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1.  Mandibular reconstruction using an axially vascularized tissue-engineered construct 
Background
Current reconstructive techniques for continuity defects of the mandible include the use of free flaps, bone grafts, and alloplastic materials. New methods of regenerative medicine designed to restore tissues depend mainly on the so-called extrinsic neovascularization, where the neovascular bed originates from the periphery of the construct. This method is not applicable for large defects in irradiated fields.
Methods
We are introducing a new animal model for mandibular reconstruction using intrinsic axial vascularization by the Arterio-Venous (AV) loop. In order to test this model, we made cadaveric, mechanical loading, and surgical pilot studies on adult male goats. The cadaveric study aimed at defining the best vascular axis to be used in creating the AV loop in the mandibular region. Mechanical loading studies (3 points bending test) were done to ensure that the mechanical properties of the mandible were significantly affected by the designed defect, and to put a base line for further mechanical testing after bone regeneration. A pilot surgical study was done to ensure smooth operative and post operative procedures.
Results
The best vascular axis to reconstruct defects in the posterior half of the mandible is the facial artery (average length 32.5 ± 1.9 mm, caliber 2.5 mm), and facial vein (average length 33.3 ± 1.8 mm, caliber 2.6 mm). Defects in the anterior half require an additional venous graft. The defect was shown to be significantly affecting the mechanical properties of the mandible (P value 0.0204). The animal was able to feed on soft diet from the 3rd postoperative day and returned to normal diet within a week. The mandible did not break during the period of follow up (2 months).
Conclusions
Our model introduces the concept of axial vascularization of mandibular constructs. This model can be used to assess bone regeneration for large bony defects in irradiated fields. This is the first study to introduce the concept of axial vascularization using the AV loop for angiogenesis in the mandibular region. Moreover, this is the first study aiming at axial vascularization of synthetic tissue engineering constructs at the site of the defect without any need for tissue transfer (in contrast to what was done previously in prefabricated flaps).
doi:10.1186/1750-1164-5-2
PMCID: PMC3069948  PMID: 21418603
2.  GMP-level adipose stem cells combined with computer-aided manufacturing to reconstruct mandibular ameloblastoma resection defects: Experience with three cases 
Annals of Maxillofacial Surgery  2013;3(2):114-125.
Background:
The current management of large mandibular resection defects involves harvesting of autogenous bone grafts and repeated bending of generic reconstruction plates. However, the major disadvantage of harvesting large autogenous bone grafts is donor site morbidity and the major drawback of repeated reconstruction plate bending is plate fracture and difficulty in reproducing complex facial contours. The aim of this study was to describe reconstruction of three mandibular ameloblastoma resection defects using tissue engineered constructs of beta-tricalcium phosphate (β-TCP) granules, recombinant human bone morphogenetic protein-2 (rhBMP-2), and Good Manufacturing Practice (GMP) level autologous adipose stem cells (ASCs) with progressively increasing usage of computer-aided manufacturing (CAM) technology.
Materials and Methods:
Patients’ three-dimensional (3D) images were used in three consecutive patients to plan and reverse-engineer patient-specific saw guides and reconstruction plates using computer-aided additive manufacturing. Adipose tissue was harvested from the anterior abdominal walls of three patients before resection. ASCs were expanded ex vivo over 3 weeks and seeded onto a β-TCP scaffold with rhBMP-2. Constructs were implanted into patient resection defects together with rapid prototyped reconstruction plates.
Results:
All three cases used one step in situ bone formation without the need for an ectopic bone formation step or vascularized flaps. In two of the three patients, dental implants were placed 10 and 14 months following reconstruction, allowing harvesting of bone cores from the regenerated mandibular defects. Histological examination and in vitro analysis of cell viability and cell surface markers were performed and prosthodontic rehabilitation was completed.
Discussion:
Constructs with ASCs, β-TCP scaffolds, and rhBMP-2 can be used to reconstruct a variety of large mandibular defects, together with rapid prototyped reconstruction hardware which supports placement of dental implants.
doi:10.4103/2231-0746.119216
PMCID: PMC3814659  PMID: 24205470
Adipose-derived stem cells; beta-tricalcium phosphate; bone morphogenetic protein; computer-aided design
3.  Tissue engineering of bone: the reconstructive surgeon's point of view 
Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an “interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function”. It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of largevolume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone-tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.
doi:10.1111/j.1582-4934.2006.tb00287.x
PMCID: PMC3933098  PMID: 16563218
tissue engineering; bone replacement; vascularization; flap prefabrication; microsurgery; AV loop
4.  Inferiorly based buccinator myomucosal island flap in oral and pharyngeal reconstruction. Four techniques to increase its application 
Graphical abstract
Axial view of the cheek at the level of upper lip showing the layers included in the flap. Small part of orbicularis muscle, partial fibers of buccinator muscle, facial artery and vein are compositions of this flap. Buccopharyngeal fascia separates the buccal fat pad () from the buccinator muscle.
Highlights
•We introduced a literature review on the inferiorly based buccinator myomucosal flap.•With four cases, all possible applications for this flap in oral and oropharyngeal reconstruction are explained.•Indications, limitations and considerations for this flap are explained.•Surgical technique, the ways for reducing donor site morbidity and who to increase pedicle length is demonstrated.
Introduction
Reconstruction of oral and pharyngeal defects after pathologic resections with the same tissue is an optimal and ideal target. Islanded variety of inferiorly pedicled facial artery musculomucosal flap, in which facial artery and vein are skeletonized (referred to as inferiorly based BUMIF), is suitable for reconstruction of medium-sized mucosal defects.
