Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses.

[212Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope 203Pb; thus, [203Pb]VMT01 can be used as an imaging surrogate for [212Pb]VMT01. [212Pb]VMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [212Pb]VMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human [212Pb]VMT01 tissue absorbed doses were estimated from murine [203Pb]VMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for [212Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over [212Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the [212Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.

The Diagnostic Yield of Cone-Beam Computed Tomography for Degenerative Changes of the Temporomandibular Joint in Dogs.

Degenerative changes of the temporomandibular joint (DTMJ) may be diagnosed via cone - beam computed tomography (CBCT). However, despite advancement in CBCT imaging, correlation of DTMJ features identified on CBCT with gross and histological findings is currently limited. This study aimed to correlate CBCT findings of DTMJ of dogs with gross and histopathologic changes. Temporomandibular joints (TMJ) (n = 38) from fresh cadaver heads of asymptomatic dogs (n = 19) were examined radiologically, macroscopically, and microscopically. Association of CBCT - detected DTMJ changes with gross and histological findings were statistically evaluated via kappa statistics and ordinal logistic mixed-effects models. The radiological changes observed on CBCT included joint space narrowing, subchondral/cortical bone changes (i.e., erosions or lysis), osteophytes, and subchondral bone sclerosis. Upon macroscopic evaluation, the majority of examined specimens had mild changes with cartilage defects and osteophytes affecting <10% of the total articular surface area. Histopathologic changes comprised splitting and degeneration of the fibrous cartilage layers, subchondral bone exposure, subchondral bone sclerosis, focal subchondral bone lysis, and occasional cell death. Subchondral sclerosis was the most prevalent finding radiologically and histologically with a fair to excellent agreement. Importantly, the more severe the TMJ degenerative changes, the higher the agreement between CBCT and histology. Based on the correlative results of statistical analysis, CBCT was found to be a suitable modality to evaluate DTMJ.

Ferumoxytol-enhanced magnetic resonance angiography provides comparable vascular conspicuity to CT angiography in dogs with intrahepatic portosystemic shunts.

Computed tomography angiography (CTA) is currently the gold standard imaging modality for anatomically characterizing canine hepatic vascular anomalies; with conventional, gadolinium-enhanced MR angiography being less frequently utilized. However, both imaging modalities are limited by a brief, first pass peak of contrast medium in the vasculature that necessitates precisely timed image acquisition. A long-acting purely intravascular magnetic resonance imaging (MRI) contrast agent, ferumoxytol, offers the potential to reduce complexity of magnetic resonance angiography (MRA) protocol planning by ensuring diagnostic contrast medium concentration in all the vessels that are targeted for imaging. Aims of this prospective, pilot, methods comparison study were to develop an optimized MRA protocol using ferumoxytol in dogs with hepatic vascular anomalies, perform a dose escalation trial to compare image quality with four-dose regimens of ferumoxytol, and compare accuracy of vascular anatomic depiction based on the gold standard of CTA. Six dogs (10.7-36.1 kg) with portosystemic shunts (four intrahepatic left divisional shunts and two intrahepatic right divisional shunts) were recruited for inclusion in the study. A dose-escalation trial was performed to compare image quality at four incremental dose levels of ferumoxytol (1, 2, 3, and 4 mg/kg) and to compare the accuracy of vascular anatomic detection to CTA. Ferumoxytol contrast-enhanced MRA (CE-MRA) at 4 mg/kg provided similar conspicuity of normal and abnormal vasculature compared to CTA with a minimal decrease in spatial resolution. Findings indicated that ferumoxytol holds promise for comprehensive, single breath hold CE-MRA of all abdominal vessels in dogs with portosystemic shunts. Background information provided in this study can be used to support development of other future applications such as intracranial and cardiac MRA, real-time imaging, flow quantification, and potentially sedated MRI imaging.

Classification of neoplastic and inflammatory brain disease using MRI texture analysis in 119 dogs.

