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Achieving fusion in osseous procedures about the foot and ankle presents unique challenges to the surgeon. Many patients have comorbidities that reduce osseous healing rates, and the limited space and high weightbearing demand placed on fusion sites makes the choice of bone graft, bone graft substitute, or orthobiologic agent of utmost importance. In this review, we discuss the essential characteristics of grafts, including their osteoconductive, osteoinductive, osteogenic, and angiogenic properties. Autologous bone graft remains the gold standard and contains all these properties. However, the convenience and lack of donor site morbidity of synthetic bone grafts, allografts, and orthobiologics, including growth factors and allogenic stem cells, has led to these being used commonly as augments.Level of Evidence:Level V, expert opinion.

This is the first report, to our knowledge, of a fracture, unrelated to trunnion corrosion, through the midneck of a well-fixed uncemented cobalt-chromium alloy femoral component that had been implanted via a total hip revision arthroplasty 25 years ago. Three years after a second revision for polyethylene wear, the patient noted an acute onset of pain in the left hip. There was no antecedent pain in the hip or thigh. Radiographs and intraoperative findings showed a well-fixed femoral component. Electron microscopic retrieval analysis showed intergranular material cracks. Revision of the femoral component was performed with an extended trochanteric osteotomy. This fracture of the femoral component neck was likely related to metal fabrication techniques, and surveillance of this component may be warranted. Keywords: Femoral component neck fracture, Total hip arthroplasty, Revision, Catastrophic failure

Political tolerance ­­­–– the willingness to afford basic civil rights to individuals or groups that one finds disagreeable –– is fundamental to liberal democracy. For several decades, political scientists believed that widespread religious adherence in the United States threatened political tolerance. Recent research casts doubt on the direct relationship between religiosity and political tolerance. However, this research is based on decades-old data or a sample collected from a single county. My study tests the relationship between religiosity and political tolerance using more recent national survey data. It confirms that, although religiosity is related to dogmatism, no direct relationship exists between religiosity and political tolerance.

We document a basic characteristic of adverse selection in secondhand markets for durable goods: goods with higher observed quality may have more adverse selection and hence lower unobserved quality. We provide a simple theoretical model to demonstrate this result, which is a consequence of the interaction of sorting between drivers over observed quality and adverse selection over unobserved quality. We then offer empirical support using data on secondhand prices and repair rates of used cars from the Consumer Expenditure Survey, and discuss a number of implications for everyday advertising and consumer questions. Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2016.2495 . This paper was accepted by J. Miguel Villas-Boas, marketing.

Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).

Delivered by every president since Eisenhower (and annually since 1961), the presidents' remarks at the National Prayer Breakfast represent the most succinct presidential expressions of religion in...

Periprosthetic infection remains a frequent complication after total knee arthroplasty. The most common treatment is a two-stage procedure involving removal of all implants and cement, thorough debridement, insertion of some type of antibiotic spacer, and a course of antibiotic therapy of varying lengths. After some interval, and presumed eradication of the infection, new arthroplasty components are implanted in the second procedure. These knee spacers may be static or mobile spacers, with the latter presumably providing improved function for the patient and greater ease of surgical reimplantation. Numerous types of antibiotic cement spacers are available, including premolded cement components, surgical molds for intraoperative spacer fabrication, and the use of new metal and polyethylene knee components; all these are implanted with surgeon-prepared high-dose antibiotic cement. As there are advantages and disadvantages of both static and the various mobile spacers, surgeons should be familiar with several techniques. There is inconclusive data on the superiority of any antibiotic spacer. Both mechanical complications and postoperative renal failure may be associated with high-dose antibiotic cement spacers.