Presentation of cases
In this article, with four cases, modifications of this flap are demonstrated in reconstruction of large intraoral and oropharyngeal defects and coverage of alveolar ridge in the mandible.
Discussion
In some situations, there is a need for more mucosal paddle, longer vascular pedicle and more adaptation to the recipient bed.
Conclusion
Relocating Stensen’s duct increases the mucosal paddle with cranial extension of superior limit while differential incision of the mucosa and buccinator muscle in mandibular vestibule extend the lower limit of this flap. Bone suture is a good complementary technique when this flap is used for coverage of mandibular alveolar ridge. Inferiorly based BUMIF with added length is indicated for oropharyngeal and contralateral mouth floor reconstructions.
doi:10.1016/j.ijscr.2015.06.025
PMCID: PMC4573210  PMID: 26218177
Buccinator flap; Facial artery; Oral cavity reconstruction; Oropharyngeal reconstruction
5.  Mandibular Reconstruction Using the Free Vascularized Fibula Graft: An Overview of Different Modifications 
Archives of Plastic Surgery  2016;43(1):3-9.
The reconstruction of the mandible is a complex procedure because various cosmetic as well as functional challenges must be addressed, including mastication and oral competence. Many surgical techniques have been described to address these challenges, including non-vascularized bone grafts, vascularized bone grafts, and approaches related to tissue engineering. This review summarizes different modifications of the free vascularized fibula graft, which, since its introduction by Hidalgo in 1989, has become the first option for mandibular reconstruction. The fibula free flap can undergo various modifications according to the individual requirements of a particular reconstruction. Osteocutaneous flaps can be harvested for reconstruction of composite defects. 'Double-barreling' of the fibula can, for instance, enable enhanced aesthetic and functional results, as well as immediate one-stage osseointegrated dental implantation. Recently described preoperative virtual surgery planning to facilitate neomandible remodeling could guarantee good results. To conclude, the free fibula bone graft can currently be regarded as the "gold standard" for mandibular reconstruction in case of composite (inside and outside) oral cavity defects as well as a way of enabling the performance of one-stage dental implantation.
doi:10.5999/aps.2016.43.1.3
PMCID: PMC4738125  PMID: 26848439
Mandibular reconstruction; Fibula; Microsurgery
6.  Anatomic basis for an algorithmic approach for free fibula flap donor side selection in composite oro-mandibular defects 
Introduction:
Head and neck oncological resections may result in composite oro-mandibular defects involving the oral mucosa (lining), mandibular bone and the skin (cover). Reconstructive options for such defects have evolved over a period. Free fibula flap reconstruction is currently accepted the world over as the gold standard for oro-mandibular defect reconstruction. Existing literature provides conflicting views about the use of a particular side and orientation of the fibula flap for achieving the optimal outcome. The purpose of this study is to confirm anatomically the effect of bone, soft tissue and vessel orientation on the ease of doing reconstruction.
Materials and Methods:
This is a cadaveric study. A mandibular model with a defect was used. This was pre plated to maintain continuity. Composite fibula flaps of the same dimension were harvested from both legs of a fresh cadaver. The harvested flaps were used to reconstruct the mandibular defect in different orientations and the best configuration for each reconstructive requirement was assessed.
Results:
Keeping the peroneal surface for plating, that is, facing outwards, four different configurations of the fibula flap are possible for a given mandibular defect. With a posterior vascular pedicle ipsilateral fibula is suitable for skin cover and contralateral for mucosal lining and the reverse for an anteriorly placed pedicle.
Conclusion:
The algorithm based selection of appropriate sided fibula flap facilitates complex mandibular reconstruction by placing the right kind of tissue at the right place and helps in reducing the donor site morbidity by allowing the surgeon to harvest only the required amount of skin.
doi:10.4103/0970-0358.155268
PMCID: PMC4413489  PMID: 25991885
Free fibula flap; ideal side of fibula; mandibular reconstruction
7.  Engineering of pre-vascularized urethral patch with muscle flaps and hypoxia-activated hUCMSCs improves its therapeutic outcome 
Tissue engineering has brought new hopes for urethral reconstruction. However, the absence of pre-vascularization and the subsequent degradation of materials often lead to the failure of in vivo application. In this study, with the assistance of hypoxia-activated human umbilical cord mesenchymal stem cells (hUCMSCs), pedicled muscle flaps were used as materials and pre-incubated in ventral penile subcutaneous cavity of rabbit for 3 weeks to prepare a pre-vascularized urethral construct. We found that small vessels and muscle fibres were scattered in the construct after 3 weeks' pre-incubation. The construct presented a fibrous reticular structure, which was similar to that of the corpus spongiosum under microscope examination. The produced constructs were then used as a patch graft for reconstruction of the defective rabbit urethra (experimental group), natural muscular patch was used as control (control group). Twelve weeks after the reconstructive surgery, urethrography and urethroscope inspections showed wide calibres of the reconstructed urethra in the experimental group. Histopathological studies revealed that fibrous connective tissues and abundant muscle fibres constituted the main body of the patch-grafted urethra. In contrast, in the control group, only adipose tissue was found in the stenosis-reconstructed urethra, replacing the originally grafted muscular tissue. To our knowledge, this is the first report that successfully constructed a pre-vascularized urethral construct by using hypoxia-activated hUCMSC and pedicled muscle flaps. More importantly, the pre-vascularized construct showed a good performance in urethral reconstruction when applied in vivo. The study provided a novel strategy for tissue engineering of pre-vascularized urethral construct for the defective urethra, representing a further advancement in urethral reconstruction.