Magnetic resonance imaging is the primary method used to diagnose canine glial cell neoplasia and noninfectious inflammatory meningoencephalitis. Subjective differentiation of these diseases can be difficult due to overlapping imaging characteristics. This study utilizes texture analysis (TA) of intra-axial lesions both as a means to quantitatively differentiate these broad categories of disease and to help identify glial tumor grade/cell type and specific meningoencephalitis subtype in a group of 119 dogs with histologically confirmed diagnoses. Fifty-nine dogs with gliomas and 60 dogs with noninfectious inflammatory meningoencephalitis were retrospectively recruited and randomly split into training (n = 80) and test (n = 39) cohorts. Forty-five of 120 texture metrics differed significantly between cohorts after correcting for multiple testing (false discovery rate < 0.05). After training the random forest algorithm, the classification accuracy for the test set was 85% (sensitivity 89%, specificity 81%). TA was only partially able to differentiate the inflammatory subtypes (granulomatous meningoencephalitis [GME], necrotizing meningoencephalitis [NME], and necrotizing leukoencephalitis [NLE]) (out-of-bag error rate of 35.0%) and was unable to identify metrics that could correctly classify glioma grade or cell type (out-of-bag error rate of 59.6% and 47.5%, respectively). Multiple demographic differences, such as patient age, sex, weight, and breed were identified between disease cohorts and subtypes which may be useful in prioritizing differential diagnoses. TA of MR images with a random forest algorithm provided classification accuracy of inflammatory and neoplastic brain disease approaching the accuracy of previously reported subjective radiologist evaluation.

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.

Regional and disease-related differences in properties of the equine temporomandibular joint disc.

Temporomandibular joint (TMJ) disorders affect up to 12% of the human population, and naturally occurring TMJ diseases are increasingly recognized in animals. The TMJ disc plays a major role in TMJ disorders in people, but little is known about its role in TMJ pathology in animals. This study characterizes differences in properties of equine TMJ discs associated with age, disc region, and presence of TMJ osteoarthritis (OA). Discs were dissected from both TMJ's of sixteen horses euthanized for reasons unrelated to this study. Each joint was grossly evaluated and scored as normal, mild OA, or severe OA. Samples from the rostral, caudal, lateral, central, and medial regions of the disc were subject to compressive testing, quantitative biochemistry, and histology. Samples from the lateral, central, and medial region were tested for tensile properties in the rostrocaudal and mediolateral directions. We found that the equine TMJ disc is highly anisotropic, and its glycosaminoglycan (GAG) content and compressive stiffness vary between disc regions. The disc also exhibits increasing GAG content and compressive stiffness with increasing age. While equine TMJ disc properties are generally similar to other herbivores, greater compressive stiffness throughout the disc and greater GAG content in its rostral region suggest that mechanical demands on the TMJ disc differ between horses and other species. Importantly, a region-specific decrease in compressive stiffness was observed associated with joint disease and corresponded to cartilage erosions in the underlying condylar surface.

Clinical Features and Computed Tomography Findings Are Utilized to Characterize Retrobulbar Disease in Dogs.

The objective of this study is to describe the clinical features and computed tomography (CT) findings of dogs with retrobulbar disease. There are two facets to this study: a retrospective case series in which findings of dogs with primary vs. secondary retrobulbar disease are described, and a retrospective cross-sectional study in which computed tomography findings of dogs with retrobulbar neoplasia vs. infection/inflammation are described and compared. The medical records of 66 client-owned dogs diagnosed with retrobulbar disease between 2006 and 2016 were reviewed. Clinical information including signalment, the specialty service to which the dog was presented, clinical signs, physical examination findings, diagnostic results, treatment, and outcome were documented. Diagnostic imaging and histopathology were reviewed. Forty-one dogs (62.1%) were diagnosed with primary disease of the retrobulbar space; 25 dogs (37.9%) were considered to have secondary retrobulbar disease. Of the 41 dogs with primary retrobulbar disease, 19 were diagnosed with neoplasia, 19 with infectious/inflammatory disease, and 3 suffered traumatic insult to the retrobulbar space. Of the 25 dogs with secondary retrobulbar disease, 21 were diagnosed with neoplasia, 3 with infectious/inflammatory disease, and 1 with a cyst. Dogs had a combination of ocular, oral, and/or nasal clinical signs. CT findings of orbital osteolysis, orbital periosteal reaction, and presence of a retrobulbar mass were significantly associated with neoplasia, while zygomatic salivary gland enlargement, retrobulbar mass effect, and mandibular lymphadenopathy were more often associated with infectious/inflammatory disease. CT findings overlap among different retrobulbar diseases, but new bone formation and lysis are more often associated with neoplasia. Disease originating from the retrobulbar space was equally likely to be infectious/inflammatory (n = 19) or neoplastic (n = 19), based on definitive diagnostic results of dogs with primary retrobulbar disease. Due to the clinical ramifications of these disorders, the diagnosis and treatment of these cases should be managed with a multi-specialty approach.