Background Periarticular injection or anesthesiologist-performed adductor canal block are commonly used for pain management after total knee arthroplasty. A surgeon-performed, intra-articular saphenous nerve block has been recently described. There is insufficient data comparing the efficacy and safety of these methods. Methods This is a retrospective two-surgeon cohort study comparing short-term perioperative outcomes after primary total knee arthroplasty, in 50 consecutive patients with surgeon-performed high-dose periarticular injection and intra-articular saphenous nerve block (60 mL 0.5% bupivacaine, 30 mL saline, 30mg ketorolac) and 50 consecutive patients with anesthesiologist-performed adductor canal catheter (0.25% bupivacaine 6 mL/h infusion pump placed postoperatively with ultrasound guidance). Chart review assessed pain scores through POD #1, opioid use, length of stay, and short-term complications, including local anesthetic systemic toxicity. Statistical analysis was performed with two-tailed Student's T-test. Results The high-dose periarticular injection cohort had significantly lower pain scores in the postanesthesia care unit (mean difference 1.4, P = .035), on arrival to the inpatient ward (mean difference 1.7, P = .013), and required less IV narcotics on the day of surgery (mean difference 6.5 MME, P = .0004). There was no significant difference in pain scores on POD #1, total opioid use, day of discharge, or short-term complications. There were no adverse events related to the high dose of bupivacaine. Conclusion Compared with postoperative adductor canal block catheter, an intraoperative high-dose periarticular block demonstrated lower pain scores and less IV narcotic use on the day of surgery. No difference was noted in pain scores on POD #1, time to discharge, or complications. There were no cardiovascular complications (local anesthetic systemic toxicity) despite the high dose of bupivacaine injected. Level of Evidence III.

Three-dimensional (3D) printing is an exciting form of manufacturing technology that has transformed the way we can treat various medical pathologies. Also known as additive manufacturing, 3D printing fuses materials together in a layer-by-layer fashion to construct a final 3D product. This technology allows flexibility in the design process and enables efficient production of both off-the-shelf and personalized medical products that accommodate patient needs better than traditional manufacturing processes. In the field of orthopaedic surgery, 3D printing implants and instrumentation can be used to address a variety of pathologies that would otherwise be challenging to manage with products made from traditional subtractive manufacturing. Furthermore, 3D bioprinting has significantly impacted bone and cartilage restoration procedures and has the potential to completely transform how we treat patients with debilitating musculoskeletal injuries. Although costs can be high, as technology advances, the economics of 3D printing will improve, especially as the benefits of this technology have clearly been demonstrated in both orthopaedic surgery and medicine as a whole. This review outlines the basics of 3D printing technology and its current applications in orthopaedic surgery and ends with a brief summary of 3D bioprinting and its potential future impact.

Diabetic trauma patients exhibit delayed postsurgical wound, bony healing, and dysregulated bone development. However, the impact of diabetes on the pathologic development of ectopic bone or heterotopic ossification (HO) following trauma is unknown. In this study, we use leptin-deficient mice as a model for type 2 diabetes to understand how post-traumatic HO development may be affected by this disease process. Male leptin-deficient (ob/ob) or wild-type (C57BL/6 background) mice aged 6-8 weeks underwent 30% total body surface area burn injury with left hind limb Achilles tenotomy. Micro-CT (μCT) imaging showed significantly lower HO volumes in diabetic mice compared with wild-type controls (0.70 vs. 7.02 mm(3), P < 0.01) 9 weeks after trauma. Ob/ob mice showed evidence of HO resorption between weeks 5 and 9. Quantitative real time PCR (qRT-PCR) demonstrated high Vegfa levels in ob/ob mice, which was followed by disorganized vessel growth at 7 weeks. We noted diminished chondrogenic gene expression (SOX9) and diminished cartilage formation at 5 days and 3 weeks, respectively. Tartrate-resistant acid phosphatase stain showed increased osteoclast presence in normal native bone and pathologic ectopic bone in ob/ob mice. Our findings suggest that early diminished HO in ob/ob mice is related to diminished chondrogenic differentiation, while later bone resorption is related to osteoclast presence.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment (“drug on”), the impact of drug withdrawal (“drug off”) implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment (“drug on”) and subsequent withdrawal (“drug off”) through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the “drug on” (Cre-mediated inactivation) and “drug off” (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766–778

BACKGROUND: By understanding the global inflammatory effects on distant myopathies, surgeons can better guide the rehabilitative process for burn patients. The authors tested the systemic effect of burn injury on distant injured muscle and native bone using immunohistochemistry and validated a new morphometric analytic modality to reproducibly quantify muscle atrophy using computed tomographic imaging. METHODS: In vivo studies were performed on C57/BL6 mice using an Achilles tenotomy with concurrent burn injury model. Total muscle and bone (tibia and fibula) volume/density were quantified near the site of Achilles tenotomy using micro-computed tomography at 5, 7, and 9 to 12 weeks after surgery. The impact of burn injury on the inflammatory cascade [nuclear factor (NF)-κB, p-NF-κB] and the interconnected protein catabolism signaling pathway (Atrogin-1) was assessed by immunohistochemistry. RESULTS: Muscle volume and density at the site of Achilles tenotomy in burned mice were significantly diminished compared with nonburned mice at 5 weeks and 9 to 12 weeks. Similar decreases in muscle volume and density were observed when comparing tenotomy to no tenotomy. Cortical bone health remained stable in burn/tenotomy mice compared with tenotomy. Muscle atrophy was associated with up-regulation of p-NF-κB, NF-κB, and Atrogin-1 assessed by immunohistochemistry. CONCLUSIONS: Burn injury significantly decreases muscle volume and density. Increased muscle atrophy using our computed tomographic morphometric analysis correlated with a significant increase in intramuscular inflammatory markers and proteolysis enzymes. This study demonstrates a unique characterization of how burn injuries may worsen local myopathy. Moreover, it provides a novel approach for quantifying muscle atrophy over an expanded period. Language: en

Patients with severe burns suffer functional, structural, and esthetic complications. It is important to explore reconstructive options given that no ideal treatment exists. Transfer of adipose and adipose-derived stem cells (ASCs) has been shown to improve healing in various models. The authors hypothesize that use of fat isografts and/or ASCs will improve healing in a mouse model of burn injury. Twenty 6 to 8 week old C57BL/6 male mice received a 30% surface area partial-thickness scald burn. Adipose tissue and ASCs from inguinal fat pads were harvested from a second group of C57BL/6 mice. Burned mice received 500 μl subcutaneous injection at burn site of 1) processed adipose, 2) ASCs, 3) mixed adipose (adipose and ASCs), or 4) sham (saline) injection (n = 5/group) on the first day postinjury. Mice were followed by serial photography until being killed at days 5 and 14. Wounds were assessed for burn depth and healing by hematoxylin and eosin (H&E) and immunohistochemistry. All treated groups showed improved healing over controls defined by decreased wound depth, area, and apoptotic activity. After 5 days, mice receiving ASCs or mixed adipose displayed a non-significant improvement in vascularization. No significant changes in proliferation were noted at 5 days. Adipose isografts improve some early markers of healing postburn injury. The authors demonstrate that addition of these grafts improves specific structural markers of healing. This improvement may be because of an increase in early wound vascularity postgraft. Further studies are needed to optimize use of fat or ASC grafts in acute and reconstructive surgery.

Recent research into adipose-derived stem cells (ASCs) suggests that anatomical location has a major impact on the metabolic profile and differentiation capacity of ASCs. By having a better understanding of how various ASCs respond to cellular stressors such as hypoxia, which are induced during routine surgical procedures, we can facilitate future development of cell-based therapies to improve wound healing.Human ASCs were isolated from the superficial and deep adipose layers of four patients undergoing elective abdominoplasty. ASCs were cultured in hypoxic (1% O2, 5% CO2, and 94% N2) conditions. After 12 and 48 hours, ASCs were assessed for markers of angiogenesis by mRNA levels of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and hypoxia inducible factor 1 α (HIF-1α). Western blot analysis was performed to assess levels of VEGF-A, p-NF-κB, and NF-κB. In addition, in vitro analysis of angiogenesis was performed using Matrigel assay (BD Biosciences, Franklin Lakes, NJ).We observed significant increases in deep ASC's VEGF-A, VEGF-B, and HIF-1α mRNA expression compared with the superficial layer after 24-hour hypoxia (p0.05). Similar results were found when examining protein expression levels, with the deep ASCs expressing significantly larger amounts of VEGF-A and p-NF-κB (p0.05) compared with the superficial layer.Our results suggest that significant variations exist in the angiogenic profile of superficial and deep ASCs. We demonstrate that superficial ASCs are less prone to transcribe potent chemokines for angiogenesis, such as VEGF-A, VEGF-B, and HIF-1α and are less likely to translate VEGF-A and NF-κB. This may help with the selection of specific stem cell donor sites in future models for stem cell therapy.

