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Table 17.1 Comparison of cortical cancellous graft (autogenous), tissue engineering
(rhBMP-2+allogeneic bone),and free bula microvascular reconstruction
Fig. 17.2 Large tissueengineered graft in
particulate form condensed
into post-ablative defect
J. S. Marschall et al.
Tissue engineering can eliminate donor site morbidity, reduce operating times
and overall costs, and return patients back to their work and families sooner. As
stated above, the cornerstone of tissue engineering is delivering cells, growth factors, and a scaffold to regenerate a target tissue. Current methods of maxillofacial
tissue engineering have been referred to as “in situ tissue engineering” (Figs.17.2,
17.3, 17.4, 17.5, and 17.6) [7]. Currently, clinicians can access autogenous stem and
progenitor cells via bone marrow aspirate concentrate (BMAC). BMAC is obtained
at the point of care and can yield a clinically signicant amount of mesenchymal
stem cells (MSCs) and osteoprogenitor cells (OPCs) [38]. Combined with an immediate centrifugation method, the percentage of MSCs can be exponentially increased
[39]. Another important component to the tissue engineering triangle is the scaffold.
Particulate allogeneic bone can be utilized as a biological scaffold. Lastly, rhBMP-2
is used to provide the required cellular signals to promote tissue (i.e., bone)
17 Tissue Engineering inMaxillofacial Reconstruction: Past, Present, andFuture
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Fig. 17.3 Immediate reconstruction with tissue-engineered grafts are reliable and predicable with
proper surgical technique and most importantly adequate soft tissue coverage
regeneration [40]. Using this composite tissue-engineered grafting method, Melville
etal. demonstrated success in 30 of 34 patients with large mandibular continuity
defects [7]. The synergistic relationship between BMAC and rhBMP-2 has been
studied at the histologic level [41]. Using animal models, Egashria etal. showed
that the use of BMAC will accelerate the bone formation rate in the early transplantation phase when rhBMP-2 has been used concurrently and will allow for a reduction of the rhBMP-2 dosage [41].
Although the free bula ap is an excellent option for composite, hemi/complete
mandibular defects or patients who have been radiated, donor site morbidity and the
cost of the procedure should be considered. A retrospective, multicenter study
reported mean hospital charges and duration for 42 patients who received a bula
free ap of $140,747 and 10.5days, respectively [42]. The advantages of in situ
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J. S. Marschall et al.
Fig. 17.4 Tissue-engineered grafts are excellent for reconstruction of nature shape and contours
of the mandible. Ideal shape and dimensions are propagated by masticatory muscle attachment and
function
tissue engineering composite graft are severalfold; rst, there is much lower morbidity especially when compared to free ap harvest. Furthermore, there are lower
healthcare costs and proven surgical efciency [7].
The Cells
The specics of in situ tissue engineering for mandibular reconstruction have been
worked out to predictably regenerate genetically normal human bone that matures
and remodels as do other parts of the skeleton. The cells are derived from a bone
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Fig. 17.5 Excellent regeneration of mandible with secondary grafting. Size and shape of mandibular regeneration is 100% on soft tissue bed
marrow aspirate (BMA) that has in the past been centrifuged to concentrate the
osteoprogenitor cells (OPCs) and mesenchymal stem cells (MSC). However,
recent studies have identied a 20% or greater death rate of OPC and MSC due to
the g-forces of centrifugation. Today, the preferred bone marrow harvesting devices
do not use centrifugation and those with exible cannulas produce the higher
yields of OPC/MSC as shown by cultured explants referred to as colony-forming
units- broblast- like (CFU-f). Such higher yields of stem cells have been shown to
regenerate bone faster and produce more bone and bone with a greater mineral
content. Therefore, yields of CD34+ cells should be on the order of 330×103cells/
mL and grow 3000 or more viable bone-producing cells documented by CFU-f
(Table17.2).
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J. S. Marschall et al.
Fig. 17.6 Osteoradionecrosis patient with multiple failed salvage surgeries. Successfully reconstructed with anterior lateral thigh free ap and tissue-engineered graft. By optimizing biology, we
expect once difcult cases to become routine and predictable
Table 17.2 Stem cell counts
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The Signal
The signal is a recombinant human bone morphogenetic protein-2/acellular collagen sponge (rhBMP-2/ACS Infuse Bone Graft® Medtronic). The dose of rhBMP-2/
ACS has been determined to be 1mg/1cm length of mandibular bony continuity
defect. The rhBMP-2/ACS acts over the rst 21days of the graft with its greatest
activity being within the rst 14days. As a specic bone morphogen, it will induce
the required proliferation of the OPC/MSCs in the BMA and their differentiation
and actual bone production. By day 21, the rhBMP-2/ACS has been used and is no
longer present. However, osteoid and a complete revascularization of the graft have
occurred. The graft now goes into a self-remodeling cycle toward maturity, which
can be seen radiographically as a consolidation.
The Matrix
The matrix is a cancellous freeze-dried mineralized allogeneic bone, with a particle
size of 100–300 μm. The matrix also includes the proteins in the bone marrow
plasma, brin, bronectin, and vitronectin, as well as the exosomes in the bone marrow plasma released by the OPC/MSCs prior to harvesting. One such exosomal
protein, stromal-derived activation factor 1-alpha (SDAF1-alpha), is a critical support protein for stem cells.
