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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4496_Библиотеки_им_академика_М_И_Перельмана
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20 Craniofacial Tissue Regeneration Through Distraction Osteogenesis
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61. Barber S, etal. Distraction osteogenesis part 1: history and uses in the craniofacial region. Orthodontic
Update. 2018;11(1):14–20.
62. McCarthy JG, et al. Distraction osteogenesis of
the craniofacial skeleton. Plast Reconstr Surg.
2001;107(7):1812–27.
63. Mod MM, etal. Craniofacial distraction osteogenesis: a review of 3278 cases. Plast Reconstr Surg.
2001;108(5):1103–14.
64. Swennen G, Dempf R, Schliephake H.Cranio-facial
distraction osteogenesis: a review of the literature.
Part II: experimental studies. Int J Oral Maxillofac
Surg. 2002;31(2):123–35.
65. Alonso-Rodriguez E, et al. Polyetheretherketone
custom-made implants for craniofacial defects:
report of 14 cases and review of the literature. J
Craniomaxillofac Surg. 2015;43(7):1232–8.
66. Punchak M, etal. Outcomes following polyetheretherketone (PEEK) cranioplasty: systematic review and
meta-analysis. J Clin Neurosci. 2017;41:30–5.
67. Neovius E, Engstrand T. Craniofacial reconstruction with bone and biomaterials: review over
the last 11 years. J Plast Reconstr Aesthet Surg.
2010;63(10):1615–23.
68. Jalbert F, et al. One-step primary reconstruction
for complex craniofacial resection with PEEK
custom-made implants. J Craniomaxillofac Surg.
2014;42(2):141–8.
Part X
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Biological Procedures in Craniofacial
Reconstruction: Tissue Engineering
Bone andCartilage Tissue
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Engineering andRegenerative
Medicine inCraniofacial Surgery
ValentinKerkfeld, HansPeterWiesmann,
JörgHandschel, andUlrichMeyer
21
Introduction
Tissue engineering is the attempt to produce
complex biological structures and tissues from
simpler structures, such as cells. The aim here is
to produce functional constructs in order to
restore destroyed tissue or even entire organs. In
this process, biological tissue is articially
grown by cultivating cells. The cells are then
stimulated to form tissue with the aid of scaffolds, inuence of growth factors, and mechanical stimuli.
There are four elementary components for tis-
sue engineering:
• Scaffold
• Living cells
V. Kerkfeld (*)
Clinic for Maxillofacial and Plastic Facial Surgery,
Westdeutsche Kieferklinik; University of Düsseldorf,
Düsseldorf, Germany
H. P. Wiesmann
Institute for Biomaterials, Max-Bergmann-Zentrum
für Biomaterialien, Dresden, Germany
J. Handschel
Klinik am Kaiserteich, Düsseldorf, Germany
e-mail: handschel@klinikamkaiserteich.de
U. Meyer
Center for Jaw-, Face- and Skull Surgery,
Münster, Germany
e-mail: praxis@mkg-muenster.de
• Control of signal transduction (growth
factors)
• Culture medium
Tissue engineering and regenerative medicine
is a relatively new, expanding, and multidisciplinary eld (for review, see Meyer, Meyer [1]).
Whereas the term tissue engineering focuses on
the use of cells and scaffolds, the term regenerative medicine is connected with the use of stem
cells. Different approaches to tissue engineering
can be distinguished. Thus, there is an invivo and
an in vitro approach. In addition, grafts can be
divided according to their origin and their relationship to the recipient into:
• Xenogeneic, i.e., originating from another liv-
ing being (for example, heart valves, such as
TAVIs, of bovine or porcine origin)
• Allogenic, i.e., derived from a living organism
of the same species (e.g., kidney transplanta-
tion between two human beings)
• Autologous, i.e., from the patient himself
(e.g., skin coverage in the context of a free ap
reconstruction)
Currently, there are already some medical
applications. In particular, tissues with little or no
vascular supply are leading the way, as there is
little to no immune response here. For example,
tissue engineering is already reliably and commercially used in vascular endoprosthetics and
© Springer Nature Switzerland AG 2023
U. Meyer (ed.), Fundamentals of Craniofacial Malformations,
https://doi.org/10.1007/978-3-031-28069-6_21
279
280
s
In situ tissue regeneration
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heart valve replacement as endothelial tissue [2].
Another well-studied tissue type is cartilage tissue [3]. Even in living organisms, these structures
are composed of only one cell type and are
largely avascular. Other complex organs, such as
liver parenchyma, have not yet been articially
produced. This is partly because these organs are
composed of many different cells. These include
the diffuse stroma, specialized cells, and more.
