Peter F. M. Choong

Does Accurate Anatomical Alignment Result in Better Function and Quality of Life? Comparing Conventional and Computer-Assisted Total Knee Arthroplasty

This is a randomized prospective controlled trial comparing the alignment, function, and patient quality-of-life outcomes between patients undergoing conventional (CONV) and computer-assisted (CAS) knee arthroplasty. One hundred and fifteen patients (60 CAS, 55 CONV) underwent cemented total knee arthroplasty. Three patients were lost to follow-up. Eighty-eight percent (CAS) vs 61% (CONV) of knees achieved a mechanical axis within 3 degrees of neutral (P = .003). Aligning femoral rotation with the epicondylar axis was accurately achieved in CAS and CONV with no significant difference. Patients with coronal alignment within 3 degrees of neutral had superior International Knee Society and Short-Form 12 physical scores at 6 weeks, 3 months, 6 months, and 12 months after surgery. Computer-assisted total knee arthroplasty achieves greater accuracy in implant alignment and this correlates with better knee function and improved quality of life.

Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review

One of the critical issues in orthopaedic regenerative medicine is the design of bone scaffolds and implants that replicate the biomechanical properties of the host bones. Porous metals have found themselves to be suitable candidates for repairing or replacing the damaged bones since their stiffness and porosity can be adjusted on demands. Another advantage of porous metals lies in their open space for the in-growth of bone tissue, hence accelerating the osseointegration process. The fabrication of porous metals has been extensively explored over decades, however only limited controls over the internal architecture can be achieved by the conventional processes. Recent advances in additive manufacturing have provided unprecedented opportunities for producing complex structures to meet the increasing demands for implants with customized mechanical performance. At the same time, topology optimization techniques have been developed to enable the internal architecture of porous metals to be designed to achieve specified mechanical properties at will. Thus implants designed via the topology optimization approach and produced by additive manufacturing are of great interest. This paper reviews the state-of-the-art of topological design and manufacturing processes of various types of porous metals, in particular for titanium alloys, biodegradable metals and shape memory alloys. This review also identifies the limitations of current techniques and addresses the directions for future investigations.

Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery

Proteins and peptides are increasingly recognized as potential leads for the development of new therapeutics for a variety of human ailments. Due to their relatively specific mode of action, proteins and peptides can be administered at relatively low doses for therapeutic effects. As natural biological products, these low doses reduce the risk otherwise caused by other small molecular drugs or larger charged molecules. Unfortunately, their therapeutic potential and clinical application is frequently hampered by various obstacles to their successful delivery. This review discusses the recent developments in the fields of liposome, microparticle and nanoparticle pertinent to protein and peptide delivery covering those systems tested and/or validated in vivo.

Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice

Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed beta-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma cell lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased beta-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma.

Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy.

Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase–polymerase chain reaction (RT‐PCR) demonstrated an increase in the level of expression of myostatin, insulin‐like growth factor‐1 (IGF‐1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle‐wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF‐1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.

Obesity is a Major Risk Factor for Prosthetic Infection after Primary Hip Arthroplasty

AbstractThe incidence of obesity and the number of hip arthroplasties being performed in Australia each year are increasing. Although uncommon, periprosthetic infection after surgery can have a devastating effect on patient outcomes. We therefore asked whether obesity correlated with periprosthetic infection after primary hip arthroplasty. We further asked whether variables such as patient comorbidities, operative time, blood transfusions, use of drains, and cementation practices correlated with periprosthetic infection. We hypothesized obesity was an independent risk factor for the development of acute periprosthetic infection after primary hip arthroplasty. We reviewed 1207 consecutive primary hip arthroplasties separating patients into four weight groups, normal, overweight, obese, and morbidly obese, and compared for incidence of periprosthetic infection between the groups. We observed a considerably higher infection rate in obese patients; the correlation was independent of patient comorbidities such as diabetes and cardiovascular disease. We also observed a correlation between infection rates and using a posterior approach in obese patients. The incidence of periprosthetic infection was not influenced by operative time, transfusion requirements, use of drains, and cementation practices. In this series, obesity was an independent risk factor for acute periprosthetic infection after primary hip arthroplasty. Level of Evidence: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Osteosarcoma treatment: state of the art

Osteosarcoma (OS) is a class of cancer originating from bone, mainly afflicting children or young adults. It is the second highest cause of cancer-related death in these age groups, mainly due to development of often fatal metastasis, usually in the lungs. Survival for these patients is poor despite the aggressive use of surgery, chemotherapy, and/or radiotherapy. Thus, new effective drugs and other forms of therapy are needed. This article reviews the biology and the state of the art management of OS. New experimental drugs and potential therapies targeting molecular pathways of OS are also discussed.

A review of clinical and molecular prognostic factors in osteosarcoma

Traditional prognostic determinants in osteosarcoma have included demographics (age, sex), tumour size, site, stage, and the response to chemotherapy. Many of these are determined using varying techniques and units of measurement, which can make comparison between studies difficult. The absence of survival difference between limb sparing surgery and amputation has been repeatedly demonstrated in primary disease, and even in the setting of pathological fracture. On the other hand, there is still some controversy over the existence of increased local recurrence for limb-sparing surgery, and the implications of this. Commonly used prognostic determinants such as metastases, and response to chemotherapy enable a high degree of prognostic accuracy but usually at a late stage in the course of disease. Leading on from this, there is a need to uncover molecular pathways with specific influence over osteosarcoma progression to facilitate earlier treatment changes. Some important pathways are already being defined, for example the association of CXCR4 with metastases on presentation, the likelihood of doxorubicin resistance with positive P-glycoprotein, and the reduced survival prediction of over expressed survivin. It is anticipated that the future of osteosarcoma treatment will involve treatment tailored to the molecular profile of tumours at diagnosis, adjuvant therapy directed towards dysfunctional molecular pathways rather than the use of cytotoxics, and a more standardised approach to the measurement of clinical prognostic factors.

The molecular pathogenesis of osteosarcoma: a review.

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management.

Thrombin cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins

Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express alpha(9)beta(1) integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the alpha(9)beta(1) and alpha(4)beta(1) integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with alpha(9)beta(1) and alpha(4)beta(1) integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.