Ross Crawford

Strategies for Zonal Cartilage Repair using Hydrogels

Articular cartilage is a highly hydrated tissue with depth-dependent cellular and matrix properties that provide low-friction load bearing in joints. However, the structure and function are frequently lost and there is insufficient repair response to regenerate high-quality cartilage. Several hydrogel-based tissue-engineering strategies have recently been developed to form constructs with biomimetic zonal variations to improve cartilage repair. Modular hydrogel systems allow for systematic control over hydrogel properties, and advanced fabrication techniques allow for control over construct organization. These technologies have great potential to address many unanswered questions involved in prescribing zonal properties to tissue-engineered constructs for cartilage repair.

Risk Factors for Revision for Early Dislocation in Total Hip Arthroplasty

Risk factors were investigated for revision for dislocation in primary total hip arthroplasties (THAs) between September 1, 1999, and December 31, 2004, as reported by the Australian Orthopaedic Association National Joint Replacement Registry. For 65992 primary THAs, the only initial diagnoses with significantly increased relative risk (RR) of revision for dislocation compared to osteoarthritis were fractured neck of femur (RR, 2.03; P < .001), rheumatoid arthritis (RR, 2.01; P < .01), and avascular necrosis (RR, 1.57; P < .05). A total of 58109 primary THAs for osteoarthritis were investigated for effect of age group, sex, and fixation method. There were 428 (0.7%) revisions for dislocation, 369 (0.8%) with a cementless acetabulum, and 59 (0.6%) with cemented acetabulum (RR, 1.59; P < .01). There is a significantly increasing risk of revision for dislocation as head size decreases (P < .001). Cementless acetabula, particularly with smaller heads, have a higher rate of revision for dislocation.

Diagnostic value of intra-articular anaesthetic in primary osteoarthritis of the hip

We investigated 42 patients who were being considered for primary total hip arthroplasty (THA), but in whom it was uncertain whether the hip was the source of their pain. They were given an injection of local anaesthetic into the joint space. Of 33 patients who gained pain relief from their injection, 32 subsequently had successful THA. The remaining patient has not had surgery. The intra-articular injection of local anaesthetic is thus at least 96% sensitive. Of the nine patients who had no or only minimal pain relief from injection, one has had an unsuccessful THA, three have been successfully treated for other conditions and five have unresolved pain for which no organic basis has been established. We believe that the injection of local anaesthetic into the hip is a reliable test, with low morbidity. In difficult cases it will aid in the clarification of the cause of pain which possibly arises from the hip.

Normal and prosthetic synovial joints are lubricated by surface-active phospholipid: a hypothesis☆

Much evidence supports the hypothesis that surface-active phospholipid (SAPL), which imparts the thin hydrophobic outermost lining to the normal articular surface, is the boundary lubricant reducing friction to remarkably low levels. We review this evidence and further hypothesize that SAPL produced in type B synoviocytes will also lubricate prostheses after implantation. This could explain why implanted hips display far less wear than hips in simulated wear trials do, even using protein as the lubricant whereas rougher surfaces can be tolerated in vivo. We introduce the concept that a deficiency of SAPL might explain the selective failure of prostheses just as osteoarthritic articular surfaces are deficient. This, in turn, leads to the replenishment of SAPL, as tested in OA, and the concept of prelubricating prostheses before implantation.

An influenza virus-inspired polymer system for the timed release of siRNA

Small interfering RNA silences specific genes by interfering with mRNA translation, and acts to modulate or inhibit specific biological pathways; a therapy that holds great promise in the cure of many diseases. However, the naked small interfering RNA is susceptible to degradation by plasma and tissue nucleases and due to its negative charge unable to cross the cell membrane. Here we report a new polymer carrier designed to mimic the influenza virus escape mechanism from the endosome, followed by a timed release of the small interfering RNA in the cytosol through a self-catalyzed polymer degradation process. Our polymer changes to a negatively charged and non-toxic polymer after the release of small interfering RNA, presenting potential for multiple repeat doses and long-term treatment of diseases.

Pseudotumor in a Well-Fixed Metal-on-Polyethylene Uncemented Hip Arthroplasty

The incidence of pseudotumor formation has been reported to be 1% in patients with metal-on-metal resurfacing arthroplasties. This complication is not exclusive to these patients. We report a case of pseudotumor formation secondary to femoral head-neck corrosion after a metal-on-polyethylene uncemented total hip arthroplasty.

