The Impact of Pupil Constriction on the Relationship Between Melanopic EDI and Melatonin Suppression in Young Adult Males.

The pupil modulates the amount of light that reaches the retina. Not only luminance but also the spectral distribution defines the pupil size. Previous research has identified steady-state pupil size and melatonin attenuation to be predominantly driven by melanopsin, which is expressed by a unique subgroup of intrinsically photosensitive retinal ganglion cells (ipRGCs) that are sensitive to short-wavelength light (~480 nm). Here, we aimed to selectively target the melanopsin system during the evening, while measuring steady-state pupil size and melatonin concentrations under commonly experienced evening light levels (<90 lx). Therefore, we used a five-primary display prototype to generate light conditions that were matched in terms of L-, M-, and S-cone-opic irradiances, but with high and low melanopic irradiances (~3-fold difference). Seventy-two healthy, male participants completed a 2-week study protocol. The volunteers were assigned to one of the four groups that differed in luminance levels (27-285 cd/m2). Within the four groups, each volunteer was exposed to a low melanopic (LM) and a high melanopic (HM) condition. The two 17-h study protocols comprised 3.5 h of light exposure starting 4 h before habitual bedtime. Median pupil size was significantly smaller during HM than LM in all four light intensity groups. In addition, we observed a significant correlation between melanopic weighted corneal illuminance (melanopic equivalent daylight illuminance [mEDI]) and pupil size, such that higher mEDI values were associated with smaller pupil size. Using pupil size to estimate retinal irradiance showed a qualitatively similar goodness of fit as mEDI for predicting melatonin suppression. Based on our results here, it remains appropriate to use melanopic irradiance measured at eye level when comparing light-dependent effects on evening melatonin concentrations in healthy young people at rather low light levels.

Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage.

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive surgery. Human MSC were genetically engineered with a gene cassette enabling apoptosis induction upon addition of an adjuvant. Engineered hMSC were seeded, differentiated, and devitalized within a perfusion bioreactor. The resulting HyC ECM was subsequently implanted in a 10-mm rabbit calvarial defect model, with processed human bone (Maxgraft®) as control. Human MSC cultured in the perfusion bioreactor generated a homogenous HyC ECM and were efficiently induced towards apoptosis. Following six weeks of in vivo implantation, microcomputed tomography and histological analyses of the defects revealed an increased bone formation in the defects filled with HyC ECM as compared to Maxgraft®. This work demonstrates the suitability of engineered devitalized HyC ECM as a bone substitute material, with a performance superior to a state-of-the-art commercial graft. Streamlined generation of the devitalized tissue transplant within a perfusion bioreactor is relevant towards standardized and automated manufacturing of a clinical product.

Prefabrication of a large pedicled bone graft by engineering the germ for de novo vascularization and osteoinduction.

Large and complex bone defects represent challenging clinical scenarios, typically requiring autologous vascularized bone transplants. In order to bypass the numerous associated limitations, here we aimed at ectopically prefabricating a bone graft surrogate with vascular pedicle. A hollow cylinder of devitalized cancellous bone was used to define the space of a large bone substitute. This space was filled with devitalized pellets of engineered hypertrophic cartilage as bone-inducing material, in combination or not with stromal vascular fraction (SVF) of adipose tissue as source of osteoprogenitors and endothelial cells. Vascularization of the space was targeted through axial insertion of an arterio-venous (AV) bundle. Constructs were subcutaneously implanted in nude rats for 12 weeks and analyzed for bone formation and vascularization by histology and microtomography. Retrieved constructs were extensively vascularized in all conditions, with vessels sprouting from the AV bundle and reaching a higher density in the axially central volume. Bone tissue was formed through remodeling of hypertrophic cartilage, and quantitatively correlated with de novo vascularization. Our study demonstrates feasibility to prefabricate large, pedicled bone grafts in predefined shapes. The combination of an AV bundle with engineered hypertrophic cartilage provided a germ for the coupled processes of vascularization and bone formation. The demonstrated osteoinductivity of devitalized hypertrophic cartilage offers the opportunity of implementing the proposed regenerative surgery strategy through off-the-shelf materials.

Intended Near-Total Removal of Koos Grade IV Vestibular Schwannomas: Reconsidering the Treatment Paradigm.

