Radioprotection With Amifostine Enhances Bone Strength and Regeneration and Bony Union in a Rat Model of Mandibular Distraction Osteogenesis.

BACKGROUND: Using distraction osteogenesis (DO) to regenerate robust endogenous bone could greatly enhance postoncologic reconstruction of head and neck cancer. However, radiation (XRT) corrosive effects still preclude DO's immense potential. We posit that adjunctive pretreatment with the radioprotectant amifostine (AMF) can optimize wound healing and allow for successful DO with quantifiable enhancements in bony union and strength despite previous surgical bed irradiation. METHODS: Two groups of murine left hemimandibles were exposed to a human equivalent radiation dosage fractionated over 5 daily doses of 7 Gy. AMF-XRT-DO (n = 30) received AMF before radiation, whereas XRT-DO (n = 22) was untreated. All animals underwent left hemimandibular osteotomy and external fixator placement, followed by distraction to a 5.1-mm gap. Left hemimandibles were harvested and mechanically tested for parameters of strength, yield, and breaking load. RESULTS: Radiation-related complications such as severe alopecia were significantly increased in XRT-DO compared with the AMF-treated group (P = 0.001), whereas infection and death were comparable (P = 0.318). Upon dissection, bony defects were grossly visible in XRT-DO distraction gap compared with AMF-XRT-DO, which exhibited significantly more complete unions (P = 0.004). Those results were significantly increased in the specimens prophylactically treated with AMF (yield: 39.41 N vs 21.78 N, P = 0.023; breaking load: 61.74 N vs 34.77 N, P = 0.044; respectively). CONCLUSIONS: Our study revealed that AMF enhances biomechanical strength, regeneration, and bony union after radiation in a murine model of DO. The use of prophylactic AMF in combination with DO offers the promise of an alternative reconstructive option for patients afflicted with head and neck cancer.

Significant Differences in the Bone of an Isogenic Inbred Versus Nonisogenic Outbred Murine Mandible: A Study in Rigor and Reproducibility.

Inattention to differences between animal strains is a potential cause of irreproducibility of basic science investigations. Accordingly, the authors' laboratory sought to ensure that cross-comparisons of results generated from studies of mandibular physiology utilizing the Sprague Dawley and Lewis rat strains are valid. The authors specifically investigated baseline histomorphometrics, bone mineral density, and biomechanical strength of the unaltered endogenous mandibles of the inbred, isogenic Lewis rat, and the outbred, nonisogenic Sprague Dawley rat to determine if they are indeed equal. The authors hypothesized that little difference would be found within these metrics.The authors' study utilized 20 male Lewis and Sprague Dawley rats, which underwent no manipulation other than final dissection and analysis. Ten rats from each strain underwent bone mineral density and biomechanical strength analysis. The remaining rats underwent histological analysis. Descriptive and bivariate statistics were computed and the P value was set at 0.05.Lewis rats had a significantly greater number of empty lacunae. Sprague Dawley rats exhibited a significantly greater ratio of bone volume-to-total volume, bone mineral density, tissue mineral density, bone volume fraction, and total mineral content. No differences were found during biomechanical testing.This study demonstrates that differences exist between the Lewis and Sprague Dawley rat within unaltered baseline mandibular tissue. However, these differences appear to have limited functional impact, as demonstrated by similar biomechanical strength metrics. Other specific differences not addressed in this manuscript may exist. However, the authors believe that researchers may confidently cross-compare results between the 2 strains, while taking into account the differences found within this study.

Bone marrow stem cells assuage radiation-induced damage in a murine model of distraction osteogenesis: A histomorphometric evaluation.

The purpose of this study is to determine if intraoperatively placed bone marrow stem cells (BMSCs) will permit successful osteocyte and mature bone regeneration in an isogenic murine model of distraction osteogenesis (DO) following radiation therapy (XRT). Lewis rats were split into three groups, DO only (Control), XRT followed by DO (xDO) and XRT followed by DO with intraoperatively placed BMSCs (xDO-BMSC). Coronal sections from the distraction site were obtained, stained and analyzed via statistical analysis with analysis of variance (ANOVA) and subsequent Tukey or Games-Howell post-hoc tests. Comparison of the xDO-BMSC and xDO groups demonstrated significantly improved osteocyte count (87.15 ± 10.19 vs. 67.88 ± 15.38, P = 0.00), and empty lacunae number (2.18 ± 0.79 vs 12.34 ± 6.61, P = 0.00). Quantitative analysis revealed a significant decrease in immature osteoid volume relative to total volume (P = 0.00) and improved the ratio of mature woven bone to immature osteoid (P = 0.02) in the xDO-BMSC compared with the xDO group. No significant differences were found between the Control and xDO-BMSC groups. In an isogenic murine model of DO, BMSC therapy assuaged XRT-induced cellular depletion, resulting in a significant improvement in histological and histomorphometric outcomes.

A Comparison of Vascularity, Bone Mineral Density Distribution, and Histomorphometrics in an Isogenic Versus an Outbred Murine Model of Mandibular Distraction Osteogenesis.

PURPOSE: The vascularity, bone mineral density distribution, and histomorphometric data between the inbred, isogenic Lewis rat and the outbred, nonisogenic Sprague Dawley rat within mandibular distraction osteogenesis (MDO) were evaluated to allow future researchers to compare the results generated from these 2 animals. We hypothesized that little difference would be found between the 2 strains within these metrics. MATERIALS AND METHODS: We implemented a comparative study between the Lewis and Sprague Dawley rat strains within MDO. The sample was composed of 17 male Lewis and 17 male Sprague Dawley rats that underwent surgical external fixation and distraction. The rats' hemimandibles were distracted to a total distance of 5.1 mm. After 28 days of consolidation, 9 rats from each group underwent bone mineral density distribution analysis. The remaining rats from each group were analyzed for the vascular and histologic metrics. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: We demonstrated successful MDO in all the rats, with no significant difference found in the histologic or bone mineral density distribution metrics. No significant differences were found in any of the vascular metrics, with the exception of vascular separation, which was not normalized to the mandibular volume (P = .048). CONCLUSIONS: The results of the present study have demonstrated that little dissimilarity exists between the isogenic Lewis and outbred Sprague Dawley models of MDO. Thus, researchers can confidently compare the gross results between the 2 strains, with consideration of the very small differences between the 2 models. For studies that require an isogenic strain, the Lewis rat is an apt surrogate for the Sprague Dawley strain.

Amifostine Treatment Mitigates the Damaging Effects of Radiation on Distraction Osteogenesis in the Murine Mandible.

According to the American Society of Clinical Oncology, in 2012, more than 53,000 new cases of head and neck cancers (HNCs) were reported in the United States alone and nearly 12,000 deaths occurred relating to HNC. Although radiotherapy (XRT) has increased survival, the adverse effects can be unrelenting and their management is rarely remedial. Current treatment dictates surgical mandibular reconstruction using free tissue transfer. These complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of adjuvant therapy, jeopardizing prognosis as well as quality of life. The creation of new bone by distraction osteogenesis (DO) generates a replacement of deficient tissue from local substrate and could have immense potential therapeutic ramifications. Radiotherapy drastically impairs bone healing, precluding its use as a reconstructive method for HNC. We posit that the deleterious effects of XRT on bone formation could be pharmacologically mitigated. To test this hypothesis, we used a rodent model of DO and treated with amifostine, a radioprotectant, to assuage the XRT-induced injury on new bone formation. Amifostine had a profound salutary effect on bone regeneration, allowing the successful implementation of DO as a reconstructive technique. The optimization of bone regeneration in the irradiated mandible has immense potential for translation from the bench to the bedside, providing improved therapeutic options for patients subjected to XRT.

Changes in Skin Vascularity in a Murine Model for Postmastectomy Radiation.