However, tissue engineering is developing rapidly in medicine and is capable of revolutionizing
treatments in the future. In principle, they do not
repair defective tissues or organs, but replace
defective structures [4, 5]. In 2018, for example,
Israeli doctors have already succeeded in growing tissue for a defect of the tibia from a patient’s
own fat tissue and then successfully implanting
it. In this regard, bone repair already represents
an important discipline in reconstructive orofacial surgery and is very well studied (for review,
see Shanbhag, Suliman [6]). In the current therapy of reconstructive skeletal surgery, substitutes
such as autografts or allografts are used. However,
these techniques have disadvantages. First, there
is donor-site morbidity (e.g., at the harvest site in
the retromolar space) in treatments with autografts. Second, allografts have disadvantages
such as the lack of donors [7, 8] as well as immunologic concerns; for example, infectious diseases may be transmitted or complications due to
immunosuppression may occur [9, 10]. Synthetic
materials made of metal, ceramic, or polymer can
also replace bony structures [11], but each has
disadvantages. In contrast, biomaterials offer distinct advantages in clinical applications. They
contain living cells and can induce tissue growth.
In addition, they possess biological plasticity.
Current studies are attempting to produce hybrid
materials that combine articial materials with
living cells. In this way, the replacement tissue
should remain biologically active and retain
physiological functions after implantation [12,
13].
Bone tissue engineering can be used in a variety of ways to restore, preserve, or even alter tissue function [14, 15]. Three basic therapeutic
principles underlie this [16–18] (for review, see
Eltom, Zhong [19]):
1. In situ tissue regeneration, in which new tis-
sue formation is stimulated by specic scaffolds or external stimuli that stimulate
endogenous cells and promote local tissue
repair (Fig.21.1)
2. Implantation of fresh isolated cells, in which
single cells from the patient or a donor are
injected directly into the damaged region
(Fig.21.2)
3. Implantation of bone-like tissues prepared
invitro from cells and supporting tissue
Fig. 21.1 Principal
components of tissue
engineering
Minerals
Proteins/Cytokine
Interface layer
Scaffold material
Cell implantation
Cell implantation
21 Bone andCartilage Tissue Engineering andRegenerative Medicine inCraniofacial Surgery
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Cell explantation Serum explantation
281
Implantation cell-
/scaffold-construct
Fig. 21.2 Steps of a simpler bone cell-based tissue engineering
Radiologically
controlledbone healing
282
Cell explantation
Maturation
Scaffold
Extracorporal tissue engineering
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V. Kerkfeld et al.
Cell proliferation in culture
proliferierende Zellen
Fig. 21.3 Principle of extracorporeal tissue engineering
konfluente Ein-Zill-Schicht:
die Zellen vermehren sich nicht mehr
frisches Medium wird
zwischen die Zellen gepumpt
In tissue implantation, a complete threedimensional tissue is grown invitro from autologous or donor cells in a scaffold to be
implanted after reaching “maturity” (Fig.21.3).
The aim of this chapter is to explain the above
techniques in more detail and to highlight alternatives to extracorporeal techniques that may be
important for clinical decision-making.
Bone andCartilage Repair
Strategies
der Austausch des Mediums regt
die Zellen zur Vermehrung an
Bioreactor
Tissue transplantation
Clinically applied bone tissue engineering
aims to regenerate bone in two ways: [1] (1) in a
simple approach to replace bone with bone cells,
bone cells in combination with a protein scaffold,
or bone cells with a mineralized scaffold
(Fig. 21.5, left), or in a complex approach to
replace bone with a multicellular mineralized tissue construct that mimics bone on a larger scale
(Fig.21.5, right).
Cartilage tissue engineering appears to be
simpler in some respects (Fig.21.6), particularly
due to the avascular structure of the tissue.
The use of autologous bone for reconstruction of
bony defects is currently the gold standard. Two
different approaches can be distinguished. The
activation and stimulation (augmentation) of the
already existing host cell population and the
transplantation of whole bone tissue (Fig.21.4).
Bone and cartilage tissue engineering plays a
central role in the reconstruction of cranial
defects or deciencies. Because skeletal bones
have many more bone tissue components than
cartilage components, bone tissue engineering
approaches are much more common.
Bone Augmentation
The fact that augmentation of local host cells effectively improves bone healing has already been demonstrated in many studies [21–23]. However, the
effect is strongly dependent on the condition of the
defect site. Very good results can be expected with
healthy hard and soft tissue. In this environment, the
host cells can expand well. Nevertheless, if the
wound conditions are poor, for example due to local
tissue irritation or even necrosis, the prognosis for
this repair strategy is poor.
