Three-dimensionalenvironment and vascularization induce osteogenic maturation of human adipose-derived stem cells comparable to that of bone-derived progenitors

While human adipose-derived stem cells (hADSCs) are known to possess osteogenic differentiation potential, the bone tissues formed are generally considered rudimentary and immature compared with those made by bone-derived precursor cells such as human bone marrow-derived mesenchymal stem cells (hBMSCs) and less commonly studied human calvarium osteoprogenitor cells (hOPs). Traditional differentiation protocols have tended to focus on osteoinduction of hADSCs through the addition of osteogenic differentiation media or use of stimulatory bioactive scaffolds which have not resulted in mature bone formation. Here, we tested the hypothesis that by reproducing the physical as well as biochemical bone microenvironment through the use of three-dimensional (3D) culture and vascularization we could enhance osteogenic maturation in hADSCs. In addition to biomolecular characterization, we performed structural analysis through extracellular collagen alignment and mineral density in our bone tissue engineered samples to evaluate osteogenic maturation. We further compared bone formed by hADSCs, hBMSCs, and hOPs against mature human pediatric calvarial bone, yet not extensively investigated. Although bone generated by all three cell types was still less mature than native pediatric bone, a fibrin-based 3D microenvironment together with vascularization boosted osteogenic maturation of hADSC making it similar to that of bone-derived osteoprogenitors. This demonstrates the important role of vascularization and 3D culture in driving osteogenic maturation of cells easily available but constitutively less committed to this lineage and suggests a crucial avenue for recreating the bone microenvironment for tissue engineering of mature craniofacial bone tissues from pediatric hADSCs, as well as hBMSCs and hOPs

Correlation of Intracranial Volume With Head Surface Volume in Patients With Multisutural Craniosynostosis

Intracranial volume (ICV) is an important parameter for monitoring patients with multisutural craniosynostosis. Intracranial volume measurements are routinely derived from computed tomography (CT) head scans, which involves ionizing radiation. Estimation of ICV from head surface volumes could prove useful as 3D surface scanners could be used to indirectly acquire ICV information, using a non-invasive, non-ionizing method.Pre- and postoperative 3D CT scans from spring-assisted posterior vault expansion (sPVE) patients operated between 2008 and 2018 in a single center were collected. Patients were treated for multisutural craniosynostosis, both syndromic and non-syndromic. For each patient, ICV was calculated from the CT scans as carried out in clinical practice. Additionally, the 3D soft tissue surface volume (STV) was extracted by 3D reconstruction of the CT image soft tissue of each case, further elaborated by computer-aided design (CAD) software. Correlations were analyzed before surgery, after surgery, combined for all patients and in syndrome subgroups.Soft tissue surface volume was highly correlated to ICV for all analyses: r = 0.946 preoperatively, r = 0.959 postoperatively, and r = 0.960 all cases combined. Subgroup analyses for Apert, Crouzon-Pfeiffer and complex craniosynostosis were highly significant as well (P < 0.001).In conclusion, 3D surface model volumes correlated strongly to ICV, measured from the same scan, and linear equations for this correlation are provided. Estimation of ICV with just a 3D surface model could thus be realized using a simple method, which does not require radiations and therefore would allow closer monitoring in patients through multiple acquisitions over time

A novel soft tissue prediction methodology for orthognathic surgery based on probabilistic finite element modelling

Repositioning of the maxilla in orthognathic surgery is carried out for functional and aesthetic purposes. Pre-surgical planning tools can predict 3D facial appearance by computing the response of the soft tissue to the changes to the underlying skeleton. The clinical use of commercial prediction software remains controversial, likely due to the deterministic nature of these computational predictions. A novel probabilistic finite element model (FEM) for the prediction of postoperative facial soft tissues is proposed in this paper. A probabilistic FEM was developed and validated on a cohort of eight patients who underwent maxillary repositioning and had pre- and postoperative cone beam computed tomography (CBCT) scans taken. Firstly, a variables correlation assessed various modelling parameters. Secondly, a design of experiments (DOE) provided a range of potential outcomes based on uniformly distributed input parameters, followed by an optimisation. Lastly, the second DOE iteration provided optimised predictions with a probability range. A range of 3D predictions was obtained using the probabilistic FEM and validated using reconstructed soft tissue surfaces from the postoperative CBCT data. The predictions in the nose and upper lip areas accurately include the true postoperative position, whereas the prediction under-estimates the position of the cheeks and lower lip. A probabilistic FEM has been developed and validated for the prediction of the facial appearance following orthognathic surgery. This method shows how inaccuracies in the modelling and uncertainties in executing surgical planning influence the soft tissue prediction and it provides a range of predictions including a minimum and maximum, which may be helpful for patients in understanding the impact of surgery on the face