BACKGROUND: Postmastectomy radiation causes persistent injury to the breast microvasculature, and the prevailing assumption is that longer delays before breast reconstruction allow for recovery of blood supply. This study uses a murine model to examine the effects of radiation on skin vascularity to help determine when radiation-induced effects on the microvasculature begin to stabilize. STUDY DESIGN: Isogenic Lewis rats were divided into 2 groups: radiation therapy (XRT) (n = 24) and control (n = 24). The XRT rats received a breast cancer therapy human dose-equivalent of radiation to the groin, whereas control rats received no radiation. Animals were sacrificed at 4, 8, 12, and 16 weeks after completion of radiation. The vasculature was injected with Microfil, and groin skin was harvested for radiomorphometric analysis by microcomputed tomography. One-way analysis of variance with post hoc Tukey tests was used to determine significance between groups. RESULTS: Augmentation in vascularity was observed in the XRT group at 4 weeks after radiation compared to the control group (P = 0.045). Vessel number was decreased at 12 weeks (P = 0.002) and at 16 weeks (P = 0.001) in the XRT rats compared to control rats. Vessel separation in the XRT group was higher than that in the control group at 12 weeks (P = 0.009) and 16 weeks (P = 0.001). There was no change in vessel number and separation between weeks 12 and 16. CONCLUSIONS: A period of augmented skin vascularity is seen after radiation injury followed by decreased vascularity which demonstrates stabilization at approximately 12 weeks in this murine model. This model can be used to further study breast flap vascularity and the optimization of the timing of delayed breast reconstruction.

Raman spectroscopy delineates radiation-induced injury and partial rescue by amifostine in bone: a murine mandibular model.

Despite its therapeutic role in head and neck cancer, radiation administration degrades the biomechanical properties of bone and can lead to pathologic fracture and osteoradionecrosis. Our laboratories have previously demonstrated that prophylactic amifostine administration preserves the biomechanical properties of irradiated bone and that Raman spectroscopy accurately evaluates bone composition ex vivo. As such, we hypothesize that Raman spectroscopy can offer insight into the temporal and mechanical effects of both irradiation and amifostine administration on bone to potentially predict and even prevent radiation-induced injury. Male Sprague-Dawley rats (350-400 g) were randomized into control, radiation exposure (XRT), and amifostine pre-treatment/radiation exposure groups (AMF-XRT). Irradiated animals received fractionated 70 Gy radiation to the left hemi-mandible, while AMF-XRT animals received amifostine just prior to radiation. Hemi-mandibles were harvested at 18 weeks after radiation, analyzed via Raman spectroscopy, and compared with specimens previously harvested at 8 weeks after radiation. Mineral (ρ958) and collagen (ρ1665) depolarization ratios were significantly lower in XRT specimens than in AMF-XRT and control specimens at both 8 and 18 weeks. amifostine administration resulted in a full return of mineral and collagen depolarization ratios to normal levels at 18 weeks. Raman spectroscopy demonstrates radiation-induced damage to the chemical composition and ultrastructure of bone while amifostine prophylaxis results in a recovery towards normal, native mineral and collagen composition and orientation. These findings have the potential to impact on clinical evaluations and interventions by preventing or detecting radiation-induced injury in patients requiring radiotherapy as part of a treatment regimen.

A Histomorphometric Analysis of Radiation Damage in an Isogenic Murine Model of Distraction Osteogenesis.

