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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_980_Библиотеки_им_академика_М_И_Перельмана
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In Situ Bone Regeneration in Oral and Maxillofacial Surgery: Denition, Indications…
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contact, resolved vertical discrepancies, and decreased bone resorption, in addition
to other clinical advantages of CAD-CAM-fabricated PSIs [18]. Treatment of a comminuted mandibular fracture case, with a titanium PSI to secure and contour the
displaced many fragments of mandible, revealed successful mandible restoration and
no clinical inammatory evidence over the course of follow-up. No bone resorption
was inspected in the patient’s CT image. Partial PSI covering with bone callus was
also evident [19]. Moreover, symphysis and mandibular body reconstruction with
titanium PSI have resulted in an uneventful restoration over 5 years (Figs.3 and 4).
ab
cd
Fig. 3 In situ bone regeneration in posterior mandible with titanium PSI: Computer-aided designing (CAD) of titanium PSI on virtual mandible model of patient via Mimics 21.0 software
(Materialise®, Belgium) (a, b), defect view after resection (c), resected tissue (d) (Courtesy of Dr.
Khojasteh). In situ bone regeneration in posterior mandible with titanium PSI placement of titanium PSI at site while preserving the inferior alveolar bundle continuity at core for vascularization
(e), covered PSI prior to closure (f), post-operation panoramic view (g) (Courtesy of Dr. Khojasteh).
In situ bone regeneration in posterior mandible with titanium PSI: 6 months post-operation CBCT
and 3D virtual visualizations, inserted titanium PSI and plate, and de novo bone inside (h), sole de
novo bone tissue (i). Sectional CBCT view of de novo bone within PSI (j) (Courtesy of Dr.
Khojasteh). In situ bone regeneration in the posterior mandible with titanium PSI: After 6 months,
no signs of inammation, tissue necrosis, or infection were inspected. Minimal PSI exposure in
distolingual attached gingiva region was noted. Patient reported no malfunctions during her course
of healing and had apt mastication and speech. Reentry at 6 months post-operation upon detecting
radiographic signs of bone formation, de novo bone tissue taken out from PSI (k), xation of de
novo bone segment at defect site with plates and screws (l), post-implantation panoramic view (m).
(Courtesy of Dr. Khojasteh)
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e
g
f
h
i
j
k
lm
Fig. 3 (continued)
In Situ Bone Regeneration in Oral and Maxillofacial Surgery: Denition, Indications…
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Clinical Application of In Situ Bone Regeneration PSIs
Ridge
Augmentation:
Reconstruction:
Ti or PEEK PSI + Bone Grafting
149
Maxillary Bone Defects
Mandibular Bone Defects
Fig. 4 Clinical application of in situ bone regeneration
Ti PSI + Bone Grafting
Ti PSI + Bone Grafting
2.2 Clinically Employed Materials andFabrication Methods
2.2.1 Titanium
Most clinical studies have used titanium PSIs for in situ bone regeneration. Titanium
PSI are suitable for most defects, even those with complex topographies, and offer
feasible tting after CAM [20]. Several studies have reported an average horizontal
regeneration of 4mm [21–23]. Histological evaluations have proved titanium PSIs
for in situ bone regeneration in atrophic ridges to be biocompatible, and no adverse
reactions, such as necrosis, brosis, or ectopic inltration of adipose cells, were
seen [8, 9]. However, titanium PSI cannot avert soft tissue ingrowth and formation
of pseudo-periosteum, which can occupy the anticipated space for bone regeneration. This effect has not been reported with other materials. Moreover, titanium is
radiopaque, which has a considerable exposure rate [20].
No conclusion for accurate regenerative capacity of titanium meshes is presently
available [24]. A maximum of 13.7mm vertical regeneration has been achieved by
simultaneous in situ bone regeneration and implant placement [25], but averagely
vertical regeneration ranged from 2.56 to 6mm [21].
