Large bone defects remain a tremendous clinical challenge. There is growing evidence in support of treatment strategies that direct defect repair through an endochondral route, involving a cartilage intermediate. While culture-expanded stem/progenitor cells are being evaluated for this purpose, these cells would compete with endogenous repair cells for limited oxygen and nutrients within ischaemic defects. Alternatively, it may be possible to employ extracellular vesicles (EVs) secreted by culture-expanded cells for overcoming key bottlenecks to endochondral repair, such as defect vascularization, chondrogenesis, and osseous remodelling. While mesenchymal stromal/stem cells are a promising source of therapeutic EVs, other donor cells should also be considered. The efficacy of an EV-based therapeutic will likely depend on the design of companion scaffolds for controlled delivery to specific target cells. Ultimately, the knowledge gained from studies of EVs could one day inform the long-term development of synthetic, engineered nanovesicles. In the meantime, EVs harnessed from in vitro cell culture have near-term promise for use in bone regenerative medicine. This narrative review presents a rationale for using EVs to improve the repair of large bone defects, highlights promising cell sources and likely therapeutic targets for directing repair through an endochondral pathway, and discusses current barriers to clinical translation.

Cite this article: E. Ferreira, R. M. Porter. Harnessing extracellular vesicles to direct endochondral repair of large bone defects. Bone Joint Res 2018;7:263–273. DOI: 10.1302/2046-3758.74.BJR-2018-0006.

Objectives

Secondary fracture healing is strongly influenced by the stiffness of the bone-fixator system. Biomechanical tests are extensively used to investigate stiffness and strength of fixation devices. The stiffness values reported in the literature for locked plating, however, vary by three orders of magnitude. The aim of this study was to examine the influence that the method of restraint and load application has on the stiffness produced, the strain distribution within the bone, and the stresses in the implant for locking plate constructs.

1. The use of a protein-free synthetic medium has provided a new technical approach to the study of fracture healing in vitro. 2. The tibiae of fourteen-day embryonic chicks were cut in half in the middle of the shaft, the fragments were placed in apposition and the explants grown in vitro for up to sixteen days. The process of bone repair was studied by means of histology and biochemical estimations. 3. The rate of growth in length of fractured bones was greater in an atmosphere containing 50 per cent of oxygen than in one with 20 per cent oxygen, thus emphasising the importance of an adequate oxygen supply for the regeneration of osteogenic cells. 4. The effect of varying the concentration of glucose in the medium was investigated. Two milligrams of glucose per millilitre was the most favourable for healing; higher levels caused fibroblastic changes in the cartilage cells and inhibited the proliferation of osteogenic cells at the fracture site. 5. Histological examination showed that many of the phenomena that occur in the repair of fractures in vivo can be reproduced in vitro in synthetic medium. Similar results were obtained whether the fracture was made in whole bones or in isolated shafts from which the cartilaginous ends had been removed; the latter are more favourable for biochemical study

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration.

Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

Objectives

The primary stability of the cementless Oxford Unicompartmental Knee Replacement (OUKR) relies on interference fit (or press fit). Insufficient interference may cause implant loosening, whilst excessive interference could cause bone damage and fracture.

The aim of this study was to identify the optimal interference fit by measuring the force required to seat the tibial component of the cementless OUKR (push-in force) and the force required to remove the component (pull-out force).

Aims

To determine whether there is any difference in infection rate at 90 days between trauma operations performed in laminar flow and plenum ventilation, and whether infection risk is altered following the installation of laminar flow (LF).

Objectives

External fixators are the traditional fixation method of choice for contaminated open fractures. However, patient acceptance is low due to the high profile and therefore physical burden of the constructs. An externalised locking compression plate is a low profile alternative. However, the biomechanical differences have not been assessed. The objective of this study was to evaluate the axial and torsional stiffness of the externalised titanium locking compression plate (ET-LCP), the externalised stainless steel locking compression plate (ESS-LCP) and the unilateral external fixator (UEF).