doi:10.1111/jcmm.12157
PMCID: PMC3955150  PMID: 24460735
hUCMSC; tissue engineering; urethral reconstruction; pedicled muscle flaps
8.  Regenerative Approach to Bilateral Rostral Mandibular Reconstruction in a Case Series of Dogs 
Extensive rostral mandibulectomy in dogs typically results in instability of the mandibles that may lead to malocclusion, difficulty in prehension, mastication, and pain of the temporomandibular joint. Large rostral mandibular defects are challenging to reconstruct due to the complex geometry of this region. In order to restore mandibular continuity and stability following extensive rostral mandibulectomy, we developed a surgical technique using a combination of intraoral and extraoral approaches, a locking titanium plate, and a compression resistant matrix (CRM) infused with rhBMP-2. Furthermore, surgical planning that consisted of computed tomographic (CT) scanning and 3D model printing was utilized. We describe a regenerative surgical technique for immediate or delayed reconstruction of critical-size rostral mandibular defects in five dogs. Three dogs had healed with intact gingival covering over the mandibular defect and had immediate return to normal function and occlusion. Two dogs had the complication of focal plate exposure and dehiscence, which was corrected with mucosal flaps and suturing; these dogs have since healed with intact gingival covering over the mandibular defect. Mineralized tissue formation was palpated clinically within 2 weeks and solid bone formation within 3 months. CT findings at 6 months postoperatively demonstrated that the newly regenerated mandibular bone had increased in mineral volume with evidence of integration between the native bone, new bone, and CRM compared to the immediate postoperative CT. We conclude that rostral mandibular reconstruction using a regenerative approach provides an excellent solution for restoring mandibular continuity and preventing mandibular instability in dogs.
doi:10.3389/fvets.2015.00004
PMCID: PMC4672177  PMID: 26664933
mandible; reconstruction; bone morphogenetic proteins; 3D printing; regeneration; dog
9.  The Value of SPECT/CT in Monitoring Prefabricated Tissue-Engineered Bone and Orthotopic rhBMP-2 Implants for Mandibular Reconstruction 
PLoS ONE  2015;10(9):e0137167.
Bone tissue engineering shows good prospects for mandibular reconstruction. In recent studies, prefabricated tissue-engineered bone (PTEB) by recombinant human bone morphogenetic proteins (rhBMPs) applied in vivo has found to be an effective alternative for autologous bone grafts. However, the optimal time to transfer PTEB for mandibular reconstruction is still not elucidated. Thus, here in an animal experiment of rhesus monkey, the suitable transferring time for PTEB to reconstruct mandibular defects was evaluated by 99mTc-MDP SPECT/CT, and its value in monitoring orthotopic rhBMP-2 implants for mandibular reconstruction was also evaluated. The result of SPECT/CT showed higher 99mTc-MDP uptake, indicating osteoinductivity, in rhBMP-2 incorporated demineralized freeze-dried bone allograft (DFDBA) and coralline hydroxyapatite (CHA) implants than those without BMP stimulation. 99mTc-MDP uptake of rhBMP-2 implant peaked at 8 weeks following implantation while CT showed the density of these implants increased after 13 weeks’ prefabrication. Histology confirmed that mandibular defects were repaired successfully with PTEB or orthotopically rhBMP-2 incorporated CHA implants, in accordance with SPECT/CT findings. Collectively, data shows 99mTc-MDP SPECT/CT is a sensitive and noninvasive tool to monitor osteoinductivity and bone regeneration of PTEB and orthotopic implants. The PTEB achieved peak osteoinductivity and bone density at 8 to 13 weeks following ectopic implantation, which would serve as a recommendable time frame for its transfer to mandibular reconstruction.
doi:10.1371/journal.pone.0137167
PMCID: PMC4560383  PMID: 26340447
10.  Loss of apical vertebral derotation in adolescent idiopathic scoliosis: 2-year follow-up using multi-planar reconstruction computed tomography 
European Spine Journal  2012;21(6):1111-1120.
Purpose
The objective of this study was to evaluate 2 years post-surgical loss of three-dimensional correction in adolescent idiopathic scoliosis (AIS) patients using multi-planar reconstruction computed tomography (CT).
Methods
Twenty-seven AIS patients treated by segmental pedicle screw (PS) constructs were included in this study. Correction in the axial plane was evaluated using the “relative apical vertebral rotation angle” (rAVR), defined as the difference between the axial rotation angles of the upper instrumented vertebra and the apical vertebra on reconstructed axial CT images. The Cobb angle of the main curve and apical vertebral translation was measured to evaluate the coronal correction. Thoracic kyphosis was also measured for the evaluation of sagittal profile. Measurements were performed before surgery, and 1 week and 2 years after surgery. The relationships between the correction losses and skeletal maturity, and variety of spinal constructs were also evaluated.
Results
The mean preoperative Cobb angle of the major curve was 59.1° ± 11.2° before and 13.0° ± 7.2° immediately after surgery. Two years later, the mean Cobb angle had increased significantly, to 15.5° ± 7.8°, with a mean correction loss of 2.5° ± 1.5° (p < 0.001). The mean preoperative rAVR of 28.5° ± 8.4° was corrected to 15.8° ± 7.8° after surgery. It had increased significantly to 18.5 ± 8.4 by 2 years after surgery, with a mean correction loss of 2.7° ± 1.0° (p < 0.001). The mean correction losses for both the Cobb angle and rAVR were significantly greater in the skeletally immature patients. The significant correlations were recognized between the correction losses and the proportion of multi-axial screws, and the materials of constructs.
