Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified ("gene activated") tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible

Exactech Opteon Femoral Component Fracture 12 Years after Arthroplasty

Arthroplasty implant fracture is a rare but critical complication that requires difficult revision surgery, often with poor results, patient disability, and significant cost. Several reports show component fracture either at the stem or at the neck interface after a relatively short postoperative course. We report such failure after 12 years, suggesting no safe period after which femoral implant fracture does not occur

Control of Amphiphile Self-Assembly via Bioinspired Metal Ion Coordination

Inspired by marine siderophores that exhibit a morphological shift upon metal coordination, hybrid peptide-polymer conjugates that assemble into different morphologies based on the nature of the metal ion coordination have been designed. Coupling of a peptide chelator, hexahistidine, with hydrophobic oligostyrene allows a modular strategy to be established for the efficient synthesis and purification of these tunable amphiphiles (oSt(His)6). Remarkably, in the presence of different divalent transition metal ions (Mn, Co, Ni, Cu, Zn, and Cd) a variety of morphologies were observed. Zinc(II), cobalt(II), and copper(II) led to aggregated micelles. Nickel(II) and cadmium(II) produced micelles, and multilamellar vesicles were obtained in the presence of manganese(II). This work highlights the significant potential for transition metal ion coordination as a tool for directing the assembly of synthetic nanomaterials

RAPID AND RELIABLE HEALING OF CRITICAL SIZE BONE DEFECTS WITH GENETICALLY MODIFIED SHEEP MUSCLE

Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials

A measurement of ∆Γs

Using a dataset corresponding to 9 fb−1 of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes Bs 0→J/ψη′ and Bs 0→J/ψπ+π− are studied. The decay-width difference between the light and heavy mass eigenstates of the Bs 0 meson is measured to be ∆Γs = 0.087 ± 0.012 ± 0.009 ps−1, where the first uncertainty is statistical and the second systematic

Measurement of the mass difference and relative production rate of the Ωb−\Omega^-_b and Ξb−\Xi^-_b baryons

The mass difference between the $\Omega^-_b$ and $\Xi^-_b$ baryons is measured using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of $9 \, \text{fb}^{-1}$, and is found to be \begin{equation} m(\Omega^-_b)- m(\Xi^-_b) = 248.54 \pm 0.51 \text{(stat)} \pm 0.38 \text{(syst)} \, \text{MeV}/c^2. \end{equation} The mass of the $\Omega^-_b$ baryon is measured to be \begin{equation} m(\Omega^-_b)= 6045.9 \pm 0.5 \text{(stat)} \pm 0.6 \text{(syst)} \, \text{MeV}/c^2. \end{equation} This is the most precise determination of the $\Omega^-_b$ mass to date. In addition, the production rate of $\Omega^-_b$ baryons relative to that of $\Xi^-_b$ baryons is measured for the first time in $pp$ collisions, using an LHCb dataset collected at a center-of-mass energy of $13 \, \text{TeV}$ and corresponding to an integrated luminosity of $6\,\text{fb}^{-1}$. Reconstructing beauty baryons in the kinematic region $2 < \eta < 6$ and $p_T < 20\,\text{GeV}/c$ with their decays to a $J/\psi$ meson and a hyperon, the ratio \begin{equation} \frac{f_{\Omega^-_b}}{f_{\Xi^-_b}}\times\frac{\mathcal{B}(\Omega^-_b \to J/\psi \Omega^-)}{\mathcal{B}(\Xi^-_b \to J/\psi \Xi^-)} = 0.120 \pm 0.008 \text{(stat)} \pm 0.008 \text{(syst)}, \end{equation} is obtained, where $f_{\Omega^-_b}$ and $f_{\Xi^-_b}$ are the fragmentation fractions of $b$ quarks into $\Omega^-_b$ and $\Xi^-_b$ baryons, respectively, and $\mathcal{B}$ represents the branching fractions of their respective decays.Comment: 23 pages, 3 figures. All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-053.html (LHCb public pages

First Observation of a Doubly Charged Tetraquark and Its Neutral Partner

A combined amplitude analysis is performed for the decays B0→D ̄D0s+π- and B+→D-Ds+π+, which are related by isospin symmetry. The analysis is based on data collected by the LHCb detector in proton-proton collisions at center-of-mass energies of 7, 8, and 13 TeV. The full data sample corresponds to an integrated luminosity of 9 fb-1. Two new resonant states with masses of 2.908±0.011±0.020 GeV and widths of 0.136±0.023±0.013 GeV are observed, which decay to Ds+π+ and Ds+π- respectively. The former state indicates the first observation of a doubly charged open-charm tetraquark state with minimal quark content [cs ̄ud ̄], and the latter state is a neutral tetraquark composed of [cs ̄ūd] quarks. Both states are found to have spin-parity of 0+, and their resonant parameters are consistent with each other, which suggests that they belong to an isospin triplet

Observation of strangeness enhancement with charmed mesons in high-multiplicity pPbp\mathrm{Pb} collisions at sNN=8.16 \sqrt {s_{\mathrm{NN}}}=8.16\,TeV

The production of prompt $D^+_{s}$ and $D^+$ mesons is measured by the LHCb experiment in proton-lead ($p\mathrm{Pb}$) collisions in both the forward ($1.5<y^*<4.0$) and backward ($-5.0<y^*<-2.5$) rapidity regions at a nucleon-nucleon center-of-mass energy of $\sqrt {s_{\mathrm{NN}}}=8.16\,$TeV. The nuclear modification factors of both $D^+_{s}$ and $D^+$ mesons are determined as a function of transverse momentum, $p_{\mathrm{T}}$, and rapidity. In addition, the $D^+_{s}$ to $D^+$ cross-section ratio is measured as a function of the charged particle multiplicity in the event. An enhanced $D^+_{s}$ to $D^+$ production in high-multiplicity events is observed for the whole measured $p_{\mathrm{T}}$ range, in particular at low $p_{\mathrm{T}}$ and backward rapidity, where the significance exceeds six standard deviations. This constitutes the first observation of strangeness enhancement in charm quark hadronization in high-multiplicity $p\mathrm{Pb}$ collisions. The results are also qualitatively consistent with the presence of quark coalescence as an additional charm quark hadronization mechanism in high-multiplicity proton-lead collisions.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-021.html (LHCb public pages