Genicular Artery Embolisation in Patients with Osteoarthritis of the Knee (GENESIS 2): Protocol for a Double-Blind Randomised Sham-Controlled Trial.

Knee osteoarthritis is a leading cause of chronic disability and economic burden. In many patients who are not surgical candidates, existing treatment options are insufficient. Clinical evidence for a new treatment approach, genicular artery embolisation (GAE), is currently limited to single arm cohort, or small population randomised studies. This trial will investigate the use of a permanent embolic agent for embolisation of abnormal genicular arterial vasculature to reduce pain in patients with mild to moderate knee osteoarthritis. Up to 110 participants, 45 years or older, with knee pain for ≥ 3 months resistant to conservative treatment will be randomised (1:1) to GAE or a sham procedure. The treatment group will receive embolisation using 100-micron Embozene™ microspheres (Varian, a Siemens Healthineers Company) (investigational use for this indication in the UK), and the sham group will receive 0.9% saline in an otherwise identical procedure. Patients will be followed for 24 months. At 6 months, sham participants will be offered crossover to GAE. The primary endpoint is change of 4 Knee Injury and OA Outcome Score subscales (KOOS4) at 6 months post-randomisation. The study will also evaluate quality of life, health economics, imaging findings, and psychosocial pain outcomes. The primary manuscript will be submitted for publication after all participants complete 6 months of follow-up. The trial is expected to run for 3.5 years. Trial Registration: ClinicalTrials.gov, Identifier: NCT05423587.

Safety evaluation of a strategy to restart elective orthopaedic surgery during the de-escalation phase of the COVID-19 pandemic.

AIMS: To evaluate safety outcomes and patient satisfaction of the re-introduction of elective orthopaedic surgery on 'green' (non-COVID-19) sites during the COVID-19 pandemic. METHODS: A strategy consisting of phased relaxation of clinical comorbidity criteria was developed. Patients from the orthopaedic waiting list were selected according to these criteria and observed recommended preoperative isolation protocols. Surgery was performed at green sites (two local private hospitals) under the COVID-19 NHS contract. The first 100 consecutive patients that met the Phase 1 criteria and underwent surgery were included. In hospital and postoperative complications with specific enquiry as to development of COVID-19 symptoms or need and outcome for COVID-19 testing at 14 days and six weeks was recorded. Patient satisfaction was surveyed at 14 days postoperatively. RESULTS: There were 54 females and 46 males (mean age 44 years, mean body mass index (BMI) 25.6 kg/m2). In all, 56 patients underwent major orthopaedic procedures. There were no exclusions. One patient had a postoperative positive SARS-CoV-2 RT-PCR test but had no typical symptoms of COVID-19 infection and no clinical sequelae. 99% of patients were satisfied with the process and 98% would recommend undergoing elective orthopaedic surgery in the study period. CONCLUSION: In an environment with appropriate infrastructure, patient selection, isolation, screening, and testing, elective orthopaedic surgery is safe during the COVID-19 pandemic, and associated with high patient satisfaction. Further follow-up is required to establish that safety is maintained as the clinical restrictions are eased with the phased approach described.Cite this article: Bone Joint Open 2020;1-8:450-456.

The effect of COVID-19 on the trauma burden, theatre efficiency and training opportunities in a district general hospital: planning for a future outbreak.

AIMS: The aim of this study is to determine the effects of the UK lockdown during the COVID-19 pandemic on the orthopaedic admissions, operations, training opportunities, and theatre efficiency in a large district general hospital. METHODS: The number of patients referred to the orthopaedic team between 1 April 2020 and 30 April 2020 were collected. Other data collected included patient demographics, number of admissions, number and type of operations performed, and seniority of primary surgeon. Theatre time was collected consisting of anaesthetic time, surgical time, time to leave theatre, and turnaround time. Data were compared to the same period in 2019. RESULTS: There was a significant increase in median age of admitted patients during lockdown (70.5 (interquartile range (IQR) 46.25 to 84) vs 57 (IQR 27 to 79.75); p = 0.017) with a 26% decrease in referrals from 303 to 224 patients and 37% decrease in admissions from 177 to 112 patients, with a significantly higher proportion of hip fracture admissions (33% (n = 37) vs 19% (n = 34); p = 0.011). Paediatric admissions decreased by 72% from 32 to nine patients making up 8% of admissions during lockdown compared to 18.1% the preceding year (p = 0.002) with 66.7% reduction in paediatric operations, from 18 to 6. There was a significant increase in median turnaround time (13 minutes (IQR 12 to 33) vs 60 minutes (IQR 41 to 71); p < 0.001) although there was no significant difference in the anaesthetic time or surgical time. There was a 38% (61 vs 38) decrease in trainee-led operations. DISCUSSION: The lockdown resulted in large decreases in referrals and admissions. Despite this, hip fracture admissions were unaffected and should remain a priority for trauma service planning in future lockdowns. As plans to resume normal elective and trauma services begin, hospitals should focus on minimising theatre turnaround time to maximize theatre efficiency while prioritizing training opportunities. CLINICAL RELEVANCE: Lockdown has resulted in decreases in the trauma burden although hip fractures remain unaffected requiring priorityTheatre turnaround times and training opportunities are affected and should be optimised prior to the resumption of normal services.Cite this article: Bone Joint Open 2020;1-8:494-499.

Early Peri-Prosthetic Joint Infection after Hemiarthroplasty for Hip Fracture: Outcomes of Debridement, Antibiotics, and Implant Retention.

Background: There are currently no treatment algorithms specifically for early peri-prosthetic joint infection (PJI) after hemiarthroplasty for hip fracture. Commonly, debridement, antibiotics, and implant retention (DAIR) is attempted as first-line management, despite lack of evidence supporting this strategy in this patient group. The purpose of this study was to evaluate outcomes of DAIR for early PJI after hemiarthroplasty for hip fracture in our unit. Methods: The departmental database from December 2008 to January 2019 was searched to identify all patients in our unit who were treated for early PJI after hemiarthroplasty for hip fracture. Data for included patients were collected from electronic healthcare records and analyzed. Primary outcome measure was treatment success, defined as patient survival to discharge, with eradication of infection and implant retention. Results: Twenty-six patients were identified and included in the study. Mean age was 84.7 years. All except one patient were American Society of Anesthesiologists (ASA) class 3 or 4. All patients were McPherson host grade B or C. Twenty-three of 26 patients underwent DAIR and three of 26 proceeded directly to excision arthroplasty. Debridement, antibiotics, and implant retention was successful in three of 23 patients (13%) after a single procedure, with success in two additional patients after a second procedure, giving overall success rate of five of 23 patients (22%). Conclusions: Debridement, antibiotics, and implant retention has a high failure rate in treating early PJI after hemiarthroplasty for hip fracture. These patients are generally elderly and frail with multiple host and wound compromising factors. Debridement, antibiotics, and implant retention should not be recommended as first-line management for the majority of these patients, for whom getting it right the first time is of vital importance to avoid consequences associated with failed surgical procedures. Further multicenter studies that also explore alternate treatment strategies are required to devise an algorithm specifically for hip fracture patients, to aid decisions on treatment and improve outcomes.

Medium Term Outcome For A Constrained Acetabular Component At A Single Institution: What Is Important For Success?

BACKGROUND: The use of constrained Total Hip Replacements (THR) is controversial due to lack of definite indications and potentially high failure rates because of mechanical loosening or component failure. A review was performed to assess a departmental use of a single constrained acetabular component over a ten years period. METHODS: Patient demographics, operative indications, complications and patient follow-up were recorded. Post-operative Oxford Hip Scores (OHS) were obtained via a combination of New Zealand Joint Registry interrogation and telephonic questioning. Cup version and inclination angles were obtained from standardised anteroposterior radiographs using established techniques. RESULTS: Forty-four constrained components (in 39 patients) were implanted between 2005 and 2014. The mean age was 78 years with mean ASA 2.7 and mean follow-up 37.2 months (range 13-116). The mean post-operative OHS was 36 (SD 9.25), and there were 4 failures (3 dislocations and 1 peri-prosthetic fracture). The 3 dislocations had either cup ante version (AV) or inclination angles (IA) outside the data set interquartile range (AV 13-24°, IA 40-50°). The cup inclination was significantly lower (p<0.01) in patients with pain on sitting. At post-operative follow-up, 14/39 patients had died from unrelated causes, with only 1 patient surviving beyond 6 years. CONCLUSIONS: Constrained acetabular components offer a solution to hip instability in a difficult group of patients. This study has shown good medium-term outcomes of a single component type in a predominantly frail group of low demand patients. Despite constraint, correct cup placement (particularly inclination) remains important to prevent dislocation or poor reported outcome.

Large animal in vivo evaluation of a binary blend polymer scaffold for skeletal tissue-engineering strategies; translational issues.

Binary blend polymers offer the opportunity to combine different desirable properties into a single scaffold, to enhance function within the field of tissue engineering. Previous in vitro and murine in vivo analysis identified a polymer blend of poly(l-lactic acid)-poly(ε-caprolactone) (PLLA:PCL 20:80) to have characteristics desirable for bone regeneration. Polymer scaffolds in combination with marrow-derived skeletal stem cells (SSCs) were implanted into mid-shaft ovine 3.5 cm tibial defects, and indices of bone regeneration were compared to groups implanted with scaffolds alone and with empty defects after 12 weeks, including micro-CT, mechanical testing and histological analysis. The critical nature of the defect was confirmed via all modalities. Both the scaffold and scaffold/SSC groups showed enhanced quantitative bone regeneration; however, this was only found to be significant in the scaffold/SSCs group (p = 0.04) and complete defect bridging was not achieved in any group. The mechanical strength was significantly less than that of contralateral control tibiae (p < 0.01) and would not be appropriate for full functional loading in a clinical setting. This study explored the hypothesis that cell therapy would enhance bone formation in a critical-sized defect compared to scaffold alone, using an external fixation construct, to bridge the scale-up gap between small animal studies and potential clinical translation. The model has proved a successful critical defect and analytical techniques have been found to be both valid and reproducible. Further work is required with both scaffold production techniques and cellular protocols in order to successfully scale-up this stem cell/binary blend polymer scaffold. © 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.

The scale-up of a tissue engineered porous hydroxyapatite polymer composite scaffold for use in bone repair: an ovine femoral condyle defect study.

The development of an osteogenic bone graft substitute has important practical and cost implications in many branches of medicine where bone regeneration is required. Previous in vitro and small animal (murine) in vivo studies highlighted a porous hydroxyapatite/poly (DL-lactic acid) composite scaffold in combination with skeletal stem cells (SSCs) as a potential bone graft substitute candidate. The aim of the current study was to scale up the bone cell-scaffold construct to large animals and examine the potential for repair of a critical-sized defect via an ovine model. SSC seeded scaffolds (and unseeded scaffold controls) were implanted bilaterally into ovine femoral condyle critical defects for 3 months. A parallel in vitro analysis of ovine SSC seeded scaffolds was also performed. Post mortem mechanical indentation testing showed the bone strengths of the defect sites were 20% (controls) and 11% (SSC seeded scaffolds) those of normal cancellous bone (p < 0.01). MicroCT analysis demonstrated new bone formation within all defects with a mean increase of 13.4% in the control scaffolds over the SSC seeded scaffolds (p = 0.14). Histological examination confirmed these findings, with enhanced quality new bone within the control defects. This study highlights important issues and steps to overcome in scale-up and translation of tissue engineered products. The scaffold demonstrated encouraging results as an osteoconductive matrix; however, further work is required with cellular protocols before any human trials.

Effects of setting bone cement on tissue-engineered bone graft: a potential barrier to clinical translation?

BACKGROUND: Strategies to improve mechanical strength, neovascularization, and the regenerative capacity of allograft include both the addition of skeletal stem cells and the investigation of novel biomaterials to reduce and ultimately obviate the need for allograft altogether. Use of bone cement is a common method of stabilizing implants in conjunction with impacted allograft. Curing cement, however, can reach temperatures in excess of 70°C, which is potentially harmful to skeletal stem cells. The aim of this study was to investigate the effects of setting bone cement on the survival of human adult skeletal stem cells within tissue-engineered allograft and a novel allograft substitute. METHODS: Milled allograft and a polymer graft substitute were seeded with skeletal stem cells, impacted into a graduated chamber, and exposed to curing bone cement. Sections were removed at 5-mm increments from the allograft-cement interface. A quantitative WST-1 assay was performed on each section as a measure of remaining cell viability. A second stage of the experiment involved assessment of methods to potentially enhance cell survival, including pretreating the allograft or polymer by either cooling to 5°C or coating with 1% Laponite, or both. RESULTS: There was a significant drop in cellular activity in the sections taken from within 0.5 cm of the cement interface in both the allograft and the polymer (p < 0.05), although there was still measurable cellular activity. Pretreatment methods did not significantly improve cell survival in any group. CONCLUSIONS: While the addition of bone cement reduced cellular viability of tissue-engineered constructs, this reduction occurred only in close proximity to the cement and measurable numbers of skeletal stem cells were observed, confirming the potential for cell population recovery.

The effect of porosity of a biphasic ceramic scaffold on human skeletal stem cell growth and differentiation in vivo.

Skeletal stem cell (SSC) growth on a novel porous HA/TCP scaffold has been investigated in vivo. The effect of porosity on osteogenic differentiation was assessed by comparing two groups of scaffolds with differing porosity but controlled pore size. Histology, microCT, scanning electron microscopy, and biochemical analysis were used to assess SSC proliferation and differentiation. The 45 pores per inch (ppi) scaffold demonstrated a greater increase in density than the 30 ppi scaffold following in vivo culture, and a reduction in dimensions of the pores and channels of the higher porosity scaffold was observed, indicating generation of new tissue within the pores. All scaffolds supported SSC proliferation but the higher scaffold porosity augmented osteogenic differentiation. ALP specific activity was enhanced on the 45 ppi scaffold compared to the 30 ppi scaffold. These studies demonstrate the importance of porosity in scaffold design and impact therein for tissue engineering application.

An analysis of polymer type and chain length for use as a biological composite graft extender in impaction bone grafting: a mechanical and biocompatibility study.

Impaction bone grafting (IBG) with human allograft remains the preferred approach for replacement of lost bone stock during revision hip surgery. Associated problems include cost, disease transmission, and stem subsidence. Synthetic grafts are therefore appealing, and ideally display similar mechanical characteristics as allograft, but with enhanced ability to form de novo bone. High and low molecular weight forms of three different polymers [poly(DL-lactide) (P(DL) LA), poly(DL-lactide-co-glycolide) (P(DL) LGA), and poly(ε-caprolactone) (PCL)] were milled, impacted into discs, and then examined in a shear testing rig, in comparison to allograft. In addition, skeletal stem cells (SSCs) were combined with each of the milled polymers, followed by impaction and examination for cell viability and number, via fluorostaining and biochemical assays. The shear strengths of high/low mwt P(DL) LA, and high/low mwt P(DL) LGA were significantly higher than allograft (p < 0.01). High/low mwt PCL had significantly lower shear strengths (p < 0.01). WST-1 assay and fluorstaining indicated significantly increased cell viability on high mwt P(DL) LA and high mwt P(DL) LGA over allograft (p < 0.05). Mechanical and biochemical analysis indicated improved properties of high mwt P(DL) LA and high mwt P(DL) LGA over allograft. This study indicates the potential of these polymers for use as substitute human allograft, creating a living composition with SSC for application in IBG.

Supercritical CO2 fluid-foaming of polymers to increase porosity: a method to improve the mechanical and biocompatibility characteristics for use as a potential alternative to allografts in impaction bone grafting?

Disease transmission, availability and cost of allografts have resulted in significant efforts to find an alternative for use in impaction bone grafting (IBG). Recent studies identified two polymers with both structural strength and biocompatibility characteristics as potential replacements. The aim of this study was to assess whether increasing the polymer porosity further enhanced the mechanical and cellular compatibility characteristics for use as an osteogenic biomaterial alternative to allografts in IBG. Solid and porous poly(DL-lactide) (P(DL)LA) and poly(DL-lactide-co-glycolide) (P(DL)LGA) scaffolds were produced via melt processing and supercritical CO(2) foaming, and the differences characterized using scanning electron microscopy (SEM). Mechanical testing included milling and impaction, with comparisons made using a shear testing rig as well as a novel agitation test for cohesion. Cellular compatibility tests for cell number, viability, and osteogenic differentiation using WST-1 assays, fluorostaining, and ALP assays were determined following 14 day culture with skeletal stem cells. SEM showed excellent porosity throughout both of the supercritical-foam-produced polymer scaffolds, with pores between 50 and 200 µm. Shear testing showed that the porous polymers exceeded the shear strength of allograft controls (P<0.001). Agitation testing showed greater cohesion between the particles of the porous polymers (P<0.05). Cellular studies showed increased cell number, viability, and osteogenic differentiation on the porous polymers compared to solid block polymers (P<0.05). The use of supercritical CO(2) to generate porous polymeric biodegradable scaffolds significantly improves the cellular compatibility and cohesion observed compared to non-porous counterparts, without substantial loss of mechanical shear strength. These improved characteristics are critical for clinical translation as a potential osteogenic composite for use in IBG.

The role of osteoblast cells in the pathogenesis of unicameral bone cysts.

PURPOSE: The pathogenesis of unicameral bone cysts (UBCs) remains largely unknown. Osteoclasts have been implicated, but the role of osteoblastic cells has, to date, not been explored. This study investigated the pathophysiology of UBCs by examining the interactions between the cyst fluid and human bone marrow stromal cells (hBMSCs) and the effect of the fluid on osteogenesis. METHODS: Fluid was aspirated from two UBCs and analysed for protein, electrolyte and cytokine levels. Graded concentrations of the fluid were used as culture media for hBMSCs to determine the effects of the fluid on hBMSC proliferation and osteogenic differentiation. The fibrocellular lining was analysed histologically and by electron microscopy. RESULTS: Alkaline phosphatase (ALP) staining of hBMSCs that were cultured in cyst fluid demonstrated increased cell proliferation and osteogenic differentiation compared to basal media controls. Biochemical analysis of these hBMSCs compared to basal controls confirmed a marked increase in DNA content (as a marker of proliferation) and ALP activity (as a marker of osteogenic differentiation) which was highly significant (p < 0.001). Osteoclasts were demonstrated in abundance in the cyst lining. The cyst fluid cytokine profile revealed levels of the pro-osteoclast cytokines IL-6, MIP-1α and MCP-1 that were 19×, 31× and 35× greater than those in reference serum. CONCLUSIONS: Cyst fluid promoted osteoblastic growth and differentiation. Despite appearing paradoxical that the cyst fluid promoted osteogenesis, osteoblastic cells are required for osteoclastogenesis through RANKL signalling. Three key cytokines in this pathway (IL-6, MIP-1α, MCP-1) were highly elevated in cyst fluid. These findings may hold the key to the pathogenesis of UBCs, with implications for treatment methods.

Taking tissue engineering principles into theatre: retrieval analysis from a clinically translated case.

AIM: Tissue engineering has enormous potential for the regeneration of bone defects. Approximately 4 years ago we reported on a 62 year old patient who underwent treatment of a benign cyst in the proximal femur by impaction bone grafting supplemented with autologous bone marrow. The cyst and symptoms subsequently recurred and this patient has now required a total hip replacement. This has provided a rare opportunity for ex vivo analysis of clinically applied tissue engineered bone. MATERIALS & METHODS: The femoral head was retrieved at surgery and the structural and functional characteristics of the tissue engineered bone were analyzed by micro-computed tomography, histology and mechanical testing. RESULTS: The impacted bone demonstrated a trabecular structure that contained islands of nonincorporated graft. The graft was denser than the patient's trabecular bone with comparable strength. The cyst material had penetrated along the channel of bone and an increased number of osteoclasts were observed. DISCUSSION: This study has provided detailed ex vivo analysis of retrieved human tissue engineered bone and possible reasons for the observed construct failure are discussed in this article. The impacted bone displayed some evidence of remodeled trabecular structure, although the bone marrow aspirate that was initially combined with the allograft contained a relatively low concentration of osteoprogenitor cells. Cellular augmentation was insufficient to overcome the osteoclastic process associated with renewed cyst formation. Concentration or culture expansion of osteoprogenitor cells from aspirated bone marrow is recommended for biological augmentation of bone graft.

Skeletal tissue regeneration: current approaches, challenges, and novel reconstructive strategies for an aging population.

Loss of skeletal tissue as a consequence of trauma, injury, or disease is a significant cause of morbidity with often wide-ranging socioeconomic impacts. Current approaches to replace or restore significant quantities of lost bone come with substantial limitations and inherent disadvantages that may in themselves cause further disability. In addition, the spontaneous repair capacity of articular cartilage is limited; thus, investigation into new cartilage replacement and regeneration techniques are warranted. Along with the challenges of an increasingly aging demographic, changing clinical scenarios and rising functional expectations provide the imperative for new, more reliable skeletal regeneration strategies. The science of tissue engineering has expanded dramatically in recent years, notably in orthopedic applications, and it is clear that new approaches for de novo skeletal tissue formation offer exciting opportunities to improve the quality of life for many, particularly in the face of increasing patient expectations. However, significant scientific, financial, industrial, and regulatory challenges should be overcome before the successful development of an emergent tissue engineering strategy can be realized. We outline current practice for replacement of lost skeletal tissue and the innovative approaches in tissue regeneration that have so far been translated to clinical use, along with a discussion of the significant hurdles that are presented in the process of translating research strategies to the clinic.

A correlation of time with meniscal tears in anterior cruciate ligament deficiency: stratifying the risk of surgical delay.

Two hundred and five patients with ACL rupture, who had been diagnosed pre-operatively by either MRI scan or knee arthroscopy, had reconstructions between 2003 and 2007. The diagnostic meniscal findings were compared with those at reconstruction, and any further damage along with time from diagnosis to reconstruction was recorded. Those patients with no meniscal damage at the time of diagnosis, and who had no further damage at surgery had a median time of 6 months. This time was significantly different from those with no meniscal damage at diagnosis, but who were found subsequently to have sustained damage to one meniscus, when the median time was 11 months (P = 0.0017) or both menisci, when the median time was 32 months (P = 0.0184). For patients with solitary ACL rupture undergoing a trial of conservative management, an early and thorough assessment of functional stability is essential. If the instability is unacceptable, the patient should be informed of the time dependent risk to the menisci with further delay to surgical reconstruction.