Hounsfield units are a useful predictor of pleural effusion cytological type in dogs but not in cats.

All categories of pleural effusion subjectively display as soft tissue opacity on computed tomography (CT). Quantitative measurement using Hounsfield units (HU) has the potential to bring additional information regarding the nature of the fluid in a noninvasive way. The purposes of this retrospective cross-sectional analytical study were to compare Hounsfield units of different pleural effusion categories in dogs and cats, assess association between specific cytologic parameters and Hounsfield units, and evaluate the effect of dependent vs. nondependent aspect of the effusion pool on Hounsfield unit. A total of 111 patients (74 dogs and 37 cats) with pleural effusion, that underwent thoracic CT and diagnostic thoracocentesis, were included in the study. Effusions were cytologically categorized as exudate, transudate, modified transudate, hemorrhage, or chyle. Significant differences existed in Hounsfield units between categories in dogs (P < 0.0001) but not in cats (P = 0.334). Canine chylous effusion (6.1 ± 4.7 HU (mean ± standard deviation)) and transudate (5.6 ± 2.0) were significantly lower than exudate (20.3 ± 9.5) and hemorrhage (21.4 ± 9.2). No significant differences were found between modified transudate (13.6 ± 10.3) and other categories. Significant, weak linear correlation was identified in dogs between Hounsfield units and total protein (P = 0.018, R2  = 0.089), red blood cells (P = 0.021, R2  = 0.077), and total nucleated cells (P = 0.013, R2  = 0.089). The Hounsfield units of dependent effusion was not significantly higher than the nondependent effusion, except for canine chylous effusion (P = 0.008). Fourteen Hounsfield units was identified as the most clinically useful threshold: <14 HU identified transudate or chylous effusion with a sensitivity of 100% and a specificity of 69%. A threshold >14 HU had a specificity of 100% and a sensitivity of 69% for identifying exudate, modified transudate, or hemorrhage.

Abrogation of fluid suppression in intracranial postcontrast fluid-attenuated inversion recovery magnetic resonance imaging: A clinical and phantom study.

Postcontrast, fluid-attenuated inversion recovery (FLAIR) sequences are reported to be of variable value in veterinary and human neuroimaging. The source of hyperintensity in postcontrast-T2 FLAIR images is inconsistently reported and has implications for the significance of imaging findings. We hypothesized that the main source of increased signal intensity in postcontrast-T2 FLAIR images would be due to gadolinium leakage into adjacent fluid, and that the resulting gadolinium-induced T1 shortening causes reappearance of fluid hyperintensity, previously nulled on precontrast FLAIR images. A retrospective, descriptive study was carried out comparing T2 weighted, pre- and postcontrast T1 weighted and pre- and postcontrast weighted T2 FLAIR images in a variety of intracranial diseases in dogs and cats. A prospective, experimental, phantom, in vitro study was also done to compare the relative effects of gadolinium concentration on T2 weighted, T1 weighted, and FLAIR images. A majority of hyperintensities on postcontrast-T2 FLAIR images that were not present on precontrast FLAIR images were also present on precontrast T2 weighted images, and were consistent with normal or pathological fluid filled structures. Phantom imaging demonstrated increased sensitivity of FLAIR sequences to low concentrations of gadolinium compared to T1 weighted sequences. Apparent contrast enhancement on postcontrast-T2 FLAIR images often reflects leakage of gadolinium across normal or pathology specific barriers into fluid-filled structures, and hyperintensity may therefore represent normal fluid structures as well as pathological tissues. Findings indicated that postcontrast-T2 FLAIR images may provide insight into integrity of biological structures such as the ependymal and subarachnoid barriers that may be relevant to progression of disease.