Aims

This study describes the use of the Masquelet technique to treat segmental tibial bone loss in 12 patients.

Aims

The best time for definitive orthopaedic care is often unclear in patients with multiple injuries. The objective of this study was make a prospective assessment of the safety of our early appropriate care (EAC) strategy and to evaluate the potential benefit of additional laboratory data to determine readiness for surgery.

Objectives

We have observed clinical cases where bone is formed in the overlaying muscle covering surgically created bone defects treated with a hydroxyapatite/calcium sulphate biomaterial. Our objective was to investigate the osteoinductive potential of the biomaterial and to determine if growth factors secreted from local bone cells induce osteoblastic differentiation of muscle cells.

Aims

In approximately 20% of patients with ankle fractures, there is an concomitant injury to the syndesmosis which requires stabilisation, usually with one or more syndesmotic screws. The aim of this review is to evaluate whether removal of the syndesmotic screw is required in order for the patient to obtain optimal functional recovery.

Complete fractures through bone affected by Paget's disease may not deserve their innocent reputation. This retrospective study of 182 such femoral fractures, the largest reported series to date, was carried out to discover the behaviour of these fractures in the absence of specific therapy for the Paget's disease. Most previous series have concluded that healing is uneventful but the findings in these patients from the West Midlands do not bear this out. After exclusion of the early deaths, the overall incidence of non-union was 40 per cent, the main problems being posed by the subtrochanteric fractures and those of the upper shaft. Although callus may be abundant, it may itself be involved in the disease process and is not a reliable sign of union. Based on these observations, suggestions for management in the different regions of the femur are made

1. Prosthetic acetabular cups of the Charnley and McKee-Farrar designs were cemented into cadaveric pelves using different procedures for preparing the acetabulum. 2. The torsional moments needed to loosen these cups were measured. 3. The torsional moments so measured were found to be from about four to more than twenty times higher than the frictional moments measured in independent tests on the two designs of prosthesis. 4. It is argued that late looseness of the acetabular component after total hip replacement, in the absence of infection, seems most likely to be due to thermal damage to the bone occurring at the time of polymerisation of the cement, and to subsequent bone resorption. 5. Surgical preparation of the acetabulum should include removal of all the articular cartilage and cleaning of the acetabular fossa, but the drilling of additional holes in the floor of the acetabulum seems unimportant. 6. The possibility of fatigue fracture in bone as a factor contributing to late loosening is an argument in favour of metal-on-polyethylene prostheses with their lower frictional moments, although the importance of this factor cannot be estimated

Aims

Surgical intervention in patients with bone metastases from breast cancer is dependent on the estimated survival of the patient. The purpose of this paper was to identify factors that would predict survival so that specific decisions could be made in terms of surgical (or non-surgical) management.

MicroRNAs (miRNAs ) are small non-coding RNAs that regulate gene expression. We hypothesised that the functions of certain miRNAs and changes to their patterns of expression may be crucial in the pathogenesis of nonunion. Healing fractures and atrophic nonunions produced by periosteal cauterisation were created in the femora of 94 rats, with 1:1 group allocation. At post-fracture days three, seven, ten, 14, 21 and 28, miRNAs were extracted from the newly generated tissue at the fracture site. Microarray and real-time polymerase chain reaction (PCR) analyses of day 14 samples revealed that five miRNAs, miR-31a-3p, miR-31a-5p, miR-146a-5p, miR-146b-5p and miR-223-3p, were highly upregulated in nonunion. Real-time PCR analysis further revealed that, in nonunion, the expression levels of all five of these miRNAs peaked on day 14 and declined thereafter.

Our results suggest that miR-31a-3p, miR-31a-5p, miR-146a-5p, miR-146b-5p and miR-223-3p may play an important role in the development of nonunion. These findings add to the understanding of the molecular mechanism for nonunion formation and may lead to the development of novel therapeutic strategies for its treatment.

Cite this article: Bone Joint J 2015; 97-B:1144–51.

We report the outcome of 84 nonunions involving long bones which were treated with rhBMP-7, in 84 patients (60 men: 24 women) with a mean age 46 years (18 to 81) between 2003 and 2011. The patients had undergone a mean of three previous operations (one to 11) for nonunion which had been present for a mean of 17 months (4 months to 20 years). The nonunions involved the lower limb in 71 patients and the remainder involved the upper limb. A total of 30 nonunions were septic. Treatment was considered successful when the nonunion healed without additional procedures. The relationship between successful union and the time to union was investigated and various factors including age and gender, the nature of the nonunion (location, size, type, chronicity, previous procedures, infection, the condition of the soft tissues) and type of index procedure (revision of fixation, type of graft, amount of rhBMP-7) were analysed. The improvement of the patients’ quality of life was estimated using the Short Form (SF) 12 score.

A total of 68 nonunions (80.9%) healed with no need for further procedures at a mean of 5.4 months (3 to 10) post-operatively. Multivariate logistic regression analysis of the factors affecting union suggested that only infection significantly affected the rate of union (p = 0.004).Time to union was only affected by the number of previous failed procedures (p = 0.006). An improvement of 79% and 32.2% in SF-12 physical and mental score, respectively, was noted within the first post-operative year.

Rh-BMP-7 combined with bone grafts, enabled healing of the nonunion and improved quality of life in about 80% of patients. Aseptic nonunions were much more likely to unite than septic ones. The number of previous failed operations significantly delayed the time to union.

Cite this article: Bone Joint J 2015;97-B:997–1003.

Tibial nonunion represents a spectrum of conditions which are challenging to treat, and optimal management remains unclear despite its high rate of incidence. We present 44 consecutive patients with 46 stiff tibial nonunions, treated with hexapod external fixators and distraction to achieve union and gradual deformity correction. There were 31 men and 13 women with a mean age of 35 years (18 to 68) and a mean follow-up of 12 months (6 to 40). No tibial osteotomies or bone graft procedures were performed. Bony union was achieved after the initial surgery in 41 (89.1%) tibias. Four persistent nonunions united after repeat treatment with closed hexapod distraction, resulting in bony union in 45 (97.8%) patients. The mean time to union was 23 weeks (11 to 49). Leg-length was restored to within 1 cm of the contralateral side in all tibias. Mechanical alignment was restored to within 5° of normal in 42 (91.3%) tibias. Closed distraction of stiff tibial nonunions can predictably lead to union without further surgery or bone graft. In addition to generating the required distraction to achieve union, hexapod circular external fixators can accurately correct concurrent deformities and limb-length discrepancies.

Cite this article: Bone Joint J 2015;97-B:1417–22.

The femoral head receives blood supply mainly from the deep branch of the medial femoral circumflex artery (MFCA). In previous studies we have performed anatomical dissections of 16 specimens and subsequently visualised the arteries supplying the femoral head in 55 healthy individuals. In this further radiological study we compared the arterial supply of the femoral head in 35 patients (34 men and one woman, mean age 37.1 years (16 to 64)) with a fracture/dislocation of the hip with a historical control group of 55 hips. Using CT angiography, we identified the three main arteries supplying the femoral head: the deep branch and the postero-inferior nutrient artery both arising from the MFCA, and the piriformis branch of the inferior gluteal artery. It was possible to visualise changes in blood flow after fracture/dislocation.

Our results suggest that blood flow is present after reduction of the dislocated hip. The deep branch of the MFCA was patent and contrast-enhanced in 32 patients, and the diameter of this branch was significantly larger in the fracture/dislocation group than in the control group (p = 0.022). In a subgroup of ten patients with avascular necrosis (AVN) of the femoral head, we found a contrast-enhanced deep branch of the MFCA in eight hips. Two patients with no blood flow in any of the three main arteries supplying the femoral head developed AVN.

Cite this article: Bone Joint J 2013;95-B:1453–7.