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"Lewis, P M"
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Bioengineered human skeletal muscle capable of functional regeneration
Background
Skeletal muscle (SkM) regenerates following injury, replacing damaged tissue with high fidelity. However, in serious injuries, non-regenerative defects leave patients with loss of function, increased re-injury risk and often chronic pain. Progress in treating these non-regenerative defects has been slow, with advances only occurring where a comprehensive understanding of regeneration has been gained. Tissue engineering has allowed the development of bioengineered models of SkM which regenerate following injury to support research in regenerative physiology. To date, however, no studies have utilised human myogenic precursor cells (hMPCs) to closely mimic functional human regenerative physiology.
Results
Here we address some of the difficulties associated with cell number and hMPC mitogenicity using magnetic association cell sorting (MACS), for the marker CD56, and media supplementation with fibroblast growth factor 2 (FGF-2) and B-27 supplement. Cell sorting allowed extended expansion of myogenic cells and supplementation was shown to improve myogenesis within engineered tissues and force generation at maturity. In addition, these engineered human SkM regenerated following barium chloride (BaCl
2
) injury. Following injury, reductions in function (87.5%) and myotube number (33.3%) were observed, followed by a proliferative phase with increased MyoD+ cells and a subsequent recovery of function and myotube number. An expansion of the Pax7+ cell population was observed across recovery suggesting an ability to generate Pax7+ cells within the tissue, similar to the self-renewal of satellite cells seen in vivo
.
Conclusions
This work outlines an engineered human SkM capable of functional regeneration following injury, built upon an open source system adding to the pre-clinical testing toolbox to improve the understanding of basic regenerative physiology.
Journal Article
Primary track recovery in high-definition gas time projection chambers
We develop and validate a new algorithm called primary track recovery (ptr) that effectively deconvolves known physics and detector effects from nuclear recoil tracks in gas time projection chambers (TPCs) with high-resolution readout. This gives access to the primary track charge, length, and vector direction (helping to resolve the “head-tail” ambiguity). Additionally, ptr provides a measurement of the transverse and longitudinal diffusion widths, which can be used to determine the absolute position of tracks in the drift direction for detector fiducialization. Using simulated helium recoils in an atmospheric pressure TPC with a 70:30 mixture of He:CO2 we compare the performance of ptr to traditional methods for all key track variables. We find that the algorithm reduces reconstruction errors, including those caused by charge integration, for tracks with mean length-to-width ratios 1.4 and above, corresponding to recoil energies of 20 keV and above in the studied TPCs. We show that ptr improves on existing methods for head-tail disambiguation, particularly for highly inclined tracks, and improves the determination of the absolute position of recoils on the drift axis via transverse diffusion. We find that ptr can partially recover charge structure integrated out by the detector in the z direction, but that its determination of energy and length have worse resolution compared to existing methods. We use experimental data to qualitatively verify these findings and discuss implications for future directional detectors at the low-energy frontier.
Journal Article
Annexin-enriched osteoblast-derived vesicles act as an extracellular site of mineral nucleation within developing stem cell cultures
The application of extracellular vesicles (EVs) as natural delivery vehicles capable of enhancing tissue regeneration could represent an exciting new phase in medicine. We sought to define the capacity of EVs derived from mineralising osteoblasts (MO-EVs) to induce mineralisation in mesenchymal stem cell (MSC) cultures and delineate the underlying biochemical mechanisms involved. Strikingly, we show that the addition of MO-EVs to MSC cultures significantly (P < 0.05) enhanced the expression of alkaline phosphatase, as well as the rate and volume of mineralisation beyond the current gold-standard, BMP-2. Intriguingly, these effects were only observed in the presence of an exogenous phosphate source. EVs derived from non-mineralising osteoblasts (NMO-EVs) were not found to enhance mineralisation beyond the control. Comparative label-free LC-MS/MS profiling of EVs indicated that enhanced mineralisation could be attributed to the delivery of bridging collagens, primarily associated with osteoblast communication, and other non-collagenous proteins to the developing extracellular matrix. In particular, EV-associated annexin calcium channelling proteins, which form a nucleational core with the phospholipid-rich membrane and support the formation of a pre-apatitic mineral phase, which was identified using infrared spectroscopy. These findings support the role of EVs as early sites of mineral nucleation and demonstrate their value for promoting hard tissue regeneration.
Journal Article
Debridement, antibiotics and implant retention (DAIR) following hip and knee arthroplasty: results and findings of a multidisciplinary approach from a non-specialist prosthetic infection centre
Prosthetic joint infection (PJI) is a catastrophic complication following arthroplasty surgery. Recently a debridement, antibiotics and implant retention (DAIR) procedure has gained popularity for PJI where a thorough debridement, irrigation and modular component exchange is undertaken.
We present the outcome for DAIR, data collected prospectively, in a busy orthopaedic unit but not one specialising in PJI. All patients with PJI were included without loss of data or patients from 2012 to 2018 with a minimum follow-up of 5 years.
Four total knee replacements, 17 total hip replacements, one revision total hip replacement and three hip hemiarthroplasties are included with an average duration from onset of symptoms to the DAIR procedure of 11 days (range 1-22 days).
(24%) and
(32%) were the most common causative organisms, and the most common antibiotic regimens included intravenous teicoplanin and flucloxacillin. Average follow-up was 67 months (range 9-104 months). Only four patients went on to require revision surgery. An analysis of midterm patient outcome measures for 6 of the total hip replacement (THR) DAIR patients were compared with a database of 792 THRs (with a minimum two-year follow-up) carried out by the same surgeon revealed no significant difference in Oxford hip scores at one-year post-surgery (OHS DAIR 36.2 vs 39 for control group).
This study includes 25 consecutive patients treated with DAIR with only one reinfection, with a mean follow-up period of 5 years. Using a strict protocol, DAIR appears to offer a successful treatment strategy for the management of early PJI.
Journal Article
Prospective randomized trial of laparoscopic gastrojejunostomy versus duodenal stenting for malignant gastric outflow obstruction
We prospectively compared laparoscopic gastrojejunostomy with duodenal stenting as a means of palliating malignant gastric outflow obstruction.
A total of 27 patients with malignant gastric outflow obstruction were randomized to either laparoscopic gastrojejunostomy (LGJ) or duodenal stenting (DS) over a 3-year period.
Thirteen patients underwent successful LGJ and 10 had successful DS. Eight patients had complications after LGJ, but none had complications after DS. Patients who underwent LGJ had a significant increase in visual analog pain score at day 1 (p = 0.05), and also had a longer hospital stay compared to those who underwent DS (11.4 vs. 5.2 days, p = 0.02). After DS, patients experienced an improvement in physical health at 1 month as measured using the Short Form-36 (SF-36) questionnaire (p < 0.01). There was no change following LGJ.
Duodenal stenting is a safe means of palliating malignant gastric outflow obstruction. It offers significant advantages for patients compared with minimal-access surgery.
Journal Article
Outcomes following staged bilateral total hip replacement: does first-side surgery predict the second?
Patient-reported outcome measures (PROMs) for bilateral staged total hip replacements (THRs) were reviewed to determine whether first-side surgery can predict second-side outcomes.
A retrospective review was undertaken of a consecutive cohort of staged bilateral THRs using the same approach, implant and technique, from August 2009 to February 2020. Minimal important change (MIC) in PROMs was set at ≥5.
A total of 296 consecutive staged bilateral THRs were performed in 148 patients. Mean time interval between sides was 25 months (range 2-102). Mean age was 63.2 years for the first side and 65.3 years for the second; 62.8% of patients were female. Mean body mass index was 31.08 for the first side, increasing to 31.57 for the second side (
= 0.248). One-year follow-up PROMs were available for 96.6% and 92.5% of the first and second side, respectively. Mean PROMs improvement at 1 year was 26.4 for the first side and 25.1 for the second side (
= 0.207). Some 97.9% of patients achieved MIC for the first side and 96.3% for the second side (
= 0.092). Eight patients failed to reach an MIC on one side, all were female (
< 0.001); however, MIC was achieved for the contralateral side. Seven of eight patients (87.5%) achieved MIC by 2 years.
This study identified no significant difference between first- and second-side PROMs improvements following staged bilateral THRs at 1-year follow-up. Failure to reach MIC on one side does not preclude success on the other. Female patients were more prone to not reach MIC at 1 year, but improvement was still subsequently achieved in the majority of cases. The informed consent process is able to reflect this expectation.
Journal Article
Acute mechanical overload increases IGF-I and MMP-9 mRNA in 3D tissue-engineered skeletal muscle
Skeletal muscle (SkM) is a tissue that responds to mechanical load following both physiological (exercise) or pathophysiological (bed rest) conditions. The heterogeneity of human samples and the experimental and ethical limitations of animal studies provide a rationale for the study of SkM plasticity in vitro. Many current in vitro approaches of mechanical loading of SkM disregard the three-dimensional (3D) structure in vivo. Tissue engineered 3D SkM, that displays highly aligned and differentiated myotubes, was used to investigate mechano-regulated gene transcription of genes implicated in hypertrophy/atrophy. Static loading (STL) and ramp loading (RPL) at 10 % strain for 60 min were used as mechano-stimulation with constructs sampled immediately for RNA extraction. STL increased IGF-I mRNA compared to both RPL and CON (control, p = 0.003 and 0.011 respectively) whilst MMP-9 mRNA increased in STL and RPL compared to CON (both p < 0.05). IGFBP-2 mRNA was differentially regulated in RPL and STL compared to CON (p = 0.057), whilst a reduction in IGFBP-5 mRNA was found for STL and RPL compared to CON (both p < 0.05). There was no effect in the expression of putative atrophic genes, myostatin, MuRF-1 and MAFBx (all p > 0.05). These data demonstrate a transcriptional signature associated with SkM hypertrophy within a tissue-engineered model that more greatly recapitulates the in vivo SkM structure compared previously published studies.
Journal Article
Randomised trial of laparoscopic exploration of common bile duct versus postoperative endoscopic retrograde cholangiography for common bile duct stones
The management of stones in the common bile duct in the laparoscopic era is controversial. The three major options are preoperative endoscopic retrograde cholangiography (ERCP), laparoscopic exploration of the common bile duct (LECBD), or postoperative ERCP.
Between August, 1995, and August, 1997, 471 laparoscopic cholecystectomies were done in our department. In 427 (91%), satisfactory peroperative cholangiography was obtained. In 80 (17%) of these cases there were stones in the common bile duct. 40 patients were randomised to LECBD and 40 to postoperative ERCP. If LECBD failed, patients had either open exploration of the common bile duct or postoperative ERCP. If one postoperative ERCP failed, the procedure was repeated until the common bile duct was cleared of stones or an endoprosthesis was placed to prevent stone impaction. The primary endpoints were duct-clearance rates, morbidity, operating time, and hospital stay. Analyses were by intention to treat.
Age and sex distribution of patients was similar in the randomised groups. Duct clearance after the first intervention was 75% in both groups. By the end of treatment, duct clearance was 100% in the laparoscopic group compared with 93% in the ERCP group. Duration of treatment was a median of 90 min (range 25–310) in the laparoscopic group (including ERCPs for failed LECBD) compared with 105 min (range 60–255) in the postoperative ERCP group (p=0·1, 95% Cl for difference -5 to 40). Hospital stay was a median of 1 day (range 1–26) in the laparoscopic group compared with 3·5 days (range 1–11) in the ERCP group (p=0·0001, 95% Cl 1–2).
LECBD is as effective as ERCP in clearing the common bile duct of stones. There is a non-significant trend to shorter time in the operating theatre and a significantly shorter hospital stay in patients treated by LECBD.
Journal Article