Conclusions
Statistically significant loss of correction in the Cobb angle and apical vertebral axial rotation angle (AVR) were recognized 2 years after surgery using PS constructs. The correction losses, especially AVR, were more evident in the skeletally immature patients, and in patients treated with more multi-axial screws and with titanium constructs rather than with stainless constructs.
doi:10.1007/s00586-012-2274-3
PMCID: PMC3366141  PMID: 22438165
Adolescent idiopathic scoliosis; Apical vertebral rotation; Correction loss; Coronal correction
11.  The Nature and Role of Periosteum in Bone and Cartilage Regeneration 
Cells, Tissues, Organs  2011;194(2-4):320-325.
This study was undertaken to determine whether periosteum from different bone sources in a donor results in the same formation of bone and cartilage. In this case, periosteum obtained from the cranium and mandible (examples of tissue supporting intramembranous ossification) and the radius and ilium (examples of tissues supporting endochondral ossification) of individual calves was used to produce tissue-engineered constructs that were implanted in nude mice and then retrieved after 10 and 20 weeks. Specimens were compared in terms of their osteogenic and chondrogenic potential by radiography, histology, and gene expression levels. By 10 weeks of implantation and more so by 20 weeks, constructs with cranial periosteum had developed to the greatest extent, followed in order by ilium, radius, and mandible periosteum. All constructs, particularly with cranial tissue although minimally with mandibular periosteum, had mineralized by 10 weeks on radiography and stained for proteoglycans with safranin-O red (cranial tissue most intensely and mandibular tissue least intensely). Gene expression of type I collagen, type II collagen, runx2, and bone sialoprotein (BSP) was detectable on QRT-PCR for all specimens at 10 and 20 weeks. By 20 weeks, the relative gene levels were: type I collagen, ilium >> radial ≥ cranial ≥ mandibular; type II collagen, radial > ilium > cranial ≥ mandibular; runx2, cranial >>> radial > mandibular ≥ ilium; and BSP, ilium ≥ radial > cranial > mandibular. These data demonstrate that the osteogenic and chondrogenic capacity of the various constructs is not identical and depends on the periosteal source regardless of intramembranous or endochondral ossification. Based on these results, cranial and mandibular periosteal tissues appear to enhance bone formation most and least prominently, respectively. The appropriate periosteal choice for bone and cartilage tissue engineering and regeneration should be a function of its immediate application as well as other factors besides growth rate.
doi:10.1159/000324642
PMCID: PMC3178095  PMID: 21597269
Periosteum; Bone; Cartilage; Regeneration; Tissue engineering
12.  Prefabrication of 3D Cartilage Contructs: Towards a Tissue Engineered Auricle – A Model Tested in Rabbits 
PLoS ONE  2013;8(8):e71667.
The reconstruction of an auricle for congenital deformity or following trauma remains one of the greatest challenges in reconstructive surgery. Tissue-engineered (TE) three-dimensional (3D) cartilage constructs have proven to be a promising option, but problems remain with regard to cell vitality in large cell constructs. The supply of nutrients and oxygen is limited because cultured cartilage is not vascular integrated due to missing perichondrium. The consequence is necrosis and thus a loss of form stability. The micro-surgical implantation of an arteriovenous loop represents a reliable technology for neovascularization, and thus vascular integration, of three-dimensional (3D) cultivated cell constructs. Auricular cartilage biopsies were obtained from 15 rabbits and seeded in 3D scaffolds made from polycaprolactone-based polyurethane in the shape and size of a human auricle. These cartilage cell constructs were implanted subcutaneously into a skin flap (15×8 cm) and neovascularized by means of vascular loops implanted micro-surgically. They were then totally enhanced as 3D tissue and freely re-implanted in-situ through microsurgery. Neovascularization in the prefabricated flap and cultured cartilage construct was analyzed by microangiography. After explantation, the specimens were examined by histological and immunohistochemical methods. Cultivated 3D cartilage cell constructs with implanted vascular pedicle promoted the formation of engineered cartilaginous tissue within the scaffold in vivo. The auricles contained cartilage-specific extracellular matrix (ECM) components, such as GAGs and collagen even in the center oft the constructs. In contrast, in cultivated 3D cartilage cell constructs without vascular pedicle, ECM distribution was only detectable on the surface compared to constructs with vascular pedicle. We demonstrated, that the 3D flaps could be freely transplanted. On a microangiographic level it was evident that all the skin flaps and the implanted cultivated constructs were well neovascularized. The presented method is suggested as a promising alternative towards clinical application of engineered cartilaginous tissue for plastic and reconstructive surgery.
doi:10.1371/journal.pone.0071667
PMCID: PMC3739741  PMID: 23951215
13.  A two-year audit of non-vascularized iliac crest bone graft for mandibular reconstruction: technique, experience and challenges 
Objectives
Non-vascularized iliac crest bone graft (NVIBG) is a known treatment option in mandibular reconstruction following jaw resection, but no documented review of patients treated with NVIBG exists for northern Nigeria. The experience and technique from a Nigerian tertiary hospital may serve as baseline data for comparison and improvement of practice for other institutions.