Temporal development of near-native functional properties and correlations with qMRI in self-assembling fibrocartilage treated with exogenous lysyl oxidase homolog 2.

Advances in cartilage tissue engineering have led to constructs with mechanical integrity and biochemical composition increasingly resembling that of native tissues. In particular, collagen cross-linking with lysyl oxidase has been used to significantly enhance the mechanical properties of engineered neotissues. In this study, development of collagen cross-links over time, and correlations with tensile properties, were examined in self-assembling neotissues. Additionally, quantitative MRI metrics were examined in relation to construct mechanical properties as well as pyridinoline cross-link content and other engineered tissue components. Scaffold-free meniscus fibrocartilage was cultured in the presence of exogenous lysyl oxidase, and assessed at multiple time points over 8weeks starting from the first week of culture. Engineered constructs demonstrated a 9.9-fold increase in pyridinoline content, reaching 77% of native tissue values, after 8weeks of culture. Additionally, engineered tissues reached 66% of the Young's modulus in the radial direction of native tissues. Further, collagen cross-links were found to correlate with tensile properties, contributing 67% of the tensile strength of engineered neocartilages. Finally, examination of quantitative MRI metrics revealed several correlations with mechanical and biochemical properties of engineered constructs. This study displays the importance of culture duration for collagen cross-link formation, and demonstrates the potential of quantitative MRI in investigating properties of engineered cartilages. STATEMENT OF SIGNIFICANCE: This is the first study to demonstrate near-native cross-link content in an engineered tissue, and the first study to quantify pyridinoline cross-link development over time in a self-assembling tissue. Additionally, this work shows the relative contributions of collagen and pyridinoline to the tensile properties of collagenous tissue for the first time. Furthermore, this is the first investigation to identify a relationship between qMRI metrics and the pyridinoline cross-link content of an engineered collagenous tissue.

The application of 3-dimensional printing for preoperative planning in oral and maxillofacial surgery in dogs and cats.

OBJECTIVE: To describe the application of 3-dimensional (3D) printing in advanced oral and maxillofacial surgery (OMFS) and to discuss the benefits of this modality in surgical planning, student and resident training, and client education. STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned dogs (n = 28) and cats (n = 4) with 3D printing models of the skulls. METHODS: The medical records of 32 cases with 3D printing prior to major OMFS were reviewed. RESULTS: Indications for 3D printing included preoperative planning for mandibular reconstruction after mandibulectomy (n = 12 dogs) or defect nonunion fracture (n = 6 dogs, 2 cats), mapping of ostectomy location for temporomandibular joint ankylosis or pseudoankylosis (n = 4 dogs), assessment of palatal defects (n = 2 dogs, 1 cat), improved understanding of complex anatomy in cases of neoplasia located in challenging locations (n = 2 dogs, 1 cat), and in cases of altered anatomy secondary to trauma (n = 2 dogs). CONCLUSION: In the authors' experience, 3D printed models serve as excellent tools for OMFS planning and resident training. Furthermore, 3D printed models are a valuable resource to improve clients' understanding of the pet's disorder and the recommended treatment. CLINICAL RELEVANCE: Three-dimensional printed models should be considered viable tools for surgical planning, resident training, and client education in candidates for complex OMFS.

A Modified Hydroxyproline Assay Based on Hydrochloric Acid in Ehrlich's Solution Accurately Measures Tissue Collagen Content.

Collagen quantification has long been relevant to biomedical research and clinical practice to characterize tissues and determine disease states. The hydroxyproline assay, while a broadly employed method of quantifying collagen, uses perchloric acid to dissolve Ehrlich's reagent. Since perchloric acid poses occupational safety hazards and high costs, in this study, a new hydroxyproline assay was developed that replaces perchloric acid with a relatively safer and cheaper alternative, hydrochloric acid (HCl). To validate this biochemical technique, first, using either acid to dissolve Ehrlich's reagent, the assays were completed for native and engineered collagenous tissues. No statistical differences were identified between the assays (p = 0.32). Subsequently, both biochemical techniques were compared to amino acid analysis, considered a proteomics gold standard. Interestingly, utilizing HCl in lieu of perchloric acid yielded greater concordance with amino acid analysis (ρc = 0.980) than did the traditional assay (ρc = 0.947); that is, the HCl-based assay more closely estimates hydroxyproline content, and, consequently, true collagen content. Thus, using Ehrlich's reagent containing HCl in the hydroxyproline assay represents an advance in both mitigating laboratory safety hazards and improving biochemical collagen quantification.

Clinical Application of Cone Beam Computed Tomography of the Rabbit Head: Part 2-Dental Disease.

Domestic rabbits are increasing in popularity as household pets; therefore, veterinarians need to be familiar with the most common diseases afflicting rabbits including dental disease. Current diagnostic approaches include gross oral examination, endoscopic oral examination, skull radiography, and computed tomography (CT). Cone beam computed tomography (CBCT), a new oral and maxillofacial imaging modality that has the capability to produce high-resolution images, has not yet been described for use in evaluating dental disease in rabbits. A total of 15 client-owned rabbits had CBCT, oral examination, dental charting, and dental treatment performed under general anesthesia. Images were evaluated using transverse and custom multiplanar (MPR), 3D, and panoramic reconstructed images. The CBCT findings were grouped into abnormalities that could be detected on conscious oral examination vs. abnormalities that could not be detected by conscious oral examination. Potential associations between the two categories were examined by pairwise Fisher's exact test with statistical significance determined by P < 0.05. The most common findings identified on CBCT images were periodontal ligament space widening (14/15), premolar and molar malocclusion (13/15), apical elongation (13/15), coronal elongation (12/15), inflammatory tooth resorption (12/15), periapical lucency (11/15), moth-eaten pattern of osteolysis of the alveolar bone (9/15), ventral mandibular border contour changes (9/15), and missing teeth (8/15). Of the CBCT abnormalities likely to be observed on oral examination, coronal elongation (detectable on oral examination) was significantly associated with apical elongation (P = 0.029). There were no other significant associations between CBCT findings that are also clinically detectable and CBCT findings that are not be detectable on oral examination. This suggests that pathology often exists that is not apparent upon oral examination. This study establishes the common CBCT findings associated with dental disease in rabbits and demonstrates the feasibility of this technology to diagnose and plan treatment in dental disorders in this species.

Clinical Application of Cone-Beam Computed Tomography of the Rabbit Head: Part 1 - Normal Dentition.

Domestic rabbits (Oryctolagus cuniculus) are increasingly popular as household pets; therefore, veterinarians need to be familiar with the most common diseases afflicting rabbits including dental diseases. Diagnostic approaches for dental disease include gross oral examination, endoscopic oral examination, skull radiography, and computed tomography (CT). CT overcomes many limitations of standard radiography by permitting cross-sectional images of the rabbit head in multiple planes without superimposition of anatomic structures. Cone-beam CT (CBCT) is an oral and maxillofacial imaging modality that produces high-resolution images. The objective of this study was to describe and compare the normal anatomic features of the dentition and surrounding maxillofacial structures in healthy rabbits on CBCT and conventional CT. Ten New Zealand white rabbit cadaver heads were scanned using CBCT and conventional CT. Images were evaluated using Anatomage Invivo 5 software. The maxillofacial anatomy was labeled on CBCT images, and the mean lengths and widths of the teeth were determined. The visibility of relevant dental and anatomic features (pulp cavity, germinal center, tooth outline, periodontal ligament) were scored and compared between conventional CT and CBCT. The thinnest teeth were the maxillary second incisor teeth at 1.29 ± 0.26 mm and the maxillary third molar teeth at 1.04 ± 0.10 mm. In general, it was found that CBCT was superior to conventional CT when imaging the dentition. Importantly, the periodontal ligament was significantly (P < 0.01) more visible on CBCT than on conventional CT. Ability to see the periodontal ligament with such detail may allow earlier detection and treatment of periodontal disease in rabbits. This study is the first of its kind and shows the feasibility and yield of CBCT when evaluating the maxillofacial features and dentition in rabbits.

Ankylosis and pseudoankylosis of the temporomandibular joint in 10 dogs (1993-2015).

