Summary Statement

Femorotibial constraint is a key property of a total knee arthroplasty (TKA) prosthesis and should reflect the intended function of the device. With a validated simulation methodology, this study evaluated the constraint of two TKA prostheses designed for different intentions.

Introduction

TKA prostheses are semi-constrained artificial joints. Femorotibial constraint level is a major property of a prosthesis and should be designed to match the device's intended function. Cruciate Retaining (CR) prostheses are usually indicated for patients with a functioning posterior cruciate ligament (PCL). For patients without a fully functioning PCL, CR-Constrained (CRC) prostheses with additional built-in constraint may be indicated. A CRC prosthesis usually consists of a CR femoral component and a tibial insert which has a more conforming sagittal profile to offer an increased femorotibial constraint. This study evaluated the anterior-posterior (AP) constraint behavior of two lines of prostheses (CR and CRC) from a same TKA product family. Using a validated computer simulation approach, multiple sizes of each product line were evaluated.

Summary Statement

The constraint behavior of total knee arthroplasty (TKA) prosthesis usually has to be physically tested. This study presents a computer simulation model using finite element analysis (FEA) and demonstrates its effectiveness in predicting the femorotibial constraint behavior of TKA implants.

Introduction

TKA prostheses are semi-constrained artificial joints. A well-functioning TKA prosthesis should be designed with a good balance between stability and mobility, meaning the femorotibial constraint of the artificial joint cannot be excessive or too lax. To assess the constraint behavior of a TKA prosthesis, physical testing is usually required, and an industrial test standard has been developed for this purpose. Benefiting from technological advancement, computer simulation has become increasingly useful in many industries, including medical device research and development. FEA has been extensively used in stress analysis and structural evaluation of various orthopaedic implants. This study presented an FEA-based simulation to evaluate the femorotibial constraint behavior of TKA prosthesis, and demonstrated the effectiveness of the method by validating it through physical testing.

Background

The optimal reference for rotational positioning of femoral component in total knee replacement (TKR) is debated. Navigation has been suggested for intra-op acquisition of patient's specific kinematics and functional flexion axis (FFA).

Questions/Purposes

To prospectively investigate whether pre-operative FFA in patients with osteoarthritis (OA) and varus alignment changes after TKR and whether a correlation exists between post-op FFA and pre-op alignment.

Summary Statement

A large proportion of knee arthroplasty patients are dissatisfied with their replacement. Significant differences exist between preoperative, postoperative and normal kinematics. A better understanding of the inter-relationships between kinematics, shape and prosthesis placement could lead to improved quality of life.

Introduction

Knee kinematics are altered by total knee arthroplasty (TKA) both intentionally and unintentionally. Knowledge of how and why kinematics change may improve patient outcome and satisfaction through improved implant design, implant placement or rehabilitation. Comparing preoperative to postoperative kinematics and shape of the natural and replaced joint will allow an investigation of the inter-relationships between knee shape, prosthesis placement, knee kinematics and quality of life.

Summary Statement

A prospective randomised evaluation of primary TKA utilizing patient specific instruments demonstrated great accuracy of bone resection, improved sagittal alignment and the potential to improve functional outcomes and reduce operating room costs when compared to standard TKA instrumentation.

Introduction

Patient specific instruments (PSI), an alternative to standard total knee arthroplasty (TKA) technology, have been proposed to improve the accuracy of TKA implant placement and post-operative limb alignment. Previous studies have shown mixed results regarding the effectiveness of PSI. The purposes of this study were (1) to evaluate the accuracy of the pre-operative predicted PSI plan compared to intra-operative TKA resection measurements, (2) to compare patient-reported outcome measures of PSI and standard TKA patients, and (3) to compare the incremental cost savings with PSI.

Summary Statement

The modulation of both quantity and quality of peri-implant bone with either PTH or loading may be viable options to improve implant fixation and patient outcomes.

A strong bone-implant interface is essential for successful joint replacement surgery. This study investigated the differences in bone surrounding and within a porous titanium implant after single or combined treatment with two anabolic bone therapies: intermittent parathyroid hormone (teriparatide) and mechanical loading. Porous titanium implants were inserted bilaterally on the distal lateral femurs of rabbits. The right implant was loaded daily (1 MPa, 50 cycles/day) while the left implant was not. Rabbits received daily PTH injections (20 ug/kg) or saline vehicle. Periprosthetic cancellous bone 0.5, 1.0, and 2.0 mm below the implant surface, bone at the 0.25 mm bone-implant interface and total bone within each implant were examined using tissue-level analyses (quantitative backscattered electron microscopy), cellular analyses (immunohistochemistry staining of osteoblasts with procollagen-1 and TRAP staining of osteoclasts), and shear testing (implant-bone interface).

Statistical significance was determined using GEE models (p<0.05). For tissue located 0.5 mm below the implant, significant increases in bone area per total area (BA/TA) were observed with PTH treatment (56%) and with loading (27%). Further, an 18% increase in mineralization density with PTH treatment and a 20% increase in mineralization density with loading was found. Loading effects were not present beyond the 0.5 mm periprosthetic region, but PTH significantly increased BA/TA 2.0 mm below and mineralization density 1.0 mm below the implant. Tissue-level changes were supported by increases in osteoblast activity 0.5 mm below the implant with PTH (79%) and loading (34%), as well as by minimal osteoclast changes. At the 0.25 mm implant-bone interface PTH and loading increased BA/TA (16% and 23%, respectively), but only loading increased mineralization density (7%). Further, total integrated bone area was increased 35% with PTH.

Both PTH and loading enhanced the mechanical integrity of the implant-bone; shear strength increased 34% and 60%, respectively. Although combined treatment was not synergistic, both PTH and loading individually enhanced the amount and mineralization density of bone at the implant interface and immediately below the interface, thereby increasing the mechanical strength of the metal-bone interface. This research suggests that modulation of both quantity and quality of peri-implant bone may be viable options to improve implant fixation and patient outcomes.

Summary Statement

Wear of total knee replacement (TKR) is a clinical concern. This study demonstrated low-conformity moderately cross-linked-polyethylene fixed bearing TKRs showed lower volumetric wear than conventional-polyethylene curved fixed bearing TKRs highlighting potential improvement in TKR performance through design and material selection.

Introduction

Wear of total knee replacement (TKR) continues to be a significant factor in the clinical performance of the implants. Historically, failure due to delamination and fatigue directed implant design towards more conforming implants to reduce contact stress. However, the new generations of more oxidatively-stable polyethylene have improved the long-term mechanical properties of the material, and therefore allowed more flexibility in the bearing design. The purpose of this study was to investigate the effect of insert conformity and material on the wear performance of a fixed bearing total knee replacement through experimental simulation.

Summary

Arginine supplementation is helpful in treatment of osteoporosis.

Introduction

Nitric oxide (NO) is a short-lived free radical involved in several biological processes as a bioregulator and as a second messenger. It inhibits osteoclastic bone resorption in vitro and regulates bone remodeling. Zolendronic acid has been established as a treatment for post menopausal osteoporosis. Study was done to compare the efficacy of Nitic oxide donor (L-arginine) with that of Zolendronic acid for the treatment of osteoporosis.

Summary Statement

In this study it has been considered an alternative therapeutic approach to bone resorption diseases by using plant decoctions to improve adherence from patients to the treatment. In this context, Hemidesmus indicus represents a possible therapeutic or adjuvant natural compound.

Introduction

The acceleration of bone remodelling, with an excessive osteoclastogenesis or activation of mature osteoclasts, causes the loss of bone mass which is implicated in bone resorption diseases. Conventional therapies are expensive and limited by systemic toxicity and low drug bioavailability. Alternative treatments that are not only effective but also administered employing formulations and dosages different from conventional ones, may improve adherence to therapy, having a positive influence on clinical outcomes. Experimental evidence have attributed antiproliferative and apoptosis inducing activity on different cell lines (including osteoclast precursors or mature osteoclasts) to four plants used in Ayurvedic medicine: Asparagus racemosus (AR), Emblica officinalis (EO), Hemidesmus indicus (HI) and Rubia cordifolia (RC) These properties could be helpful in the treatment of some bone resorption diseases. In order to clarify the possible therapeutic effects of these compounds, the anti-osteoclast activity of their decoctions were evaluated.

Summary Statement

Obovatol inhibits receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and prevents inflammatory bone loss in mice

Introduction

Adult skeletal mass and integrity are maintained by balancing osteoclast-mediated bone resorption and osteoblast-induced bone formation during bone remodeling. Abnormal increases in osteoclastic bone resorption can lead to excessive bone destruction as observed in osteoporosis, rheumatoid arthritis, and metastatic cancers Therefore, Modulation of osteoclast formation and function is a promising strategy for the treatment of bone-destructive diseases. To search for compounds that inhibit osteoclast formation, we tested the effect of obovatol, a natural product isolated from the medicinal plant Magnolia obovata, on osteoclastogenesis and inflammatory bone loss.

Summary Statement

The stable inhibition of miR-214 in the aged osteoporotic rats induced by OVX could be achieved by periodic administration of AntagomiR-214 at a dosage of 4 mg/kg and at an interval of 7 days, which will provide a potential bone anabolic strategy for treatment of osteoprosis.

Introduction

MiR-214 has a crucial role in suppressing bone formation and miR-214 inhibition in osteogenic cells may be a potential anabolic strategy for ameliorating osteoporosis (Wang X, et al. 2013). An aged ovariectomised rat has been regarded as a golden model to test bone anabolic agents for reversing established osteoporosis in aged postmenopausal women (Li X, et al. 2009). However, there is still lack of evidence to demonstrate bone anabolic potential of therapeutic inhibition of miR-214 within osteogenic cells in the golden model. So, it should be necessary to establish RNAi-based administration protocol toward stable inhibition of miR-214 at a low level in the golden model. A targeted delivery system specifically facilitating Antagomir-214 approaching osteogenic cells, i.e. (Asp-Ser-Ser)₆-liposome (Zhang G, et al 2012), was employed in this study.

Summary Statement

It is now possible to diagnose osteoporosis using incidental abdominal CT scans; applying this approach to fractures of the cervical spine demonstrates levels of osteoporosis in patients over 65.

Introduction

Recently published data now makes it possible to screen for osteoporosis in patients who, in the course of their hospital stay, have had Computed Tomography (CT) scans of their abdomen for reasons other than direct imaging. This is as a result of CT derived bone mineral density (BMD) in the first lumbar vertebra (L1) being correlated BMD derived from Dual-energy X-ray absorptiometry (DEXA) scans. The advantage of this is the reduction in both cost and radiation exposure. Although age has a detrimental effect on BMD, relatively few patients have formal DEXA studies. The aims of this study were to evaluate the utility of this new technique in a cohort of patients with acute fractures of the cervical spine and to compare relative values for BMD in patients aged over 65 with those aged under 65, and thus define the role of osteoporosis in these injuries.

Summary Statement

Using abdominal CT scans to evaluate bone mineral density following acute fractures of the thoracic and lumbar spine demonstrates significant levels of osteoporosis in older patients; this approach may help save on time and resources, and reduce unnecessary radiation exposure.

Introduction

While a reduction in bone mineral density (BMD) is associated with aging, relatively few patients have formal dual-energy X-ray absorptiometry (DXA) to quantify the magnitude of bone loss, as they age. This loss of bone may predispose to fractures. Recent data, which correlates mean Hounsfield units (HU) in an area of the L1 vertebra with BMD, now makes it possible to screen for osteoporosis using incidental abdominal Computed Tomography (CT) scans to measure bone density. This innovation has the potential to reduce both cost and radiation exposure, and also make it easier to identify patients who may be at risk. The aims of this study were to evaluate the utility of this approach in patients with acute thoracic and lumbar spine fractures and to evaluate the impact of aging on BMD, using CT screening.

Summary Statement

It is now possible to diagnose osteoporosis using incidental CT scans; this approach has been used to objectively demonstrate the role of osteoporosis in fracture in ankylosing spondylitis patients.

Background

In advanced disease, Ankylosing Spondylitis (AS) is frequently associated with a reduction in bone mineral density (BMD), this contributes to pain and predisposes to fractures. Quantifying this reduction in BMD is complicated by the simultaneous processes occurring, in which there is both an overgrowth of bone (syndesmophytes) and a concurrent loss of trabecular bone. Traditional methods such as dual-energy X-ray absorptiometry (DXA) struggle to generate accurate estimates for BMD in these patients. It has recently become possible to diagnose osteoporosis, with a high sensitivity and specificity, using incidental CT scans of the L1 vertebra. The purpose of this study was to evaluate the use of opportunistic CT screening in the diagnosis of osteoporosis in patients with AS who had sustained vertebral fractures.

Summary

Cytokines produced within the degenerate disc induce expression of neurotrophic factors and pain related peptides which could be important in nerve ingrowth and pain sensitisation leading to low back pain.

The intervertebral disc (IVD) is considered the largest aneural and avascular structure within the human body, yet during degeneration vascularisation of the IVD is seen to be accompanied by nociceptive nerves. Low back pain is a highly debilitating condition affecting around 80% of the population, 40% of which are attributed to IVD degeneration. Discogenic pain was largely thought to be a result of irritation and compression of the nerve root, yet recent data suggests that pain may be attributed to the sensitisation of sensory nerves by the synthesis of pain related peptides, calcitonin gene related peptide (CGRP) and substance P. It is known that cytokines and chemokines produced by nucleus pulposus cells elicit various effects including the production of matrix degrading enzymes, and decreased matrix molecules. Here, we investigate the hypothesis that cytokines regulate both neurotrophic factor and pain related peptide synthesis within nucleus pulposus and nerve cells which may elicit algesic effects.

Real-Time PCR was performed to investigate gene expression of the neurotrophic factors NGF, BDNF, NT3 and their receptors Trk A, B and C along with Substance P and CGRP on directly extracted RNA from human NP cells and NP cells cultured in alginate for 2 weeks prior to treatment for 48hours with IL-1, IL-6 or TNFα at 0–100ng/mL. Similarly SH-SY5Y neuroblastoma cells were differentiated in retinoic acid for 7 days prior to stimulation with IL-1, IL-6 or TNFα at 0ng/mL and 10ng/mL for 48hours. Immunohistochemistry was used to localise neurotrophic factor receptors Trk A, B and C in both degenerate discs and neuronal cells.

NGF expression was present in normal and degenerate disc samples, however only degenerate discs expressed the high affinity receptor TrkA. Similarly Trk B was present in 22% of normal samples increasing to 100% expression within degenerate disc samples. All cytokines increased expression of NGF in NP cells (P≤0.05). TNFα also increased BDNF significantly, whereas no significant affects were seen in NT3 expression in NP cells. Trk B expression was significantly increased by IL-1 and TNFα treatment of NP cells. Conversely Trk C was down regulated by IL-6. Substance P was significantly increased by IL-1 and TNFα treatments whilst IL-6 and TNFα increased CGRP expression in NP cells. In SH-SY5Y cells, IL-1 significantly increased BDNF whilst IL-6 and TNFα failed to induce significant differences in neurotrophic factors. All cytokines increased Trk expression in the nerve cell line; however this failed to reach significance. Immunohistochemistry confirmed the presence of Trk receptors within the neuronal cell line.

Here we have demonstrated that a number of cytokines known to be up regulated during disc degeneration and disc prolapse, induce expression of various neurotrophic factors, their receptors and pain related peptides within human NP cells, as well as SH-SY5Y cells. This data suggests that the presence and production of cytokines within the degenerate disc may be responsible for nerve ingrowth and sensitisation of nerves which may result in discogenic pain.

Introduction

In degenerative disorders of the spine such as disc herniation, intervertebral discs can affect neural tissue, which may result in pain as demonstrated in both basic science and clinical investigations. Previous in vitro and in vivo studies have shown that notochordal cells and chondrocyte-like cells in nucleus pulposus affect nervous tissue differently. The aim of the present study was to evaluate the morphology of spinal neural tissue in an in vivo rat model following application of cells derived from nucleus pulposus.

Material and method

A disc herniation model in rats (n=58) was used. The L4 nerve root was exposed to a) nucleus pulposus (3mg), b) notochordal cells (25,000 cells) or c) chondrocyte-like cells (25,000 cells). Four control groups were included: 1) application of nucleus pulposus (3 mg) and mechanical displacement of the spinal nerve complex, 2) sham operated animals, 3) application of cell diluent (50 μl) and 4) naïve animals. Seven days after surgery the L4 nerve roots with their dorsal root ganglion were harvested and prepared for blinded neuropathological examinations using light microscopy.

Summary Statement

DNA damage induced by systemic drugs or local γ-irradiation drives disc degeneration and DNA repair ability is extremely important to help prevent bad effects of genotoxins (DNA damage inducing agents) on disc.

Introduction

DNA damage (genotoxic stress) and deficiency of intracellular DNA repair mechanisms strongly contribute to biological aging. Moreover, aging is a primary risk factor for loss of disc matrix proteoglycan (PG) and intervertebral disc degeneration (IDD). Indeed, our previous evidences in DNA repair deficient Ercc1^−/Δ mouse model strongly suggest that systemic aging and IDD correlate with nuclear DNA damage. Thus the aim of the current study was to test whether systemic or local (spine) genotoxic stress can induce disc degeneration and how DNA repair ability could help prevent negative effects of DNA damage on IDD. To test this hypothesis a total of twelve Ercc1^−/Δ mice (DNA repair deficient) and twelve wild-type mice (DNA repair competent) were challenged with two separate genotoxins to induce DNA damage, i.e. chemotherapeutic crosslinking agent mechlorethamine (MEC) and whole-body gamma irradiation. Local effects of gamma irradiation were also tested in six wild-type mice.

Summary Statement

An organ culture experiment was simulated to explore the mechanisms that can link cell death to mechanical overload in the intervertebral disc. Coupling cell nutrition and tissue deformations led to altered metabolic transport that largely explained cell viability measurements.

Introduction

Part of intervertebral disc (IVD) maintenance relies on limited nutrient availability to the cells and on mechanical loads, but effective implication of these two factors is difficult to quantify. Theoretical models have helped to understand the link between solute transport and cell nutrition in deforming IVD, but omitted the direct link between tissue mechanics and cell metabolism. Hence, we explored numerically the relation between disc mechanics and cell death in relation to an organ culture experiment.

Background

Posterolateral fusion (PLF) is a commonly accepted surgical procedure and overall the most common technique performed to obtain fusion in the lumbar spine. Harvesting autologous bone from the iliac crest is associated with increased operation time, blood loss, and chronic donor site pain. Allograft material has an insufficient osteoinductive potential. Bone marrow concentrate (BMC) could be an option how to promote allograft PLF healing. The purpose of the presented study was to investigate the validity of BMC addition to allografts in instrumented lumbar PLF surgery.

Methods

The study was prospective, randomised, controlled and blinded. Eighty patients with degenerative disease of the lumbar spine underwent instrumented (S⁴, Aesculap, Tuttlingen, Germany) lumbar or lumbosacral PLF. In forty cases, the PLF was done with spongious allograft chips alone (Group I). In another forty cases, spongious allograft chips were mixed with BMC (Group II), where the mesenchymal stem cell (MSCs) concentration was 1.74 × 10⁴/L at average (range, 1.06–1.98 × 10⁴/L). Patients were scheduled for anteroposterior and lateral radiographs at 12 and 24 months after the surgery and for CT scanning at 24 months after the surgery. Fusion status and the degree of mineralization of the fusion mass were evaluated separately by two radiologists blinded to patient group affiliation.

Summary Statement

We successfully delineated the 3D micro morphology of chondrocytes in patella-patellar tendon using IL-XPCT for the first time. Compared with conventional histology, IL-XPCT can not only provide a higher resolution imgaing but also keep the 3D integrity of the specimen.

Introduction

The morphology of the bone-tendon junction was complex and quite different from other organs, which result the injured bone-tendon junction repair process too slowly. To study the micro morphology of the bone-tendon junction in 3D may have a great significant value to revealing the repair mechanisms of this pathological process and accelerating injured bone-tendon junction repair. However, it was hindered by the convention methods such as histologic section. In our study, a novel imaging tool, synchrotron radiation based in-line x-ray phase contrast imaging (IL-XPCT) was used to research the 3D micro morphology of the bone-tendon junction.

Summary

We found an increased natural expression of the growth factors bFGF, BMP-12, VEGF, and TGF-b1 during tendon healing of rat Achilles tendons. External application of these growth factors improved the tendons failure load in the early healing phase.

Introduction

Tendon ruptures recover slowly and the healing of injuries can be devastating. Growth factors are known to influence tendon healing. However, only little is understood about growth factors in a healing tendon. Aim of this study was to investigate the influence of growth factors on tendon healing of rats following their natural expression.

Summary Statement

Transportation media and injection protocol have implications for the viability of MSCs used for intra-lesional treatment of tendon injuries. Every effort should be made to implant cells within 24h of laboratory re-suspension, using a needle bore larger than 21G.

Introduction

Intra-lesional implantation of autologous mesenchymal stem cells (MSCs) has resulted in significant improvements in tendon healing in experimental animal models. Intra-tendinous injection of MSCs into naturally-occurring equine tendon injuries has been shown to be both safe and efficacious¹ and these protocols can assist in the translation to the human. Efficient transfer of cells from the laboratory into the tissue requires well validated techniques for transportation and implantation. The aim of this study was to determine the influence of transport media and injection procedure on cellular damage.

Summary

In an in vitro tendon cell model, the tendon-specific gene expression up-regulation induced by PEMF negatively correlates with field intensity; moreover repeated lower-intensity PEMF treatments (1.5 mT) provokes a higher release of anti-inflammatory cytokines respect to the single treatment.

Introduction

Tendon disorders represent a diagnostic and therapeutic challenge for physicians. Traditional treatments are characterised by a long recovery time and a high occurrence of injury relapses. Despite the growing clinical interest in pulsed electromagnetic fields (PEMFs) few studies on their effect on tendons and ligaments have been conducted. Tendon resident cells (TCs) are a mixed population, made up mostly by tenocytes and tendon stem/progenitor cells, which are responsible of the tissue homeostasis. Since studies on the effect of PEMFs on this cell population are conflicting, we evaluated the possible relation between PEMFs dosage and TCs’ response. In particular, we compared the in vitro effect of low and high PEMFs on TCs (PEMF-1.5 mT; PEMF-3 mT); moreover we assessed the results of repeated treatments (R-PEMF-1.5mT).

Summary Statement

A novel biomimetic polydioxanone tendon patch with woven and electrospun components is biocompatible, recapitulates native tendon architecture and creates a tissue-healing microenvironment directed by a subpopulation of regenerative macrophages. The woven component provides tensile strength while the tendon heals.

Introduction

There is great interest in the use of biomimetic devices to augment tendon repairs. Ideally, implants improve healing without causing adverse local or systemic reactions. Biocompatibility remains a critical issue prior to implantation into humans, as some implants elicit a foreign body response (FBR) involving inflammation, poor wound healing and even fistulae formation. Additionally, the effect on articular cartilage locally or systemically with placement of a juxta-articular implant has not been examined. The purpose of this study is to test the in vivo biocompatibility of a novel hybrid woven and electrospun polydioxanone patch in a rat tendon transection model.

Summary

A novel in vivo animal model to establish new surgical interventions for patients with ACL insufficiency.

Introduction

After ACL reconstruction, recruited cells from surrounding tissues play crucial roles in ligamentization to obtain adequate structural properties. To allow athletes to return sports activity sooner, these remodeling processes should be elucidated and be accelerated. However, in conventional animal models, it has been difficult to differentiate donor and recipient cells. Here we introduce the transgenic Kusabira-Orange pigs, in which cells produce fluorescence systemically, as in vivo model to trace cell recruitment after ACL reconstruction.

Summary Statement

This data may help explain the variability in physical function after primary TKR as compared to primary THR.

Introduction

Total knee replacement (TKR) and total hip replacement (THR) reliably relieve pain, restore function, and ensure mobility in patients with advanced joint arthritis; however these results are not uniform across all patient populations. We compared baseline demographic and symptom profiles in patients from a US national cohort undergoing primary TKR and THR.

Summary

Movement analysis (IMA) and activity monitoring (AM) using a body-fixed inertia-sensor can discriminate patients with ankle injuries from controls and between patients of different pathology or post-injury time. Weak correlations with PROMs show its added value in objectifying outcome assessment.

Introduction

Ankle injuries often result in residual complaints calling for objective methods to score outcome alongside subjective patient-reported outcome measures (PROMs). Inertial motion analysis (IMA) and activity monitoring (AM) using a body-fixed sensor have shown clinical validity in patients suffering knee, hip and spine complaints. This study investigates the feasibility of IMA and AM 1) to differentiate patients suffering ankle injuries from healthy controls, 2) to compare different ankle injuries, 3) to monitor ankle patients during recovery.

Summary

Cognitive testing scores do not correlate with physical braking performance. Psychological questioning shows patients are more dependent on driving than a control group.

Introduction

Returning to driving after surgery is a multifaceted issue. There are the medical aspects to consider- whether the patient is medically fit to drive. The term ‘medically fit to drive’ can encompass a range of issues which fall to doctors to solve, including the psychological and mental wellbeing. Groups whose governance involves patients or driving do not issue sound advice for patients or doctors to follow. Investigation of aspects affecting a driver's ability to control their vehicle in a safe manner could go towards providing an evidence base for guidance to be issued in the future.

Summary Statement

Service industry metrics (the net promoter score) are being introduced as a measure of UK healthcare satisfaction. Lower limb arthroplasty, as a ‘service’, scores comparably with the most successful commercial organisations.

Background

Satisfaction with care is important to both the patient and the payer. The Net Promoter Score, widely used in the service industry, has been recently introduced to the UK National Health Service as an overarching metric of patient satisfaction and to monitor performance. This questionnaire asks ‘customers’ if they would recommend a service or products to others. Scores range from −100 (everyone is a detractor) to +100 (everyone is a promoter). In industry, a positive score is well regarded, with those over 50 regarded as excellent. Our aims were to assess net promoter scores for joint arthroplasty, to compare these scores with direct measures of patient satisfaction, and to evaluate which factors contributed to net promoter response.

Summary Statement

Using current analysis/methodology, new implant technology is unlikely to demonstrate a large enough change in patient function to impact on the cost-effectiveness of the procedure.

Purpose

Cost effectiveness is an increasingly important metric in today's healthcare environment, and decisions surrounding which arthroplasty prosthesis to implant are not exempt from such health economic concerns. Quality adjusted life years (QALYs) are the typical assessment tool for this type of evaluation. Using this methodology, joint arthroplasty has been shown to be cost effective, however studies directly comparing the QALY achieved by differing prostheses are lacking.

Summary Statement

With increasing emphasis on evidence-based medicine in healthcare, there is global increase in proportion of Level-1 and -2 articles in PUBMED. This study shows the trend of orthopaedic publications from different countries in comparison to other specialties.

Introduction

New medical knowledge is expected to improve health through change in existing practices. Articles need to convince readers of the validity of conclusions in order to bring about a change in practice. The last few decades have witnessed an increasing interest in critical appraisal of research aimed at assessing the ‘quality’ of evidence, a trend towards ‘Evidence Based Medicine’. Whether orthopaedic publications are also becoming more evidence-based has hitherto not been reported. This study aimed to compare the trend of publications originating from orthopaedic services versus other specialties, across different countries, with respect to major categories of levels of evidence.

Summary Statement

The purpose is to evaluate the effects of internet usage on new patient referral patterns to identify optimal patient recruitment and communication. Overall, social networking and internet may be an effective way for surgeons to recruit a wider patient population.

Introduction

Prior studies in other medical specialties have shown that social networking and internet usage has become an increasingly important means of patient communication and referral. However, this information is lacking in the orthopaedics literature. In this study, we evaluate the means by which new patients arrive at orthopaedic clinics in a major academic center. The purpose is to evaluate the effects of internet or social media usage on new patient referral patterns to identify avenues to optimise patient recruitment and communication.

Summary Statement

Description of an original in vitro protocol for assessing combined bacteria and cell competitive adherence on the surface of biomaterials of medical interest

Objectives

Biomaterial-related infections are a major clinical problem. The pathogenesis of this syndrome has been described as a competitive adherence between bacteria and human cells in the so-called “race for the surface” theory. The aim of this study is to develop an in vitro protocol method that can be used to investigate this competence and its implications in the development of materials aimed to be used in orthopedic surgery.

Summary Statement

Developing titanium (Ti) surfaces that are biocompatible yet serve as deterrents for bacterial attachment and growth are particularly appealing in tackling the ongoing problem of sepsis-induced implant failures. Realising this could include coating Ti with the bioactive lipid, lysophosphatidic acid.

Introduction

Surgical revision for failed total joint replacements costs a staggering £300m/yr and approximately 20% of this burden is attributed to implant failure through bacterial infection. Producing biomaterials that deter microbial attachment as well as securing robust osseointegration continues to be a significant research challenge in contemporary bone biomaterials design. Steps to realising novel improvements are further compounded by the concerns raised over resistance of bacteria to many antimicrobial agents. Clearly this is a major constraint necessitating an entirely novel approach to minimising implant infection risk. We therefore turned our attention to certain lysophosphatidic acids (LPAs) for Ti functionalisation. We have found LPA to enhance calcitriol-induced human osteoblast (hOB) maturation. Of further significance is the discovery that LPA can directly inhibit the growth of certain bacteria and even co-operate with some antibiotics to bring about their demise. Herein we describe the fabrication of a hOB-compatible Ti surface with palmitoyl-LPA (P-LPA) which we also find hinders bacterial attachment.

Summary Statement

Conventional culture techniques have poor sensitivity for detecting bacteria growing in biofilms, which can result in under-diagnosis of infections. Sonication of biofilm colonised orthopaedic biomaterials can render bacteria in biofilm more culturable, thereby improving diagnosis of orthopaedic implant infections.

Introduction

Prosthetic joint infection (PJI) is a potentially devastating complication in arthroplasty. Biofilm formation is central to PJI offering protection to the contained bacteria against host defence system and antimicrobials. Orthopaedic biomaterials generally have a proclivity to biofilm colonisation. Conventional culture technique has a low sensitivity for detecting bacteria in biofilm. Sonication can disrupt bacteria biofilms aggregations and dislodge them from colonised surfaces, rendering them culturable and consequently improve the diagnosis of otherwise culture-negative PJI. We investigated the effect of ultrasonication on biofilms adherent to poylmethylmethacrylate PMMA cement.

Purpose

Gustilo type III open fractures are associated with high infection rates in spite of instituting a standard of care (SOC) consisting of intravenous antibiotics, irrigation and debridement (I&D), and delayed wound closure. Locally-delivered antibiotic has been proven to assist in reducing infection in open fractures. The aims of this study are to determine the effectiveness and safety of a new implantable and biodegradable antibacterial product¹ in preventing bacterial infections and initiating bone growth in open fractures.

Methods

The osteoconductive antibacterial BonyPid^TM used is a synthetic bone void filler (comprised of ≤1 mm β-tricalcium phosphate granules) coated by a thin layer (≤20 µm) of PolyPid nanotechnology formulation⁻. Upon implantation, the coating releases doxycycline at a constant rate for a predetermined period of 30 days. One BonyPid^TM vial of 10 grams contains 65 mg of formulated doxycycline. After approval, sixteen subjects with Gustilo type III open tibia fractures, were implanted with the BonyPid^TM immediately on the first surgical intervention (I&D), followed by external fixation. Patients had periodic laboratory, bacteriology and radiology follow-up.

Summary Statement

Combination of antibiotics with N-acetylcisteine and sub-MIC concentration of erythromycin was evaluated in two collection and 16 clinical strains of staphylococci isolated from PJI. The results were strain-dependent, so it evidences the necessity of perform individual studies of biofilm susceptibility.

Objectives

Staphylococci are the most common cause of prosthetic joint infections (PJI) (1), making the treatment of this disease difficult due to the increased resistance to antibiotics of biofilms. Combination between antibiotics and other compounds could be a good alternative. The aim of this study was to evaluate the effect of the combination of two compounds with nine antibiotics in biofilms formed by staphylococcal strains isolated from PJI.

Summary

There is little knowledge in surgeons about the guidelines for prophylactic antibiotics in patients with prosthetic joints when undergoing a dental procedure. This study confirms this and there is need for robust and universal guidelines given the disastrous nature of prosthetic infection.

Introduction

Infection as an indication for revision has increased to 12 % of the total revisions (NJR 9^th report). However, it is next to impossible to find out the cause for a delayed prosthetic infection. With increasing number of arthroplasty procedures, is there a need for prophylactic antibiotics in patients with prostheses?

Summary

open tibia fractures are best treated in an orthopaedic-plastic surgical multidisciplinary setting.

Introduction

Open fractures of the leg represent a severe trauma. It is often stated that combining the skills of Plastic and Orthopaedic surgeons can optimise the results of limb salvage in complex limb injury. The multidisciplinary approach, shared between plastic and orthopaedic surgeons, is likely to provide the optimal treatment of these injuries, although this mutidisciplinary simultaneous treatment is not routinely performed. Given the relatively low incidence of these traumas, a multicentric recruitment of these patients can contribute in providing an adequately numerous cohort of patients to be evaluated through the long process of soft tissue and bone healing following an open tibia fracture. We compared three centres with different protocols for management of these challenging cases.

Summary

Osteoporosis reduces particle-induced osteolysis in rat model.

Introduction

Wear particle induced osteolysis is considered to be a vital factor that reduces the life span of joint prosthesis. Osteoporosis is not rare in patients with indication for arthroplasty. However, the influence of osteoporosis on wear particles induced osteolysis is not clear. This study is aimed to explore on this issue by using animal model.

Summary

Particulate wear debris with different chemical composition induced similar periprosthetic tissue reactions in patients with loosened uncemented and cemented titanium hip implants, which suggests that osteolysis can develop independent of particle composition.

Introduction

Periprosthetic osteolysis is a serious long-term complication in total hip replacements (THR). Wear debris-induced inflammation is thought to be the main cause for periprosthetic bone loss and implant loosening. The aim of the present study was to compare the tissue reactions and wear debris characteristics in periprosthetic tissues from patients with failed uncemented (UC) and cemented (C) titanium alloy hip prostheses. We hypothesised that implant wear products around two different hip designs induced periprosthetic inflammation leading to osteolysis.

Summary

Wear particles from joint replacements may result in loosening and periprosthetic osteolysis. Interference with systemic macrophage trafficking to the implant, modulation of macrophage phenotype from M1 to M2, and inhibition of NFκB may mitigate these adverse effects.

Introduction

Joint replacement of the lower extremity is highly successful in alleviating pain, and improving ambulation and function. However, prosthetic byproducts of different materials, in sufficient amounts, may lead to loosening and periprosthetic osteolysis. Debris from polymers (such as polyethylene and PMMA), metals and ceramics are capable of inciting an adverse tissue reaction, which is orchestrated by cells of the monocyte/macrophage lineage. Three experimental approaches have been taken by our group to potentially mitigate the adverse biological sequela of particle disease. These include: 1) interfering with ongoing migration of monocyte/macrophages to the implant site by inhibiting the chemokine system 2) altering the functional activities of local macrophages by converting pro-inflammatory M1 macrophages to an anti-inflammatory pro-tissue healing M2 phenotype and 3) modulating the production and release of pro-inflammatory cytokines, chemokines and other potentially harmful factors by inhibiting the key transcription factor NFκB.

Summary Statement

Using the latest Next Generation Sequencing technologies, we have investigated miRNA expression profiles in human trabecular bone from total hip replacement (THR) revision surgery where wear particle associated osteolysis was evident.

Introduction

A major problem in orthopaedic surgery is aseptic loosening of prosthetic implants caused by wear particle associated osteolysis. Wear debris is known to impact on a variety of cellular responses and genes in multiple pathways associated with the development of the periprosthetic osteolysis. MicroRNAs (miRNAs) act as negative regulators of gene expression and the importance of miRNAs in joint pathologies has only recently been addressed. However, miRNA profiles in osteolytic bone are largely unknown. Using the latest Next Generation Sequencing technologies, we have investigated miRNA expression profiles in human trabecular bone sourced from bone discarded during total hip replacement (THR) revision surgery where wear particle associated osteolysis was evident.

Summary

RNAi targeting TNF-alpha inhibits particle-induced inflammation and osteolysis.

Introduction

Over 1000,000 joint prostheses are implanted every year in the world. Aseptic joint loosening is a key factor that reduces the longevity of joint prosthesis. Prosthetic wear particles are thought to play a central role in the initiation and development of periprosthetic osteolysis, leading to aseptic loosening of prostheses. This study aims to investigate the effect of RNA interference (RNAi) targeting tumor necrosis factor-alpha (TNF-α) gene on particle-induced inflammation and osteolysis in macrophages in vitro and in vivo.

Summary Statement

Proximal femoral bony deficits present a surgical and biomechanical challenge to implant longevity in revision hip arthroplasty. This work finds comparable primary stability when a distally fixing tapered fluted stem was compared with a conical design in cadaveric tests.

Introduction

Proximal bony deficits complicate revision hip surgery and compromise implant survival. Longer distally fixing stems which bypass such defects are therefore required to achieve stability compatible with bony ingrowth and implant longevity.

Summary Statement

The circle theorem is a simple and effective measurement tool for estimating acetabular version after total hip arthroplasty

Introduction

Position of the acetabular cup is a major factor in the range of motion and risk of dislocation after total hip arthroplasty. However, there is no well established technique for accurately and easily estimating acetabular cup version intraoperatively or postoperatively. The objective of this study was to evaluate a recently proposed method for measuring acetabular cup version on a single plain radiograph of the hip, which is based on one of the circle theorems in basic geometry.

Summary Statement

Pincer deformities are involved in the genesis of femoro-acetabular impingement (FAI). Radiographic patterns suggestive of pincer deformities are common among general population. Prevalence of the pincer deformities among general population may be overestimated if only plain radiographs are considered.

Background

Pincer deformities (coxa profunda, protrusio acetabuli, global retroversion, isolated cranial over-coverage) have been advocated as a cause of femoro-acetabular impingement (FAI) and early hip osteoarthritis (OA). Different radiographic patterns may advocate the presence of a pincer deformity. The prevalence of these radiographic patterns among general adult population, as their role in early hip OA, is poorly defined.

Summary Statement

Corin has developed bone conserving prosthesis (MiniHip™) to better replicate the physiological load distribution in the femur. This study assessed whether the MiniHip™ prosthesis can better match the pre-osteoarthritic head centre for patient demographics when compared to contemporary long stem devices.

Introduction

Leg length and offset discrepancy resulting from Total Hip Replacement (THR) is a major cause of concern for the orthopaedic community. The inability to substitute the proximal portion of the native femur with a device that suitably mimics the pre-operative offset and head height can lead to loss of abductor power, instability, lower back pain and the need for orthodoses. Contemporary devices are manufactured based on predicate studies to cater for the variations within the patient demographic. Stem variants, modular necks and heads are often provided to meet this requirement. The number of components and instruments that manufacturers are prepared to supply however is limited by cost and an unwillingness to introduce unnecessary complexity. This can restrict the ability to achieve the pre-osteoarthritic head centre for all patient morphologies. Corin has developed MiniHip™ to better replicate the physiological load distribution in the femur. This study assessed whether the MiniHip™ prosthesis can better match the pre-osteoarthritic head centre for patient demographics when compared to contemporary long stem devices.

Summary

162 patient cohort with serial Metal Artefact Reduction Sequence MRI scans. Patients with normal initial scans can be followed up at 1 year. Those with abnormal scans should be followed up at a shorter interval of 6 months.

Introduction

Cross-sectional imaging is a key investigation in the assessment and surveillance of patients with metal-on-metal (MoM) hip arthroplasty. We present our experience of Metal Artefact Reduction Sequence (MARS) MRI scanning in metal on metal hip arthroplasty. We aimed to investigate the natural history and radiological disease progression from Adverse Reactions to Metallic Debris.

Summary

At the clinical CT image resolution level, there is no influence of the image voxel size on the derived finite element human cancellous bone models

Introduction

Computed tomography (CT)-based finite element (FE) models have been proved to provide a better prediction of vertebral strength than dual-energy x-ray absorptiometry [1]. FE models based on µCTs are able to provide the golden standard results [2], but due to the sample size restriction of the µCT and the XtremeCT machines, the clinical CT-based FE models is still the most promising tool for the in vivo prediction of vertebrae's strength. It has been found [3] that FE predicted Young's modulus of human cancellous bone increases as the image voxel size increases at the µCT resolution level [3]. However, it is still not clear whether the image voxel size in the clinical range has an impact on the predicted mechanical behavior of cancellous bone. This study is designed to answer this question.

Summary

This work proposes a novel, automatic method to obtain an anatomical reconstruction for 3D segmented bones with large acetabular defects. The method works through the fitting of a Statistical Shape Model to the non-defect parts of the bone.

Introduction

Patient-specific implants can be used to treat patients with large acetabular bone defects (IIa-c, IIIb, Paprosky 1994). These implants require a full 3D preoperative planning that includes segmentation of volumetric images (CT or MRI), extraction of the 3D shape, reconstruction of the bone defect into its anatomic (non-defect) state, design of an implant with a perfect fit and optimal placement of the screws. The anatomic reconstruction of the bone defect will play a key role in diagnosing the amount of bone loss and in the design of the implant. Previous reconstruction methods rely on a healthy contralateral (Gelaude 2007); however this is not always available (e.g. partial scan or implant present). Statistical shape models (SSM) of healthy bones can help to increase the accuracy and usability of the reconstruction and will decrease the manual labor and user dependency. Skadlubowicz (2009) illustrated the use of an SSM to reconstruct pelvic bones with tumor defects; however tumors generally affect a smaller region of the bone so that the reconstruction will be easier than in large acetabular bone defects. Also, the tumor reconstruction method uses 80 manually indicated landmarks, while the proposed method only uses 14.

Summary Statement

Prophylactic vertebroplasty treatment of ‘at-risk’ vertebrae may reduce fracture risk, however which areas weaken, thus providing surgical targets? Direct spatial 3D mapping of ReTm overcomes the constraints of 2D histology, and by application may provide insight into specific regional atrophy.

Introduction

Insidious bone loss with age makes the skeleton fracture-prone in the rapidly expanding elderly population. Diagnosis of osteoporosis is often made after irreversible damage has occurred. There are over 300,000 new fragility fractures annually in the UK, more than 120,000 of these being vertebral compression fractures (VCF). Some VCFs cause life-altering pain, requiring surgical intervention. Vertebroplasty is a minimally invasive procedure whereby bone cement is injected into the damaged vertebral body with the aim of stabilisation and pain alleviation. However, vertebroplasty can alter the biomechanics of the spine, apparently leaving adjacent vertebrae with an increased VCF risk. Prophylactic augmentation of intact, though ‘at-risk’, vertebrae may reduce the risk of adverse effects. The question therefore arises as to which areas of a non-fractured vertebral body, structurally weakened with age, and thus should be targeted. Frequent reports of an overlap in BMD (bone mineral density) between fracture and non-fracture subjects suggest the combination of bone quantity and its ‘quality’ (microarchitectural strength) may be a more reliable fracture predictor than BMD alone. Providing a reliable method of cancellous connectivity measurement (a highly significant bone strength factor) is challenging. Traditional histological methods for microarchitectural interconnection are limited as they usually indirectly extrapolate 3D structure from thin (8 µm) 2D undecalcified sections. To address this difficulty, Aaron et al (2000) developed a novel, thick (300 µm) slicing and superficial staining procedure, whereby unstained real (not stained planar artifactual) trabecular termini (ReTm) are identified directly within their 3D context.

The aim of this study was to automate a method of identifying trabecular regions of weakness in vertebral bodies from ageing spines. Patients and methods. 27 Embalmed cadaveric vertebral bodies (T10-L3) from 5 women (93.2±8.6 years) and 3 men (90±4.4 years) were scanned by µCT (micro-computerised tomography; µCT80, Scanco Medical, Switzerland, 74 µm voxel size), before plastic-embedding, slicing (300µm thick), and surface-staining with the von Kossa (2% silver nitrate) stain. The ReTm were mapped using light microscopy, recording their coordinates using the integrated stage, mapping them within nine defined sectors to demonstrate any apparent loci of structural disconnectivity that may cause weakness disproportionate to the bone loss. A transparent 3D envelope corresponding to the cortex, was constructed using code developed in-house (Matlab 7.3, Mathworks, USA), and was modulated and validated by overlay of the previous µCT scan and the coordinate data.

Summary Statement

We used three-dimensional software to assess different anatomic variables in the femur. The canal of Femur twisted slightly below the lesser trochanter in cases with a larger angle of anteversion.

Introduction

Accurate positioning of the joint prosthesis is essential for successful total hip arthroplasty (THA). To aid in tailoring of the prosthesis, we used three-dimensional software to assess different anatomic variables in the femur.

Summary Statement

Computational models are the primary tools for efficient design-phase exploration of knee replacement concepts before in vitro testing. To improve design-phase efficiency, a subject-specific computational platform was developed that allows designers to assess devices in realistic conditions by directly integrating subject-specific experimental data in these models.

Introduction

Early in the design-phase of new implant design, numerous in vitro tests would be desirable to assess the influence of design parameters or component alignment on the performance of the device. However, cadaveric testing of knee replacement devices is a costly and time-consuming procedure, requiring manufacture of parts, preparation of cadaveric specimens, and personnel to carry of the experiments. Validated computational models are ideally suited for pre-clinical, high-volume design evaluation. Initial development of these models requires substantial time and expertise; once developed, however, computational simulations may be applied for comparative evaluation of devices in an extremely efficient manner [Baldwin et al. 2012]. Still, computational models are complementary of experimental testing and for this reason, computational models tuned with subject-specific experimental data, e.g. soft tissue parameters, could bring even more efficiency in the design phase. The objective of the current study was to develop a platform of tools that easily allows for subject-specific knee simulations. The system integrates with commercially available medical imaging and finite element software to allow for direct, efficient comparison of designs and surgical alignment under a host of different boundary conditions.

Summary

Computer assisted surgery (CAS) during total knee arthroplasty (TKA) is known to improve prosthetic alignment in coronal and sagittal plane. In this systematic review, no evidence is found that CAS also improves axial component orientation when used during TKA.

Introduction

Primary total knee arthroplasty (TKA) is a safe and cost-effective treatment for end-stage knee osteoarthritis. Correct prosthesis alignment is essential, since malpositioning of the prosthesis leads to worse functional outcome and increased wear, which compromises survival of the prosthesis. Computer assisted surgery (CAS) has been developed to enhance prosthesis alignment during TKA. CAS significantly improves postoperative coronal and sagittal alignment compared to conventional TKA. However, the influence of CAS on rotational alignment is a matter of debate. Therefore purpose of this review is to assess published evidence on the influence of CAS during TKA on postoperative rotational alignment.

Summary Statement

Bio-impedance analysis (BIA) provides a convenient method for the estimation of whole body and segmental measurement of skeletal muscle mass (SMM). BIA-measured SMM parameters may be effectively used for the normalisation of muscle strength and removing body-size dependence.

Introduction

Despite an increasing interest in using bio-impedance analysis (BIA) for the estimation of segmental skeletal muscle mass (SMM); existing data is sparse. On the other hand, there is a need for better understanding of the influence of SMM on gender-related differences in muscle strength. Using BIA technique, this study aimed to measure the SMM, determine its correlation with muscle strength, and examine its relation with gender-related differences in muscle strength.

Summary Statement

Paraspinal muscle contain higher proportion of slow-twich fibers. The fixation of the rat tail induced transition of muscle fiber types in the paravertebral muscles characterised by the decrease in the proportion of the slow type myosin heavy chain.

Introduction

Lumbar degenerative kyphosis often accompanies back pain, easy fatigability, fatty degeneration and atrophy of back muscles. There are two types of skeletal muscle fibers according to oxidative activities: slow-twich (Type 1) and fast-twitch (Type 2) fibers. Type 2 fibers were subdivided into three types: Type 2A, 2B and 2D/X. Each fiber type primarily expresses a specific isoform of myosin heavy chain (MHC). It has been known that back muscles contain higher proportion of MHC type 1. However, the impact of kyphosis on the proportion of fiber types in the paravertebral muscles has not been fully understood. The aim of this study is to analyze the transition of muscle fiber types after kyophotic or straight fixation using a rat tail model.

Summary Statement

Patients with adolescent idiopathic scoliosis show clear signs of abnormal motor coordination between the long superficial paraspinal muscles and the deep rotators. These findings suggest an abnormal behavior of the deep rotator muscles at the concave side.

Introduction

An imbalance between the myoelectric activity of the muscles of the convexity and the concavity has been described in patients with adolescent idiopathic scoliosis (AIS). These findings are based on EMG patterns recorded with surface electrodes that do not distinguish between deep and superficial muscles. This work was aimed at analyzing the coupled behavior of the superficial and deep paraspinal muscles in subjects with AIS at both sides of the curve.

Summary Statement

This experimental study showed that platelet rich fibrin matrix can improve muscle regeneration and long-term vascularization without local adverse effects.

Introduction

Even though muscle injuries are very common, few scientific data on their effective treatment exist. Growth Factors (GFs) may have a role in accelerating muscle repair processes and a currently available strategy for their delivery into the lesion site is the use of autologous platelet-rich plasma (PRP). The present study is focused on the use of Platelet Rich Fibrin Matrix (PRFM), as a source of GFs.

Summary Statement

A resorbable and biocompatible polymer-based scaffold was used for the proliferation and delivery of adipose derived stromal cells, as well as delivery of a cell growth/differentiation promoting factor for improved tendon defect regeneration.

Introduction

Surgeons perform thousands of direct tendon repairs annually. Repaired tendons fail to return to normal function following injury, and thus require continued efforts to improve patient outcomes. The ability to produce regenerate tendon tissue with properties equal to pre-injured tendon could lead to improved treatment outcomes. The aim of this study was to investigate in vivo tendon regeneration using a biodegradable polymer for the delivery of adipose derived stromal cells (ADSCs) and a polypeptide, growth/differentiation factor-5/(GDF-5), in a tendon gap model.

Significance

Acute compartment syndrome (ACS) occurs after muscle injury and is characterised by increased pressure in the muscle compartment that can result in devastating complications if not diagnosed and treated appropriately. ACS is currently confirmed by repeated needle sticks to measure the compartment pressure using a hand-held compartment pressure monitor. This approach is often not reproducible and is not appropriate for continuous monitoring. To address the shortcomings of currently available technology we are developing an implantable micro-device that will measure compartment pressure directly and continuously over the 24 hours critical period following injury using a radio frequency identification (RFID) platform integrated with a MEMS capacitive pressure sensor.

Methods

The prototype implantable device measuring 3mmx3mm consists of a capacitive pressure sensor, a sensor readout circuitry, an antenna and a radio frequency reader. A prototype sensor was packaged in Silicone gel (MED-6640, Nusil Technology LLC) for ex vivo and in vivo testing in three compartment models. First, it was tested ex vivo in an airtight vessel using a blood pressure monitor to pump air and increase the pressure inside the vessel. Second, it was implanted in a muscle compartment of a fresh porcine hind limb and an infusion pump with normal saline was used to raise the tissue pressure. Third, it was implanted in the posterior thigh muscle of a rat where the pressure was increased by applying a tourniquet around the thigh. The readings were compared with those from a hand-held Stryker Intra-compartmental Pressure Monitor System used in the trauma room.

Summary

Based upon genetic analysis, decorin is an exciting pharmacologic agent of potential anti-fibrogenic effect on arthrofibrosis in our animal model.

Introduction

While the pathophysiology of arthrofibrosis is not fully understood, some anti-fibrotic molecules such as decorin could potentially be used for the prevention or treatment of joint stiffness. The goal of this study was to determine whether intra-articular administration of decorin influences the expression of genes involved in the fibrotic cascade ultimately leading to less contracture in an animal model.

Summary Statement

Mesenchymal stem cells from minced umbilical cord fragments may represent a valuable cell population for cartilage and bone tissue engineering

Introduction

A promising approach for cartilage and bone repair is the use of umbilical cord mesenchymal stem cell (UC-MSC)-based tissue engineering. Through a simple and efficient protocol based on mincing the umbilical cord, a consistent number of multipotent UC-MSCs can be obtained. The aim of this in-vitro study is to investigate the pluripotency of UC-MSCs and, in particular, the chondrogenic and osteogenic potential of UC-MSCs grown in tridimensional scaffold, in order to identify a potential clinical relevance for patients who might benefit from MSCs-therapy.

Summary

The donor-matched comparison between mesenchymal stem cells from knee infrapatellar and subcutaneous adipose tissue revealed their preferential commitment towards the chondrogenic and osteogenic lineage, respectively. These peculiarities could be relevant for the development of successful bone and cartilage cell-based applications.

Introduction

Mesenchymal stem cells (MSCs) have been proposed in bone and cartilage tissue engineering applications as an alternative to terminally differentiated cells. In the present study we characterised and performed a donor-matched comparison between MSCs resident within the infrapatellar fat pad (IFP-MSCs) and the knee subcutaneous adipose tissue (ASCs) of osteoarthritic patients. These two fat depots, indeed, can be considered appealing candidates for orthopaedic cell-based therapies since they are highly accessible during knee surgery.

Introduction

Despite the high regenerative capacity of bone, large bone defects often require treatment involving bone grafts. Conventional autografting and allografting treatments have disadvantages, such as donor site morbidity, immunogenicity and lack of donor material. Bone tissue engineering offers the potential to achieve major advances in the development of alternative bone grafts by exploiting the bone-forming capacity of osteoblastic cells. However, viable cell culture models are essential to investigate osteoblast behavior. Three-dimensional (3D) cell culture systems have become increasingly popular because biological relevance of 3D cultures may exceed that of cell monolayers (2D) grown in standard tissue culture. However, only few direct comparisons between 2D and 3D models have been published. Therefore, we performed a pilot study comparing 2D and 3D culture models of primary human osteoblasts with regard to expression of transcription factors RUNX2 and osterix as well as osteogenic differentiation.

Patients and Methods

Primary human osteoblasts were extracted from femoral neck spongy bone obtained during surgery procedures. Primary human osteoblasts of three donor patients were cultured in monolayers and in three different 3D culture models: 1) scaffold-free cultures, also referred to as histoids, which form autonomously after multilayer release of an osteoblast culture; 2) short-term (10-day) collagen scaffolds seeded with primary human osteoblasts (HOB); 3) long-term (29-day) collagen scaffolds seeded with HOB. Expression levels of transcription factors RUNX2 and osterix, both involved in osteoblast differentiation, were investigated using quantitative PCR and immunohistochemical staining. Furthermore, markers of osteogenic differentiation were evaluated, such as alkaline phosphatase activity, osteocalcin expression, and mineral deposition, as well as the expression of collagen type I and fibronectin extracellular matrix proteins.

Summary

This study helps to elucidate how ColVI and Dcn within the pericellular matrix (PCM) of differentiating hMSCs directly impacts dynamic cytoskeletal response to load, and demonstrates an important role for the PCM in mechanotransduction during chondrogenesis.

Introduction

Mechanosignaling events in differentiating human mesenchymal stem cells (hMSCs) are dependent on their temporally changing micromechanical environment and their dynamic cytoskeleton. During chondrogenic differentiation, hMSCs develop a matrix composed of type VI collagen (ColVI) and proteoglycans such as decorin (Dcn). We have previously demonstrated that this developing PCM is important in cellular mechanotransduction. The aim of this study was to determine the functional roles of ColVI and Dcn in modulating load-induced changes in the organization of vimentin intermediate filaments (VIF), actin microfilaments (AM), and vinculin.

Summary Statement

This work raises the potential of utilizing stem cells to catalyze cartilage regeneration by a minimal number of neonatal chondrocytes via controlling cell distribution in 3D matrices, and may solve the challenge of scarce donor availability associated with cell-based therapy.

Introduction

Cartilage loss is a leading cause of disability among adults and represents a huge socio-economical burden. Allogeneic neonatal articular chondrocytes (NChons) is a promising cell source for cartilage regeneration because these cells are highly proliferative, immune-privileged, and readily produce abundant cartilage matrix. However, scarce donor availability for NChons greatly hinders their broad clinical application. Besides their ability to differentiate into different tissue types, stem cells may contribute to tissue regeneration through the secretion of paracrine factors. Here we examined the potential for using a minimal number of NChons to catalyze cartilage tissue formation by co-culturing them with adipose-derived stem cells (ADSCs) in 3D biomimetic hydrogels.

Introduction

Mesenchymal stem cells (MSCs) are identified by having the ability to differentiate into various tissues and typically used to generate bone tissue by a process of resembling intramembranous ossification, namely by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, namely via remodeling of hypertrophic cartilaginous templates. To date, reconstruction of bone defects by endochondral ossification using mesenchymal stem cell-derived chondrocytes (MSC-DCs) have not been reported. The purpose of this study was to evaluate the effects of the transplantation of MSC-DCs on bone healing in segmental defects in rat femurs.

Methods

Segmental bone defects (5, 10, 15-millimeter) were produced in the mid-shaft of the femur of the Fisher 344 rats and stabilised with an external fixator. Bone marrow was aspirated from the rat's femur and tibia at 4 weeks before operation. MSCs were isolated and grown in culture and seeded on a Poly dl-lactic-co glycolic acid (PLGA) scaffold. Subsequently, the scaffold was cultured using chondrogenic inducing medium for 21 days. The characteristics of the PLGA scaffold are radiolucent and to be absorbed in about 4 months. The Treatment Group received MSC-DCs, seeded on a PLGA scaffold, locally at the site of the bone defect, and Control Group received scaffold only. The healing processes were monitored radiographically and studied biomechanically and histologically.

Summary Statement

One of the most challenging problems in osteogenic 3D-tissue engineering is, to quantify the amount of new hydroxylapatite deposition. ¹⁸F-NaF-Labeling is a new, high-sensitive method to proof and quantify the osteogenic potential of hMSCs in an in vitro 3D-model.

Introduction

¹⁸F-labeled sodium fluorine was the first widely used agent for skeletal scintigraphy in the 1960s. ¹⁸F-NaF is rapidly exchanged for hydroxylgroups of the hydroxylapatite, covalently binding to the surface of new bone, which results in the formation of fluoroapatite. Three dimensional scaffolds are used to favor osteogenic differentiation of precursor cells. Cell-loaded scaffolds are investigated for their healing potential of critical size bone defects. Assessing the osteogenic potential of MSCs in 3D-in vitro cultures is of major interest in tissue engineering in order to maximise bone formation in vitro and in vivo.

One of the most challenging problems is, to quantify directly the amount of new hydroxylapatite deposition without destroying the evaluated cell-loaded scaffold. Within this abstract, we present a novel, non-destructive, high-sensitive method to quantify the amount of local hydroxylapatite deposition in 3D-cultures using ¹⁸F-NaF.

Summary

Despite similar, early and massive death, hMSCs promote bone formation which was higher in orthotopic than ectopic site suggesting a trophic effect of hMSCs. Ectopic implantation is suitable to evaluate cell survival, but assessment of bone formation requires orthotopic implantation

Introduction

Tissue constructs containing mesenchymal stem cells (MSCs) are appealing strategies for repairing large segmental bone defects but they do not allow consistent bone healing and early and massive MSCs death was identified as a cause of failure. However, little is known about cell survival in the clinical micro-environment encountered during bone healing process, whereas ectopic evaluation is well documented.

In vivo, luciferase-labelled human MSCs survival, within osteoconductive scaffold, was compared in orthotopic and ectopic locations, and bone formation ability of LF-hMSCs-Acropora constructs was evaluated. Interest and limits of each model were highlighted.

Summary Statement

A biomimetic tissue engineering strategy involving culture on bone scaffolds in perfusion bioreactors allows the construction of stable, viable, patient-specific bone-like substitutes from human induced pluripotent stem cells.

Introduction

Tissue engineering of viable bone substitutes represents a promising therapeutic strategy to mitigate the burden of bone deficiencies. Human induced pluripotent stem cells (hiPSCs) have an excellent proliferation and differentiation capacity, and represent an unprecedented resource for engineering of autologous tissue grafts, as well as advanced tissue models for biological studies and drug discovery. A major challenge is to reproducibly expand, differentiate and organize hiPSCs into mature, stable tissue structures. Based on previous studies (1,2,3), we hypothesised that the culture conditions supporting bone tissue formation from adult human mesenchymal stem cells (hMSCs) and human embryonic stem cell (hESC)-derived mesenchymal progenitors could be translated to hiPSC-derived mesenchymal progenitors. Our objectives were to: 1. Derive and characterise mesenchymal progenitors from hiPSC lines. 2. Engineer bone substitutes from progenitor lines exhibiting osteogenic potential in an osteoconductive scaffold – perfusion bioreactor culture model. 3. Assess the molecular changes associated with the culture of hiPSC-progenitors in perfusion bioreactors, and evaluate the stability of engineered bone tissue substitutes in vivo.

Summary Statement

Treatment of non-union is a highly demanding field with respect to bone healing. BMP 7 is a useful, wide-ranged tool in treating non-union of the foot and benign bone tumors. It represents a low-risk procedure with a high level of reliability.

Introduction

Treatment of non-union is a highly demanding field with respect to bone healing. Treatment of tibial fracture non-union with the bone morphogenetic protein 7 (BMP-7) has been successfully reported. BMP 7 is a recombinant human protein produced in ovary cells of the Chinese hamster. It is responsible for the differentiation of mesenchymal stem cells from the periost, muscle and sponious bone and stimulates bone formation. It is the aim of our study to investigate the use of BMP 7 for other locations than the tibia, such as the foot and benign bone tumors. We strive for union or revision in each medical case.

Summary Statement

A population based finite element study that accounts for subject-specific morphology, density and load variations, suggests that osteoporosis does not markedly lower the mechanical compliance of the proximal femur to routine loads.

Introduction

Osteoporosis (OP) is a bone disease defined by low bone density and micro-architectural deterioration. This deterioration is neither uniform nor symmetric at the proximal femur. Evidence from analyses performed at the tissue level suggests that the cortical shell at the femoral neck is thinner in OP patients, especially in the superior regions, but not in the infero-anterior ones [Poole, Rubinacci]. Analogously, OP femurs show a higher anisotropy of the trabecular bone than controls [Ciarelli], suggesting a preservation of load bearing capacity in the principal loading direction vs. the transverse one. There is general consensus that the regions subjected to higher loads during walking, which is the predominant motor activity in the elderly, are mostly preserved. All these findings suggest that the OP femur should exhibit an almost normal mechanical competence during daily activities. This would be in accordance with the very low incidence of spontaneous fractures [Parker] and with the moderate fracture predictivity of BMD. Although reasonable, this hypothesis has never been tested at the organ level. Aim of the present study was to verify it with a population-based finite element (FE) study.

Summary Statement

Burst fractures were simulated in vitro on human cadaveric spine segments. Displacement of the facet joints and pedicles were measured throughout the fracture process showing how these bony structures behave when an impact load is delivered.

Introduction

Burst fractures account for almost 30% of all spinal injuries, which may result in severe neurological deficit, spinal instability and hence life impairment¹. The onset of the fracture is usually traumatic, caused by a high-energy impact loading. Comminution of the endplates and vertebral body, retropulsion of fragments within the canal and increase of the intrapedicular distance are typical indicators of the injury. Experimental and numerical studies have reported strain concentration at the base of the pedicles, suggesting that the posterior processes play a fundamental role in the fracture initiation^2,3. However, little is known about the dynamic behaviour of the vertebra undergoing an impact load. The aim of this study was to provide an in vitro cadaveric investigation on burst fracture, focusing on the widening of the facet joints and pedicles during the fracture development.

Summary

A retrospective study on 98 patients shows that FE-based bone strength from CT data (using validated FE models) is a suitable candidate to discriminate fractured versus controls within a clinical cohort.

Introduction

Subject-specific Finite element models (FEM) from CT data are a promising tool to non-invasively assess the bone strength and the risk of fracture of bones in vivo in individual patients. The current clinical indicators, based on the epidemiological models like the FRAX tool, give limitation estimation of the risk of femoral neck fracture and they do not account for the mechanical determinants of the fracture. Aim of the present study is to prove the better predictive accuracy of individualised computer models based a CT-FEM protocol, with the accuracy of a widely used standard of care, the FRAX risk indicator.

Summary

A rotational limit for screw insertion may improve screw purchase and plate compression by reducing stripping, as compared to a torque based limit.

Introduction

Over-tightening screws results in inadvertent stripping of 20% of cortical bone screws. The current method of “two-fingers tight” to insert screws relies on the surgeon receiving torque feedback. Torque, however, can be affected by screw pitch, bone density and bone-thread friction. An alternative method of tightening screws is the “turn-of-the-nut” model, commonly used in engineering applications. In the “turn-of-the-nut” method, nuts used to fasten a joint are rotated a specific amount in order to achieve a pre-specified bolt tension. When applied to orthopaedics, bone assumes the role of the nut and the screw is the bolt. The screw is turned a set angular rotation that is independent of torque feedback. Potentially the “turn-of-the-nut” method provides an easier way of screw insertion that might lessen inadvertent screw stripping. The purpose of the current study was to use the “turn-of-the-nut” method to determine the angular rotation that results in peak plate compression and peak screw pullout force.

Summary Statement

Tibia plateau split fracture fixation with two cancellous screws is particularly suitable for non-osteoporotic bone, whereas four cortical lag screws provide a comparable compression in both non-osteoporotic and osteoporotic bone. Angle-stable locking plates maintain the preliminary compression applied by a reduction clamp.

Introduction

Interfragmentary compression in tibia plateau split fracture fixation is necessary to maintain anatomical reduction and avoid post-traumatic widening of the plateau. However, its amount depends on the applied fixation technique. The aim of the current study was to quantify the interfragmentary compression generated by a reduction clamp with subsequent angle-stable locking plate fixation in an osteoporotic and non-osteoporotic synthetic human bone model in comparison to cancellous or cortical lag screw fixation.

Summary

Shear stress and hydrostatic effects on the hMSCs early mechano gene response were similar. For the same magnitude gene response, the hydrostatic compression (1.5×10⁵ Pascal) is a 200000 times greater than the force exerted by shear stress (0.7 Pascal).

Introduction

In the lab, a perfusion bioreactor designed to automate the production of bone constructs was developed. The proof of concept was established in a large animal model of clinical relevance. The cells perfused in the bioreactor are likely to perceive 2 types of stresses: shear stress and hydrostatic pressure. Optimization of this bioreactor implies a better understanding of the effects of these forces on the cells in order to have better proliferation and differentiation. An understanding of the response of one cell layer submit to various strength is relevant. The primary objective of this study was to test the hypothesis that hMSCs have the fundamental ability to distinguish between different types of mechanical signals as evidenced by distinct gene expression. The effect of shear stress on one cell layer cultures of hMSCs will be evaluated using a commercially available system called Ibidi. For the hydrostatic pressure as there is no commercial device available, our group has developed a prototype capable of delivering a well-defined mechanical loading to cells in culture.

Validation of the techniques: In order to validate the systems (shear stress and cyclic pressure apparatus) used in this study, we have used an osteocytes-like cell line, MLO-Y4. When stimulated by a 30 minutes PFF at 7 dyn/cm² or hydrostatic compression at 1.5 bar, cells responded by producing NO in the culture media

NO release after mechanical stimulation of hMSCs: hMSCs were subjected to increased PFF (7 to 42 dyn/cm²) for 30 minutes. This stimulation resulted in an increased release of NO in the media compared to non-stimulated cells (p<0.05). Interestingly the level of NO was maximal at 7 dyn/cm² and decreased with higher flow rate. Similar observation was made after hMSCs stimulation by hydrostatic pressure for 30 minutes: a peak of NO release at 1.5 bar was observed

Early gene expression of known mechano-sensitive genes: Gene expression analysis immediately after stimulation (PFF or hydrostatic compression) was performed on a range of known mechano-sensitive genes: NOS2, PTGS2, PTGES, IER3 and EGR1. Immediately after stimulation by PFF at 7 dyn/cm² or hydrostatic pressure at 1.5 bars, the expression of all the genes of interest appear to be up regulated in stimulated cells

Summary

Micromotions between stem and neck adapter depend on prosthesis design and material coupling. Based on the results of this study, the amount of micromotion seems to reflect the risk of fretting-induced fatigue in vivo.

Introduction

Bimodular hip prostheses were developed to allow surgeons an individual reconstruction of the hip joint by varying length, offset and anteversion in the operation theatre. Despite these advantages, the use of these systems led to a high rate of postoperative complications resulting in revision rates of up to 11% ten years after surgical intervention. During daily activities taper connections of modular hip implants are highly stressed regions and contain the potential of micromotions between adjacent components, fretting and corrosion. This might explain why an elevated number of fretting-induced neck fractures occurred in clinics. However, some bi-modular prostheses (e.g. Metha, Aesculap, Ti-Ti) are more often affected by those complications than others (e.g. H-Max M, Limacorporate, Ti-Ti or Metha, Ti-CoCr) implying that the design and the material coupling have an impact on this failure pattern. Therefore, the purpose of this study was to clarify whether clinical successful prostheses offer lower micromotions than those with an elevated number of in vivo fractures.

Summary

The required torque leading to an abrasion of the passive layer in the stem-head interface positively correlates to the assembly force. In order to limit the risk of fretting and corrosion a strong hammer blow seems to be necessary.

Introduction

Modular hip prostheses are commonly used in orthopaedic surgery and offer a taper connection between stem and ball head. Taper connections are exposed to high bending loads and bear the risk of fretting and corrosion, as observed in clinical applications. This is particularly a problem for large diameter metal bearings as the negative effects may be enhanced due to the higher moments within the taper connection. Currently, it is not known how much torque is required to initiate a removal of the passive layer, which might lead to corrosion over a longer period and limits the lifetime of prostheses. Therefore, the purpose of this study was to identify the amount of torque required to start an abrasion of the passive layer within the interface dependent on the assembly force and the axial load.

Summary

This work uses a mathematical method to correlate the forces calculated to push-on and pull off a femoral head from a stem and correlate the results of in vitro testing.

Introduction

This work aimed to mathematically model the force needed to disassemble the THR unit for a given assembly load. This work then compared these results with the results of an in vitro experiment. The research presented aimed to determine the assembly forces necessary to prevent movement of the head on the stem through friction. By assessing the forces necessary to push the head onto the stem securely enough to prevent any movement of the head through friction, it is likely that the fretting and corrosion of the head taper interface will be reduced.

Summary Statement

ACL reconstruction using a quadriceps tendon autograft was quantitatively evaluated using a robotic testing system. Biomechanical results on joint stability and graft function support its use as an alternative to the hamstrings.

Introduction

Recently, a number of surgeons have chosen the quadriceps tendon (QT) autograft as an alternative autograft over the hamstrings tendon for ACL reconstruction because its bone-to-bone healing on one side, large size, and preservation of lateral and rotatory knee function could lead to fewer post-operative complications. However, there have been little or no biomechanical studies that quantitatively evaluate knee function after reconstruction using a QT autograft. Therefore, the objective of this study was to assess the function of a reconstructed knee with a QT autograft and compare the results with a quadrupled semitendinosus and gracilis (QSTG) tendon autograft on the same knee.

Summary

Prosthetic UHMWPE added with vitamin E and crosslinked UHMWPE are able to decrease significantly the adhesion of various bacterial and fungal strains limiting biomaterial associated infection and consequent implant failure.

Introduction

Polyethylene abrasive and oxidative wear induces overtime in vivo a foreign-body response and consequently osteolysis, pain and need of implant revision. To solve these problems the orthopaedic research has been addressed to develop new biomaterials such as a crosslinked polyethylene with a higher molecular mass than standard Ultra High Molecular Weight Polyethylene (UHMWPE), and consequently a higher abrasive wear resistance and an antioxidant (vitamin E)-added UHMWPE to avoid oxidative wear. Nevertheless a feared complication of implant surgery is bacterial or fungal infection, initiated by microbial adhesion and biofilm formation, and related to the biomaterial surface characteristics. Staphylococci are the most common microorganisms causing biomaterial associated infection (BAI), followed by streptococci, Gram-negative bacilli and yeasts. With the aim to prevent BAI, the purpose of this study was to evaluate the adhesion of various microbial strains on different prosthetic materials with specific surface chemical characteristics, used in orthopaedic surgery.

Summary Statement

A study to evaluate biofilm development on different coatings of UHMWPE was performed. We observed a species-specific effect, with S. aureus affected mainly by DLC-F and S. epidermidis by DLC. These data correlates with previous adherence studies.

Introduction

Prosthetic joint infection is intimately related to bacterial biofilms on implant biomaterials. Recently, diamond-like carbon (DLC) coating has been suggested to improve the antibacterial performance of medical grade GUR1050 ultra high molecular weight polyethylene (UHMWPE) supplied by Orthoplastics bacup, UK versus collection and clinical staphylococcal strains. The aim of this study was to make an approximation towards the actual impact of such coatings in biofilm formation.

Summary Statement

Supercritical fluid (SCF) sterilization produces clean and osteoconductive allograft bone capable of healing a critical-sised bony defect. SCF treated graft induces an increased anabolic response and decreased catabolic reponse compared to gamma irradiated graft.

Introduction

Clinically, allogeneic bone graft is used extensively because it avoids the donor site morbidity associated with autograft. However, there are concerns over the optimal sterilization method to eliminate immunological risks whilst maintaining the biological efficacy of the graft. This study compared the effect of Supercritical fluid (SCF) sterilization and gamma irradiation on the osteoconductivity of allograft bone in a bilateral critical-sised defect rabbit model.

Summary Statement

The problem facing this research is to promote rapid osteointegration of titanium implants and to minimise the risks of infections by the functionalization with different agents, each designed for a specific action. A patented process gives a multifunctional titanium surface.

Introduction

A patented process of surface modification is described. It gives a multifunctional surface with a multiscale roughness (micro and nano topography), that is excellent for osteoblast adhesion and differentiation. It has a high degree of hydroxylation, that is relevant for inorganic bioactivity (apatite-HA precipitation) and it is ready for a functionalization with biological factors. A direct grafting of ALP has been obtained. Moreover, the growth of an antibacterial agent within the surface oxide layer can be useful in order to combine the osteoinduction ability to antimicrobial effects. The selection of an inorganic agent (metal nanoparticles) has the advantage to avoid an eventual development of antibiotic resistance by bacteria.

Summary Statement

Repetitive concavities threaded on the surface of bone implants have been already demonstrated to be effective on ectopic bone formation in vivo. The aim of this study was to investigate the effect of concavity on the mineralization process in vitro.

Introduction

The role of implant surface geometry in bone formation has been extensively investigated. Ripamonti and co. investigated the possibility to induce bone formation by threading concavities on the surface of calcium phosphate implants, without the need for exogenous osteogenic soluble factors. The underlying hypothesis was that this geometry, by resembling the hemi-osteon trench observable during osteoclastogenesis, was able to activate the ripple-like cascade of bone tissue induction and morphogenesis. Despite several studies indicating a positive effect of concavities on bone induction, so far no attempts have rationalised this phenomenon by means of in vitro tests. Consequently, this study aimed to evaluate the effect of surface concavities on the mineralization of hydroxyapatite (HA) and beta-tricalciumphosphate (b-TCP) ceramics in vitro. Our hypothesis was that concavities could effectively guide the mineralization process in vitro.

Summary Statement

The present study demonstrates the beneficial effects of strontium (Sr) modified calcium phosphate cement to improve new bone formation in a metaphyseal osteoporotic fracture defects in rats compared to calcium phosphate cement and empty defects. Keywords: strontium, fracture, calcium phosphate, bone formation

Introduction

Impaired fracture healing with subsequent implant failure is a dramatic problem in osteoporotic fractures. Biomaterials are of interest to stimulate fracture healing in osteoporotic defects and the objective of the current study is to investigate the effects of Strontium modified calcium phosphate cement (SrCPC) in a critical-size metaphyseal fracture defect of osteoporotic rats compared to calcium phosphate (CPC) and empty defect control group.

Summary Statement

This work features a new approach to overcome drawbacks of commercial calcium phosphate cements in terms of application by on-site preparation and bone ingrowth by introduction of macropores in the material using a hydrofluoroalkane based aerosol foam.

Introduction

The application of calcium phosphate bone cements (CPCs) into a void for example of an osteoporotic bone is very difficult as the cement paste is made outside the application site and subsequently applied into the damaged bone. A common drawback of especially apatitic cements is a very low resorption rate due to small pore size Therefore different approaches have been described to add macropores into the cement², leading to bone ingrowth and tissue penetration. The aim of this project is the use of two separate formulations in pressurised systems – a suspension and an emulsion – which can be mixed in a specially developed device and can be applied easily and efficiently into a bone directly during surgery leading to a self-hardening macro porous CPC foam. The intention is to fill voids in osteoporotic bones to ensure stability for implants like e.g. screws for femur neck fractures. An increased stability for implants can allow the possibility of a less invasive femur neck preserving therapy in contrast to a femur neck replacement. Other indications for such foam (i.e. kyphoplasty) are under evaluation.

Summary

Coating of titanium implants with BMP-2-loaded polyelectrolyte multilayer films conferred the implant surface with osteoinductive properties which are fully preserved upon both air-dried storage and γ-sterilization.

Although BMP-2 is recognised as an important molecule for bone regeneration, its supraphysiological doses currently used in clinical practice has raised serious concerns about cost-effectiveness and safety issues. Thus, there is a strong motivation to engineer new delivery systems or to provide already approved materials with new functionalities. Immobilizing the growth factor onto the surface of implants would reduce protein diffusion and increase residence time at the implantation site. To date, modifying the surfaces of metal materials, such as titanium or titanium alloys, at the nanometer scale for achieving dependable, consistent and long-term osseointegration remains a challenging approach.

In this context, we have developed an osteoinductive coating of a porous titanium implant using biomimetic polyelectrolyte multilayer (PEM) films used as carriers of BMP-2. The PEM films were prepared by alternate deposition of 24 layer pairs of poly(L-lysine) (PLL) and hyaluronic acid (HA) layers (∼3.5 µm in thickness); such films were then cross-linked by means of a water-soluble carbodiimide (EDC) at different degrees. The amount of BMP-2 loaded in these films was tuned (ranging from 1.4 to 14.3 µg/cm²) depending on the cross-linking extent of the film and of the BMP-2 initial concentration. Because packaging, and storage of the devices are important issues that may limit a wide application of biologically functionalised materials, we assessed in the present study the osteoinductive performance of the BMP-2 loaded PEM coatings onto custom-made 3D porous scaffolds made of Ti-6Al-4V in vitro and in vivo pertinent to long-term storage in a dry state and to sterilization by gamma irradiation.

Analysis of PEM films by infrared spectroscopy evidenced that the air-dried films were stable for at least one year of storage at 4°C and they resisted exposure to γ-irradiation at clinically approved doses. The preservation of the growth factor bioactivity was evaluated both in vitro (using C2C12 cell model) and in vivo (in a rat ectopic model). In vitro, BMP-2 loaded in dried PEM films exhibited shelf-life stability at 4°C over a one-year period. However, its bioactivity decreased from 50 to 80% after γ-irradiation at 25 and 50 kGy, respectively. Remarkably, the in vivo studies showed that the amount of new bone tissue formation induced by BMP-2 contained in PEM-coated Ti implants was not affected after air-drying of the implants and sterilization at 25 kGy indicating the full preservation of the growth factor bioactivity.

Altogether, our results provided evidence of the remarkable property of PEM film coatings that both sequester BMP-2 and preserve its full in vivo osteoinductive potential upon both storage and γ-sterilization. The protective effects of PEM films on the growth factor bioactivity may be attributed to both the high water content in (PLL/HA) films (∼90%) and to their porosity, which may provide a “protein-friendly” environment similar to the natural extracellular matrix. This novel “off-the-shelf” technology of functionalised implants opens promising applications in prosthetic and tissue engineering fields.

Summary

Osseointegrated Amputation Prostheses can be functionalised by both biological augmentation and structural augmentation. These augmentation techniques may aid the formation of a stable skin-implant interface.

Introduction

Current clinical options are limited in restoring function to amputees, and are associated with contact dermatitis and infection at the stump-socket interface. Osseointegrated Amputation Prosthesis attempts to solve issues at the stump-socket interface by directly transferring axial load to the prosthesis, via a skin-penetrating abutment. However, development is needed to achieve a seal at the skin-implant interface to limit infection. Fibronectin, an Extracellular Matrix protein, binds to integrins during wound healing, with the RGD tripeptide being part of the recognition sequence for its integrin binding domain. In vitro work has found silanization of RGD to polished titanium discs up regulates fibroblast attachment compared to polished control. Electron Beam Melting can produce porous titanium alloy implants, which may encourage tissue attachment. This study aims to test whether a combination of biological RGD coatings and porous metal manufacturing techniques can encourage the formation of a seal at the skin-implant interface.

Summary

A promising approach to stimulate in vivo bone formation by using our newly developed magnesium-based bone substitutes, which can be an alternative to treat the patients with bone loss in addition to the anticatabolic drugs and growth factors.

Introduction

Bone impairment arising from osteoporosis as well as other pathological diseases is a major health problem. Anti-catabolic drugs such as bisphosphonates and other biological agents such as bone morphogenetic proteins and insulin-like growth factor can theoretically apply to stimulate bone formation. However, the formation of more brittle bone and uncontrolled release rate are still a challenge nowadays. Hence, we propose to stimulate bone formation by using a newly developed magnesium-based bone substitute. Indeed, the presence of magnesium ions can stimulate bone growth and healing by enhancing osteoblastic activity. This study aims to investigate the mechanical, in vitro and in vivo properties of this novel bone substitute.

Summary Statement

We observed that severe muscle weakness leads to OA, whereas a transient inflammatory stimulus did not have a significant effect on cartilage degradation. This arises the thought that a severe but transient inflammation may not be an independent risk factor for OA.

Introduction

Biomechanical disturbances and joint inflammation are known risk factors, which may provoke or advance osteoarthritis (OA). However, the effect of interactions of such risk factors on the onset and progression of OA are still poorly understood. Therefore, the goal of this study was to investigate the in vivo effects of muscle weakness, joint inflammation, and the combination of these two risk factors, on the onset and progression of OA in the rabbit knee.

Summary

This study describes the use of a quasi-static, 6DOF knee loading simulator using cadaveric specimens. Muscle force profiles yield repeatable results. Intra-articular pressure and contact area are dependent on loading condition and ACL integrity.

Introduction

Abnormal contact mechanics of the tibiofemoral joint is believed to influence the development and progression of joint derangements. As such, understanding the factors that regulate joint stability may provide insight into the underlying injury mechanisms. Muscle action is believed to be the most important factor since it is the only dynamic regulator of joint stability. Furthermore, abnormal muscle control has been experimentally linked to the development of OA [Herzog, 2007] and in vivo ACL strain [Fleming, 2001]. However, the individual contributions to knee joint contact mechanics remain unclear. Thus, the purpose of this study was to examine the effects of individual muscle contributions on the tibiofemoral contact mechanics using an in-vitro experimental protocol.

Summary

In a rabbit model of early osteoarthritis, structural changes in femoral condyle cartilage were severer in the lateral compartment and preceded alterations in the underlying bone. In the medial compartment, altered bone properties occurred together with structural changes in cartilage.

Introduction

Early osteoarthritic changes in cartilage have been previously studied through anterior cruciate ligament transection (ACLT) in rabbits. However, parallel changes in the structure of subchondral and trabecular bone at 4 weeks after ACLT are not known.

Summary Statement

Cross-talk between cells from immune and bone system might play a role in molecular regulation of subchondral bone sclerosis in osteoarthritis. Macrophages, B-lymphocytes and tartrate-resistant acid phosphatase activity are specifically increased in sclerotic subchondral bone of patients with knee osteoarthritis.

Background

Recent investigations have provided substantial evidence that distinct molecular and morphological changes in subchondral bone tissue, most notably sclerosis, play an active and important role in the pathogenesis of OA. The cellular and molecular regulation of this pathological process remains poorly understood. Here, we investigated whether osteoimmunology, the reciprocal signaling between cells from the immune and bone system, is involved in OA subchondral bone sclerosis.

Summary Statement

OA knee with subchondral cyst formation presented differential microstructure and mechanical competence of trabecular bone. This finding sheds light on the pivot role of subchondral cyst in OA bone pathophysiology.

Introduction

Subchondral bone cyst (SBC) is a major radiological finding in knee osteoarthritis (OA), together with joint space narrowing, osteophyte and sclerotic bone formation. There is mounting evidence showing that SBC originates in the same region as bone marrow lesions (BMLs). The presence of subchondral bone cyst (SBCs), in conjunction with BMLs, was associated with the severity of pain, and was able to predict tibial cartilage lolume loss and risk of joint replacement surgery in knee OA patient. It is speculated that the presence of SBCs might increase intraosseous pressure of subchondral bone, and trigger active remodeling and high turnover of surrounding trabecular bone. Yet the exact effect of SBC on the structural and mechanical properties trabecular bone, which provides the support to overlying articular cartilage, remains to be elucidated. Therefore, this study aimed to investiate the microstructure and mechanical competence of trabecular bone of knee OA in presence or absence of SBC.

Summary

The dGEMRIC index correlates more strongly with the pattern of radiographic joint space narrowing in hip osteoarthritis at five year follow-up than morphological measurements of the proximal femur. It therefore offers potential to refine predictive models of hip osteoarthritis progression.

Introduction

Longitudinal general population studies have shown that femoroacetabular impingement increases the risk of developing hip osteoarthritis, however, morphological parameters have a low positive predictive value. Arthroscopic debridement of impingement lesions has been proposed as a potential strategy for the prevention of osteoarthritis, however, the development of such strategies requires the identification of individuals at high risk of disease progression. We investigated whether delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) predicts disease progression. This imaging modality is an indirect measure of cartilage glycosaminoglycan content.

Summary Statement

This work proved by prospective clinical and radiological controlled study that the best regimen for treatment of early KOA is combination of NSAIDS, physiotherapy, vasoprotective and vasodilator drugs, and alendronate.

Introduction

There is controversy in the literatures regarding the best treatment for early knee osteoarthritis because there is a more controversy regarding the initiating factor of KOA The Objectives of this work were to evaluate the efficacy of various treatment regimens for the prevention of progression of early knee osteoarthritis (KOA). Also, to elucidate the factors for initiation and progression of KOA

Introduction

Osteoarthritis (OA) involves pathological change in all joint tissues, including cartilage degradation and synovitis. Synovial inflammation is significantly associated with pain severity and incidence in knee OA. It is becoming evident that synovitis also plays an active role in the initiation and progression of cartilage erosion in OA, through direct secretion of catabolic enzymes as well as factors that stimulate chondrocyte catabolic activity. Therapeutic agents that target both synovitis and cartilage pathology are likely to be maximally beneficial in treating pain and slowing cartilage breakdown in OA. We have previously shown that an amide-derivative of HA (HYMOVIS™) was superior to native HA of the same MW in improving gait, and reducing synovial hyperplasia in a sheep OA model. In the present study the mechanisms whereby the chemically modified HA may be beneficial were examined using chondrocytes and synovial fibroblasts from knees of OA patients.

Patients & Methods

Chondrocytes (HAC, n=6) and synovial fibroblasts (HSF, n=6) were isolated from OA patients at the time of knee replacement. HYMOVIS™ (0, 0.5, 1.0 or 1.5mg/mL) was added to simultaneously or 1 hour before interleukin-1β (IL1, 2ng/mL). Cultures were terminated 30 minutes later for Bioplex^® quantitation of p-JNK, p-NFκB and p-p38; or 24 hours later for RNA isolation and analysis of gene expression by real time RT-PCR, and measurement of MMP13 activity in the media. Only statistically significant results are reported.

Summary Statement

For RA patients undergoing TKR, the gain in function at 6 months following surgery is less than that experienced by OA patients; for THR, however, gains are similar in OA and RA patients.

Introduction

Total joint replacement (TJR) is commonly used in rheumatoid arthritis (RA) patients and yet little information is available to quantify their functional gain following surgery and how it differs from what the osteoarthritis (OA) population experiences. Therefore, we examined 6-month functional outcomes of TJR in a population-based observational cohort of RA and OA patients who underwent total hip (THR) or knee (TKR) replacement.

Summary Statement

Progenitor cells from the periosteal niche are of great clinical interest due to their remarkable regenerative capacity. Here we report on progenitor cells from arthritic patients whose femoral neck periosteum was resected over the course of hip replacement.

Introduction

This study aims to determine whether periosteum derived cells (PDCs) can be isolated from tissue resected in the normal course of hip arthroplasty. Further, it aims to determine how different isolation protocols affect PDC behavior (surface marker expression, proliferation, and differentiation). In addition, the study aims to characterise the populations of PDCs, isolated through either enzymatic digestion or migration, and their relative capacity to differentiate down multiple capacities; direct comparison with commercially available human marrow-derived stromal cells cultured under identical conditions will enable the placement of the PDC data in context of the current state of the field.

Summary

We demonstrate that osteoclast-like cells of GCT result from the spontaneous fusion and differentiation of CD14+ cells of the monoblastic lineage by an autocrine mechanism mediated by RANKL, rather than induced by stromal cells. This process is further enhanced by the simultaneous impairment of the negative feed-back regulation of osteoclastogenesis by interferon β.

Introduction

Giant cell tumor of bone (GCT) is a benign osteolytic lesion with a complex histology, comprising prominent multinucleated osteoclast-like cells (OC), mononuclear stromal cells (SC), and monocyte-like elements. So far, most studies have focused on SC as the truly transformed elements that sustain osteoclast differentiation, while less attention has been paid on the monocyte-like cell fraction. On the contrary, we have previously shown that SC are non-transformed element that can induce osteoclastogenesis of monocytes at levels that do not exceed that of normal mesenchymal stromal cells. We therefore focused on CD14+ monocyte-like cells as an alternative key candidate for the pathogenesis of GCT.

Summary Statement

In this study we suggested a possible role of prion proteins genes in osteosarcoma. Therefore, the inhibition of prion proteins expression must be tested because it could represent a new approach to the molecular treatment of osteosarcoma.

Introduction

Although osteosarcoma is the most common bone malignancy, the molecular and cellular mechanisms influencing its pathogenesis have remained elusive. Prion proteins (PRNP and PRND), known mostly for its involvement in neurodegenerative spongiform encephalopathies, have been recently demonstrated to be involved in resistance to apoptosis, tumorigenesis, proliferation and metastasis.

Summary

Reciprocal metabolic reprogramming of MSCs and osteosarcoma cells influences tumor-stroma cross talk. Drugs targeting Warburg metabolism may define innovative therapeutic approaches in osteosarcoma.

Introduction

Osteosarcoma (OS) is a malignant primary bone tumour of mesenchymal origin, in which cells with stem-like characteristics (CSCs) have been described. Recent studies have demonstrated a mutual interaction between stroma and tumor cells in exploiting a role in the pathogenesis and progression of cancer, and also in the enhancing stemness phenotype. Here we take in consideration the complex juxtacrine and paracrine intercellular cross talk played by mesenchymal stromal cells (MSCs) with adherent osteosarcoma cells and OS cells with stem-like characteristics (CSCs).

Summary

Starting from human musculoskeletal sarcomas, we isolated a subset of cells that display cancer stem cell properties. The control of culture conditions is crucial to enhance the isolation of this cell population.

Introduction

Cancer stem cells (CSCs) have emerged as the real responsible for the development, chemoresistance, and metastatic spread of different human cancers, including musculoskeletal sarcomas. However, unlike most leukemias and solid tumors, so far, data on musculoskeletal sarcomas refer to CSCs obtained from established cell lines, and only a few authors have reported on the isolation of CSCs from tissue samples [1-7]. Reasonably due to some peculiar features of mesenchymal tumors, including the lack of unique surface markers that identify tumor progenitors, there are still partial clues on the existence of a CSC population in these cancers. Here, we report the identification of putative CSCs in musculoskeletal sarcomas using the most general accepted isolation method, the sphere culture system. Accordingly to recent reports, we also analyzed the effects of reduced oxygen availability on the behavior of sarcoma CSCs.

Summary Statement

Survivin is a member of the inhibitor of apoptosis family, which may contribute to the progression of human MFH via inhibiting the mitochondrial apoptosis, and may be considered as a potent therapeutic target for the treatment of human MFH.

Introduction

Survivin is a member of the inhibitor of apoptosis (IAP) family, which usually expresses in the embryonic lung and fetal organs in the developmental stages, but is undetectable in normal adult tissues other than thymus, placenta, CD34⁺ stem cells, and basal colonic epitherial cells. However, several studies reported that survivin is highly expressed in various human malignancies, including sarcomas, and increased expression of survivin is an unfavorable prognostic marker correlating with decreased overall survival in cancer patients. We have previously reported that survivin was strongly expressed in human malignant fibrous histiocyoma (MFH), however, the roles of survivin in human MFH have not been studied. The aim of this study was to evaluate the effect of survivin inhibition on apoptotic activity in human MFH cells.

Summary Statement

A novel transcutaneous CO₂ therapy significantly enhanced the antitumor effectiveness of X-ray irradiation in human MFH xenografts The results strongly suggest that transcutaneous CO₂ therapy could be a novel therapeutic tool for overcoming radioresistance in human malignancies.

Introduction

Hypoxia contributes to tumor radioresistance. In the presence of oxygen, reactive oxygen species (ROS) play crucial roles in cellular apoptosis to irradiation. We previously showed that a novel transcutaneous application of CO₂ can improve hypoxia and that it induces apoptosis and decreases the expression of HIF-1α in sarcoma. Therefore, we hypothesised that a transcutaneous application of CO₂ may increase radiosensitivity in sarcoma by improvement of hypoxic condition and increasing ROS production in tumors. The purpose of this study is to examine the effect of transcutaneous application of CO₂ on radiosensitivity in human malignant fibrous histiocytoma (MFH) cells.

Summary Statement

RANK is expressed in 18% of human osteosarcomas and is likely to provide additional prognostic information for clinical purposes in osteosarcoma patients at the time of diagnosis.

Introduction

The receptor activator of nuclear factor kappa (RANK), a member of the tumor necrosis factor family, is activated by its ligand and regulates the differentiation of osteoclasts and dendritic cells. Local growth of osteosarcoma involves destruction of the host bone by osteoclasts and proteolytic mechanisms. Although prognosis of osteosarcoma has been improved by chemotherapy during the last decades, the problem of non responders and the lack of prognostic markers remains. It is the aim of this study to investigate the prognostic and predictive value of RANK expression in human osteosarcoma.

Summary Statement

Combination of sorafenib with irradiation achieved synergistic effect with dose reduction in both 143B and HOS cell lines. This demonstrated the potential application of sorafenib in the treatment of osteosarcoma metastasis and radiation resistance.

Introduction

More than 20% of patients with osteosarcoma die of the disease within 5 years due to tumour relapse and metastasis. Identifying new treatment that works singly or in combination with conventional therapies is urgently required. We previously found that the Ras/Raf/MAPK pathway was associated with lung metastasis in a 143B inoculated osteosarcoma orthotopic mouse model¹. Sorafenib, a multi-kinase inhibitor, has shown potent anticancer effect including in osteosarcoma² through the inhibition of Raf-1 and other targets³. The aims of this study were to investigate effect of sorafenib on osteosarcoma cell lines with or without activated Ras/Raf/MAPK signalling and to decide whether sorafenib could enhance irradiation on these cells.

Summary

Photodynamic therapy with ICG lactosome and near-infrared light has phototoxic effects on human breast cancer cells. With the same total energy, phototoxic effects depend on output of irradiation light rather than irradiation time.

Introduction

The phototoxic effects of indocyanine green (ICG) and near-infrared light have been studied in various fields. Plasma proteins bind strongly to ICG, which is followed by rapid clearance by the liver, resulting in no tumor selectivity after systemic administration. We have proposed a novel nanocarrier labeled with ICG (ICG lactosome) that has tumor selectivity due to its enhanced permeation and retention (EPR) effect. The aim of this study was to investigate in vitro phototoxic effects and to optimise the irradiation conditions by changing the output and time of near-infrared light as excitation light.

Summary

Human amniotic membrane has interesting properties for regenerative medicine. To use it as an Advanced Therapeutic Medicinal Product in bone surgery, we are evaluating: the necessity of its osteodifferentiation and the impact on immunogenicity; its optimal condition for storage.

Introduction

The human Amniotic Membrane (hAM) is known to have a good potential to help the regeneration of tissues. It has been used for 100 years in many medical disciplines because of its properties: a flexible scaffold containing stem cells and growth factors, with low immunogenicity and anti-microbial, anti-inflammatory, anti-fibrotic and analgesic properties. Previous published data showed the possibility of in vitro osteodifferentiation of the whole tissue. We aim to use this «boosted membrane» as an Advanced Therapeutic Medicinal Product for bone repair to treat large defects or pseudarthrosis, so, we are studying:

The necessity to osteodifferentiate the tissue and its consequence on the immunogenicity; Its in vivo osteogenic potential; The effects of the cryopreservation on cell viability and function.

Summary

Properties of human amniotic membrane are particularly interesting. To use it as an Advanced Therapeutic Medicinal Product in bone surgery, we are evaluating its association with a potentially osteoinductive scaffold.

Introduction

The human Amniotic Membrane (hAM) is known to have a good potential to help the regeneration of tissues. It has been used for 100 years in many medical disciplines because of its properties: a membrane containing stem cells and growth factors, with low immunogenicity and anti-microbial, anti-inflammatory, anti-fibrotic and analgesic properties. Moreover, previous published data showed the possibility of in vitro osteodifferenciation of the whole tissue.

We aim to use hAM as an Advanced Therapeutic Medicinal Product for bone repair to treat large defects or pseudarthrosis. So we are studying the association of hAM with nanofiber jet sprayed polycaprolactone (PCL) scaffolds and the possibility to induce its osteodifferenciation.

Short Summary

The present study demonstrated the feasibility of culturing a large number of standardised granular MSC-containing constructs in a packed bed/column bioreactor that can produce sheep MSC-containing constructs to repair critical-size bone defects in sheep model.

Introduction

Endogenous tissue regeneration mechanisms do not suffice to repair large segmental long-bone defects. Although autologous bone graft remains the gold standard for bone repair, the pertinent surgical technique is limited. Tissue constructs composed of MSCs seeded onto biocompatible scaffolds have been proposed for repairing bone defects and have been established in clinically-relevant animal models. Producing tissue constructs for healing bone defects of clinically-relevant volume requires a large number of cells to heal an approximately 3 cm segmental bone defect. For this reason, a major challenge is to expand cells from a bone marrow aspirate to a much larger, and sufficient, number of MSCs. In this respect, bioreactor systems which provide a reproducible and well-controlled three-dimensional (3D) environment suitable for either production of multiple or large size tissue constructs are attractive approaches to expand MSCs and obtain MSC-containing constructs of clinical grade. In these bioreactor systems, MSCs loaded onto scaffolds are exposed to fluid flow, a condition that provides both enhanced access to oxygen and nutrients as well as fluid-flow-driven mechanical stimulation to cells. The present study was to evaluate bioreactor containing autologous MSCs loaded on coral scaffolds to repair critical-size bone defects in sheep model.

Summary

Within hours after exposure to hypoxic circumstances hMSCs start producing AGFs. Initially hypoxia does not affect hMSC proliferation and metabolic activity, but after 7 days both are decreased, compared to hMSCs cultured under ambient oxygen conditions.

Introduction

At the moment of implantation of a large cell seeded scaffold, usually a vascular network is lacking within the scaffold. Therefore, the cells seeded on the scaffold are exposed to hypoxic circumstances. Human mesenchymal stem cells (hMSCs) exposed to hypoxic circumstances, start to produce angiogenic factors (AGF)¹ and to proliferate faster than at ambient oxygen levels². Under severe, continued hypoxia, hMSC metabolism slows down and ultimately stops³. We hypothesise that there is a threshold oxygen level above which hMSCs at hypoxia will both produce AGF and still proliferate, and below which cells slow down their metabolism. If hMSCs are provided with oxygen levels just above this threshold, effective tissue regeneration, which requires cell proliferation and vascular ingrowth, may be accomplished.

Summary Statement

Flow chambers have been implemented in stem cell research to apply controlled dilational (volume changing) and deviatoric (shape changing) mechanical cues to living cells. Studies implementing such chambers demonstrate that controlled delivery of mechanical cues correlates strongly to changes in stem cell shape, structure, and fate.

Introduction

A custom designed flow chamber, capable of delivering highly controlled stresses at the cellular scale, enables the study of flow-induced normal and shear stresses on cell behavior. Specifically, computational fluid dynamics (CFD) and multiphysics modeling (coupling of CFD with finite element models) allow for controlled delivery of mechanical cues via fluid flow and cell seeding protocols, concomitant to optical mapping of cell displacements due to mechanical load, and calculation of flow velocities, imbued stresses, and cellular strains within a given volume of interest. Akin to conducting a mechanical loading test on single cells and groups of cells, paired experimental and computational experiments using the custom-designed chamber enabled calculation of the flow field's effect on the cell(s) as well as the cells’ effect on the flow field, a critical step in predicting the local stress and strain fields at the cell-fluid interface within the chamber, during exposure to fluid flow. These stresses-strains experienced by stem cells demonstrate significant correlation to cell gene expression, and strongly suggest that stresses at the cell-fluid interface influence cell fate. The current study uses a parametric approach to define next steps to prospectively guide mechanically-modulated lineage commitment.

Introduction

The use of mesenchymal stem cells in regenerative medicine remains a promising approach due to the ability of these cells to differentiate into a variety of cell types of mesodermal lineage. Today, however, it is not clear whether long-term differentiation of MSCs is necessary or alternatively whether the benefits of MSCs can be conferred by transitory paracrine effects (via secreted chemical compounds). Human MSCs secrete a broad variety of cytokines, chemokines and growth factors that may potentially be involved in tissue repair. Nevertheless, hMSCs secretome profile is closely related to cells biological and chemical environment (pO₂, inflammation, nutrients disponibility…). In the context of stem-cell-based regenerative medicine, upon implantation, hMSC are exposed to stresses such as ischemia, oxidative stress and inflammatory mediators. Knowledge of the paracrine properties of stem cells under hypoxic conditions is essential for planning appropriate strategies that overcome the potential negative impacts of all levels of low oxygen content (from hypoxiato anoxia) leading to ischemia and tissue necrosis pertinent to MSC-based tissue engineered constructs. Since the beneficial effects of stem cells may be confered predominantly indirectly through paracrine mechanisms, the present study was designed to characterise the hMSC secretome and to assess its biological effects considering oxygen level and nutrients disponibility.

Methods

hMSCs were exposed in vitro either to sustain ischemic environment (pO₂ ≤ 0.1%, serum deprived), to hypoxia (pO₂ ≤ 0.1%, 5g/L glucose) or to normoxic conditions (pO₂=21%). We used an hypoxic station (Biospherix, US) to ensure sustained hypoxia during 21 days. Levels of angiogenic, chemo-attractant, inflammatory and immunomodulative mediators were assessed in supernatants using the luminex technology (milliplex KIT, Millipore, USA). The chemo-attractant potential of conditioned media (CM) was assessed in vitro using Boyden chambers (BD, USA). To assess angiogenic potential of CM, HEPC were seeded on matrigel for 18 hours with CM obtained from hMSCs. Functionnality of secreted mediators was also assessed in vivo: briefly, CM media were lyophilyzed on collagen sponges and ectopically implanted in nude mice. Chemo-attraction and vascularization of the implants were determined using histological and CTscan analysis.

Summary

45S5 bioactive glass combined with hMSC did not permit de novo ectopic bone formation. Such absence of osteogenicity was most likely due to the alkalinization of the 45S5 microenvironment that affects adversely the osteogenic differentiation of stem/precursor cells.

Bone marrow stromal cells (BMSCs) are capable of bone formation and can promote the repair of osseous defects when implanted in appropriate scaffolds. The most promising biomaterials for application in bone tissue engineering (TE) are hydroxyapatite (HA), tricalcium phosphate (TCP), calcium carbonate (coral) ceramics or bioactive glasses (BG) because of their osteoconductive properties and ability to enhance bone formation. However, information regarding the osteogenic potential of hBMSCs in combination with BG scaffolds is strikingly lacking in the TE field. The present study focused on evaluating the osteogenicity of bone constructs prepared from particles of 45S5 BG combined with hBMSCs in comparison with biphasic HA/TCP or coral particles, in a mouse ectopic model.

The in vivo osteogenicity was then correlated with various aspects of the effects of the scaffold materials tested on hBMSCs functions pertinent to bone tissue formation. Particular attention was given to the pH in the microenvironment where the cells reside in TE constructs and its effect on the osteoblastic differentiation of hBMSCs. In vivo experiments evidenced that 45S5 BG constructs with hBMSCs failed to form ectopic bone. In contrast, the cell constructs prepared with either HA/TCP or coral ceramics displayed great and consistent capacity for the ectopic bone formation. The cytocompatibility of hBMSCs on BG material was addressed and no differences were evidenced between HA/TCP and coral substrates related to the adhesion of hBMSCs and their proliferation in vitro. The hBMSCs viability was even higher within the 45S5 BG-containing constructs compared to the other two types of material constructs tested both in vitro and in vivo. These findings indicated that the absence of de novo bone formation in the hBMSCs-containing 45S5 BG constructs was not the result of cytotoxic effects of the BG material.

The potential of osteogenic differentiation of hBMSCs cultured on material substrates was next addressed and the ALP activity of hBMSCs was significantly diminished when these cells were cultured on 45S5 BG as compared to either HA/TCP or coral substrates. Because BG materials are well-known for causing external alkalinisation, the pH was specifically measured in TE constructs. The pH inside the cell-containing BG constructs, measured ex vivo, was 8.0 (i.e. 0.4–0.5 units more alkaline than that measured in the coral- or HA/TCP-constructs). The impact of such external alkalinisation on the osteogenic differentiation of hBMSCs was assessed by culturing the cells over a wide range of alkaline pH. The hBMSCs expression of osteogenic markers, ALP activity and mineralization were not significantly affected at moderate external alkaline pH (≤ 7.90) but were dramatically inhibited at higher pH.

Altogether, these findings provided evidence that despite 45S5 BG are reported to be good osteoconductive materials, they are not necessarily good scaffolds for TE, most likely due to the alkalinization of the 45S5 microenvironment that affects adversely the osteogenic differentiation of precursor cells. Controlling the shifts of pH in the local engineered extracellular environment is a critical issue for the development of bioactive TE scaffolds.

Summary Statement

Routine metal allergy screening prior to joint arthroplasty is not essential and the use of cobalt chromium or stainless steel implants is recommended regardless of the patient's metal allergy status.

Introduction

This study was undertaken to obtain a consensus amongst joint arthroplasty experts with regards to metal allergy screening prior to joint arthroplasty and the choice of implant in patients with potential metal allergy.

Summary Statement

There were significant differences in the pain experience, behaviors, and perceptions on analgesics, between the Australia and Singapore cohorts, after hospital discharge following TKR. These findings may be influenced by the ethnicity and cultural differences between these two countries.

Introduction

In recent years the hospital length of stay after total knee replacement (TKR) has shortened. Hence, patients have to self-manage their pain earlier after the surgery. The aim of this study was to examine if the pain experience, self-management behaviors and potential barriers to optimal analgesia after hospital discharge for TKR differed in different ethnicity groups.

Summary

Alignment results did not differ between PSG and conventional instrumentation. A small reduction in operation time and blood loss was found with the PSG system, but is unlikely of clinical significance. Length of hospital stay was identical for both groups.

Introduction

Several techniques for aligning a TKA exist nowadays. Patient-specific guiding (PSG) has relatively recently been introduced to try to resolve the shortcomings of existing techniques while optimising the operative procedure. Still few reports have been published on the clinical outcome and on the peroperative results of this new technique. This prospective, double-blind, randomised controlled trial was designed to address the following research questions: 1. Is there a significant difference in outliers in alignment in the frontal and sagittal plane between PSG TKA and conventional TKA. 2. Is there a significant difference in operation time, blood loss and length of hospital stay between the 2 techniques.

Summary Statement

Navigated total knee arthroplasty (TKA) is becoming increasingly popular in the United States. Compared to traditional unnavigated TKA, the use of navigation is associated with decreased blood transfusions and shorter hospital stays.

Introduction

Navigated total knee arthroplasty (TKA) is a recent modification to standard TKA with many purported benefits in regards to component positioning. Controversy currently exists though regarding its clinical benefits. The purpose of this study was to assess recent national trends in navigated and unnavigated total knee arthroplasty and to evaluate perioperative outcomes for each group.

Summary Statement

This is the first report of a new technique for unicompartmental to total knee arthroplasty revision surgery in which patient specific guides are formed based on preoperative CT imaging. This technique can help to make revision surgery less technically demanding.

Introduction

Unicompartmental to total knee arthroplasty revision surgery can be a technically demanding procedure. Joint line restoration, rotation and augmentations can cause difficulties. This study describes a new technique in which single way fitting guides serve to position knee system cutting blocks.

Introduction

Ostochondral lesion of the knee is a common cause of chronic knee pain. Arthroscopic treatment with subcondral microfracture is a widespread technique leading to noticeable improvement of knee function and pain. To improve the effectiveness of this treatment options, we thought to add intra (PRF) or post-operative (PRP) growth factors. Platelet rich plasma (PRP) is obtained by centrifugation of the blood to produce a plasma with high concentration of platelets and growth factors. This latter represents a promising method to manage degenerative cartilage lesion and can be used postoperatively to improve clinical results of patients treated arthroscopically. Platelet Rich Fibrin (PRF) has been presented as a second-generation platelet concentrate, and it is used intraoperatively to cover the microfracuteres’ holes. No literature was found about using of PRF intraoperative in association with arthroscopic microfracture technique. The aim of this study is to compare clinical outcomes of the treatment of knee osteochondral lesion using arthroscopic microfracture technique alone or in association with PRF Intraoperative application using “Vivostat” system or with PRP “ReGen Lab” postoperative injection.

Patients & Methods

90 patients with clinical and radiographic evidence of osteochondral lesion of the medial or lateral compartment of the knee were enrolled. All patients received arthroscopic debridement and Microfractures and were randomised into 3 groups: 30 patients received microfractures and intraoperative PRF “Vivostat” injection(Group A), 30 patients received microfracture and 3 intra-articular injections of 5.5 mL PRP “Regen”(Group B), 30 patients received microfracture only. IKDC, KOOS and VAS score were administered to all patients before starting the treatment, at 1, 6 and 12 months from the end of the management.

Summary

Anatomical variations in hip joint anatomy are associated with both the presence and location of tibiofemoral osteoarthritis (OA).

Introduction

Variations in hip joint anatomy can alter the moment-generating capacity of the hip abductor muscles, possibly leading to changes in the magnitude and direction of ground reaction force and altered loading at the knee. Through analysis of full-limb anteroposterior radiographs, this study explored the hypothesis that knees with lateral and medial knee OA demonstrate hip geometry that differs from that of control knees without OA.

Summary Statement

We evaluated the mechanical strength of two cortical suspension devices by reproducing clinical situation for ACL reconstruction. A most important factor affecting the displacement during cyclic load was the length of the tendon rather than the length of the device.

Introduction

A definite consensus for the optimal graft fixation technique to the femur in an anterior cruciate ligament (ACL) reconstruction has not been reached, although there have been several fixation techniques such as cortical suspension devices, transfixation devices, and interference screws. The purpose of this study was to evaluate the mechanical strength of two cortical suspension devices by reproducing actual clinical situation for ACL reconstruction in order to compare the TightRope^TM as a new adjustable-length loop device and the EndoButton^TM as a well-known fixed-length loop device under the consistent conditions.

Summary Statement

Simulated increases in body weight led to increased displacement, von Mises stress, and contact pressure in finite element models of the extended and flexed knee. Contact shifted to locations of typical medial osteoarthritis lesions in the extended knee models.

Introduction

Obesity is commonly associated with increased risk of osteoarthritis (OA). The effects of increases in body weight and other loads on the stresses and strains within a joint can be calculated using finite element (FE) models. The specific effects for different individuals can be calculated using subject-specific FE models which take individual geometry and forces into account. Model results can then be used to propose mechanisms by which damage within the joint may initiate.

Summary

Biomechanical studies comparing fixation constructs are predictable and do not relate to the significant clinical problems. We believe there is a need for more careful use of resources in the lab and better collaboration with surgeons to enhance clinical relevance.

Introduction

It is our impression that many biomechanical studies invest substantial resources studying the obvious: that open reduction and internal fixation with more and larger metal is stronger. Studies that investigate “which construct is the strongest?” are distracted from the more clinically important question of “how strong is strong enough?”. The aim of this study is to show that specific biomechanical questions do not require formal testing. This study tested our hypothesis that the outcome of a subset of peer reviewed biomechanical studies comparing fracture fixation constructs can be predicted based on common sense with great accuracy and good interobserver reliability.

Summary

The quantification of T1Rho relaxation times is not related with internal loading. Improvements in modeling and imaging techniques might lead to better understanding of the pathomechanics of the knee.

Introduction

The onset and progression of knee osteoarthritis has been associated with an increased external knee adduction moment (EKAM). However, this external measure has no direct relationship with internal loading of the knee. For a better understanding of the pathomechanics of the knee musculoskeletal models could be used to relate external and internal knee loading. Consequently, high internal loading might cause cartilage degeneration in patients with OA. T1RhoMRI can detect changes in proteoglycan content and is therefore a non-invasive measure of cartilage degeneration in knee OA. The purpose of this study was to relate internal loading of the knee simulated by musculoskeletal models with cartilage health using T1rhoMRI.

Summary

Biomechanically, a 2° screw deviation from the nominal axis in the PFLCP leads to significantly earlier implant failure. Screw deviation relies on a technical error on insertion, but in our opinion cannot be controlled intraoperatively with the existing instrumentation devices.

Background

Several cases of clinical failure have been reported for the Proximal Femoral Locking Compression Plate (PFLCP). The current study was designed to investigate the failure mode and to explore biomechanically the underlying mechanism. Specifically, the study sought to determine if the observed failure was due to technical error on insertion or due to implant design.

Summary Statement

Creep behaviour can only be quantified accurately when the testing time exceeds the estimated time constant of the creep process. The new parameters obtained in this paper can be used to describe normal behaviour up to 24 hrs.

Background

Diurnal loading on the human spine consists of 16hrs loading and 8hrs rest. After an initial load increase, due to rising in the morning, an axial loading is maintained throughout the day. As a consequence subsidence of the intervertebral disc (IVD) occurs during the day while disc height recovers during the night. This behaviour is time dependent (non-linear). In literature different constitutive equations have been used to describe creep. A stretched exponential (Kolraush-Wilson-Watts, KWW) and a double Voight (DV) model have both been used to quantify the creep behaviour. Using these models, time constants and the deformation at equilibrium are estimated. It is unsure whether these different approaches yield to valid predictions. In this study we compared the validity of different equations for the prediction of creep behavior.

Summary

Both endogenous lubricin and injectable hyaluronic acid reduced cartilage friction coefficients, but by distinct mechanisms. Lubricin operated in boundary mode and hyaluronic acid shifted lubrication to mixed or hydrodynamic mode.

Introduction

Intra-articular injections of viscous agents and boundary lubricants have been presented as options to mitigate the progression of articular cartilage damage after the onset of osteoarthritis^1,2. Mechanically, these injections are predicted to lower the friction coefficient within a load bearing joint and consequently slow the propagation of damage at the articular surface. Tribologically, boundary lubricants and viscous agents are hypothesised to be effective through different mechanisms affecting boundary-mode lubrication and transition to mixed-mode lubrication, respectively. By normalizing sliding speeds on a Stribeck curve, this study evaluated the efficacy of injectable hyaluronic acid (HA) supplements and endogenous lubricin to alter tribological properties.

Summary

Our statistical shape analysis showed that size is the primary geometrical variation factor in the medial meniscus. Shape variations are primarily focused in the posterior horn, suggesting that these variations could influence cartilage contact pressures.

Introduction

Variations in meniscal geometry are known to influence stresses and strains inside the meniscus and the articulating cartilage surfaces. This geometry-dependent functioning emphasizes that understanding the natural variation in meniscus geometry is essential for a correct selection of allograft menisci and even more crucial for the definition of different sizes for synthetic meniscal implants. Moreover, the design of such implants requires a description of 3D meniscus geometry. Therefore, the aim of this study was to quantify 3D meniscus geometry and to determine whether variation in medial meniscus geometry is size or shape driven.

Summary Statement

A three dimensional meniscal scaffold with controlled fibre diameter and orientation was fabricated by an improved E-Jetting system that mimic the internal structure of natural meniscus. In vitro cellular tests proved its feasibility in meniscal tissue engineering applications.

Introduction

Current surgical and repair methods for complex meniscal injuries still do not often give satisfactory long-term results. Thus, scaffold-based grafts are the subject of much research interest. However, one major hurdle is that current techniques are unable to replicate the precise 3D microstructure of meniscus, nor the variations in the fibrillar structure and tissue content from layer to layer. In this work, an improved electrohydrodynamic jet printing system (E-Jetting system) was developed to fabricate biomimetic meniscal scaffold for tissue regeneration.

Summary Statement

Re-biopsies of five patients after spheroid-based, scaffold-free autologous chondrocyte transplantation revealed regeneration of cartilage with immunohistochemical characteristics of articular cartilage.

Introduction

Traumatic lesions of articular cartilage represent a crucial risk-factor for cartilage degradation and osteoarthritis, because the regenerative capacity of articular cartilage is highly limited. Even if there exist several strategies to treat traumatic cartilage damages such as the classical autologous chondrocyte transplantation (ACT) or matrix assisted ACT, the optimal solution is not yet been found since transplantation errors are known. A relatively new strategy represents the scaffold-free spheroid based autologous chondrocyte transplantation. After harvesting articular cartilage in this strategy spheroids of chondrocytes will be synthesised after chondrocyte isolation and expansion. The spheroids will be implanted and rest at the transplantation site by adhesion.

Summary

Despite high revision rates, the mean two year migration of the ASR^TM cup is within an acceptable threshold. Slightly higher migration rates found for the M2a- Magnum™ Porous Coated Acetabular Component but longer follow up is needed to establish if this implant is at risk.

Introduction

RSA can detect the migration of an implant, and continuous migration is a predictor for failure (1). The ASR^TM resurfacing implant was withdrawn from the marked due to excessive failure rate but showed initial femoral component stability. The aim of this study was to investigate the initial implant stability for the ASR cup as a possible explanation for the high revision rate, and to compare it to another metal on metal (MoM) cup.

Summary

Comparison of accuracy and precision in measuring wear using 4 commonly used uncemented cup designs shows small differences in mean and data scatter for marker and model-based RSA.

Introduction

The disadvantage with conventional RSA is that implant has to be supplied with tantalum markers, which may be difficult to visualise. This problem can be resolved with model-based RSA, but it is uncertain if this method has the same precision as marker-based RSA to measure wear. We compared these methods and studied different prosthesis geometries represented by four different uncemented cup designs (Trilogy, TMT-Trabecular Metal, Zimmer, Warsaw, USA, Ringloc, Biomet, Inc., Warsaw, Indiana, and ABG, Howmedica International, Staines, UK).

Summary

In this study we validate that weight-bearing images are needed for accurate polyethylene liner wear measurement in total knee prostheses by measuring the difference in minimum joint space width between weight-bearing and non-weight-bearing RSA views.

Introduction

Recent studies show that Model-based Roentgen Stereophotogrammetric Analysis is superior to the conventional in vivo measurements of polyethylene liner wear in total knee prostheses. Although it is generally postulated that weight-bearing (standing) views are required to detect liner wear, most RSA images are acquired in non-weight-bearing (supine) view for practical reasons. Therefore, it would be of interest to know if supine views would be sufficient for measuring TKA liner wear, defined as a change in minimum joint space width (mJSW). As a difference in mJSW between weight-bearing and non-weight-bearing RSA images has never been validated, the aim of this study is to compare the outcome of in vivo measurements of mJSW in total knee prosthesis when conducted with weight-bearing and non-weight-bearing RSA views.

Summary Statement

In young, active patients cementless THR demonstrates excellent prosthetic stability by RSA and outstanding clinical outcomes at 5 years using a tapered titanium femoral stem, crosslinked polyethylene liners and either titanium or tantalum shells.

Introduction

Early femoral implant stability is essential to long-term success in total hip replacement. Radiostereometric analysis (RSA) provides precise measurements of micromotion of the stem relative to the femur that are otherwise not detectable by routine radiographs. This study characterised micromotion of a tapered, cementless femoral stem and tantalum porous-coated vs. titanium acetabular shells in combination with highly cross-linked UHMWPE or conventional polyethylene liners using radiostereometric analysis (RSA) for 5 years following THR.

Summary

Five year migration results of 49 large-head metal-metal (MoM) total hip arthroplasties show good implant stability and no association between implant migration and metal-ions levels, stem and cup position, or femoral bone mineral density.

Introduction

The failure mechanism of metal-metal (MoM) total hip arthroplasty has been related to metal wear-debris and pseudotumor, but it is unknown whether implant fixation is affected by metal wear-debris.

Summary

The EOS stereography system has been developed for the evaluation of prosthetic alignment. This new low-dose device provides reliable 2D/3D measurements of knee prosthesis alignment.

Introduction

Achieving optimal prosthetic alignment during Total Knee Arthroplasty (TKA) is an essential part of the surgical procedure since malpositioning can lead to early loosening of the prosthesis and eventually revision surgery. Conventional weight-bearing radiographs are part of the usual clinical follow-up after both primary TKA and revision TKA (rTKA), to assess alignment in the coronal and sagittal planes. However, proportions and angles may not be correct on radiographs since divergence exists in the vertical and horizontal planes. Furthermore estimating the exact planes by looking at the position of the patella depends on rotation in the hip joint and this may be misinterpreted by the investigator. A computed tomography (CT) scanogram can also be used. However, due to high levels of radiation and costs it is not routinely used. To this end, a new device, the EOS stereography system, has been developed. With this biplanar low-dose X-ray technique, orthogonally made 2D images and 3D reconstructions can be obtained. Advantages of EOS are that images of the leg are obtained on a 1:1 scale with an amount of radiation 800–1000 times lower than CT-scans and 10 times lower than conventional radiographs. Another advantage is that the 3D reconstructions lead to determination of the real coronal and sagittal planes. However, the software for creating 3D reconstructions is developed for the lower limbs without knee prosthesis material. Consequently a reliability study concerning the generation of 2D images and 3D reconstructions of a leg containing a knee prosthesis has not been performed yet. Therefore objective of this study was to investigate interobserver and intraobserver reliability of knee prosthetic alignment measurements after rTKA using EOS.

Summary Statement

We analysed impaction bone grafting used together with cemented or uncemented fixation in acetabular revision surgery. The overall risk for re-revision did not differ between the cemented and uncemented group. However, aseptic loosening was more common in the cemented group.

Background

Several surgical techniques address bone defects in cup revision surgery. Bone impaction grafting, introduced more than thirty years ago, is a biologically and mechanically appealing method. The primary aim of this study was to evaluate the effect of bone impaction grafting when used with uncemented and cemented fixation in cup revision surgery. Uncemented cups resting on more than 50% host bone were used as controls.

Summary Statement

A new 28mm-diameter ceramic-on-ceramic (COC) acetabular bearing couple (Biomet Orthopedics) showed extremely low wear, even under adverse microseparation conditions∗. The wear results are similar or more favorable than those reported for clinical retrievals and wear testing of similar ceramic bearings.

Introduction

A new acetabular shell and ceramic insert design (Biomet) incorporates features to help prevent malalignment during implantation, while still providing secure fixation within the acetabular shell. The incorporation of Biolox^® Delta (zirconia toughened alumina, CeramTec) material should provide improved wear resistance over pure alumina ceramics. The goal of this study is to evaluate the wear durability of this system for standard and microseparation testing.

Summary Statement

The frictional torque of ceramic-on-ceramic bearings tended to increase with increasing the bearings size (32, 48, 56mm). However, the frictional torque was significantly lower than that measured on metal-on-metal bearings under well positioned and well lubricated conditions.

Introduction

Larger head size in total hip replacement theoretically provides increased range of motion and enhanced stability. However, there are potential clinical concerns regarding increased frictional torques with large diameter metal-on-metal bearings causing loosening of the acetabular cups and corrosion at the taper. The aim of this study was to determine the frictional torques of large diameter BIOLOX® delta ceramic-on-ceramic bearings.

Summary Statement

Fretting and corrosion has been identified as a clinical problem in modular metal-on-metal THA, but remains poorly understood in modern THA devices with polyethylene bearings. This study investigates taper damage and if this damage is associated with polyethylene wear.

Introduction

Degradation of modular head-neck tapers was raised as a concern in the 1990s (Gilbert 1993). The incidence of fretting and corrosion among modern, metal-on-polyethylene and ceramic-on-polyethylene THA systems with 36+ mm femoral heads remains poorly understood. Additionally, it is unknown whether metal debris from modular tapers could increase wear rates of highly crosslinked PE (HXLPE) liners. The purpose of this study was to characterise the severity of fretting and corrosion at head-neck modular interfaces in retrieved conventional and HXLPE THA systems and its effect on penetration rates.

Summary

Corrosion and fretting damage at the head-neck interface of artificial hip joints is more severe with larger head sizes. This is a concern, as the release of metal particles and ions can cause adverse tissue reactions, similar to those observed high wear metal-on-metal articulations.

Introduction

In the last few years corrosion was increasingly observed at head-neck interfaces of artificial hip joints, especially in joints with larger heads. There has always been evidence of some corrosion at modular junctions of artificial joints, but except for few designs, it was not seen as a real problem. It is important to better understand the factors contributing to corrosion at modular interfaces, so that necessary improvements can be made to minimise or completely avoid corrosion, in order to avoid possible adverse tissue reactions.

Summary

From a large 3D Caucasian bone data base, female population had significantly larger acetabular anatomical anteversion angle and combined acetabular-femoral anteversion angle than that of male population. There was no significant difference in femoral neck anteversion angles between the groups.

Introduction

Combined Anteversion (CA) angle of acetabular component and femoral neck is an important parameter for a successful Total Hip Arthroplasty (THA). The purpose of this study was to electronically measure the version angles of native acetabulum and femur in matured normal Caucasian population from large 3D CT data base. Our question was if there was any significant difference in CA between male and female population.

Summary

The M2a-38^tm metal on metal total hip arthroplasty showed a high incidence of pseudotumors and an unexpected high revision rate in our thoroughly screened cross sectional cohort.

Introduction

After the revival of the metal on metal (MoM) bearing in total hip arthroplasty (THA) at the beginning of this century, there are now serious questions about this type of bearing. The advantage of large head MoM bearing is the increase in range of motion and stability. In our institution the choice was made for 38 mm heads. During the last few years concerns have been raised about the relationship of MoM bearing and elevated serum cobalt and chromium ion levels, their local and systemic toxicological effects and the incidence of local tumorous masses (pseudotumors). Are these findings applicable for all MoM bearings or are there also product specific issues. We present the outcome of a cementless MoM THA using a 38mm head in a unique consecutive series of 377 THA who were performed in our institution.

Summary

Management of metal on metal hip replacements can be accomplished with a simple algorithm including easily available metal ion levels and hip MRI with metal artifact reducing software. After revision serum metal ion levels can be expected to fall rapidly.

Introduction

Metallic ion release may be related to bearing surface wear and thus serves as an indicator of the in-vivo performance of metal on metal articulations. The purpose of this prospective, controlled study was to compare new large head metal on metal hip components with established modular metal on metal and metal on polyethylene and to determine their effects on serum metal levels before and after revision.

Summary Statement

This study assesses the service provision of viscosupplementation within an NHS (British National Health System) hospital. The results of this study show long term efficacy of the treatment, when provided by a dedicated, orthopaedic unit.

Introduction

The service provision of viscosupplementation for osteoarthritis within the National Health System (NHS) remains controversial. The treatment was recommended in the 2007 NICE guidelines but support was withdrawn the following year. Furthermore, whether it should be provided by orthopaedic surgeons or in primary care is also a matter of debate. St Helens and Knowsley Trust, runs an orthopaedic outpatient clinic dedicated to the administration of viscosupplementation to patients with symptomatic knee osteoarthritis. This study aims to assess the efficacy of viscosupplementation for knee osteoarthritis when that is provided by a highly specialised, orthopaedic, dedicated service

Summary Statement

Our data suggest that postoperative component positioning in TKA with PSPG is not consistent with pre-operative software planning. More studies are needed to rule out possible learning curve in this study.

Introduction

Patient specific positioning guides (PSPGs) in TKA are based on MRI or CT data. Preoperatively, knee component positions can be visualised in 3-dimensional reconstructed images. Software allows anticipation of component position. From software planning PSPGs are manufactured and those PSPGs represent intra-operative component alignment. To our knowledge, there are no studies comparing pre-operative software planning with post-operative alignment. Aim of this study is to investigate the correlation between pre-operative planning of component positioning and the post-operative achieved alignment with PSPG technique.

Summary Statement

Uptake of robotically-assisted orthopaedic surgery may be limited by a perceived steep learning curve. We quantified the technological learning curve and 5 surgeries were found to bring operating times to appropriate levels. Implant positioning was as planned from the outset.

Introduction

Compared to total knee replacement, unicondylar knee replacement (UKR) has been found to reduce recovery time as well as increase patient satisfaction and improve range of motion. However, contradictory evidence together with revision rates concern may have limited the adoption of UKR surgery. Semi-active robotically-assisted orthopaedic tools have been developed to increase the accuracy of implant position and subsequent mechanical femorotibial angle to reduce revision rates. However, the perceived learning curve associated with such systems may cause apprehension among orthopaedic surgeons and reduce the uptake of such technology. To inform this debate, we aimed to quantify the learning curve associated with the technological aspects of the NavioPFS™ (Blue Belt Technologies Inc., Pittsburgh, USA) with regards to both operation time and implant accuracy.

Summary Statement

Antioxidant containing UHMWPE particles induced similar levels of in vitro macrophage proliferation and in vivo inflammation in the mouse air pouch model as UHMWPE particles alone. Benefit of antioxidant in reducing wear particle induced inflammation requires further investigation.

Introduction

Wear particles derived from UHMWPE implants can provoke inflammatory reaction and cause osteolysis in the bone, leading to aseptic implant loosening. Antioxidants have been incorporated into UHMWPE implants to improve their long term oxidative stability. However it is unclear if the anti-inflammatory property of the antioxidant could reduce UHMWPE particle induced inflammation. This study evaluated the effect of cyanidin and vitamin E on UHMWPE induced macrophage activation and mouse air pouch inflammation.

Summary Statement

This study assesses oxidation, mechanical behavior and revision reasons of 2^nd generation HXLPE used in total hip and knee arthroplasty. While oxidation was low for both X3 and E1 HXLPEs, oxidative regional variations were detected in the sequentially annealed cohort.

Introduction

First generation highly crosslinked polyethylenes (HXPLEs) have proven successful in lowering both penetration and osteolysis rates. However, 1^st generation annealing and remelting thermal stabilization have been associated with in vivo oxidation or reduced mechanical properties. Thus, 2^nd generation HXLPEs were developed to improve oxidative stability while still maintaining material properties. Little is known about the in vivo clinical failure modes of these 2^nd generation HLXPEs. The purpose of this study was to assess the revision reasons, wear, oxidative stability, and mechanical behavior of retrieved sequentially annealed Vitamin E diffused HXLPE in THA and TKA.

Summary

The 80% porous structure of trabecular metal allows for bone ingrowth in more than 90% of the available surface. The Nexgen LPS Uncemented Knee using a trabecular metal tibial component has performed well at minimum of 5 years’ follow-up.

Introduction

Total Knee Arthroplasty prostheses most frequently used in today's practice have cemented components. These have shown excellent clinical results. The fixation can however weaken with time, and cement debris within the articulation can lead to accelerated wear. Cementless implants are less commonly used, but some have also shown good long-term clinical results. The potential advantages of cementless implants are retention of bone stock, less chance of third-body wear due to the absence of cement, shorter operative time, and easier treatment of periprosthetic fractures. The posterior stabilised knee replacement has been said to increase tangential shear stresses on the tibial component and increases contact stresses on the cam and post mechanism hence the great debate of cruciate retaining or cruciate sacrificing implants.

Summary Statement

The tensile properties of a number of synthetic fibre constructs and porcine MCLs were experimentally determined and compared to allow the selection of an appropriate synthetic collateral ligament model for use in a kinematic knee simulator.

Introduction

As patient expectations regarding functional outcomes of total knee arthroplasty rise the need to assess the kinematics of new implants in vitro has increased. This has traditionally been done using cadaveric models, which can demonstrate high physiological relevance but also substantial inter-specimen variability. More recently there has been a shift towards the use of in silico and non-cadaveric methods. Such methods require significant simplifications of the joint and the modelling of soft tissue structures such as the collateral ligaments. Collateral ligaments are often modelled in in silico studies but have not, in the published literature, been modelled in in vitro knee kinematic simulators. Tensile testing of ligament tissue, to provide reference data, and the subsequent analysis of potential synthetic analogues was carried out. The overall aim of the study was to develop a synthetic ligament analogue for use in kinematic knee simulators.

Summary Statement

Demineralised bone matrix augmented tendon-bone fixations in the animal model show less scar tissue and an enthesis morphology closer to the physiologic one which may lead to a more resistant repair construct.

Introduction

Rotator cuff repair is one of the most common operative procedures in the shoulder. Yet despite its prevalence recurrent tear rates of up to 94% have been reported in the literature. High failure rates have been associated with tendon detachment from bone at the tendon – bone interface. Exogenous agents as biological strategies to augment tendon – bone healing in the shoulder represent a new area of focus to improve patient outcomes. Demineralised bone matrix (DBM) contains matrix bound proteins, exposed through acid demineralization step of DBM manufacture, and has long been recognised for its osteoinductive and osteoconductive properties. We hypothesised that DBM administered to the bone bed prior to the reattachment of the tendon, will upregulate healing and result in enhanced tissue morphology that more closely resembles that of a normal enthesis. An established ovine transosseous equivalent rotator cuff model was used.

Summary

Our results prove that Demineralised Cortical Bone (DCB) can be used as biological tendon graft substitute, combined with correct surgical technique and the use of suture bone anchor early mobilisation can be achieved.

Introduction

Surgical repair of tendon injuries aims to restore length, mechanical strength and function. In severe injuries with loss of tendon substance a tendon graft or a substitute is usually used to restore functional length. This is usually associated with donor site morbidity, host tissue reactions and lack of remodelling of the synthetic substitutes which may result in suboptimal outcome. In this study we hypothesise that DCB present in biological tendon environment with early mobilisation and appropriate tension will result in remodelling of the DCB into ligament tissue rather that ossification of the DCB at traditional expected. Our preparatory cadaveric study (abstract submitted to CORS 2013) showed that the repair model used in this animal study has sufficient mechanical strength needed for this animal study.

Summary

Our study shows that a tendon rupture can be successfully augmented with Demineralised Cortical Bone (DCB) giving initial appropriate mechanical strength suitable for in vivo use providing the biological reactions to the graft are favourable.

Introduction

Treatment of tendon and ligament injuries remains challenging; the aim is to find a biocompatible substance with mechanical and structural properties that replicate those of normal tendon and ligament. Because of its structural and mechanical properties, we proposed that DCB can be used in repair of tendon and ligament as well as regeneration of the enthesis. DCB is porous, biocompatible and has the potential to be remodelled by the host tissues. 2 studies were designed; in the first we examined the mechanical properties of DCB after gamma irradiation (GI) and freeze drying (FD). In the second we used different techniques for repairing bone-tendon-bone with DCB in order to measure the mechanical performance of the construct.

Summary Statement

Tendon-bone interface becomes matured with the perforating fiber and the cells striding over the bone area. We suggest that both “perforating fiber” and “cell stride” could play a crucial role in regeneration after rotator cuff repair.

Introduction

To obtain a successful outcome after rotator cuff repair, repaired tendon requires to be anchored biologically to the bone. However, it is well known that the histological structure of the repaired tendon-bone insertion is totally different from the normal insertion. This morphological alteration may contribute to biological instability after surgical repair. To address these issues, it is fundamental to clarify the difference of the structure between the normal and the repaired insertion in detail. Surprisingly, few studies on the tendon-bone insertion using electron microscopy has been performed so far, since the insertion area is solid (bone/cartilage) and extremely limited for the analysis. Recently, a new scanning electron microscopical method (FIB/SEM tomography) has been developed, making it possible to analyze the wider area with the higher resolution and reconstruct 3D ultrastructures. The purpose of this study was to analyze the ultrastructure of the repaired supraspinatus tendon-bone insertion in rat using FIB/SEM tomography.

Summary Statement

We have shown that integrin mRNA expression is regulated by the application of mechanical load. This indicates that mechanical loading may modify cell sensitivity to perceive further load through increased interaction with the ECM.

Introduction

Tendinopathies are a range of diseases characterised by pain and insidious degeneration. Although poorly understood, onset is often associated with physical activity. We have previously investigated the regulation by mechanical strain of metalloproteinase gene expression in human tenocyte in a 3D collagen matrix. Integrins are important in cellular interaction with the ECM and are reported to mediate mechanotransduction in various non-tendon tissues. We have reported that TGFbeta activation is a key player in the regulation of metalloproteinases in response to mechanical load, which may be mediated by integrins. This project aims to investigate the effect of cyclic loading and TGFbeta stimulation on integrin expression by human tenocytes, in collagen and fibrin matrices.

Summary Statement

Fatigue loading has an age-specific effect on tendon fascicle micro-mechanics, with greater fibre sliding in aged samples indicating a decreased mechanical integrity, and a reduced ability to withstand cyclic loading, which may partially explain the age-related risk of tendon injury.

Introduction

The human Achilles and equine superficial digital flexor (SDFT) tendons function as energy stores, experiencing large, repetitive stresses and strains¹ and are therefore highly susceptible to injury, particularly in aged individuals. We have previously observed rotation within SDFT fascicles in response to applied strain, which indicates the presence of helical sub-structures within this tendon. Further, we have shown that this rotation decreases with ageing, suggesting alterations to the helix sub-structure and a difference in the extension mechanisms in aged tendons. We therefore hypothesise that cyclic fatigue loading (FL) will result in alterations in fascicle extension mechanisms which are age specific.

Summary

Tissue grafts fail to recapitulate native tendon function, imposing the need for development of functional regeneration strategies. Herein, we describe advancements in tendon repair and regeneration using functionalised natural and synthetic devices and scaffold-free cell-based therapies.

Introduction

Tendon and ligament injuries constitute an unmet clinical need with approximately 100,000 new cases annually in US alone. Tissue grafts are considered the gold standard in clinical practice. However, allografts and xenografts can lead to potential disease transmission, whilst the limited supply of autografts in severe injuries and degenerative conditions restricts their use. To this end, scaffold and scaffold-free therapies are under development to address the tissue grafts shortage. Herein, we describe biophysical, biochemical and biological methods to maintain tendon derived cell phenotype and/or differentiation of other cell types towards tenogenic lineage; development of tendon-equivalent facsimiles; and ultimately functional neotendon formation.