Materials and Methods
A retrospective review of medical records and patient case files from January 2012 to December 2013 was undertaken. All case files and other medical records of patients who had reconstruction with NVIBG for benign or malignant lesions with immediate or delayed reconstruction were selected for review.
Results
Twenty patients had mandibular reconstruction with NVIBG during the study period. Two patients were excluded because of incomplete medical records. Eighteen patients' (male=14, female=4) records were reviewed. Their ages ranged from 13 to 62 years (mean 26.0±10.6 years). Indications for NVIBG included jaw tumors (n=16; 88.3%), jaw cyst (n=1; 5.6%) and gunshot injury (n=1; 5.6%). Jaw tumors seen were ameloblastoma (n=15; 83.3%) and osteosarcoma (n=1; 5.6%). Treatments done were mandibular resection with condylar resection (n=7; 38.9%), mandibular segmental resection (n=10; 55.6%) and subtotal mandibulectomy (n=1; 5.6%). Patients' postoperative reviews and radiographs revealed good facial profile and continued bone stability up to 1 year following NVIBG.
Conclusion
NVIBGs provide an acceptable alternative to vascularized bone grafts, genetically engineered bone, and distraction osteogenesis for mandibular reconstruction in resource-limited centers.
doi:10.5125/jkaoms.2014.40.6.272
PMCID: PMC4279977  PMID: 25551091
Mandibular resection; Mandibular reconstruction; Non-vascularized iliac crest bone graft
14.  Development of Scaffold-Free Elastic Cartilaginous Constructs with Structural Similarities to Auricular Cartilage 
Tissue Engineering. Part A  2014;20(5-6):1012-1026.
External ear reconstruction with autologous cartilage still remains one of the most difficult problems in the fields of plastic and reconstructive surgery. As the absence of tissue vascularization limits the ability to stimulate new tissue growth, relatively few surgical approaches are currently available (alloplastic implants or sculpted autologous cartilage grafts) to repair or reconstruct the auricle (or pinna) as a result of traumatic loss or congenital absence (e.g., microtia). Alternatively, tissue engineering can offer the potential to grow autogenous cartilage suitable for implantation. While tissue-engineered auricle cartilage constructs can be created, a substantial number of cells are required to generate sufficient quantities of tissue for reconstruction. Similarly, as routine cell expansion can elicit negative effects on chondrocyte function, we have developed an approach to generate large-sized engineered auricle constructs (≥3 cm2) directly from a small population of donor cells (20,000–40,000 cells/construct). Using rabbit donor cells, the developed bioreactor-cultivated constructs adopted structural-like characteristics similar to native auricular cartilage, including the development of distinct cartilaginous and perichondrium-like regions. Both alterations in media composition and seeding density had profound effects on the formation of engineered elastic tissue constructs in terms of cellularity, extracellular matrix accumulation, and tissue structure. Higher seeding densities and media containing sodium bicarbonate produced tissue constructs that were closer to the native tissue in terms of structure and composition. Future studies will be aimed at improving the accumulation of specific tissue constituents and determining the clinical effectiveness of this approach using a reconstructive animal model.
doi:10.1089/ten.tea.2013.0159
PMCID: PMC3938945  PMID: 24124666
15.  Guanylate-binding protein 1 expression from embryonal endothelial progenitor cells reduces blood vessel density and cellular apoptosis in an axially vascularised tissue-engineered construct 
BMC Biotechnology  2012;12:94.
Background
Guanylate binding protein-1 (GBP-1) is a large GTPase which is actively secreted by endothelial cells. It is a marker and intracellular inhibitor of endothelial cell proliferation, migration, and invasion. We previously demonstrated that stable expression of GBP-1 in murine endothelial progenitor cells (EPC) induces their premature differentiation and decreases their migration capacity in vitro and in vivo. The goal of the present study was to assess the antiangiogenic capacity of EPC expressing GBP-1 (GBP-1-EPC) and their impact on blood vessel formation in an axially vascularized 3-D bioartificial construct in vivo.
Results
Functional in vitro testing demonstrated a significant increase in VEGF secretion by GBP-1-EPC after induction of cell differentiation. Undifferentiated GBP-1-EPC, however, did not secrete increased levels of VEGF compared to undifferentiated control EPC expressing an empty vector (EV-EPC). In our In vivo experiments, we generated axially vascularized tissue-engineered 3-D constructs. The new vascular network arises from an arterio-venous loop (AVL) embedded in a fibrin matrix inside a separation chamber. Total surface area of the construct as calculated from cross sections was larger after transplantation of GBP-1-EPC compared to control EV-EPC. This indicated reduced formation of fibrovascular tissue and less resorption of fibrin matrix compared to constructs containing EV-EPC. Most notably, the ratio of blood vessel surface area over total construct surface area in construct cross sections was significantly reduced in the presence of GBP-1-EPC. This indicates a significant reduction of blood vessel density and thereby inhibition of blood vessel formation from the AVL constructs caused by GBP-1. In addition, GBP-1 expressed from EPC significantly reduced cell apoptosis compared to GBP-1-negative controls.