Bone histology
Bone histology
Innere
Generallamelle
Cartilage histology
Cartilage histology
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283
simplified
Speziallamellen
n
Endost
Havers-Kanal
Volkmann-Kanal
Periost
Außere
Generallamellen
Fig. 21.4 Bone repair by autologous cells. Adopted from Meyer, Wiesmann [20]
principle
a Hyaline cartilage
Chondrocytes
in lacunae
real
section
Matrix
b Fibrocartilage
Chondrocyte
in lacuna
Fig. 21.5 Simplied (left) and real (right) bone histology
Collagen fiber
in matrix
c Elastic cartilage
Chondrocyte
in lacuna
Elastic fibers
in matrix
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Cartilage engineering
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V. Kerkfeld et al.
Cell explantationCell / scaffold culture
Fig. 21.6 Cartilage forms and histology
Membrane Techniques
Membranes can signicantly improve defect
healing and represent a popular and widely used
technique in maxillofacial surgery as guided
bone regeneration (GBR) [24]. Membranes act as
a barrier between the surrounding soft tissue and
the bone defect. This allows the local host cells to
thrive protected from external inuences by the
soft tissue [25]. Guided bone regeneration has
proven to be a successful therapeutic concept in
controlled animal studies as well as in many clinical trials [26–28]. Basic studies have also established that the healing pattern in this type of
tissue healing resembles the physiological steps
known from de novo bone formation [29]: after
the formation of a blood clot, the invasion of
osteoprogenitor cells, and their differentiation
into osteoblasts, the extracellular matrix (ECM)
subsequently mineralizes to form lamellar bone.
Despite the promising results from studies and
daily practice, this type of augmentation is also
highly dependent on defect spread and geometry.
If a bone defect is limited by more than two walls,
even large defects can be successfully treated by
GBR [30]. However, geometrically more com-
plex or larger defect sites represent severe limitations of this technique.
Biophysical Stimuli
It is assumed that the bone absorbs many external
inuences and thus specically controls regeneration. This is known not least from the onset of
bone atrophy when no load is applied, e.g., in
immobile, senile patients or also after tooth
removal in the jawbone, which then no longer
experiences any mechanical load [31, 32].
Biophysical effects, such as distraction, use of
ultrasound, and electromagnetic elds, are
important factors in the regulation of new bone
formation [33]. The application of these stimulation methods has therefore entered clinical practice. The efcacy of all these measures has been
conrmed by many randomized clinical trials
[34] (for review, see Massari, Benazzo [35]).
Ultrasound
When biophysical stimuli are applied by ultrasound, adjacent anatomical structures such as
joints, muscles, and ligaments are minimally
deformed and deected. The procedure is highly
Cell control in culture
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dependent on the biological situation in the
patient and on the technical application of the
stimuli. Therefore, for biophysical stimuli, the
dose, timing, and method of application must be
carefully determined and validated. Currently,
the science and development are still in their
infancy, with some clinical trials and animal
studies already showing promise (for review,
see [36]).
Electromagnetic Fields
The inuence due to electric eld exposure has
already been well studied [37–41]. The electrical stimuli act on various levels of the patient’s
anatomy and biology, i.e., on the organ level, the
tissue level, the cell level, and even the molecular level. However, when considering the individual levels, the inuence on each other must
not be disregarded. Accordingly, one can consider the response of electrical stimuli to the
whole bone, the surrounding tissue, or the individual osteocyte.
Due to this heterogeneous approach, it has not
yet been possible to create a clinically applicable
concept despite extensive research efforts.
Distraction Osteogenesis
Distraction osteogenesis is a widely used therapeutic option to autologously augment local bone
[42]. This technique makes it possible to achieve
new bone formation even after growth has been
completed. The surrounding tissue, soft tissues,
and vascular supply are adapted to the distraction. The principle of this technique goes back to
the Russian surgeon G.A. Ilizarov, who discovered this procedure rather accidentally in the
1950s [43].
Technically, a fracture gap must rst be created iatrogenically. The two fracture fragments
are then anchored to a “distractor,” which allows
the fragment ends to be gradually pushed apart. A
physiological healing process is created with the
regenerative tissue (callus), which subsequently
grows along with the fracture. The regeneration
tissue corresponds histologically almost to the
fetal tissue growth or the usual fracture gap healing [44, 45]. After reaching the desired length,
the stable bone can now develop.