PURPOSE: The devastation radiation therapy (XRT) causes to endogenous tissue in patients with head and neck cancer can be a prohibitive obstacle in reconstruction of the mandible, demanding a better understanding of XRT-induced damage and options for reconstruction. This study investigated the cellular damage caused by radiation in an isogenic murine model of mandibular distraction osteogenesis (DO). The authors posited that radiation would result in fewer osteocytes, with increased empty lacunae and immature osteoid. MATERIALS AND METHODS: Twenty Lewis rats were randomly assigned to a DO group (n = 10) or a XRT/DO group (n = 10). These groups underwent an osteotomy and mandibular DO across a 5.1-mm gap. XRT was administered to the XRT/DO group at a fractionated human equivalent dose of 35 Gy before surgery. Animals were sacrificed on postoperative day 40 and mandibles were harvested and sectioned for histologic analysis. RESULTS: Bone that underwent radiation showed a significantly decreased osteocyte count and complementary increase in empty lacunae compared with non-XRT bone (P = .019 and P = .000). In addition, XRT bone exhibited increased immature osteoid and decreased mature woven bone compared with nonradiated bone (P = .001 and P = .003, respectively). Furthermore, analysis of the ratio of immature osteoid to woven bone volume exhibited a significant increase in the XRT bone, further showing the devastating damage from XRT (P = .001). CONCLUSION: These results clearly show the cellular diminution that occurs as a result of radiation. This foundational study provides the groundwork on which to investigate cellular therapies in an immuno-privileged model of mandibular DO.

Vascular analysis as a proxy for mechanostransduction response in an isogenic, irradiated murine model of mandibular distraction osteogenesis.

INTRODUCTION: Head and neck cancer is a debilitating and disfiguring disease. Although numerous treatment options exist, an array of debilitating side effects accompany them, causing physiological and social problems. Distraction osteogenesis (DO) can avoid many of the pathologies of current reconstructive strategies; however, due to the deleterious effects of radiation on bone vascularity, DO is generally ineffective. This makes investigating the effects of radiation on neovasculature during DO and creating quantifiable metrics to gauge the success of future therapies vital. The purpose of this study was to develop a novel isogenic rat model of impaired vasculogenesis of the regenerate mandible in order to determine quantifiable metrics of vascular injury and associated damage. METHODS: Male Lewis rats were divided into two groups: DO only (n=5) AND Radiation Therapy (XRT)+DO (n=7). Afterwards, a distraction device was surgically implanted into the mandible. Finally, they were distracted a total of 5.1mm. Animals were perfused with a radiopaque casting agent concomitant with euthanasia, and subsequently demineralization, microcomputed tomography, and vascular analysis were performed. RESULTS: Vessel volume fraction, vessel thickness, vessel number, and degree of anisotropy were diminished by radiation. Vessel separation was increased by radiation. CONCLUSION: The DO group experienced vigorous vessel formation during distraction and neovascularization with a clear, directional progression, while the XRT/DO group saw weak vessel formation during distraction and neovascularization. Further studies are warranted to more deeply examine the impairments in osteogenic mechanotransductive pathways following radiation in the murine mandible. This isogenic model provides quantifiable metrics for future studies requiring a controlled approach to immunogenicity.

Amifostine preserves osteocyte number and osteoid formation in fracture healing following radiotherapy.

PURPOSE: Radiation is known to decrease osteocyte count and function, leading to bone weakening. A treatment strategy to mitigate these consequences could have immense therapeutic ramifications. The authors previously reported significantly decreased osteocyte count and mineralization capacity in a rat model of fracture healing after radiotherapy. They hypothesized that amifostine (AMF) would preserve osteocyte number and function in this model. MATERIALS AND METHODS: Thirty-six rats were divided into 3 groups: fracture, radiated fracture, and radiated fracture with AMF. Radiated groups underwent human-equivalent radiotherapy to the mandible before fixator placement and mandibular osteotomy. The AMF group received a subcutaneous injection before each dose of radiotherapy. After 40 days, mandibles were harvested for histologic processing. Quantification of osteocyte count (Oc), empty lacunae (EL), and osteoid ratio (osteoid volume [OV] to tissue volume [TV]) was performed and the results were compared using analysis of variance (P < .05). RESULTS: Radiated fractures showed significantly decreased Oc, increased EL, and a decreased capacity to produce new osteoid at the fracture site as measured with OV/TV compared with nonradiated fractures. In mandibles treated with AMF, these metrics were not statistically different than the control, indicating a preservation of osteocyte number and function. CONCLUSIONS: These results support the hypothesis that AMF preserves osteocyte number and function, thereby preventing the pernicious effects of radiotherapy on the cellular environment of fracture healing. Based on these findings, the authors encourage future investigation of this promising therapy for use in the prevention of pathologic fractures and osteoradionecrosis.