ERK-1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts

OBJECTIVE Previous studies have shown the influence of subchondral bone osteoblasts (SBOs) on phenotypical changes of articular cartilage chondrocytes (ACCs) during the development of osteoarthritis (OA). The molecular mechanisms involved during this process remain elusive, in particular, the signal transduction pathways. The aim of this study was to investigate the in vitro effects of OA SBOs on the phenotypical changes in normal ACCs and to unveil the potential involvement of MAPK signaling pathways during this process. METHODS Normal and arthritic cartilage and bone samples were collected for isolation of ACCs and SBOs. Direct and indirect coculture models were applied to study chondrocyte hypertrophy under the influence of OA SBOs. MAPKs in the regulation of the cell-cell interactions were monitored by phosphorylated antibodies and relevant inhibitors. RESULTS OA SBOs led to increased hypertrophic gene expression and matrix calcification in ACCs by means of both direct and indirect cell-cell interactions. In this study, we demonstrated for the first time that OA SBOs suppressed p38 phosphorylation and induced ERK-1/2 signal phosphorylation in cocultured ACCs. The ERK-1/2 pathway inhibitor PD98059 significantly attenuated the hypertrophic changes induced by conditioned medium from OA SBOs, and the p38 inhibitor SB203580 resulted in the up-regulation of hypertrophic genes in ACCs. CONCLUSION The findings of this study suggest that the pathologic interaction of OA SBOs and ACCs is mediated via the activation of ERK-1/2 phosphorylation and deactivation of p38 phosphorylation, resulting in hypertrophic differentiation of ACCs.

Total hip replacement: indications for surgery and risk factors for failure

Total hip replacement is one of the most successful and cost effective interventions in medicine.1 2 It offers reliable relief of pain and considerable improvement in function in patients suffering with osteoarthritis or inflammatory arthritis of the hip.3-7 Currently about 50 000 hip replacements are performed in the United Kingdom annually while worldwide the number is over 300 000. Two thirds of these are performed in patients over 65 years of age.8 Ninety to ninety five per cent of patients can expect to have their total hip replacement functioning at 10 years,8 and in 85% they will still be functioning at 20 years.9 Although 85% of patients undergoing total hip replacement have a diagnosis of osteoarthritis,8 inflammatory arthritis, both seropositive and seronegative, is an important indication for total hip replacement and can offer tremendous improvements in quality of life even in the very young.10 In rheumatoid arthritis it has been estimated that the cost to the community of total hip replacement will be recuperated within an average 1.5 years because of savings made on medical and social care.2 Quality of life after surgery approximates that of a healthy reference population.4 Improvements in pain, energy levels, sleep, social, and sexual function are all observed.4 7 Oxygen demands on activity are decreased and walking ability improves.5 11 Most of these improvements are seen within three months of surgery.5 These gains in quality of life allow large numbers of patients to retain their independence and function more actively in society. ### PAIN Pain is the principal indication for hip replacement and is reliably relieved as early as one week after surgery.12 Pain from an arthritic hip is classically located in the groin and buttock. Radiation into the thigh may occur and at times pain …

Bioactive mesopore-glass microspheres with controllable protein-delivery properties by biomimetic surface modification

Microsphere systems with the ideal properties for bone regeneration need to be bioactive, and at the same time possess the capacity for controlled protein/drug-delivery; however, the current crop of microsphere system fails to fulfill these properties. The aim of this study was to develop a novel protein-delivery system of bioactive mesoporous glass (MBG) microspheres by a biomimetic method through controlling the density of apatite on the surface of microspheres, for potential bone tissue regeneration. MBG microspheres were prepared by using the method of alginate cross-linking with Ca(2+) ions. The cellular bioactivity of MBG microspheres was evaluated by investigating the proliferation and attachment of bone marrow stromal cell (BMSC). The loading efficiency (LE) and release kinetics of bovine serum albumin (BSA) on MBG microspheres were investigated after coprecipitating with biomimetic apatite in simulated body fluids (SBF). The results showed that MBG microspheres supported BMSC attachment and the Si-containing ionic products from MBG microspheres stimulated BMSCs proliferation. The density of apatite on MBG microspheres increased with the length of soaking time in SBF. BSA-LE of MBG was significantly enhanced by coprecipitating with apatite. Furthermore, the LE and release kinetics of BSA could be controlled by controlling the density of apatite formed on MBG microspheres. Our results suggest that MBG microspheres are a promising protein-delivery system as a filling material for bone defect healing and regeneration.

Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone ☆

The development of effective therapeutic strategies against prostate cancer bone metastases has been impeded by the lack of adequate animal models that are able to recapitulate the biology of the disease in humans. Bioengineered approaches allow researchers to create sophisticated experimentally and physiologically relevant in vivo models to study interactions between cancer cells and their microenvironment under reproducible conditions. The aim of this study was to engineer a morphologically and functionally intact humanized organ bone which can serve as a homing site for human prostate cancer cells. Transplantation of biodegradable tubular composite scaffolds seeded with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone construct including a large number of human mesenchymal cells which were shown to be metabolically active and capable of producing extracellular matrix components. Micro-CT analysis demonstrated that the newly formed ossicle recapitulated the morphological features of a physiological organ bone with a trabecular network surrounded by a cortex-like outer structure. This microenvironment was supportive of the lodgement and maintenance of murine haematopoietic cell clusters, thus mimicking a functional organ bone. Bioluminescence imaging demonstrated that luciferase-transduced human PC3 cells reproducibly homed to the humanized tissue engineered bone constructs, proliferated, and developed macro-metastases. This model allows the analysis of interactions between human prostate cancer cells and a functional humanized bone organ within an immuno-incompetent murine host. The system can serve as a reproducible platform to study effects of therapeutics against prostate cancer bone metastases within a humanized microenvironment.