Heterotopic ossification (HO) is the abnormal formation of bone in soft tissue. Current diagnostics have low sensitivity or specificity to incremental progression of mineralization, especially at early time points. Without accurate and reliable early diagnosis and intervention, HO progression often results in incapacitating conditions of limited range of motion, nerve entrapment, and pain. We hypothesized that non-invasive near-infrared (NIR) optical imaging can detect HO at early time points and monitor heterotopic bone turnover longitudinally. C57BL6 mice received an Achilles tenotomy on their left hind limb in combination with a dorsal burn or sham procedure. A calcium-chelating tetracycline derivative (IRDye 680RD BoneTag) was injected bi-weekly and imaged via NIR to measure accumulative fluorescence for 11 wk and compared to in vivo microCT images. Percent retention of fluorescence was calculated longitudinally to assess temporal bone resorption. NIR detected HO as early as five days and revealed a temporal response in HO formation and turnover. MicroCT could not detect HO until 5 wk. Confocal microscopy confirmed fluorophore localization to areas of HO. These findings demonstrate the ability of a near-infrared optical imaging strategy to accurately and reliably detect and monitor HO in a murine model.

We analyze adverse selection in the used-car market using a new approach that considers a car as an assemblage of parts, some with symmetric information and others with asymmetric information. Using data from the Consumer Expenditure Survey and Consumer Reports, we examine turnover and repair patterns. We find evidence of adverse selection due to the conditions of the transmission, engine, and, during colder months, air-conditioning; and sorting due to the conditions of the vehicle body and, during warmer months, air-conditioning. Our quantification exercises indicate that adverse selection may have a meaningful effect on trade volume and quality in the secondhand market.

Category: Arthroscopy Introduction/Purpose: Ankle impingement and ankle osteochondral defects are common problems seen by foot and ankle specialist that often go on to require surgical managment. After conservative treatment fails, ankle impingement is often managed by arthroscopic debridement, whereas ankle OCDs are often treated with ankle arthroscopy and microfracture as a first line treatment. However, surgeons have various treatment protocols post-operatively after these procedures, with some surgeons allowing immediate weight bearing, were as other surgeons restrict patients weight bearing. There is similar heterogeneity in the manner of immobilization post-operatively. The purpose of this study is to retrospectively review the outcomes of patients undergoing ankle arthroscopy and micro fracture, to determine if immediate weight bearing or removable immobilization had any impact on outcomes. Methods: We retrospectively reviewed 79 patients at our institution who underwent ankle arthroscopy with microfracture for talar osteochondral defects over 3 years. This included surgeries performed by one of 7 fellowship trained foot and ankle surgeons at our institution. Each surgeon had different protocols for post-operative weight bearing and immobilization, allowing for a comparison of various post-operative protocols. Patient outcomes were reviewed pre-operatively and post-operatively including age, sex, comorbidities, etiology of talar pathology, post-operative weight bearing status, time to first weight bearing, as well as method and length of immobilization, VAS scores, range of motion, and complications. Clinical outcomes such as time to return to work and return to sport were also evaluated. Results: The average patient age was 38. 42 patients (53%) had an additional procedure performed at the time of ankle arthroscopy and microfracture. There was no significant difference in the average pre-op and post-op VAS or range of motion between the immediate weight bearing group and the delayed weight bearing group. There was interestingly a trend towards lower VAS scores in the immediate weight bearing group (1.4 vs 2.6). Conclusion: Following ankle arthroscopy and microfracture, we found no difference in VAS, range of motion, or complications when allowing immediate, full weight bearing as well as using removable immobilization as compared to a variety of other protocols at early follow up. In fact, there was a trend towards lower VAS scores in the immediate full weight bearing group. Though this study has early follow up, it does suggest at least the equivalency of allowing immediate weight bearing and removable immobilization following ankle arthroscopy and talar microfracture.

Introduction: Analytical morphomics focuses on extracting objective and quantifiable data from clinical computed tomography (CT) scans to measure patients’ frailty. Studies are currently retrospective in nature; therefore, it would be beneficial to develop animal models for well-controlled, prospective studies. The aim of this study is to develop an in vivo microCT protocol for the longitudinal acquisition of whole-body images suitable for morphomic analyses of bone. Methods: The authors performed phantom studies on 2 microCT systems (Inveon and CT120) to study tissue radiodensity and further characterize system performance for collecting animal data. The authors also describe their design of a phantom-immobilization device using phantoms and an ovariectomized (OVX) mouse. Results: The authors discovered increased consistency along the z-axis for scans acquired on the Inveon compared with CT120, and calibration by individual slice reduces variability. Objects in the field of view had more impact on measurement acquired using the CT120 compared with the Inveon. The authors also found that using the middle 80% of slices for data analysis further decreased variability, on both systems. Moreover, bone-mineral-density calibration using the QCT Pro Mini phantom improved bone-mineral-density estimates across energy spectra, which helped confirm our technique. Comparison of weekly body weights and terminal uterine mass between sham and OVX groups validated our model. Discussion: The authors present a refined microCT protocol to collect reliable and objective data. This data will be used to establish a platform for research animal morphomics that can be used to test hypotheses developed from clinical human morphomics.

Heterotopic ossification (HO) is the pathologic formation of bone separate from the normal skeleton. Although several models exist for studying HO, an understanding of the common in vitro properties of cells isolated from these models is lacking. We studied three separate animal models of HO including two models of trauma-induced HO and one model of genetic HO, and human HO specimens, to characterize the properties of cells derived from tissue containing pre-and mature ectopic bone in relation to analogous mesenchymal cell populations or osteoblasts obtained from normal muscle tissue. We found that when cultured in vitro, cells isolated from the trauma sites in two distinct models exhibited increased osteogenic differentiation when compared to cells isolated from uninjured controls. Furthermore, osteoblasts isolated from heterotopic bone in a genetic model of HO also exhibited increased osteogenic differentiation when compared with normal osteoblasts. Finally, osteoblasts derived from mature heterotopic bone obtained from human patients exhibited increased osteogenic differentiation when compared with normal bone from the same patients. These findings demonstrate that across models, cells derived from tissues forming heterotopic ossification exhibit increased osteogenic differentiation when compared with either normal tissues or osteoblasts. These cell types can be used in the future for in vitro investigations for drug screening purposes.

Heterotopic ossification (HO) is the formation of bone outside of the skeleton which forms following major trauma, burn injuries, and orthopaedic surgical procedures. The majority of animal models used to study HO rely on the application of exogenous substances, such as bone morphogenetic protein (BMP), exogenous cell constructs, or genetic mutations in BMP signaling. While these models are useful they do not accurately reproduce the inflammatory states that cause the majority of cases of HO. Here we describe a burn/tenotomy model in mice that reliably produces focused HO. This protocol involves creating a 30% total body surface area partial thickness contact burn on the dorsal skin as well as division of the Achilles tendon at its midpoint. Relying solely on traumatic injury to induce HO at a predictable location allows for time-course study of endochondral heterotopic bone formation from intrinsic physiologic processes and environment only. This method could prove instrumental in understanding the inflammatory and osteogenic pathways involved in trauma-induced HO. Furthermore, because HO develops in a predictable location and time-course in this model, it allows for research to improve early imaging strategies and treatment modalities to prevent HO formation.

BACKGROUND Heterotopic ossification most commonly occurs after burn injury, joint arthroplasty, and trauma. Male gender has been identified as a risk factor for the development of heterotopic ossification. It remains unclear why adult male patients are more predisposed to this pathologic condition than adult female patients. In this study, the authors use their validated tenotomy/burn model to explore differences in heterotopic ossification between male and female mice. METHODS The authors used their Achilles tenotomy and burn model to evaluate the osteogenic potential of mesenchymal stem cells of male and female injured and noninjured mice. Groups consisted of injured male (n = 3), injured female (n = 3), noninjured male (n = 3), and noninjured female (n = 3) mice. The osteogenic potential of cells harvested from each group was assessed through RNA and protein levels and quantified using micro-computed tomographic scan. Histomorphometry was used to verify micro-computed tomographic findings, and immunohistochemistry was used to assess osteogenic signaling at the site of heterotopic ossification. RESULTS Mesenchymal stem cells of male mice demonstrated greater osteogenic gene and protein expression than those of female mice (p < 0.05). Male mice in the burn group formed 35 percent more bone than female mice in the burn group. This bone formation correlated with increased pSmad and insulin-like growth factor 1 signaling at the heterotopic ossification site in male mice. CONCLUSIONS The authors demonstrate that male mice form quantitatively more bone compared with female mice using their burn/tenotomy model. These findings can be explained at least in part by differences in bone morphogenetic protein and insulin-like growth factor 1 signaling.