BACKGROUND: The goals of treating Koos grade IV vestibular schwannomas are to relieve brainstem compression, preserve or restore neurological function, and achieve long-term tumor control while minimizing tumor- and treatment-related morbidity. OBJECTIVE: To propose a treatment paradigm involving the intentional near-total removal of Koos grade IV vestibular schwannomas, in which a small amount of residual tumor is not dissected off the cisternal portion of the facial nerve. Patients are then followed by a wait-and-scan approach. Any subsequent volumetric progression of the residual tumor is treated with radiosurgery. METHODS: This is a case series of 44 consecutive unselected patients who underwent intended near-total resection of a Koos grade IV vestibular schwannoma through a retrosigmoid approach from January 2009 to December 2015. Pre- and postoperative volumetric analyses were performed on routine magnetic resonance imaging sequences (constructive interference in steady state and gadolinium-enhanced T1-weighted sequence). RESULTS: The mean preoperative tumor volume was 10.9 cm3. The mean extent of resection was 89%. At the last clinical follow-up, facial nerve function was good [House and Brackmann (HB) I-II] in 89%, fair (HB III) in 9%, and poor (HB IV-VI) in 2% of the patients. At the last radiological follow-up, the residual tumor had become smaller or remained the same size in 84% of patients. Volumetric progression was negatively correlated with the original extent of resection and positively correlated with postoperative residual tumor volume (P = .01, P < .001, respectively). CONCLUSION: Intended near-total removal results in excellent preservation of facial nerve function and has a low recurrence rate. Any progressive residual tumor may be treated by radiosurgery.

Capturing Plastic Surgery on Film-Making Reconstruction Visible.

The Swiss Plastic Surgery Association (https://plasticsurgery.ch/en/) decided to produce a corporate video to illustrate the concept of "plastic surgery of confidence" to the public. We show the diversity of specializations and the vast range of tasks that surgeons passionately handle day in and day out. We wanted to convey 2 main messages: first, that plastic surgery is more than just cosmetic surgery, and second, that plastic surgery in Switzerland is synonymous with quality and confidence. We selected 17 topics that we felt had good filmic potential and would best explain to the public what plastic surgery is about. This included the selection of appropriate patients, experts, and locations from all over the country. We thought it crucial to show the initial preoperative situation, as only in this case would the achievement of reconstruction be evident and comprehensive to the layman audience. The actual production was filmed in 5 different locations and took 5 days of shooting. We recorded 17 surgeons, 9 patients, and about 30 voluntary background actors. From 23 hours of footage, we created a 7 minute, 22 second corporate video, recorded in 3 of the Swiss national languages. The video was presented to the public online in June 2016, on the same day as the National Open Day of Plastic Surgery in Switzerland. The video is available online. We evaluated the impact of the video using a questionnaire for lay people and observed that it could substantially improve the perception of our specialty, especially regarding the reconstructive aspect. We feel that a freely available corporate video is a very useful means to promote plastic surgery and help patients better understand what it is all about.

Engineered, axially-vascularized osteogenic grafts from human adipose-derived cells to treat avascular necrosis of bone in a rat model.

BACKGROUND: Avascular necrosis of bone (AVN) leads to sclerosis and collapse of bone and joints. The standard of care, vascularized bone grafts, is limited by donor site morbidity and restricted availability. The aim of this study was to generate and test engineered, axially vascularized SVF cells-based bone substitutes in a rat model of AVN. METHODS: SVF cells were isolated from lipoaspirates and cultured onto porous hydroxyapatite scaffolds within a perfusion-based bioreactor system for 5days. The resulting constructs were inserted into devitalized bone cylinders mimicking AVN-affected bone. A ligated vascular bundle was inserted upon subcutaneous implantation of constructs in nude rats. After 1 and 8weeks in vivo, bone formation and vascularization were analyzed. RESULTS: Newly-formed bone was found in 80% of SVF-seeded scaffolds after 8weeks but not in unseeded controls. Human ALU+cells in the bone structures evidenced a direct contribution of SVF cells to bone formation. A higher density of regenerative, M2 macrophages was observed in SVF-seeded constructs. In both experimental groups, devitalized bone was revitalized by vascularized tissue after 8 weeks. CONCLUSION: SVF cells-based osteogenic constructs revitalized fully necrotic bone in a challenging AVN rat model of clinically-relevant size. SVF cells contributed to accelerated initial vascularization, to bone formation and to recruitment of pro-regenerative endogenous cells. STATEMENT OF SIGNIFICANCE: Avascular necrosis (AVN) of bone often requires surgical treatment with autologous bone grafts, which is surgically demanding and restricted by significant donor site morbidity and limited availability. This paper describes a de novo engineered axially-vascularized bone graft substitute and tests the potential to revitalize dead bone and provide efficient new bone formation in a rat model. The engineering of an osteogenic/vasculogenic construct of clinically-relevant size with stromal vascular fraction of human adipose, combined to an arteriovenous bundle is described. This construct revitalized and generated new bone tissue. This successful approach proposes a novel paradigm in the treatment of AVN, in which an engineered, vascularized osteogenic graft would be used as a germ to revitalize large volumes of necrotic bone.