Distraction osteogenesis following low-dose hyperfractionated irradiation in the rat mandible.

PURPOSE: The investigators hypothesized that low-dose hyperfractionated radiation would impair mandibular distraction osteogenesis (DO) in a murine mandibular model. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent fractionated radiation (30 Gy) of the left mandible. After a 2-week recovery period, an external frame distractor was applied and gradual distraction of the mandible was performed. Tissue was harvested after a 28-day consolidation period. Gross, radiologic, and histologic evaluations were undertaken. Control animals underwent surgery for an identical time frame without preoperative radiation. RESULTS: Animals subjected to preoperative radiation (n = 10) showed suboptimal bone formation, including bone atrophy, incomplete bridging of the distraction gap, and gross bony defects or nonunion, compared with controls (n = 10). Although physical lengthening was achieved, irradiation consistently led to a detrimental effect on the normal process of DO. CONCLUSION: This set of experiments establishes a valuable rodent model to evaluate the effects of radiation on DO and may help to formulate strategies to optimize DO before it is widely applied in oncologic reconstruction.

An isogenic model of murine mandibular distraction osteogenesis.

The advent of stem cell-based therapies makes current models of mandibular distraction osteogenesis unwieldy. We thereby designed an isogenic model of distraction osteogenesis whose purpose was to allow for the free transfer of cells and components between rats. As immune response plays a significant role in healing and prevention of infection, an immune-competent mode is desirable rather than an athymic rat/xenograft model. The purposes of this study were as follows: (1) to replicate established models of distraction osteogenesis in a rodent model using an isogenic rat strain, and (2) to characterize the differences between inbred, isogenic rats and outbred rats in mandibular distraction osteogenesis via radiomorphometry and biomechanical response analysis. We demonstrated successful distraction osteogenesis to 5.1 mm in all Lewis (isogenic) rat mandibles as well as all Sprague-Dawley (outbred) rat mandibles, with no significant difference in volume-normalized radiomorphometrics, trending difference in non-volume-normalized radiomorphometrics and significant differences in biomechanical response parameters. We attribute the differences demonstrated to the decreased size of the Lewis rat mandible in comparison to Sprague-Dawley mandibles. We also provide information with caring with the additional needs of the Lewis rat. Given these differences, we find that Lewis rats function as an excellent model for isogenic mandibular distraction osteogenesis, but data procured may not be comparable between isogenic and nonisogenic models.

Bone regeneration in distraction osteogenesis demonstrates significantly increased vascularity in comparison to fracture repair in the mandible.

BACKGROUND: Tissue analysis of bone regenerate has suggested an intense vascular response after mandibular distraction osteogenesis (DO). Quantifying and three-dimensionally imaging this vascular response could be of immense clinical import in efforts to advance the utility of bone regeneration and repair. Conventional quantification of vascular responses has heretofore focused on inexact, cumbersome measurements of blood flow and histologic vessel counting. Using micro-computed tomography after vessel perfusion, we posit that quantitative vascular metrics will be significantly higher in mandibular DO compared with those observed in fracture repair (FxR) after bony union. METHODS: Sprague-Dawley rats underwent mandibular osteotomy and external fixator placement. A DO group (n=9) underwent a 5.1-mm distraction, whereas a FxR group (n=12) had a 2.1-mm fixed gap set. Forty days after surgery, Microfil was perfused into the vasculature, and imaging ensued. Vascular radiomorphometrics were calculated for the regions of interest. Independent-samples t-test was performed for comparison, with statistical significance set at P≤0.05. RESULTS: Stereological analysis demonstrated statistically significant increases in the distracted vasculature compared with fracture repair: vessel volume fraction (5.4% versus 2.8%, P=0.030) and vessel number (0.86 versus 0.50 mm, P=0.014). CONCLUSIONS: We report robust and quantifiable increases in vascular density in DO compared with FxR. Our findings support a significant distinction between the regenerative processes of mandibular DO from the reparative mechanisms controlling fracture healing. A better understanding of the differences between the 2 types of bone formation may enable clinicians to selectively optimize therapeutic outcomes in the future.

Quantifying mineralization using bone mineral density distribution in the mandible.

BACKGROUND: Micro-computed tomography is an efficient method for quantifying the density and mineralization of mandibular microarchitecture. Conventional radiomorphometrics such as bone and tissue mineral density are useful in determining the average overall mineral content of a scanned specimen; however, relying solely on these metrics has limitations. Using bone mineral density distribution (BMDD), the complex array of mineralization densities within a bone sample can be portrayed. This information is particularly useful as a computational feature reflective of the rate of bone turnover. We demonstrate the utility of BMDD analyses in the rat mandible and generate a platform for further exploration of mandibular pathology and treatment. METHODS: Male Sprague-Dawley rats (n = 8) underwent micro-computed tomography, and histogram data were generated from a selected volume of interest. A standard curve was derived for each animal, and reference criteria were defined. An average histogram was produced for the group, and descriptive analyses including the means and SDs are reported for each of the normative metrics. RESULTS: M(peak) (3444 Hounsfield units [SD, 138]) and M(width) (2221 Hounsfield units [SD, 628]) are 2 metrics demonstrating reproducible parameters of BMDD with minimal variance. A total of 8 valuable metrics quantifying biologically significant events concerning mineralization are reported. CONCLUSIONS: We quantify the vast wealth of information depicted in the complete spectrum of mineralization established by the BMDD analysis. We demonstrate its potential in delivering mineralization data that encompass and enhance conventional reporting of radiomorphometrics. Moreover, we explore its role and translational potential in craniofacial experimentation.

Factors impacting career satisfaction of hospitalists.

A study was undertaken to examine various factors that impact career satisfaction of hospitality. This study used data collected by the Center for Studying Health System Change's 2008 Health Tracking Physician survey. The 2008 HTP data set consisted of 4720 physicians belonging to the American Medical Association, of which 206 identified themselves as hospitalists. Results suggested that 41% of hospitalists were very satisfied with their careers in medicine. More than 26% of the hospitalists were 53 years or older. Seven of 10 hospitalists were men, whereas more than 55% were white. In addition, an average respondent earned between $150 000 and $200 000. Nearly 36% of the hospitalists in the study specialized in internal medicine. Regression analysis indicates that high-quality care had a highly significant impact on career satisfaction of hospitalists (P ≤ .00). In addition, formal written guidelines (P ≤ .07), gender (P ≤ .06), and white race (P ≤ .07) also had a significant impact on career satisfaction of hospitalists. It was concluded that perceived quality of care, presence of formal written guidelines, gender, and race were major predictors of career satisfaction of hospitalists.

Career satisfaction of surgical specialties.

OBJECTIVE: To examine the factors that impact career satisfaction for various surgical specialties. BACKGROUND: An acute shortage of surgeons is anticipated in the future. Career dissatisfaction can make this already difficult situation worse. It is important to understand and address factors that influence career satisfaction of surgeons to prolong tenure of existing surgeons and understand anticipated needs of future surgeons. METHODS: The Center for Studying Health System Change 2008 Health Tracking Physician Survey data were used in this study. Regression analysis was done to examine the impact of various practice-related factors, compensation-related factors, practice location, extent of minority patient, and various demographics on career satisfaction of various surgical specialties (n = 762). RESULTS: Among practice related factors, although threat of malpractice had a significant negative impact on career satisfaction, ability to provide quality care to patients and time with patients had a significant positive impact on career satisfaction of surgical specialists. Among compensation related factors, income and financial incentives to expand services had a significant positive impact on career satisfaction. Among practice location factors, those who primarily worked in medical schools were significantly more satisfied with their careers than others. Among minority factors, those treating a large proportion of Hispanic patients were significantly less likely to be satisfied with their careers. CONCLUSIONS: Ability to provide quality care, time with patients, income, and financial incentives had a significant positive impact on career satisfaction. Similarly, threat of malpractice and high proportion of Hispanic patients had a negative impact on career satisfaction.

An empirical investigation of the differences between male and female medical school physicians.

The purpose of this research was to investigate gender-related differences among medical school faculty in a variety of areas such as information technology, medical malpractice, compensation, patient care, and carrier satisfaction. The Center for Studying Health System Change's 2008 Health Tracking Physician survey data consisting of 326 medical school faculty belonging to the American Medical Association were used in this study. t Tests indicate that female physicians practicing in medical schools were younger, had less experience, reported lower compensation, and were more likely to be primary care physicians. Male medical school physicians were significantly more concerned about being involved in a malpractice lawsuit. They reported a significantly higher percentage on income based on productivity-related factors. Male physicians also reported getting a significantly higher level of goods and services from drug companies. They also provided more hours of medical service for no or reduced fee in the previous month and higher levels of career satisfaction. Implications of this research are discussed.

Factors impacting perceived threat of malpractice lawsuits by various medical specialists.

A study was undertaken to examine perceived threat of malpractice lawsuits affecting different physician specialties and to examine factors that impact such perceptions of those specialties. The study used data collected by the Center for Studying Health System Change's 2008 Health Tracking Physician (HTP) Survey. The 2008 HTP data set consisted of 4720 physicians belonging to the American Medical Association. Primary care physicians, medical specialists, surgical specialists, psychiatrists, and obstetricians/gynecologists (ObGyns) physicians participated in the 2008 HTP Survey. The order (from high to low) of perceived threat of malpractice lawsuits for various specialists is surgical specialists (3.87), ObGyns (3.81), medical specialists (3.60), primary care physicians (3.55), and psychiatrists (3.12). Regression results indicate that patient interaction, insufficient care quality, competition, medical school, age, and career satisfaction impacted perceived threat of malpractice lawsuits for most of the specialties. For ObGyns, white non-Hispanic was the only factor that impacted perceived threat of malpractice lawsuits. The perceived threat of malpractice lawsuits varies by specialists. Patient interaction, insufficient care quality, competition, medical school, and career satisfaction are major predictors of such threats for most physician specialties.

Implantable hyaluronic acid-deferoxamine conjugate prevents nonunions through stimulation of neovascularization.

Approximately 6.3 million fractures occur in the U.S. annually, with 5-10% resulting in debilitating nonunions. A major limitation to achieving successful bony union is impaired neovascularization. To augment fracture healing, we designed an implantable drug delivery technology containing the angiogenic stimulant, deferoxamine (DFO). DFO activates new blood vessel formation through iron chelation and upregulation of the HIF-1α pathway. However, due to its short half-life and rapid clearance, maintaining DFO at the callus site during peak fracture angiogenesis has remained challenging. To overcome these limitations, we composed an implantable formulation of DFO conjugated to hyaluronic acid (HA). This compound immobilizes DFO within the fracture callus throughout the angiogenic window, making it a high-capacity iron sponge that amplifies blood vessel formation and prevents nonunions. We investigated implanted HA-DFO's capacity to facilitate fracture healing in the irradiated rat mandible, a model whereby nonunions routinely develop secondary to obliteration of vascularity. HA-DFO implantation significantly improved radiomorphometrics and metrics of biomechanical strength. In addition, HA-DFO treated mandibles exhibited a remarkable 91% bone union rate, representing a 3.5-fold improvement over non-treated/irradiated controls (20% bone union rate). Collectively, our work proposes a unique methodology for the targeted delivery of DFO to fracture sites in order to facilitate neovascularization. If these findings are successfully translated into clinical practice, millions of patients will benefit from the prevention of nonunions.