OBJECTIVE: To describe the clinical features and results of treatment of true ankylosis and pseudoankylosis of the temporomandibular joint in dogs. METHODS: This study was a retrospective case series. Ten client-owned dogs that were presented for inability to open the mouth or a severely decreased range of motion of the temporomandibular joint were included. Information on the surgical procedures performed and the perioperative complications were documented. Three-dimensional printing of the skull was performed in four dogs. RESULTS: Two dogs were diagnosed with temporomandibular joint ankylosis and seven dogs with pseudoankylosis. One dog had evidence of combined temporomandibular joint ankylosis and pseudoankylosis. Of the seven dogs with pseudoankylosis, six had an osseous fusion involving the zygomatic arch and mandible. Surgical treatment was performed in nine dogs and a revision surgery was needed in one dog. Follow-up ranged from five months to eight years (mean: 48.6 months). Eight out of nine dogs that were treated surgically regained the ability to open their mouth, but six dogs never regained a fully normal temporomandibular joint range of motion. CLINICAL SIGNIFICANCE: Temporomandibular joint ankylosis and pseudoankylosis are uncommon in the dog. Surgical treatment for temporomandibular joint ankylosis or pseudoankylosis in dogs is a successful option and carries a prognosis dependent on patient-specific abnormalities. Computed tomography complemented with three-dimensional printing is valuable for understanding the extent of abnormalities and for preoperative planning.

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.

Regenerating Mandibular Bone Using rhBMP--2: Part 2-Treatment of Chronic, Defect Non-Union Fractures.

OBJECTIVE: To describe a surgical technique using 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 dogs, the repair was staged and extraction of teeth performed during the initial procedure. After 21-98 days (mean, 27 days) pharyngotomy intubation and temporary maxillomandibular fixation were performed. Using an extraoral approach, a locking titanium miniplate was contoured and secured to the mandible. 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 surgical wound closure. RESULTS: All dogs 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. CT findings in 1 dog 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.

Regenerating Mandibular Bone Using rhBMP-2: Part 1-Immediate Reconstruction of Segmental Mandibulectomies.

OBJECTIVE: To describe a surgical technique using a regenerative approach and internal fixation for immediate reconstruction of critical size bone defects after segmental mandibulectomy in dogs. STUDY DESIGN: Prospective case series. ANIMALS: Dogs (n = 4) that had reconstruction after segmental mandibulectomy for treatment of malignant or benign tumors. METHODS: Using a combination of extraoral and intraoral approaches, a locking titanium plate was contoured to match the native mandible. After segmental mandibulectomy, the plate was secured and a compression resistant matrix (CRM) infused with rhBMP-2, implanted in the defect. The implant was then covered with a soft tissue envelope followed by intraoral and extraoral closure. RESULTS: All dogs that had mandibular reconstruction healed with intact gingival covering over the mandibular defect and had immediate return to normal function and occlusion. Mineralized tissue formation was observed clinically within 2 weeks and solid cortical bone formation within 3 months. CT findings at 3 months showed that the newly regenerated mandibular bone had ∼50% of the bone density and porosity compared to the contralateral side. No significant complications occurred. CONCLUSION: Mandibular reconstruction using internal fixation and CRM infused with rhBMP-2 is an excellent solution for immediate reconstruction of segmental mandibulectomy defects in dogs.

Clinical translation of stem cells: insight for cartilage therapies.

The limited regenerative capacity of articular cartilage and deficiencies of current treatments have motivated the investigation of new repair technologies. In vitro cartilage generation using primary cell sources is limited by cell availability and expansion potential. Pluripotent stem cells possess the capacity for chondrocytic differentiation and extended expansion, providing a potential future solution to cell-based cartilage regeneration. However, despite successes in producing cartilage using adult and embryonic stem cells, the translation of these technologies to the clinic has been severely limited. This review discusses recent advances in stem cell-based cartilage tissue engineering and the major current limitations to clinical translation of these products. Concerns regarding appropriate animal models and studies, stem cell manufacturing, and relevant regulatory processes and guidelines will be addressed. Understanding the significant hurdles limiting the clinical use of stem cell-based cartilage may guide future developments in the fields of tissue engineering and regenerative medicine.