Conclusion
Transgenic EPC expressing the proinflammatory antiangiogenic GTPase GBP-1 can reduce blood vessel density and inhibit apoptosis in a developing bioartificial vascular network and may become a new powerful tool to manipulate angiogenetic processes in tissue engineering and other pathological conditions such as tumour angiogenesis.
doi:10.1186/1472-6750-12-94
PMCID: PMC3610105  PMID: 23217187
Angiogenesis; Endothelial progenitor cells; Guanylate-binding protein 1; In vivo tissue engineering
16.  Defining the critical-sized defect in a rat segmental mandibulectomy model 
Importance
Advances in tissue engineering offer potential alternatives to current mandibular reconstructive techniques; however, prior to clinical translation of this technology, a relevant animal model must be used to validate possible interventions.
Objective
This study aims to establish the critical-sized segmental mandibular defect that does not heal spontaneously in the rat mandible.
Design
Prospective study using an animal model.
Setting
Animal laboratory.
Participants
Sprague-Dawley rats.
Interventions
Twenty-nine Sprague-Dawley rats underwent creation of one of four segmental mandibular defects: 0-mm, 1-mm, 3-mm and 5-mm. All mandibular wounds were internally fixated with 1-mm microplates and screws and allowed to heal for 12-weeks.
Main Outcomes and Measures
Mandibles were analyzed with micro-computed tomography (microCT) and bony healing was graded on a semi-quantitative scale.
Results
Seven animals were utilized in each experimental group. No 5-mm segmental defects successfully developed bony union, whereas all 0-mm and 1-mm defects had continuous bony growth across the original defect on micro-CT. Three of the 3-mm defects had bony continuity, and three had no healing of the bony wound. Bony union scores were significantly lower in the 5-mm defects compared to 0-mm, 1-mm and 3-mm defects (all p < 0.01).
Conclusion and Relevance
The rat segmental mandible model cannot heal a 5-mm segmental mandibular defect. Successful healing of 0-, 1- and 3-mm defects confirms adequate stabilization of bony wounds with internal fixation with 1-mm microplates. The rat segmental mandibular critical-sized defect provides a clinically relevant testing ground for translatable mandibular tissue engineering efforts.
doi:10.1001/jamaoto.2013.5669
PMCID: PMC4343284  PMID: 24232293
Critical-sized defect; Craniofacial; Mandible; Tissue Engineering
17.  Efficacy of engineered FVIII-producing skeletal muscle enhanced by growth factor-releasing co-axial electrospun fibers 
Biomaterials  2010;32(6):1669-1677.
Co-axial electrospun fibers can offer both topographical and biochemical cues for tissue engineering applications. In this study, we demonstrate the sustained treatment of hemophilia through a non-viral, tissue engineering approach facilitated by growth factor-releasing co-axial electrospun fibers. FVIII-producing skeletal myotubes were first engineered on aligned electrospun fibers in vitro, followed by implantation in hemophilic mice with or without a layer of core-shell electrospun fibers designed to provide sustained delivery of angiogenic or lymphangiogenic growth factors, which serves to stimulate the lymphatic or vascular systems to enhance the FVIII transport from the implant site into systemic circulation. Upon subcutaneous implantation into hemophilic mice, the construct seamlessly integrated with the host tissue within one month, and specifically induced either vascular or lymphatic network infiltration in accordance with the growth factors released from the electrospun fibers. Engineered constructs that induced angiogenesis resulted in sustained elevation of plasma FVIII and significantly reduced blood coagulation time for at least two months. Biomaterials-assisted functional tissue engineering was shown in this study to offer protein replacement therapy for a genetic disorder such as hemophilia.
doi:10.1016/j.biomaterials.2010.10.049
PMCID: PMC3053058  PMID: 21084118
Hemophilia; skeletal muscle engineering; angiogenesis; lymphangiogenesis; electrospinning; protein replacement therapy
18.  Skin paddle vascularity of free fibula flap – A study of 386 cases and a classification based on contribution from axial vessels of the leg 
Objective:
The skin paddle of the free fibula flap receives its vascular supply from septocutaneous perforators, musculocutaneous perforators or from both, and these perforators might originate from the peroneal or posterior tibial vessels or from both. The objective of this study was to classify the skin paddles based on the dominance of vascular contribution by these axial vessels through their different perforator systems.
Materials and Methods:
A retrospective analysis of 5-year data of 386 free fibula flaps used in oro-mandibular reconstruction was done and the skin paddle vascularity was studied. While majority of the skin paddles received their blood supply from the peroneal septocutaneous perforators, a few had their dominant supply from the soleus musculocutaneous perforators in addition to peroneal septocutaneous perforators. In few cases, the soleus musculocutaneous perforators were the sole source of blood supply to the skin paddle. The limitation in this study was the inability to augment the clinical observation with cadaveric study.
Results:
The skin paddle of the free fibula flap was classified into four different types (a–d) based on the dominance of vascular contribution by axial vessels of the leg.
Conclusion:
The skin paddle of the free fibula flap has reliable blood supply, but a thorough knowledge of the variations in vascular pattern of the skin paddle is required especially to salvage the larger paddles used in the reconstruction complex oro-mandibular defects.
doi:10.4103/0970-0358.96586
PMCID: PMC3385400  PMID: 22754154
Free fibula flap; musculocutaneous perforators; septo cutaneous perforators; skin paddle; vascular supply
19.  Tissue-Engineered Mandibular Bone Reconstruction for Continuity Defects: A Systematic Approach to the Literature 
Background: Despite significant surgical advances over the last decades, segmental mandibular bone repair remains a challenge. In light of this, tissue engineering might offer a next step in the evolution of mandibular reconstruction.
Purpose: The purpose of the present report was to (1) systematically review preclinical in vivo as well as clinical literature regarding bone tissue engineering for mandibular continuity defects, and (2) to analyze their effectiveness.
Materials and Methods: An electronic search in the databases of the National Library of Medicine and ISI Web of Knowledge was carried out. Only publications in English were considered, and the search was broadened to animals and humans. Furthermore, the reference lists of related review articles and publications selected for inclusion in this review were systematically screened. Results of histology data and amount of bone bridging were chosen as primary outcome variables. However, for human reports, clinical radiographic evidence was accepted for defined primary outcome variable. The biomechanical properties, scaffold degradation, and clinical wound healing were selected as co-outcome variables.
Results: The electronic search in the databases of the National Library of Medicine and ISI Web of Knowledge resulted in the identification of 6727 and 5017 titles, respectively. Thereafter, title assessment and hand search resulted in 128 abstracts, 101 full-text articles, and 29 scientific papers reporting on animal experiments as well as 11 papers presenting human data on the subject of tissue-engineered reconstruction of mandibular continuity defects that could be included in the present review.
Conclusions: It was concluded that (1) published preclinical in vivo as well as clinical data are limited, and (2) tissue-engineered approaches demonstrate some clinical potential as an alternative to autogenous bone grafting.
doi:10.1089/ten.teb.2013.0131
PMCID: PMC3967381  PMID: 23865639
20.  Regenerating mandibular bone using rhBMP-2: part 2 – treatment of chronic, defect non-union fractures 
Veterinary surgery : VS  2014;44(4):410-416.
Objective
To describe a surgical technique utilizing a regenerative approach and internal fixation for reconstruction of critical size bone defect non-union mandibular fractures.
Study design
Case series
Animals
Dogs (n = 6) that had internal fixation of defect non-union mandibular fracture.
Methods
In 5 of the 6 cases the repair was staged and extraction of teeth performed during the first procedure. After 21-98 days (mean 27 days) a pharyngotomy intubation and temporary maxillomandibular fixation were performed. Using an extraoral approach, a locking titanium miniplate plate was contoured and secured. A compression resistant matrix (CRM) infused with rhBMP-2, was implanted in the defect. The implant was then covered with a soft tissue envelope followed by routine closure.
Results
All dogs had healed with intact gingival covering over the mandibular fracture site defect and had immediate return to normal function and correct occlusion. Hard-tissue formation was observed clinically within 2 weeks and solid cortical bone formation within 3 months. Computed tomographic findings in one case at 3 months postoperatively demonstrated that the newly regenerated mandibular bone had 92% of the bone density and porosity compared to the contralateral side. Long-term follow-up revealed excellent outcome.
Conclusion
Mandibular reconstruction using internal fixation and CRM infused with rhBMP-2 is an excellent solution for the treatment of critical size defect non-union fractures in dogs.
Clinical Relevance
In dogs with a mandibular critical size defect non-union fractures, reconstruction using rhBMP-2 and a CRM should be considered as a viable surgical option.
doi:10.1111/j.1532-950X.2014.12122.x
PMCID: PMC4451182  PMID: 24410723
21.  Reconstruction of Irradiated Mandible after Segmental Resection of Osteoradionecrosis—A Technique Employing a Microvascular Latissimus Dorsi Flap and Subsequent Particulate Iliac Bone Grafting 
The fibula osteocutaneous flap has revolutionized the options of mandibular segmental defect bridging in osteoradionecrosis (ORN). In selected cases, however, the fibula flap is not an option because of atherosclerosis or other features that compromise the vascularity of the lower leg and foot. The aim of this study is to present an alternative method of mandibular segmental reconstruction employing a latissimus dorsi (LD) flap and subsequent particulate iliac free bone graft reconstruction. In 15 patients with ORN, a mandibular segmental defect was bridged with a reconstruction plate, and the defect site was primed with a LD musculocutaneous flap wrapped around the reconstruction plate to bring in vascularized tissue and optimize healing conditions for a subsequent particulate iliac free bone graft reconstruction. The management of defect closure was successful in all 15 patients. Twelve patients had a subsequent bone grafting from the posterior ileum for repair of defects up to 14 cm length. Three patients had no bone graft for various reasons. In three patients dental rehabilitation was achieved with implant supported prosthodontic appliances. Ten patients met the success criteria of uneventful graft healing with restitution of osseous continuity, mandibular height, symmetry and function, and avoidance of reconstruction plate fracture.
doi:10.1055/s-0034-1371003
PMCID: PMC4130753  PMID: 25136407
segmental defect; mandible; reconstruction; latissimus dorsi flap; particulate iliac bone grafting
22.  Mandibular Repair in Rats with Premineralized Silk Scaffolds and BMP-2-modified bMSCs 
Biomaterials  2009;30(27):4522-4532.
Premineralized silk fibroin protein scaffolds (mSS) were prepared to combine the osteoconductive properties of biological apatite with aqueous-derived silk scaffold (SS) as a composite scaffold for bone regeneration. The aim of present study was to evaluate the effect of premineralized silk scaffolds combined with bone morphogenetic protein-2 (BMP-2) modified bone marrow stromal cells (bMSCs) to repair mandibular bony defects in a rat model. bMSCs were expanded and transduced with adenovirus AdBMP-2, AdLacZ gene in vitro. These genetically modified bMSCs were then combined with premineralized silk scaffolds to form tissue engineered bone. Mandibular repairs with AdBMP-2 transduced bMSCs/mSS constructs were compared with those treated with AdLacZ transduced bMSCs/mSS constructs, native (nontransduced) bMSCs/mSS constructs and mSS alone. Eight weeks post-operation, the mandibles were explanted and evaluated by radiographic observation, micro-CT, histological analysis and immunohistochemistry. The presence of BMP-2 gene enhanced tissue engineered bone in terms of the most new bone formed and the highest local bone mineral densities (BMD) found. These results demonstrated that premineralized silk scaffold could serve as a potential substrate for bMSCs to construct tissue engineered bone for mandibular bony defects. BMP-2 gene therapy and tissue engineering techniques could be used in mandibular repair and bone regeneration.
doi:10.1016/j.biomaterials.2009.05.021
PMCID: PMC2871698  PMID: 19501905
23.  In Vivo Bioreactors for Mandibular Reconstruction 
Journal of Dental Research  2014;93(12):1196-1202.
Large mandibular defects are difficult to reconstruct with good functional and aesthetic outcomes because of the complex geometry of craniofacial bone. While the current gold standard is free tissue flap transfer, this treatment is limited in fidelity by the shape of the harvested tissue and can result in significant donor site morbidity. To address these problems, in vivo bioreactors have been explored as an approach to generate autologous prefabricated tissue flaps. These bioreactors are implanted in an ectopic site in the body, where ossified tissue grows into the bioreactor in predefined geometries and local vessels are recruited to vascularize the developing construct. The prefabricated flap can then be harvested with vessels and transferred to a mandibular defect for optimal reconstruction. The objective of this review article is to introduce the concept of the in vivo bioreactor, describe important preclinical models in the field, summarize the human cases that have been reported through this strategy, and offer future directions for this exciting approach.
doi:10.1177/0022034514547763
PMCID: PMC4237633  PMID: 25139360
bioengineering; craniomaxillofacial surgery; bone graft(s); bone remodeling/regeneration; clinical studies/trials; tissue engineering
24.  Tissue-engineered trachea for airway reconstruction 
The Laryngoscope  2009;119(11):2118-2123.
Introduction
Scaffold-free cartilage has been used to engineer a biocompatible and stable neotrachea that, when implanted into the abdomen, produces a vascularized neotrachea with excellent mechanical stability. The purpose of this animal study was to determine if neotracheal constructs implanted in the neck, could successfully be used for segmental tracheal reconstruction.
Design
Animal study
Material and methods
Auricular chondrocytes from New Zealand White rabbits were used to engineer scaffold-free cartilage. Engineered cartilage and a strap muscle flap were wrapped around a silicone tube and implanted paratracheally. Twelve and 14 weeks post-implantation neotracheas were used to reconstruct a 20mm tracheal defect. In 2 of the 6 rabbits, the neotrachea with its intraluminal situated strap muscle flap was dropped into the defect followed by an end-to-end anastomosis; in 2 animals the muscle flap was partially followed immediately by tracheal reconstruction; and in the remaining 2 animals the muscle flap was partially removed, the silicone re-inserted and the construct temporarily re-implanted to allow formation of a fibrous lining over the exposed cartilage followed by tracheal reconstruction 6 weeks later.
Results
All implanted neotracheal constructs were well vascularized and mechanically sound. Following tracheal reconstruction, none of the animals showed immediate signs of respiratory distress, however, 2 rabbits died after 24 hours due to extensive endotracheal muscle flap edema. The remaining 4 rabbits developed fibrous stenosis of the neotrachea and died after 12 to 39 days.
Conclusion
Tissue engineered neotracheas proved to have adequate stability, but lacked adequate endotracheal lining which lead to neotracheal stenosis.
doi:10.1002/lary.20700
PMCID: PMC4811374  PMID: 19806650
25.  Growth Factor Stimulation Improves the Structure and Properties of Scaffold-Free Engineered Auricular Cartilage Constructs 
PLoS ONE  2014;9(8):e105170.
The reconstruction of the external ear to correct congenital deformities or repair following trauma remains a significant challenge in reconstructive surgery. Previously, we have developed a novel approach to create scaffold-free, tissue engineering elastic cartilage constructs directly from a small population of donor cells. Although the developed constructs appeared to adopt the structural appearance of native auricular cartilage, the constructs displayed limited expression and poor localization of elastin. In the present study, the effect of growth factor supplementation (insulin, IGF-1, or TGF-β1) was investigated to stimulate elastogenesis as well as to improve overall tissue formation. Using rabbit auricular chondrocytes, bioreactor-cultivated constructs supplemented with either insulin or IGF-1 displayed increased deposition of cartilaginous ECM, improved mechanical properties, and thicknesses comparable to native auricular cartilage after 4 weeks of growth. Similarly, growth factor supplementation resulted in increased expression and improved localization of elastin, primarily restricted within the cartilaginous region of the tissue construct. Additional studies were conducted to determine whether scaffold-free engineered auricular cartilage constructs could be developed in the 3D shape of the external ear. Isolated auricular chondrocytes were grown in rapid-prototyped tissue culture molds with additional insulin or IGF-1 supplementation during bioreactor cultivation. Using this approach, the developed tissue constructs were flexible and had a 3D shape in very good agreement to the culture mold (average error <400 µm). While scaffold-free, engineered auricular cartilage constructs can be created with both the appropriate tissue structure and 3D shape of the external ear, future studies will be aimed assessing potential changes in construct shape and properties after subcutaneous implantation.
doi:10.1371/journal.pone.0105170
PMCID: PMC4134285  PMID: 25126941

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