Although the biomechanical, histological,
and ultrastructural changes have been largely
studied, the molecular mechanisms contributing to bone neogenesis have not been fully
explored. However, there is increasing evidence that osteocytes and progenitor cells, as
well as angioneogenesis, contribute to bone
neogenesis [46]. Recent studies have focused
intensively on intercellular communication
and cytokines during distraction osteogenesis
[47, 48]. Certain genes encoding cytokines
were found to be amplified.
Due to the long clinical application in various
medical disciplines, the surgical procedure of
distraction osteogenesis has been signicantly
rened [42]. Thus, distraction osteogenesis is one
of the most important therapeutic approaches in
the treatment of bone augmentation (for review,
see Sahoo, Issar [49] and Hopper, Ettinger [50]).
Biological Stimuli
As described in the chapter Distraction
Osteogenesis, many basic studies indicate that
cytokines have a decisive inuence on bone and
cartilage healing and bone neogenesis. Therefore,
part of the research is specically focused with
the question of what potency and efcacy bioactive factors have on bone neogenesis [28, 51].
Among cytokines, growth factors in particular
play a major role [52–55]:
• Transforming growth factor beta (TGF-β)
– Bone matrix protein (BMP)
– Growth differentiation factors (GDF)
• Insulin-like growth factor (IGF)
• Platelet-derived growth factor (PDGF)
Different healing environments induce specic growth factors that form different bone tissues. In the healing of transverse fractures in long
bones, cortical bone is most needed. In the augmentation of maxillary bones, on the other hand,
cancellous bone is required above all.
It is assumed that different healing
approaches are followed depending on the
presence of the individual growth factors and
their interaction with each other (e.g., inhibition and amplication).
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Three different treatment strategies have
become established in clinical and scientic
application:
1. Purication and mixing of human and animal
proteins from cortical bone [56]
2. Use of recombinant proteins [57, 58]
3. Administration of DNA encoding a growth
factor (gene therapy) [59–61]
Among these, the third strategy is still the
least developed but is likely to be promising due
to steady advances in the eld of biotechnology.
Presumably, not only one therapeutic strategy
will establish itself as the best, but each has its
specic advantages and disadvantages. In the
end, manufacturing costs as well as practicality
must also be factored into the decision-making
process.
Transplantation
In contrast to augmentation, transplantation follows the approach that autologous tissue is taken
from a healthy donor site and implanted at the
diseased site. In this way, even larger defects can
be treated adequately. However, transplantation
can lead to secondary morbidity of the donor site.
The bone defect is decisive in the choice of transplantation procedure.
Cell Transplantation Approach
Bone grafts can be classied according to their
vascularization status (Fig. 21.4). Nonvascularized grafts are mainly cancellous bone
and cortical bone. Vascularized grafts can be
divided into pedicled bone grafts and free bone
grafts. While smaller bone defects can be treated
adequately with non-vascularized bone grafts,
vascularized bone grafts should be used for larger
bone defects.
Non-vascularized Grafts
Non-vascularized aps are very popular among
surgical practitioners. Cortical or cancellous
bone chips are often used for minor bone defects.
In principle, any bony harvesting site is possible
and can be individually selected by the practitioner and patient. In clinical practice, the iliac crest
graft and facial skull grafts (e.g., from the mandible) have become the most popular. However, it
must be noted that the facial skull may have better long-term survival of the transplant due to its
intramembranous ossication, as animal studies
show membranous bone to be less susceptible to
resorption [39]. In clinical routine, it is important
that the grafts are xed without external mechanical action. Accordingly, it is also important to
sufciently avoid the formation of hematomas. In
addition, the grafts are susceptible to infections
and the survival of the cells as well as the possible extent of resorption cannot be clearly predicted. Resorption is largely dependent on graft
volume, time to loading, and condition of the
graft bed.
Vascularized Grafts
The use of vascularized bone grafts has opened a
tremendous advance in the treatment of bony
defects. A distinction can be made between pedicled aps and microvascularized, free aps. Bone
can be used with or without its surrounding soft
tissue, whereby the surrounding soft tissue has
good effects regarding healing. It adequately
shields both mechanical and infectious external
factors and can also replace lost soft tissue [62].
Among pedicled osteocutaneous or osteomuscular aps, some donor sites have become established in clinical routine [63]:
• M. sternocleidomastoid in combination with
the clavicle [64]
• M. trapezius with parts of the scapula
[65–67]
• M. pectoralis with part of the rib or sternum
[68–70]
• M. latissimus dorsi [71]
• M. temporalis with calvarian bone [72, 73]
However, freely vascularized bone grafts also
offer very good results in the treatment of larger
bone defects. In this case, a soft tissue paddle is
also harvested together with the vascularized
bone. Several proven donor sites have emerged in
clinical routine [74]:
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