesia, or
donor site pain. In a few cases, infection, hypertrophic scarring, contour irregularities, and damage to the underlying structures occur, due to
intraperitoneal or intramuscular penetration of
the cannula [32, 124–128]. Multiple complications were reported in the literature concerning
the recipient region, including edema, bruising,
bleeding, dysesthesia, infection, fat necrosis, less
than expected benecial outcome, microcyst,
microcalcications, fat embolism, and severe
complications including stroke, vision loss, systemic infection, sepsis, or death [121, 129, 130].
117]. Nowadays, autologous fat
120]. Some
23 Translational Challenges inSoft Tissue Regeneration
https://t.me/medicina_free
253
Fig. 23.3 Surgical algorithm of peripheral nerve repair (modied based on[150])
254
https://t.me/medicina_free
J. Liu et al.
23.5 Advancing Surgery forSoft
Tissue Regeneration
23.5.1 Surgical Techniques
23.5.1.1 Skin andSubcutaneous
Tissue Defects
Vacuum-assisted closure (VAC) after debridement is a popular technique in wound care
which speeds up wound healing by improving
tissue perfusion, suctioning the exudates and
thus increasing the granulation tissue regeneration [131]. Skin graft transplantation is needed
thereafter to completely close the defect.
The application of transosseous-osteosynthesis
with the Ilizarov technique, which is expected
to improve local microcirculation, showed
great effect in promoting wound healing in diabetic foot ulcer [132]. Tissue expansion is
commonly used for skin and subcutaneous tissue defects after excision of tumor lesions or
severe scar [133, 134]. In addition, a continuous external tissue expansion system
(DermaClose RC) has been reported to be an
effective technique for achieving denitive
large wound closure, potentially reducing the
donor-site morbidities needed for larger reconstruction measures [135].
23.5.1.2 Muscle, Tendon,
andLigament Tissue Defects
Autologous muscle or tendon transfer is commonly performed in the clinical situation, when
there is muscle loss following trauma, tumor
resection, or nerve injury, which impairs the
irreplaceable motor function [136, 137].
Latissimus dorsi muscle transfer showed safe
and efcient restoration of elbow exion after
injuries [136]. Tendon transfer of the exor
carpi ulnaris is considered as a good option to
restore the hand extension function following
high radial nerve injuries[138]. When no adjacent muscle is available because of high-level
nerve injuries, autologous muscle transplantation together with neurorrhaphy is typically
applied [139, 140]. It can also be used for muscle weakness after facial palsy or for pelvic
oor reconstruction [141, 142].
In addition to tendon transfer, autologous tendon grafting can facilitate restoring tendon length
and strength when there is a tendon defect at the
level of the hand or wrist [143]. Palmaris longus
tendon is one of the most commonly used grafts
in hand surgery [144, 145]. Tendon allografts
(Achilles tendon) processed from cadavers is
another good option, which avoids injuries in the
donor area [146].Tendon allografts are commonly applied for both tendon reconstruction and
ligament revision [146, 147].
After establishment in mouse models, restoration of vastus medialis muscle in patients could
be performed with the use of a multilayered scaffold made of extracellular matrix derived from
porcine submucosa [15, 20]. Abdominal musculoskeletal wall defects were restored with a porcine small intestinal submucosa-extracellular
matrix that was sutured at the defect corners and
subcuticularly closed with a Vicryl suture [93].
23.5.1.3 Nerve Defects
If a direct tension-free end-to-end or end-to-side
neurorrhaphy is not possible, the interposition of
a graft between the nerve stumps is required to
bridge the gap and support axonal regrowth [78].
To ensure a tension-free repair it is advised to
choose a graft that is 10% to 20% longer than the
existing nerve gap [76, 148]. Implantation of an
autologous nerve graft, which is a functionally
less important nerve segment from another site
of the body, remains the most reliable repair
technique [76, 148]. Autografts are ideal nerve
conduits for longer gaps (>3 cm), critical nerves
and proximal injuries [78, 149]. They provide a
permissive and stimulating scaffold, including
Schwann cell basal laminae, adhesion molecules, and neurotrophic factors and they constitute a supportive structure for the ingrowing
axons [78, 150, 151].
Only approximately 25% of the axon will,
however, successfully regenerate through the
graft’s two coaptation sites with an estimated
loss of 50% of axons at each of them [78].
Single grafts describe a segment of a donor
nerve of similar diameter [78, 152]. Cable grafts
join nerve gaps with large diameter by using
multiple lengths of a smaller diameter (sensory)
Harvesting
Processing
Reinjection
23 Translational Challenges inSoft Tissue Regeneration
https://t.me/medicina_free
255
donor nerve. They are reversed in orientation
[152]. Trunk grafts mix motor and sensory
grafts and are integrated as a large donor nerve
of an entire segment of a very proximal nerve
injury. Trunk grafts showed no convincing
results due to poor vascularity and internal
brosis [78, 152]. Interfascicular grafts close
the gap between groups of fascicles in the damaged nerve [78, 153].
Nerve transfer is another surgical technique. It
involves isolating nerves with less important
roles or branches of a nerve that perform redundant functions, and “transferring” them to restore
the function of a more crucial nerve which has
been severely damaged. Typically, the functioning nerve that is close to the target muscle or sensory area is transferred or “plugged in” to the
injured nerve that no longer functions (Fig.23.4).
Fig. 23.4 Illustration of selective nerve transfer of the
ulnar nerve (UN) to the anterior interosseus nerve (AIN)
for neuroma treatment of the distal forearm. The challenge of this nerve repair is the correction of the size mismatch resulting from the end-to-end adaptation performed
nerve transfer to avoid following misdirecting of sprouting axons compromising the sensory and motor recovery.
23.5.1.4 Fat Tissue Defects
It is widely accepted that less traumatic methods
of fat harvesting result in increased graft survival
of the transplanted fat [154]. It has been shown
that a number of possible harvesting options allow
the collection of regenerative adipose tissuederived stem cells [155–157]. However, there is
an ongoing discussion about which methods
increase intact and viable adipocytes. The main
techniques are vacuum aspiration, syringe aspiration, and surgical excision. Similarly to adipocytes, lipoaspirate contains collagen bers, blood,
and debris. Those elements can cause inammation in the recipient site, and thus fat processing is
advisable. Various processing techniques such as
centrifugation, sedimentation, washing with
physiologic solution, and gauze ltration have
been proposed (Fig. 23.5) [50, 158–166]. The
most common technique is centrifugation as
described by Coleman [50].
Principles of fat reimplantation are based on
optimal recipient site vascularity for increased fat
survival [167]. Through a skin incision, which is
sized corresponding to the diameter of the
cannula, the fat graft is inserted into the area of
the anatomical region affected. On the one hand,
small-gauge cannulas reduce the risks of bleeding and hematoma formation, but on the other
hand they cause poor graft oxygen diffusion
[167]. It is thus suggested to use cannula with
similar hole sizes for aspiration and utilize minimal amounts of suction force to avoid mechanical damage. Because revascularization starts at
the periphery, ischemic time is longer in the center of the graft; therefore, fat reinjection in multiple small-volume sessions is preferred rather
than one single injection [168]. Fat grafts are
vacuum aspiration
(low vacuum)
syringe aspiration
(10ml with 2ml
negative pressure)
surgical excision
Fig. 23.5 Common procedures of fat/ADMSCs harvesting and reimplantation
centrifugation
(1200-3000 rpm for 1-3
min)
sedimentation
washing
gauze filtration
small cannula (with
similar hole sizes as
aspiration cannula)
very small quantity of
tissue per passage
fanned out in multiple
tissue planes and to
verying depths
256
https://t.me/medicina_free
J. Liu et al.
therefore distributed in small aliquots and fanned
out in multiple tissue planes and to varying
depths in the soft tissue to create a threedimensional network and to avoid excessive
interstitial pressure at the recipient site [167].
23.6 Scaold-Based Treatments
23.6.1 Skin andSubcutaneous Tissue
Defects
Tissue-derived matrix has been widely applied
for treating skin and subcutaneous defects
(Table 23.1). It can be processed either from
cadaveric allografts of skin tissue, placenta tissue (Dehydrated Human Amnion/Chorion
Membrane, DHACM), or from porcine small
intestinal submucosa (PSIS) [169]. Those scaffolds provide nearly perfect extracellular matrix
architectures for three-dimensional cell growth
and rebuilding of multilayer tissue structures
within scaffolds after implantation, promoting
tissue regeneration [170]. Biomaterials including natural and synthetic polymers have also
been employed to fabricate skin substitutes
(Table23.1). Gelatin-sulfonated silk composite
scaffolds have been produced based on 3D printing and showed favorable properties for skin
regeneration by stimulating epidermal growth
and dermal neovascularization [171]. Gold
nanoparticles (GNPs) whose surface has been
functionalized with PEG show accelerated cell
migration, successful scaffold colonization, and
regeneration [172]. Collagen-GAG scaffolds
have been cocultured with autologous broblasts
and keratinocytes or used directly with uncultured keratinocytes or stem cells obtained at the
point of care in the operation room [173].
23.6.2 Muscle, Tendon, andLigament
Tissue Defects
ECM scaffolds can ll the defect and restore
morphology temporarily [21]. The in vivo
microenvironment needs to facilitate remodeling of the neo-tissue [174]. Functional muscu-
lar impairment can therefore be addressed by a
musclebone marrow-derived mesenchymal stem cells
(MSCs) after implantation and growth of the
layer. This enriched matrix gains more blood
vessels and regenerates more myobers than
“conventional” extracellular matrix [21, 175].
Comparable to muscle-derived matrix, small
intestinal submucosa- extracellular matrix can
lead to contractile sheets of skeletal muscle
with comparable contractile force [93]. One
obstacle in muscle regeneration is the musculotendinous junction. This can be partly restored
in the absence of implanted cells by extracellular matrix-based platforms and has been shown
to withstand half of the force of the contralateral site after complete resection in a mammalian model [
myoblasts have been preconditioned on a porcine bladder acellular matrix in a bioreactor and
then been implanted in nude mice at a muscledefect to restore muscular tissue [176]. The
newly formed muscle cells show better adherence to 3D polyurethane-based porous scaffolds
with low stiffness and larger roughness values
[177]. Another hydrogel with the composition
of brinogen and Laminin-111 (LM-111), combined with electromechanical stimulation,
delivered a promising scaffold for myoblast cultures [178]. Laminin seems to play a crucial role
for muscle injury since a novel synthesized laminin-mimetic bioactive peptide (LM/E-PA) was
shown to stimulate activation of satellite cells
and lead to myobrillar regeneration in rat models reducing the time necessary for functional
recovery [179].
formation and low vascularization [180, 181].
For ACL-replacement, ligamentous regeneration
has recently gained attention. PLLA (Poly lactic acid) nanobers with a shell of electrospun
PCL nanobers (with bFGF and platelet-derived
growth factor (PDGF)) helped hMSCs to proliferate in vitro with subsequent upregulation of
collagen I and III and multiple ligament markers,
forming bers similar to the natural ligamentous
structure [182].
derived matrix, which is lled with
174].
For in vitro muscle tissue engineering, rat
Ligaments and tendons often heal with scar
23 Translational Challenges inSoft Tissue Regeneration
https://t.me/medicina_free
257
Tendon regeneration is similarly challenging
because of the long time for rehabilitation and
lack of regeneration to native composition and
structure. It may therefore need additional cell/
molecular elements for treatment approaches
[183, 184]. One promising report used PLGA
(polylactic-co-glycolic acid) bers for release of
bFGF (Basic broblast growth factor) which
increased collagen production in tendon regeneration. In the rat model, promising invitro and
in vivo results with a collagen-BDDGE-elastin
(CBE)-based device for tendon tissue engineering were reported [95, 180, 185].
23.6.3 Nerve Defects
One major drawback for current nerve graft
techniques is the requirement of a secondary
donor site and subsequently injury, the limited
supply of donor nerves, and a mismatch
between the donor nerve and the recipient site
[186–188]. The limits have encouraged collective development of alternatives to autologous
nerve grafts mainly through tubulization.
Tubulization means bridging the gap between
the nerve stumps by using nonnervous tubes
[189–192]. Good results of this method were
reported for bridging nerve gaps less than 3cm
long (Fig.23.6) [193]. Natural biomaterials for
such neural scaffolds fall into two categories:(1)
autologous nonneural tissues and allogeneic/
xenogeneic neural/nonneural tissues that have
been decellularized [194]; (2) naturally derived
polymers, including extracellular matrix (ECM)
molecules (collagen, laminin, brin, bronectin, and hyaluronan), polysaccharides(chitosan,
alginate, agarose), and proteins (silk broin,
keratin) [195]. Used tubes include hollow veins,
arterial and soft tissues (muscle, tendon) grafts
[78, 196]. Veins alone and in combination with
intraluminal muscle inlays have a high tendency
to collapse. Another strategy for avoiding collapse is filling the vein lumen with small
pieces of nerve tissue [197]. Muscle–veincombined conduits have been used in the clinical practice filling gaps up to 6cm with good
results in to 85% of the cases [104, 189]. An
effective nervous tissue construct seems to
require a combination of a scaffold, cells, and
signaling factors [
should be porous to provide sufficient diffusion of oxygen and metabolites for supporting
Schwann cells proliferation, as well, be lowantigenic, biocompatible, biodegradable, conductive and resistant to infections and
fibroblast infiltration [76, 78, 198, 199].
The idea of employing muscle bers for axonal regeneration is based on the similarities
between the muscle basal lamina and the endoneurial tube [
tured muscle conduits led to reported successful
nerve repair. A comparison of nerve regeneration
through nerve and muscle grafts has been
reported for the rat sciatic nerve [202]. Results
indicate the suitability of either acellular muscle
or nerve grafts for nerve repair compared with
conventional fresh nerve grafts [203–208]. The
advantage of autologous conduits is that they are
almost cost free (apart from the increased operation time) and prepared according to reconstructive needs after consideration of nerve size and
length defect [209]. Despite all advances in
microsurgery, satisfactory results of motor
recovery from nerve injury are still reported in
less than 40% of cases [210].
Current methods of advancing nerve regeneration in Tissue Engineered Nerve Grafts (TENGs)
have emerged as a potential alternative to autologous nerve grafts. To overcome the limits of autografts, various articial and biologically based
nerve conduits have been developed varying in
the levels of success. TENGs can be categorized
into biological and articial nerve grafts [188].
Biologically nondegradable inert silicone elastomer was the principal material used in the
beginning. More recently, different classes of
biodegradable synthetic polymers including
aliphatic polyesters, poly(phosphoesters), polyurethanes, piezoelectric polymers, and some
electrically conducting polymers have served as a
scaffold in neural tissue engineering [188].
Today, commercially available products are made
of polyglycolic acid (PGA) and poly(D,L-lactideco-ε-caprolactone) (PLC) (Neurotube® and
Neurolac®) (Fig.23.7) [211, 212].
78, 149]. Nerve conduits
200, 201]. Both fresh and dena-
258
https://t.me/medicina_free
J. Liu et al.
Fig. 23.6 Systematic overview for autografting techniques, natural and synthetic conduits if the nerve gap is <3cm.
The majority of approved commercially
available products are made of Type I
collagen (Neurotube®, NeuroGen®, NeuroFlex®,
NeuroMax®, NeuroWrap®, NeuroMend®), or
chitosan- based nerve grafts (Reaxon®) [211–213].
In addition to natural and synthetic polymers,
ceramic, carbon, and metallic-based materials
have been investigated (Fig.23.7) [214–220].
The selection is decisively inuenced by a
high priority of avoiding unwanted inammationinducing properties of the biomaterial, especially
regarding long-term stability [221, 222]. To meet
these requirements, biomaterials are usually
modied or blended with each other [188].
Recently, nanoscale fabrication technologies
have made it possible to synthesize neural scaffolds with submicron architecture closely resembling the architecture of natural ECM [223].
They provide a greater surface-area-to-volume
ratio, which enhances cell attachment, differentiation, and growth when compared to microscale
scaffolds [224]. Nanotechnological fabrication
techniques as electrospinning, phase separation,
self-assembly, and computer-aided design-based
23 Translational Challenges inSoft Tissue Regeneration
https://t.me/medicina_free
259
Fig. 23.7 Examples of commercially available natural
and synthetic conduits (modied based on [150]) which
successfully bridge gaps <3 cm. Within the German
Health System exists a code for reimbursement of
fabrication techniques improved regeneration
regarding neurite length and linear orientation
invitro and invivo [225–234].
23.6.4 Fat Tissue Defects
For the formation of large-volume threedimensional fat tissues, scaffolds are used. These
scaffolds stabilize the growing tissue and should
enable stronger proliferation of adipocytes and
endothelial cells [235]. Therefore, various natural and synthetic scaffolds have been tested
invitro and invivo. Natural polymers that have
been explored include collagen, silk, brin, gelatin, hyaluronan, adipose-derived ECM, decellularized human placenta, and matrigel. Matrigel is
both angiogenic and adipogenic and improves the
adipose graft longevity and volume maintenance
when mixed with adipocytes [236, 237]. Synthetic
materials have also been widely tested in adipose
tissue engineering [238]. Polymers such as polyactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), and the copolymer poly
CE-certied nerve conduits (Operations and Procedures
Key (OPS), Codes: 5-085.40, 5-058.41, 5-058.42,
5-058.43, 5-058.4x).
lactic-co-glycolic acid (PLGA) have been extensively used for soft tissue applications. The
chemical-physical properties of PLA and PGA
showed potential in supporting tissue regeneration in invitro and invivo studies as 3D scaffolds
or grafts for adipose tissue engineering [239–
241].The long-term availability of PGA meshes
in vivo supported evident adipogenesis and vascularization [242].