MRI-targeted or standard biopsy for prostate-cancer diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P&lt;0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .)

Quantifying the effect of corrective surgery for trigonocephaly: A non-invasive, non-ionizing method using three-dimensional handheld scanning and statistical shape modelling

Trigonocephaly in patients with metopic synostosis is corrected by fronto-orbital remodelling (FOR). The aim of this study was to quantitatively assess aesthetic outcomes of FOR by capturing 3D forehead scans of metopic patients pre- and post-operatively and comparing them with controls. Ten single-suture metopic patients undergoing FOR and 15 age-matched non-craniosynostotic controls were recruited at Great Ormond Street Hospital for Children (UK). Scans were acquired with a three-dimensional (3D) handheld camera and post-processed combining 3D imaging software. 3D scans were first used for cephalometric measurements. Statistical shape modelling was then used to compute the 3D mean head shapes of the three groups (FOR pre-op, post-op and controls). Head shape variations were described via principal component analysis (PCA). Cephalometric measurements showed that FOR significantly increased the forehead volume and improved trigonocephaly. This improvement was supported visually by pre- and post-operative computed mean 3D shapes and numerically by PCA (p < 0.001). Compared with controls, post-operative scans showed flatter foreheads (p < 0.001). In conclusion, 3D scanning followed by 3D statistical shape modelling enabled the 3D comparison of forehead shapes of metopic patients and non-craniosynostotic controls, and demonstrated that the adopted FOR technique was successful in correcting bitemporal narrowing but overcorrected the rounding of the forehead

A population-specific material model for sagittal craniosynostosis to predict surgical shape outcomes

Sagittal craniosynostosis consists of premature fusion (ossification) of the sagittal suture during infancy, resulting in head deformity and brain growth restriction. Spring-assisted cranioplasty (SAC) entails skull incisions to free the fused suture and insertion of two springs (metallic distractors) to promote cranial reshaping. Although safe and effective, SAC outcomes remain uncertain. We aimed hereby to obtain and validate a skull material model for SAC outcome prediction. Computed tomography data relative to 18 patients were processed to simulate surgical cuts and spring location. A rescaling model for age matching was created using retrospective data and validated. Design of experiments was used to assess the effect of different material property parameters on the model output. Subsequent material optimization—using retrospective clinical spring measurements—was performed for nine patients. A population-derived material model was obtained and applied to the whole population. Results showed that bone Young’s modulus and relaxation modulus had the largest effect on the model predictions: the use of the population-derived material model had a negligible effect on improving the prediction of on-table opening while significantly improved the prediction of spring kinematics at follow-up. The model was validated using on-table 3D scans for nine patients: the predicted head shape approximated within 2 mm the 3D scan model in 80% of the surface points, in 8 out of 9 patients. The accuracy and reliability of the developed computational model of SAC were increased using population data: this tool is now ready for prospective clinical application

Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0→J/ψK−p{\Lambda_b^0\to J/\psi K^-p} decays

Observations of exotic structures in the $J/\psi p$ channel, that we refer to as pentaquark-charmonium states, in $\Lambda_b^0\to J/\psi K^- p$ decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the $J/\psi p$ mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of $4380\pm 8\pm 29$ MeV and a width of $205\pm 18\pm 86$ MeV, while the second is narrower, with a mass of $4449.8\pm 1.7\pm 2.5$ MeV and a width of $39\pm 5\pm 19$ MeV. The preferred $J^P$ assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure