Objectives. Salubrinal is a synthetic agent that elevates phosphorylation
of eukaryotic translation initiation factor 2 alpha (eIF2α) and
alleviates stress to the endoplasmic reticulum. Previously, we reported
that in chondrocytes, Salubrinal attenuates expression and activity
of matrix metalloproteinase 13 (MMP13) through downregulating nuclear
factor kappa B (NFκB) signalling. We herein examine whether Salubrinal
prevents the degradation of articular cartilage in a mouse model
of osteoarthritis (OA). Methods. OA was surgically induced in the left knee of female mice. Animal
groups included age-matched sham control, OA placebo, and OA treated
with Salubrinal or Guanabenz. Three weeks after the induction of
OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At
three and six weeks, the femora and tibiae were isolated and the sagittal
sections were stained with Safranin O. Results. Salubrinal suppressed the progression of OA by downregulating
p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation
level of eIF2α, it did not suppress the progression of OA. Conclusions. Administration of Salubrinal has chondroprotective effects in
arthritic joints. Salubrinal can be considered as a potential therapeutic
agent for alleviating symptoms of OA. Cite this article: Bone Joint
Tendinopathy is a debilitating musculoskeletal
condition which can cause significant pain and lead to complete rupture
of the tendon, which often requires surgical repair. Due in part
to the large spectrum of tendon pathologies, these disorders continue
to be a clinical challenge. Animal models are often used in this
field of research as they offer an attractive framework to examine
the cascade of processes that occur throughout both tendon pathology and
repair. This review discusses the structural, mechanical, and biological
changes that occur throughout tendon pathology in animal models,
as well as strategies for the improvement of tendon healing. Cite this article: Bone Joint
Construction of a functional skeleton is accomplished
through co-ordination of the developmental processes of chondrogenesis,
osteogenesis, and synovial joint formation. Infants whose movement in
utero is reduced or restricted and who subsequently suffer
from joint dysplasia (including joint contractures) and thin hypo-mineralised
bones, demonstrate that embryonic movement is crucial for appropriate
skeletogenesis. This has been confirmed in mouse, chick, and zebrafish
animal models, where reduced or eliminated movement consistently yields
similar malformations and which provide the possibility of experimentation
to uncover the precise disturbances and the mechanisms by which
movement impacts molecular regulation. Molecular genetic studies have
shown the important roles played by cell communication signalling
pathways, namely Wnt, Hedgehog, and transforming growth factor-beta/bone
morphogenetic protein. These pathways regulate cell behaviours such
as proliferation and differentiation to control maturation of the
skeletal elements, and are affected when movement is altered. Cell
contacts to the extra-cellular matrix as well as the cytoskeleton
offer a means of mechanotransduction which could integrate mechanical
cues with genetic regulation. Indeed, expression of cytoskeletal
genes has been shown to be affected by immobilisation. In addition
to furthering our understanding of a fundamental aspect of cell control
and differentiation during development, research in this area is
applicable to the engineering of stable skeletal tissues from stem
cells, which relies on an understanding of developmental mechanisms
including genetic and physical criteria. A deeper understanding
of how movement affects skeletogenesis therefore has broader implications
for regenerative therapeutics for injury or disease, as well as
for optimisation of physical therapy regimes for individuals affected
by skeletal abnormalities. Cite this article: Bone Joint
Objectives. There remains conflicting evidence regarding cortical bone strength
following bisphosphonate therapy. As part of a study to assess the
effects of bisphosphonate treatment on the healing of rat tibial
fractures, the mechanical properties and radiological density of
the uninjured contralateral tibia was assessed. Methods. Skeletally mature aged rats were used. A total of 14 rats received
1µg/kg ibandronate (iban) daily and 17 rats received 1 ml 0.9% sodium
chloride (control) daily. Stress at failure and toughness of the
tibial diaphysis were calculated following four-point bending tests. Results. Uninjured cortical bone in the iban group had a significantly
greater mean (standard deviation (. sd. )), p <
0.001, stress
at failure of 219.2 MPa (. sd. 45.99) compared with the control
group (169.46 MPa (. sd. 43.32)) following only nine weeks
of therapy. Despite this, the cortical bone toughness and work to
failure was similar. There was no significant difference in radiological
density or physical dimensions of the cortical bone. Conclusions. Iban therapy increases the stress at failure of uninjured cortical
bone. This has relevance when normalising the strength of repair
in a limb when comparing it with the unfractured limb. However,
the 20% increase in stress at failure with iban therapy needs to
be interpreted with caution as there was no corresponding increase
in toughness or work to failure. Further research is required in
this area, especially with the increasing clinical burden of low-energy
diaphyseal femoral fractures following prolonged use of bisphosphonates. Cite this article: Bone Joint
High-quality randomised controlled trials (RCTs)
evaluating surgical therapies are fundamental to the delivery of
evidence-based orthopaedics. Orthopaedic clinical trials have unique
challenges; however, when these challenges are overcome, evidence
from trials can be definitive in its impact on surgical practice.
In this review, we highlight several issues that pose potential
challenges to orthopaedic investigators aiming to perform surgical randomised
controlled trials. We begin with a discussion on trial design issues,
including the ethics of sham surgery, the importance of sample size,
the need for patient-important outcomes, and overcoming expertise
bias. We then explore features surrounding the execution of surgical
randomised trials, including ethics review boards, the importance
of organisational frameworks, and obtaining adequate funding. Cite this article: Bone Joint
The aim of this study was to review the role
of clinical trial networks in orthopaedic surgery. A total of two
electronic databases (MEDLINE and EMBASE) were searched from inception
to September 2013 with no language restrictions. Articles related
to randomised controlled trials (RCTs), research networks and orthopaedic
research, were identified and reviewed. The usefulness of trainee-led
research collaborations is reported and our knowledge of current
clinical trial infrastructure further supplements the review. Searching
yielded 818 titles and abstracts, of which 12 were suitable for
this review. Results are summarised and presented narratively under
the following headings: 1) identifying clinically relevant research
questions; 2) education and training; 3) conduct of multicentre
RCTs and 4) dissemination and adoption of trial results. This review
confirms growing international awareness of the important role research
networks play in supporting trials in orthopaedic surgery. Multidisciplinary
collaboration and adequate investment in trial infrastructure are crucial
for successful delivery of RCTs. Cite this article: Bone Joint
Objectives. The purpose of this study was to evaluate in vivo biocompatibility
of novel single-walled carbon nanotubes (SWCNT)/poly(lactic-co-glycolic
acid) (PLAGA) composites for applications in bone and tissue regeneration. Methods. A total of 60 Sprague-Dawley rats (125 g to 149 g) were implanted
subcutaneously with SWCNT/PLAGA composites (10 mg SWCNT and 1gm
PLAGA 12 mm diameter two-dimensional disks), and at two, four, eight
and 12 weeks post-implantation were compared with control (Sham)
and PLAGA (five rats per group/point in time). Rats were observed
for signs of morbidity, overt toxicity, weight gain and food consumption,
while haematology, urinalysis and histopathology were completed
when the animals were killed. Results. No mortality and clinical signs were observed. All groups showed
consistent weight gain, and the rate of gain for each group was
similar. All groups exhibited a similar pattern for food consumption.
No difference in urinalysis, haematology, and absolute and relative
organ weight was observed. A mild to moderate increase in the summary toxicity
(sumtox) score was observed for PLAGA and SWCNT/PLAGA implanted
animals, whereas the control animals did not show any response.
Both PLAGA and SWCNT/PLAGA showed a significantly higher sumtox
score compared with the control group at all time intervals. However,
there was no significant difference between PLAGA and SWCNT/PLAGA
groups. Conclusions. Our results demonstrate that SWCNT/PLAGA composites exhibited in
vivo biocompatibility similar to the Food and Drug Administration
approved biocompatible polymer, PLAGA, over a period of 12 weeks.
These results showed potential of SWCNT/PLAGA composites for bone
regeneration as the low percentage of SWCNT did not elicit a localised
or general overt toxicity. Following the 12-week exposure, the material
was considered to have an acceptable biocompatibility to warrant
further long-term and more invasive in vivo studies. Cite this article: Bone Joint
Objective . A clinical investigation into a new bone void filler is giving
first data on systemic and local exposure to the anti-infective
substance after implantation. Method . A total of 20 patients with post-traumatic/post-operative bone
infections were enrolled in this open-label, prospective study.
After radical surgical debridement, the bone cavity was filled with
this material. The 21-day hospitalisation phase included determination
of gentamicin concentrations in plasma, urine and wound exudate, assessment
of wound healing, infection parameters, implant resorption, laboratory
parameters, and adverse event monitoring. The follow-up period was
six months. . Results . Systemic exposure to gentamicin after implantation was very low
as local gentamicin concentrations were measured in wound exudate
after six to ten hours. There were no signs of infectious complication
throughout the clinical phase. Four patients had recurrent infections
several weeks to months after implantation. The outcome was deemed successful
by remission of infection in 16 (80%) of these problematic long-term
treated patients. Safety laboratory measurements did not indicate
nephrotoxic or hepatotoxic effects. . Conclusions . Local application of calcium sulphate/carbonate bone void filler
comprising gentamicin revealed sufficient active local levels of
the antibiotic by simultaneous significant low systemic exposure
in patients with mostly chronic osteomyelitis/osteitis. The material
was safe and well tolerated. Cite this article: Bone Joint