The proteins in the bone marrow plasma connect and bind the allogeneic bone
particles together. It is on this surface that the new bone will regenerate and fuse
together with adjacent niduses of bone formation that are recognized radiographically as the graft consolidates and becomes more mineral dense. By the time of
maturity at 6months, the graft can receive dental implants with good primary stability. At that time, all the allogeneic bone particles have been resorbed and replaced
by the patient’s own bone. The bone is all the patient’s own bone. It will osseointegrate implants, it will heal, it will respond to orthodontic tooth movement, and it
will grow normally in growing children without overgrowth or undergrowth.
During composite resection of the mandible (and other areas of the facial skeleton), the bone, soft tissue, nerve, and teeth are removed. Recently, nerve allografts
have become available, which have demonstrated excellent results [43]. However, if
a patient wishes to have complete reconstruction and dental rehabilitation completed in a single surgery, currently, the only option is the “Jaw-in-a-Day” procedure.
Future Methods ofMaxillofacial Tissue Engineering
The future of maxillofacial tissue engineering and bone regeneration has been centered around several areas: rst, 3D printing of bioactive scaffolds to provide tailored osteoconduction [44] and second the delivery of specic bioactive molecules
from materials [16].
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Over the last decade, the geometric design of implants on several orders of magnitude has been demonstrated to play a profound role on osteoconduction and ultimately bone healing [45]. The original studies were completed with metallic
implants. More recently, these principles have been translated to biomolecules that
are much more osteogenic such as calcium phosphate-based bioactive ceramics
[46]. Usually calcium phosphate-based bio-ceramics are powder based. The advent
of 3D printing has led to the development of personalized scaffolds by using CAD/
CAM methods. Promising data is being developed utilizing 3D-printed bioactive
β-tricalcium phosphate scaffolds that selectively stimulate A2AR receptors. Another
area of future development is the use of layer-by-layer deposition of robotic printed
hydrogels and cells with precise position of growth factor presenting matrices and
microtissues [16]. For example, a custom-tailored material could selectively release
the factors required for ideal bone healing, that is, migration-inducing growth factors, proliferation-inducing growth factors, and lastly, differentiation-inducing
growth factors (Fig.17.6) [16].
Conclusion
Maxillomandibular reconstruction is a controversial and essential component to
craniomaxillofacial surgery. The basic and clinical science behind reconstruction of
ablative and traumatic defects has progressed considerably. Progenitor and stem cell
use in in situ tissue engineering today is in its infancy. For now, bone regeneration
has led the way. The next horizon is cartilage, which is already underway with intrajoint injections of stem cells. The skin and oral mucosa are very doable but are only
at the beginning stages. Teeth and major organs (i.e., kidney, liver, and heart) are a
very long way off in the future due to the complexity of these organs. Treatment of
stroke through intraarterial stem cell injections and even intravenous injections for
lung congestion in COVID cases has shown signicant benet in a few cases.
However, FDA and their governmental restrictions limit its expansion.
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Chapter 18
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The New Norm: Examining Quality ofLife
withTrigeminal Nerve Decits andNew
Standards ofNerve Repair—A Systematic
Review andMeta-analysis
VictoriaA.Manon, HuyQ.Tran, RamzeyTursun, PauloG.Coelho ,
LukaszWitek, MarkE.Wong, SimonYoung , andJamesC.Melville
V. A. Manon · H. Q. Tran
Bernard and Gloria P.Katz Department of Oral and Maxillofacial Surgery, University of
Texas Health Science Center at Houston, Houston, TX, USA
e-mail: victoria.a.manon@uth.tmc.edu; huy.q.tran@uth.tmc.edu
R. Tursun
Clinical Surgery, University of Miami, Miami, FL, USA
Oral, Head & Neck Oncologic, University of Miami, Miami, FL, USA
Microvascular Reconstructive Surgery, University of Miami, Miami, FL, USA
Division of Oral Maxillofacial Surgery, DeWitt Daughtry Family Department of Surgery,
Leonard M.Miller School of Medicine, University of Miami, Miami, FL, USA
Security Forces Hospital, Riyad, Saudi Arabia
P. G. Coelho
School of Medicine, New York University, New York, NY, USA
e-mail: pc92@nyu.edu
L. Witek
Department of Biomaterials and Biomimetics, New York University College of Dentistry,
New York, NY, USA
Department of Biomedical Engineering, New York University Tandon School of Engineering,
New York, NY, USA
Craniomaxillofacial Orthopaedic Biomaterials Regenerative Applications Lab, New York, NY, USA
e-mail: lw901@nyu.edu
M. E. Wong
Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Texas
Health Science Center at Houston, Houston, TX, USA
e-mail: Mark.E.Wong@uth.tmc.edu
S. Young · J. C. Melville (*)
Department of Oral and Maxillofacial Surgery, The University of Texas Health Science
Center at Houston, Houston, TX, USA
e-mail: Simon.Young@uth.tmc.edu; James.C.Melville@uth.tmc.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
J. C. Melville et al. (eds.), Advancements and Innovations in OMFS, ENT, and
Facial Plastic Surgery, https://doi.org/10.1007/978-3-031-32099-6_18
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