23.7 Drug-Based Therapy
23.7.1 Skin andSubcutaneous Tissue
Defects
Exogenous administration of growth factors,
such as platelet-derived growth factor (PDGF),
epidermal growth factor (EGF), insulin-like
growth factor (IGF), vascular endothelial growth
factor(VEGF), broblast growth factor (FGF),
and transforming growth factor (TGF), has
potential benets in wound healing and tissue
regeneration [243]. They can affect chemotaxis
260
https://t.me/medicina_free
J. Liu et al.
and stimulate mitosis of quiescent cells, angiogenesis, and synthesis and degradation of the
extracellular matrix (ECM) [244]. EGF stimulates epidermal and mesenchymal regeneration
and cell motility through interaction with the
EGF receptor on epidermal cells and broblasts
[245]. IGF-1 plays an important role in stimulating collagen synthesis in broblasts, the proliferation of broblasts and keratinocytes, and
angiogenesis [246]. PDGF can regulate the maturation of blood vessels and re-epithelialization
and also stimulate proliferation of broblasts,
thus increase ECM production [247]. Because
each growth factor has specic functions and is
present at different stages of wound healing and
tissue regeneration, recently researchers suggested a cocktail of growth factors to be a more
promising treatment [248]. The low-molecularweight protamine (LMWP) conjugated with
EGF, IGF-1, and PDGF-A via genetic modication accelerated wound re-epithelialization signicantly, accompanied by the formation of
healthy granulation tissue within 9 days
(Fig.23.2) [243].
Deferoxamine (DFO), an FDA-approved ironchelating agent, currently corrects impaired HIF1a- mediated transactivation in diabetes by
preventing iron-catalyzed reactive oxygen stress.
Duscher etal. reported that transdermal delivery
of DFO was found to prevent diabetic ulcer formation and improve wound healing in preexisting ulcers by decreasing oxidative stress [249].
23.7.2 Muscle, Tendon, andLigament
Tissue Defects
Pathogenesis of sarcopenia as one of the most
frequent muscular diseases involves different
molecular pathways, out of which BMP and
myostatin pathways seem to be most promising
[250]. Medication with human recombinant
BMP-2/7 and anti-myostatin can help to reduce
sarcopenic symptoms [251]. Cachexia is
addressed with anamorelin, a ghrelin agonist and
selective androgen receptor modulator as well as
anti-cytokines/myokines [252]. Another factor
involved in muscle healing seems to be TGF-β.
Increased TGF-β1 levels, which could be detected
after the use of nonsteroidal anti-inammatory
drugs, helped to regenerate muscle tissue
[
253–255].
Ameliorating tendon repair is especially of
interest in rotator cuff tear reparation. Here, HIF
prolyl 4-hydroxylase (PHDs)-inhibitors have
been shown to improve enthesis mechanics in a
rat model [256]. For further tendon reparation,
tendon multipotent stem cells (tendon-derived
stem cells, TDSCs) may be the key to biological
drug delivery therapies (BDDT). Blood-derived
TDSCs can be applied intratendinous and
intraligamentous with brin scaffolds to repair
tendon tears [257, 258]. As another factor of tendon regeneration, platelet-derived growth factor
(PDGF-BB) can increase exor tendon broblast
proliferation and matrix synthesis in vitro, yet
without effecting improvements in biomechanical properties [259, 260].
23.7.3 Nerve Defects
Neural cells in the distal nerve stump secrete
endogenous growth factors and support axon
regeneration. This stimulus declines over time.
To maintain the supportive action additional of
exogenous growth factors, Gu etal. [188] classied the existing growth factor into two classes:
(1) neurotrophins: NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-
3); (2) growth factors with neurotrophic actions:
glial cell line-derived neurotrophic factor
(GDNF), ciliary neurotrophic factor (CNTF) and
broblast growth factors (FGFs) [261, 262].
For continuous release of growth factors
from TENGs, different delivery systems were
compared [236]. Classical delivering strategies
are adsorption of growth factors to the surface,
the bulk of a scaffold, incorporation of growth
factors into the scaffold materials during the
scaffold fabrication, entrapment of growth factor-loaded microspheres into a scaffold, covalent immobilization of factors onto the scaffold,
and installation of an osmotic minipump or
injection device. Different microsphere designs
allow effective technologies to encapsulate
Соседние файлы в папке @xirurgi_2025