Titanium PSIs are mostly fabricated using selective laser melting (SLM) that are
used for single metal elements. Moreover, selective laser sintering (SLS) methods,
including electron beam melting (EBM) [5, 26] and direct metal laser sintering
(DMLS) [10, 27], can be used for titanium alloys and provide a exible selection [6,
8, 9, 12, 15, 16, 28]. EBM uses a concentrated electron beam with mostly tungsten
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– Selective Laser Melting (SLM)
)
(PLLA)
Clinically-Employed PSI Materials
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laments, to fuse metallic powders that are spread upon a preheated platform. The
whole procedure is conducted under vacuums, and the nal PSI is solidied through
cooling [29]. DMLS trajectory includes heating the titanium powder until particles
are fused. Structural support is attained with DMLS through designing additional
supporting structures [28]. EBM holds a higher energy density owing to its electron
beam and has a higher printing speed than both DMLS or SLM.
2.2.2 Polyether-Ether-Ketone (PEEK)
PEEK PSIs have also been applied for in situ bone regeneration. PEEK PSIs were
fabricated from medical grade PEEK blocks using milling machines. They cannot
be manually shaped and are often suitable for jaw anatomical morphology. PEEK
offers apt tensile strength and elasticity with high resemblance to native human
bone [20]. Filling the intaglio surface of a PEEK PSI with autologous and xenograft
and delivering the combination onto maxillary ridges has demonstrated successful
reconstruction with mostly uneventful or manageable postoperative period, and
implant placement could be performed afterwards. Obtained CBCT images at 6
months revealed sufcient vertical and horizontal regeneration with the site [14,
30]. Of note, PEEK is radiolucent. On the other hand, PEEK preparation can be
costly and non-osteoconductive.
2.2.3 Hydroxyapatite (HA)/Poly-L-Lactide (PLLA)
HA/PLLA composite PSIs have been used for mandibular reconstruction along
with particulate cancellous bone and marrow and PRP. Supplemental HA was
aimed to increase osteo-inducing capabilities of pure PLLA.The employed HA/
PLLA sheets were machined. Its smooth shape allows facile removal upon reentry
and reduces mucosal irritation during operation, leading to diminished exposure
time. Moreover, HA/PLLA is radiolucent and bioresorbable [20]. No bone resorption over 2 years and no complications over 1 year of follow-up have been reported.
In addition, the in situ regenerated bone held 790 Hounseld units (HU) for the
average CT value [31]. However, preparation of HA/PLLA PSI can be challenging
in terms of its complex fabrication process and relatively more minimum thickness
[20] (Fig.5).
Titanium (Ti) Alloys
Poly-Ether-Ether-Ketone (PEEK)
Hydroxyapatite(HA)/Poly-L-Lactide
Fig. 5 Clinically employed PSI materials
– Selective Laser Sintering (SLS)
– Milling
– Milling
1. Electron Beam Melting (EBM)
2. Direct Metal Laser Sintering (DMLS
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2.3 Clinical Advantages
The main advantages of CAD-CAM-based regeneration workow include four
components:
2.3.1 Operation Time
Owing to the preoperative testing of fabricated titanium meshes or chambers, the
manual mesh bending process in operation room is obviated. This leads to an overall reduction in operation time and its associated risks.
Preoperative virtual designing of fabricated containment compartments allows a
precise tting and employing natural anatomical undercuts as xating point. This
can minimize the number of implanted screws [27, 32].
In terms of treatment outcomes, CAD-CAM-fabricated titanium PSIs and customized trays can provide symmetrical facial contours and dimensions. The virtually designed PSI adapts facial specics while anchors upon remaining bony
segments. Accordingly, Ma etal. implicated a 3D-printed mesh tray for coupled in
situ bone regeneration and xation of comminuted mandibular segments. In this
light, predictability and morphological restoring is improved. Compared with traditional reconstructive plates, the 3D-printed mesh tray provided promoted stability
and nal appearance. For patients wherein a segmental and/or large mandibular
defects is to be reconstructed, these technologies can offer appropriate condylar
positioning and maintain occlusal stability [19].
2.3.2 Necessity andExtension ofGrafting
CAD-CAM-fabricated PSI for in situ bone regeneration intends to compromise
the amount and, at times, the necessity of synthetic bone substitute application. In
addition, in case of autologous bone harvesting, the harvesting extension is
decreased.
2.3.3 Surgical Quality andAccuracy
Sagacious selection of CAD-CAM and, especially, CAM methods for the working material or efcient system can promote conduction of surgical phase. The
yielded results are more prone to be high-quality, accurate, and similar to the
preplanned predicted outcomes. Upon successful performance, CAD-CAMfabricated PSIs can sufciently help with homogenous bone formation and preservation of protected healing space. Later on, this leads to a sufcient bed for
implant placement, not only in best anatomical position but also according to the
opposing dentition.
2.3.4 Postoperative Period
The postoperative duration and healing period can benet from CAD-CAM-based
in situ bone regeneration, in terms of feasible and relatively promoted rigidity of
PSIs. Of note, commercial exible titanium meshes come in 0.1-, 0.2-, or 0.3-mm
thicknesses and are less rigid and able to xate the lling bone substitute material
or preserve the healing space [26, 27, 33].
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2.4 Complications
2.4.1 Potential Complications After Applying InSitu Bone
Regeneration PSIs
Wound Dehiscence andPSI Exposure
Wound dehiscence and PSI exposure are most documented complications occurring
after in situ bone regeneration [5, 10, 13, 26, 34]. Dehiscence is not always clinically presented with thorough PSI exposure. It can occur partially and be restricted
to shimmering of PDI through a thinned overlying mucosa [35]. PSI exposure may
occur intraorally or in orbital fossa [15, 18].
Dehiscence can result in impeded bone ll and/or failed graft consolidation with
minimal chances. In addition, it can necessitate compensative adjustments in terms
of selection of implant types and placement specics. PSI exposure can also dictate
secondary regeneration [5, 8–10, 13, 27, 32, 34, 36].
Higher risk of PSI exposure can be associated with extended preoperative resorption, beyond 9cm extension of mandibular defect passing the midline, impaired
tissue healing following adjuvant radiotherapy, and inevitable coupled resection of
bony segments and their overlying soft tissue [8, 15, 18, 26]. However, certain
parameters may be associated with elevated risks of PSI exposure: for instance,
patient age, gender, presence of multiple isolated defects, tobacco abuse, simultaneous grafting and sinus lifting procedures, autologous grafts’ donor site, mesiodistal
defect dimension, and surgical specics (i.e., PSI size, ap design, defect location)
[8, 34, 37, 38].
Wound dehiscence and PSI exposure can be accompanied by infection and graft
loss. Dehiscence-associated infection holds a low incidence. However, it can highly
impede alveolar regeneration. Poorly handled PSI exposure can result in bacterial
contamination, infection, and impaired PSI/membrane integrity, leading to ingrowth
of soft tissue and up to 74% decrease in bone ll. If local and systemic antibiotics
administration does not successfully inhibit dehiscence-associated infection, PSI
and graft removal is aimed for [8, 39, 40]. On the other hand, the other way around
is also possible, meaning infection in the recipient site can be followed by subsequent PSI exposure [36]. Regarding graft loss, the bone substitute material can be
lost mostly partially or at times, completely. PSI exposure and the amount of lost
bone substitute material are signicantly related [8].
Histological evaluation of mucosa around a dehiscence area demonstrated three
prominent ndings: (a) immersed biomaterial blocks in connective tissue, (b) a concentrated population of elongated broblast-like cells, and (c) scattered presence of
inammatory cells. These cues can conrm the ingrowth of soft tissue between PSI
and de novo bone [9]. Wound re-epithelization in exposed regions can curb risk of
dehiscence-associated infection; however, the anticipated rates of regeneration
might not be attained [9, 13, 32, 41].
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Transient Paresthesia
Following the application of CAD-CAM-fabricated PSIs, a transient paresthesia of
adjacent nerve branches may take place. The paresthesia may involve mental, infraorbital, or inferior alveolar bundles and is often resolved over 4–52weeks postoperation [8, 36].
Postoperative Deviation andNonoptimal Reproducibility
Deviated treatment outcomes are most likely presented in the orbital oor and alveolar process. Other in situ regenerated bony regions hold a below 2 mm risk of
deviation with a generally acceptable chance of reproducibility. However, soft tissue holds a mean 2.9mm error. Postoperative outcome deviation with PSIs can be
attributed to erroneous performance of multi-staged computer-assisted surgical trajectory. For instance, preoperative designing, CAM procedure, or even the thickness
of implemented PSI can contribute to deviation from preplanned treatment results
[15, 17] (Fig.6).
2.4.2 Regenerative Rates After Complications
An uneventful postoperative healing process holds a higher mean of regenerative
rates comparing to patients who have dealt with one or more complications during
their healing period. While the former has an 82.6±17.9% bone regeneration rate,
the latter meets anticipated rates up to 64.2±22.5% [36].
Infection
Wound Dehiscence
&
PSI Exposure
Dehiscence-Associated Graft Loss
Transient Paresthesia
Hard Tissue
Potential Complications After In Situ Bone Regeneration
Post-Operative Deviation
Non-Optimal Reproducibility
&
Soft Tissue
Fig. 6 Potential complications after in situ bone regeneration
Dehiscence-Associated Infection
Dehiscence After Infection
Partial
Complete
Mental, Infra-Orbital & Inferior Alveolar Nerve
Orbital Floor & Alveolar Process:
> 2 mm
Other Regions:
< 2, mm
Mean 2.9 mm
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2.4.3 How toPrevent Complications After Applying InSitu Bone
Regeneration PSIs
Hartmann etal. reported a signicant decrease in PSI exposure when A®-plateletrich brin (PRF) is applied along with their customized meshes [34]. In addition,
the mechanical strength and permeability of PSIs can be optimized through customized designing of PSI congurative specics. This enables PSIs to withstand
the occlusal loads, xate better, and effectively preserve the healing space for
uneventful vascularization and regeneration. Further studies regarding ways to
provide preventive stress-shielding, select optimized PSI material, and assess the
long-term performance of implanted CAD-CAM-fabricated PSIs are warranted [19].
3 Recipient Site Characteristics
Bone formation within the recipient site largely depends on its regenerative
potential. Since different anatomical locations differ in terms of vascularization,
bone quality, alveolar ridge morphology, etc., their regeneration potential can
alter accordingly. This accentuates the importance of homogeneous compared
with the regenerative outcomes based on anatomic location [42]. A signicant
inverse correlation exists between bone gain and alveolar process; namely, the
thinner the alveolar process at baseline, the higher the bone gain rate. Resemblance
of resorptive patterns and natural anatomy of original ridge may be a possible
reason [43].
3.1 Enhancing Regenerative Potential ofRecipient Site
Effective recruitment of host stem and/or progenitor cells within the protected
healing space, along with induction of inltrated cells toward osteogenic lineage,
determines in situ bone regeneration outcomes [1, 3]. Sustained delivery of apt
biological and signaling cues provides host cells with a feasible environment to
form new bone tissue [4]. Stem cells can be innately attracted and lodged onto
site using chemoattractant materials [44, 45]. This process was primarily
described for hematopoietic stem cells, migrating from peripheral bone ow
toward the bone marrow. Further thriving of hematopoietic stem cells is dependent upon niches that support their stemness, function, and proliferation of cells
[44, 46, 47]. In this light, manipulated regulation and/or delivery of certain substances could result in boosted regeneration capacities of defect site, in terms of
host stem cell lodging and regeneration [45, 48–51]. An interesting strategy
would be the downregulation of heme-oxyganse-1, an intracellular enzyme. This
enzyme has recently been found to be a negative regulator of stem cell migration [52].
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3.2 Clinical Applications
3.2.1 RhPDGF-BB
Platelet-derived growth factor (PDGF) is a well-characterized mediator that
enhances bone and soft tissue regeneration. It can induce cell growth, bone metabolism, and angiogenesis [53]. RhPDGF-BB has been used for 3D ridge augmentation. De Angelis and colleagues employed titanium mesh lled with a mixture of
rhPDGF-BB and anorganic bovine bone particles for vertical ridge augmentation
[54]. Similarly, Funato etal. placed titanium meshes lled with a mixture of rhPDGF- BB, autogenous bone, and organic bovine bone particles, covered with an
overlying collagen membrane The mean vertically augmented bone height was
8.6±4.0mm [55].
3.2.2 RhBMP-2
Recombinant human bone morphogenic protein 2 (rhBMP-2) plays a prime role
in modulation and differentiation of mesenchymal cells into osteoblasts [56, 57].
In 2007, the Food and Drug Administration (FDA) approved the clinical application of rhBMP-2in sinus lifting procedures and augmentation of localized ridge
defects [57]. De Freitas etal. compared rhBMP-2-rich absorbable collagen sponge
(ACS) versus autogenous bone graft for horizontal augmentation in reconstruction of atrophic ridges. Horizontal bone gain was inspected to be signicantly
higher with rhBMP-2/ACS group. In addition, rhBMP-2/ACS biopsies histologically demonstrated formation of de novo woven and lamellar bone tissue, with
bone marrow rich in cells and blood vessel buddings. Enhanced rhBMP-2/ACSassociated bone formation was also conrmed by gene expression [58]. Alraei
et al. reconstructed an extended maxillary bone defect, using a mixture of
rhBMP-2/ACS, bone marrow aspirate concentrate (BMAC), and allograft, placed
in a titanium mesh covered in platelet-rich brin (PRF). Follow-up of 3 years after
bone augmentation and implant placement revealed a satisfactory quantity of
bone around the implants [59].
3.2.3 PRF
Application of an autologous blood concentrate system, the so-called platelet-rich
brin (PRF), is a promising technique for enhancing the regenerative capacity of
bone substitute materials. PRF is attained through centrifuging a patient’s own
peripheral blood, to eliminate additional anticoagulants and achieve solid and uid
PRF-matrices [60]. PRF-treated osteoblasts and broblasts have shown signicantly enhanced cell proliferation, migration, and metabolic activity [61, 62].
Ghanaati etal. aimed for open healing, using combined solid and liquid PRF and
particulate bone substitute materials with no autologous bone and CAD-CAMfabricated titanium meshes for 3D augmentation [63]. PRF tends to release growth
factors (e.g., EGF, PDGF, TGF, EGF) in high concentrations. Post-operation histologic evaluation of augmented bone specimen at month 7 revealed the presence of
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relatively wide osteocyte lacunae and abundant population of osteocytes, indicative
of active new bone formation and remodeling. Moreover, inspection of a highly
vascularized, cell-abundant, and non-mineralized tissue revealed potential mineralization, developing into bone tissue over time.
H. S. H. Boroojeni et al.
3.3 Potential Methods
3.3.1 Antibody-Mediated Osseous Regeneration (AMOR)
Despite the positive osteogenic impacts of recombinant growth factors clinical
administration (e.g., rhBMP2), alternative solutions are sought due to certain drawbacks (i.e., the optimal clinical dosage must be orders of magnitude larger than
physiologic concentrations, leading to an increased risk of malignancy and fatal
edema) [50, 64–68]. Among alternative approaches, application of monoclonal antibodies (mAbs) has led to the advent of antibody-mediated osseous regeneration
(AMOR) [69]. According to Khojasteh etal., the local administration of chimeric
anti-BMP-2 monoclonal antibody-functionalized anorganic bovine bone mineral
with 10% collagen (ABBM-C) yielded a comparable bone density and osteoid formation to the rhBMP2 group upon 12 weeks. Moreover, histological evaluations
revealed no signicant signs of inammation or other adverse reactions in the
regenerated bone specimen [70].
Expression of CD271 (p75NTR) antigen takes place in human bone marrow
cells and tends to continue despite further culturing with no growth factor stimulation invitro [71]. CD271+ cells sorted by the CD271 antibody had high differentiation potential for osteogenic precursor cells [72, 73]. These ndings lead to the
conclusion that CD271+ cells act similarly to the human bone marrow-derived mesenchymal stem cells (BM-MSCs). Moreover, CD271 antigen also plays an important role in cell migration [74, 75]. Therefore, Sun etal. showed that the CD271
antibody could benet recruiting BM-MSCs for in situ bone regeneration [76].
3.3.2 Bioactive Molecules
Stromal cell-derived factor-1α (SDF-1α), also known as CXCL12, is a stem cell
homing factor that is present in immature osteoblasts and endothelial cells in bone
marrow [77]. Delivery of SDF-1α can increase the local recruitment of stem cell
populations, both MSCs and HSCs, to the recipient site of scaffold implantation.
SDF-1α treatment also tends to inhibit mast cell degranulation, resulting in signicant downstream alterations in inammatory and brotic responses [78].
Substance P, an 11-amino-acid peptide and a nociceptive factor that functions as
a neuromodulator and neurotransmitter, locally and systemically contributes in
reparative neovascularization [79]. SP can dose-dependently stimulate cell proliferation, osteoblastic function and differentiation, and bone formation in vitro.
Moreover, SP facilitated osteoclastic function of isolated bone marrow macrophages
and bone resorptive activity of mature osteoclasts [80]. In mural models, SP has
demonstrated induction of MSCs recruitment to ischemic sites and effective regeneration without exogenous cell injection [81].
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