Bony non-unions arising in the aftermath of collateral radiation injury are commonly managed with vascularized free tissue transfers. Unfortunately, these procedures are invasive and fraught with attendant morbidities. This study investigated a novel, alternative treatment paradigm utilizing adipose-derived stem cells (ASCs) combined with angiogenic deferoxamine (DFO) in the rat mandible.Rats were exposed to a bioequivalent dose of radiation and mandibular osteotomy. Those exhibiting non-unions were subsequently treated with surgical debridement alone or debridement plus combination therapy. Radiographic and biomechanical outcomes were assessed after healing.Significant increases in biomechanical strength and radiographic metrics were observed in response to combination therapy (p.05). Importantly, combined therapy enabled a 65% reduction in persisting non-unions when compared to debridement alone.We support the continued investigation of this promising combination therapy in its potential translation for the management of radiation-induced bony pathology. © 2015 Wiley Periodicals, Inc. Head Neck 38: E837-E843, 2016.

I revisit the role that bonding contracts, such as pension or minimum employment terms, have on employee turnover. I focus on efficiency of such bonds as well as the necessary contractual structure that it must have in competitive labor markets. I develop a two stage turnover model that, in the absence of bonding contracts, results in inefficiently high quit rates. I find that bonding contracts only reduce turnover if they are structured effectively; the agent who sets the workers’ wages must not have claim on the bond should the worker decide to quit. This finding is consistent with previous empirical literature that suggests that pensions given at larger companies have a greater effect on turnover and total compensation than pensions offered at smaller companies. I then show how bonding may be more or less important based on the amount of firm specific learning by doing inherent to that job. Finally, I compare the predictions of this model to the vast empirical literature on pensions and tuition reimbursement plans.

Mesenchymal stem cells (MSCs) can differentiate into several lineages during development and also contribute to tissue homeostasis and regeneration, although the requirements for both may be distinct. MSC lineage commitment and progression in differentiation are regulated by members of the transforming growth factor-β (TGF-β) family. This review focuses on the roles of TGF-β family signaling in mesenchymal lineage commitment and differentiation into osteoblasts, chondrocytes, myoblasts, adipocytes, and tenocytes. We summarize the reported findings of cell culture studies, animal models, and interactions with other signaling pathways and highlight how aberrations in TGF-β family signaling can drive human disease by affecting mesenchymal differentiation.

Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.

Access to readily available autogenous tissue that regenerates bone would greatly improve clinical care. We believe the osteogenic phenotype caused by mutations in ALK2 can be harnessed in adipose-derived stem cells (ASCs) to improve bone tissue engineering. We set out to demonstrate that ALK2 may serve as a novel target to (a) improve in vitro ASC osteogenic differentiation and (b) enhance in vivo bone regeneration and calvarial healing. Transgenic mice were designed using the Cre/lox system to express constitutively active ALK2 (caALK2) with ubiquitously inducible Cre expression after tamoxifen exposure. ASCs from caALK2+/− and caALK2−/− (control) mice were exposed to tamoxifen and assessed for pro-osteogenic gene expression, bone morphogenetic protein (BMP) signaling, and osteogenic differentiation. Next, ASCs collected from these transgenic mice were analyzed in vivo using a calvarial defect model and analyzed by micro-computed tomography (micro-CT) and histology. ASCs from caALK2+/− mice had increased BMP signaling as demonstrated by upregulation of pSmad 1/5. ASCs from caALK2+/− mice had enhanced bone signaling and osteogenic differentiation compared with caALK2−/− mice (n = 4, p < .05). Transcription of pro-osteogenic genes at day 7 was significantly higher in ASCs from caALK2-overexpressing mice (Alp, Runx2, Ocn, Opn) (n = 4, p < .05). Using micro-CT and histomorphometry, we found that bone formation was significantly higher in mice treated with caALK2-expressing ASCs in vivo. Using a novel transgenic mouse model, we show that expression of constitutively active ALK2 receptor results in significantly increased ASC osteogenic differentiation. Furthermore, we demonstrate that this increased ASC differentiation can be harnessed to improve calvarial healing.

Heterotopic ossification (HO) is a common and debilitating complication of burns, traumatic brain injuries, and musculoskeletal trauma and surgery. Although the exact mechanism of ectopic bone formation is unknown, mesenchymal stem cells (MSCs) capable of osteogenic differentiation are known to play an essential role. Interestingly, the prevalence of HO in the elderly population is low despite the high overall occurrence of musculoskeletal injury and orthopedic procedures. We hypothesized that a lower osteogenicity of MSCs would be associated with blunted HO formation in old compared with young mice. In vitro osteogenic differentiation of adipose-derived MSCs from old (18-20 months) and young (6-8 weeks) C57/BL6 mice was assessed, with or without preceding burn injury. In vivo studies were then performed using an Achilles tenotomy with concurrent burn injury HO model. HO formation was quantified using μCT scans, Raman spectroscopy, and histology. MSCs from young mice had more in vitro bone formation, upregulation of bone formation pathways, and higher activation of Smad and nuclear factor kappa B (NF-κB) signaling following burn injury. This effect was absent or blunted in cells from old mice. In young mice, burn injury significantly increased HO formation, NF-κB activation, and osteoclast activity at the tenotomy site. This blunted, reactive osteogenic response in old mice follows trends seen clinically and may be related to differences in the ability to mount acute inflammatory responses. This unique characterization of HO and MSC osteogenic differentiation following inflammatory insult establishes differences between age populations and suggests potential pathways that could be targeted in the future with therapeutics.

Heterotopic ossification (HO) is the abnormal formation of bone in soft tissue. Current diagnostics have low sensitivity or specificity to incremental progression of mineralization, especially at early time points. Without accurate and reliable early diagnosis and intervention, HO progression often results in incapacitating conditions of limited range of motion, nerve entrapment, and pain. We hypothesized that non-invasive near-infrared (NIR) optical imaging can detect HO at early time points and monitor heterotopic bone turnover longitudinally. C57BL6 mice received an Achilles tenotomy on their left hind limb in combination with a dorsal burn or sham procedure. A calcium-chelating tetracycline derivative (IRDye 680RD BoneTag) was injected bi-weekly and imaged via NIR to measure accumulative fluorescence for 11 wk and compared to in vivo microCT images. Percent retention of fluorescence was calculated longitudinally to assess temporal bone resorption. NIR detected HO as early as five days and revealed a temporal response in HO formation and turnover. MicroCT could not detect HO until 5 wk. Confocal microscopy confirmed fluorophore localization to areas of HO. These findings demonstrate the ability of a near-infrared optical imaging strategy to accurately and reliably detect and monitor HO in a murine model.

Introduction.In adipose tissue healing, angiogenesis is stimulated by adipose-derived stromal stem cells (ASCs). Ventral hernia repair (VHR) patients are at high risk for wound infections. We hypothesize that ASCs from VHR patients are less vasculogenic than ASCs from healthy controls.Methods.ASCs were harvested from the subcutaneous fat of patients undergoing VHR by the component separation technique and from matched abdominoplasty patients. RNA and protein were harvested on culture days 0 and 3. Both groups of ASCs were subjected to hypoxic conditions for 12 and 24 hours. RNA was analyzed using qRT-PCR, and protein was used for western blotting. ASCs were also grown in Matrigel under hypoxic conditions and assayed for tubule formation after 24 hours.Results.Hernia patient ASCs demonstrated decreased levels of VEGF-A protein and vasculogenic RNA at 3 days of growth in differentiation media. There were also decreases in VEGF-A protein and vasculogenic RNA after growth in hypoxic conditions compared to control ASCs. After 24 hours in hypoxia, VHR ASCs formed fewer tubules in Matrigel than in control patient ASCs.Conclusion.ASCs derived from VHR patients appear to express fewer vasculogenic markers and form fewer tubules in Matrigel than ASCs from abdominoplasty patients, suggesting decreased vasculogenic activity.

We revisit the idea that textbook publishers revise frequently in order to "kill off" the market for used books. While a popular idea, conflicting durable good models suggest alternatives to planned obsolescence. To address this particular case, we develop a model of the textbook market that generates unique empirical predictions for each of the three most relevant theories to the textbook industry. We then compare these predictions to empirical findings, such as the effect of the stock of used books on prices and revision, as well as the common practices of durability reductions and leasing; to determine which one best describes the market. The theories we model are; optimal durability, quality differences and time inconsistency. Of these models, quality differences, which generates planned obsolescence, best fits the stylized facts.

We build an infinite-horizon turnover model to address the relationship between turnover, pro- motion and wages. This paper is among a new set of turnover models that incorporate private worker taste shocks to produce non-degenerate endogenous turnover. Firms are deeply concerned with the costs of employee turnover. However, traditional labor economic theory is ill equipped to justify this concern. We explain how .firms capture rent from its continual relationships with an employee. Consistent with empirical studies, we find that an employee’s turnover rate will decrease once promoted. This paper also generates new empirical predictions as well as other well established wage and employee turnover dynamics.

BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre+ transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints – tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration.